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The South African Journal of Diabetes & Vascular Disease
September 2014
Volume 11 Number 3
Featured in this issue:

Incretins harmful to the
pancreas?
Systemic medication and
diabetic retinopathy
Role of physiotherapy in
managing diabetes
Paediatric diabetes in
adolescents
Medicinal plants, renal
function and blood pressure
The ADVANCE
cardiovascular risk model
Electrocardiographic
abnormalities in subSaharan African diabetics
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Reviews
Ethics Focus
Achieving Best Practice
Psychological
considerations in managing
diabetes
Diabetes Educators Focus
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ISSN 1811-6515
THE SOUTH AFRICAN JOURNAL OF

HYPE
RINSULINAEMIA
Diabetes & vascular disease

VOLUME 11 NUMBER 3 SEPTEMBER 2014
www.diabetesjournal.co.za
Corresponding Editor
Dr FA Mahomed
Department of Internal Medicine,
Greys Hospital, Pietermaritzburg
Consulting Editors
PROF J-C MBANYA
DR L LOMBARD
National Editorial Board
DR A AMOD
Centre for Diabetes, Endocrinology and
Metabolic Diseases, Life Healthcare,
Chatsmed Gardens Hospital, Durban
SR K BECKERT
Diabetes Nurse, Paarl
PROF F BONNICI
Emeritus Professor, Faculty of Health
Sciences, University of Cape Town and
President of Diabetes South Africa
PROF R DELPORT
Department of Family Medicine,
University of Pretoria
DR L DISTILLER
Director of the Centre of Diabetes
and Endocrinology, Houghton,
Johannesburg
DR F MAHOMED
Department of Internal Medicine,
PROF WF MOLLENTZE
Head of Department of Internal
Medicine, University of the Free State,
Bloemfontein
PROF CD POTGIETER
Specialist Nephrologist, University
of Pretoria and Jakaranda Hospital,
Pretoria
PROF K SLIWA
Associate Professor of Medicine and
Cardiology, Baragwanath Hospital,
University of the Witwatersrand,
Johannesburg
PROF YK SEEDAT
Emeritus Professor of Medicine and
Honorary Research Associate,
University of Natal, Durban
International Editorial Board
PROF IW CAMPBELL
Physician, Victoria Hospital, Kircaldy,
Scotland, UK
PROF PJ GRANT
Professor of Medicine and head of
Academic Unit of Molecular Vascular
Medicine, Faculty of Medicine and
Health, University of Leeds; honorary
consultant physician, United Leeds
Teaching Hospitals NHS Trust, UK
PROF J-C MBANYA
Professor of Endocrinology, Faculty of
Medicine and Biomedical Sciences,
University of Yaounde I, Cameroon
and President, International Diabetes
Federation
PROF N POULTER
Professor of Preventive Cardiovascular
Medicine, Imperial College, School of
Medicine, London, UK
DR H PURCELL
Senior Research Fellow in Cardiology,
Royal Brompton National Heart and
Lung Hospital, London, UK
CONTENTS

Editorial
99
The role of allied health practitioners in diabetes care and more

FA Mahomed
Reviews
100
Incretins: harmful to the pancreas or not?

N Ramsunder
102
The effects of systemic medication on diabetic retinopathy

C-H Kruse
104
An overview of the role of physiotherapy in managing diabetes and

diabetes-associated conditions
H Shanahan
108
Paediatric diabetes with a focus on the adolescent

B Dhada, D Blackbeard, G Adams
111
A review of the literature on multidisciplinary interventions in cardiac

rehabilitation
M Rabilal
115
The effects of medicinal plants on renal function and blood pressure in

diabetes mellitus
CT Musabayane
121
The ADVANCE cardiovascular risk model and current strategies for

cardiovascular disease risk evaluation in people with diabetes
AP Kengne
Research Article
126
Prevalence and determinants of

electrocardiographic abnormalities
in sub-Saharan African individuals
with type 2 diabetes
A Dzudie, S-P Choukem, AK Adam, AP
Kengne, P Gouking, M Dehayem,
F Kamdem, MS Doualla, HA Joko, MEE
Lobe, YM Mbouende, H Luma,
JC Mbanya, S Kingue
Diabetes Peronality
131
Making a difference, one patient at a

time
P Wagenaar
Patient Information Leaflet
133
Psychological considerations in the

management of diabetes
O Brown
Production Editor
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The South African Journal of Diabetes and Vascular Disease is published four times a year for Clinics
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SA JOURNAL OF DIABETES & VASCULAR DISEASE
EDITORIAL
The role of allied health practitioners in diabetes care

and more
FA MAHOMED
his edition examines the important role of allied health

practitioners in the management of diabetes and also
looks at potential risks associated with medication.
Shanahan gives an excellent review of the spectrum of diabetesassociated disease covered by physiotherapy, as well as the
principles of management. Areas covered range from neuropathic
joints to adhesive capsulitis.
Brown reviews the psychological aspects of diabetes. These are
Correspondence to: Dr FA Mahomed
Principal endocrinologist, Department of Internal
Medicine, Greys Hospital, Pietermaritzburg
Tel: +27 (0) 33 897-3213
Fax: 086 6474 729
e-mail: Fazleh.Mahomed@kznhealth.gov.za
S Afr J Diabetes Vasc Dis 2014; 11: 99
often overlooked in busy practices and hospitals in South Africa,

but contribute greatly to quality of life, and need to be detected
and managed appropriately. Important topics range from eating
disorders to depression and more.
Rabilal looks at the multidisciplinary approach to cardiac rehabilitation. Cardiac complications are common in diabetes, and
rehabilitation forms an important part of comprehensive management.
Dhada and colleagues provide valuable insight into their
experience in running a paediatric/adolescent diabetes clinic in a
resource-limited setting.
Kruse reviews the effect of systemic drugs on diabetic retinopathy.
The effect of erythropoietin, aspirin and other drugs are explained.
These are important clinical considerations.
Ramsunder looks at the debate on benefit or harm produced by
incretins. New drugs on the market need to be carefully examined
for potential risk. As always, clinicians should assess the riskbenefit
ratio when prescribing medication.
15th ANNUAL SA HEART CONGRESS
REGISTRATION & ACCOMMODATION BOOKINGS OPEN

SA Heart Congress 2014 will be held in Durban, from 16 19 October, with the central theme being Bridging the Divide. This is
the divide that exists between current best practice and the challenges encountered in implementing these ideals. All medical
and allied professionals with an interest in cardiac health are warmly invited by the organising committee to attend.
For more information:

EUROPA ORGANISATION AFRICA
Tel +27 11 325 0020
Fax: +27 11 325 0028 or 0865 102 208
Email info@eoafrica.co.za
IN SOUTH AFRICA
at the SA Heart Association Congress
Bridging the Divide | 16 - 19 October 2014

International Convention Centre Durban South Africa
Website www.saheart.org/congress2014
WW00035 SAHEART ANN_1/2HA4.indd 1
07/03/2014 13:2
REVIEW
Incretins: harmful to the pancreas or not?

Nikash Ramsunder
Introduction
Naturally occurring incretins are intestinal hormones that are released in
response to food ingestion in order to potentiate the glucose-induced
insulin response, and account for 50 to 70% of the total insulin
secretion after meal ingestion. Their effects are mediated through
binding with specific receptors as well as neural modulation.
GIP and GLP-1 are both rapidly degraded into their inactive
metabolites by the enzyme dipeptidyl dipeptidase 4.1 Their physiological actions include:
stimulation of glucose-induced insulin secretion
regulation of metabolism in the adipocytes
promotion of -cell proliferation
stimulation of insulin gene transcription and hence biosynthesis
suppression of glucagon secretion in the pancreatic islets
exertion of trophic effects on pancreatic -cell mass, with -cell
proliferation and -cell neogenesis
inhibition of gastrointestinal secretion and motility, particularly
gastric emptying
enhancement of satiety
stimulate somatostatin secretion
improvement of endothelial dysfunction in patients with stable
coronary artery disease.
The incretin mimetics GIP and GLP-1, and dipeptidyl peptidase
4 (DPP-4) inhibitors are a new class of antidiabetic agents first
introduced in 2005 (exenatide) and 2007 (sitagliptin), respectively.
The most significant of these benefits that is not found with other
antidiabetic treatments are the glucose-dependant nature of
their insulinotropic effects and that they are associated with very
low rates of hypoglycaemia.2 They have also shown the ability to
preserve the remaining -cells in diabetes and this at one stage
provided hope that enhancing GLP-1 could potentially alter the
natural progression of diabetes.3
There is no doubt that incretin-based therapies have been shown
to be effective as glucose-lowering agents, as GLP-1 receptor
agonists demonstrate an efficacy comparable to that of insulin
treatment. This was demonstrated in the AMIGO studies where,
in a comparison of exenatide and insulin glargine, the lowering of
HbA1c levels did not differ between the groups during six and 12
months of treatment.2
However, there is controversy regarding the potential regenerative
effects of incretin therapy on pancreatic -cells, as shown by a
study on pancreases from age-matched donors with diabetes
mellitus (DM) and treated with incretins, those treated with other
Correspondence to: Dr Nikash Ramsunder
Department of Internal Medicine, Tygerberg
Hospital, Cape Town
e-mail: nikashramsunder@gmail.com
100
therapeutic agents, and non-diabetic control subjects. This study

revealed an average increase in pancreatic mass of around 40% in
those treated with incretins, showing a marked expansion of the
exocrine and endocrine pancreas. The former was accompanied
by increased proliferation and dysplasia and the latter by -cell
hyperplasia with the potential for evolution into neuroendocrine
tumours.4
This has created concern as to the long-term consequences of
using such therapies. Some of these concerns include the potential
of these drugs to cause acute pancreatitis and to initiate histological
changes to suggest chronic pancreatitis and pancreatic cancer.
Type 2 diabetes mellitus and obesity are known risk factors
for acute and chronic pancreatitis and pancreatic cancer, and
patients are more prone to developing these compared to the nondiabetic population. Therefore one can assume that there would
be an increased incidence of pre-malignant pancreatic lesions. It
is therefore important to establish whether these pre-malignant
lesions undergo proliferation in response to GLP-1 mimetic therapy
and whether such an effect could explain the early reporting of
pancreatic cancer observed here.5,6
In animal studies performed on three different species, including
mice, rats and monkeys, the GLP-1 agonist liraglutide did not induce
pancreatitis macroscopically or microscopically in any of the species
when dosed for up to two years and with exposure levels up to 60
times higher than in humans.7 In another study, however, low-grade
chronic pancreatitis was noted in most rats treated with exenatide,6
and this is of concern since chronic pancreatitis increases the risk of
pancreatic cancer. There have been reports of acute pancreatitis in
humans with the use of exenetide, the first of which was in 2006.8,9
Assessment of the US Food and Drug Administration (FDA)
adverse events database (AERS) in 20116 showed a six- to 10-fold
increase in pancreatitis in patients treated with the DPP-4 inhibitor
sitagliptin (131 events) and GLP-1 receptor agonist exenatide (971
events), respectively, in comparison to patients treated with the
control drugs rosiglitazone, nateglinide, repaglinide and glipizide
(43 events). The reported event rate for pancreatic cancer was
2.9 times higher for exenatide (81 events) and 2.7 times greater
for sitagliptin (16 events) when compared with control therapies
(13 events).10
A German adverse-events database showed a high incidence of
reporting of pancreatic cancer in association with exenatide (11
cases in four years with 1500025000 patients treated annually),
with a mean treatment duration of about 12 months. There was no
significant increase for the DPP-4 inhibitors.10
As these drugs have been around for a relatively short period of
time, these findings must be reviewed with caution. This time period
seems too short to induce tumour development, given the observed
10-year interval between tumour induction, growth and clinical
diagnosis.9,10 It is also important to consider the limitations of the
FDA AERS database, including incomplete data and reporting bias
introduced by potential confounders, which influenced the choice
of drug therapy, e.g. cigarette smoking, obesity and gender.11
The above analysis shows an increased reporting of pancreatic
cancer in association with exenatide, compared with other
treatments. It may suggest that the apparent increase in pancreatic

cancer with GLP-1 mimetic therapy is through the mechanism of
chronic inflammation and increased cell turnover.6
A cohort study that included patients without claims of
prior pancreatic disease, which initiated exenatide or other
antihyperglycaemic drugs between 2005 and 2007, showed that
with exenatide (n = 25 719), 40 confirmed cases of acute pancreatitis
were found, compared to 254 among the other antihyperglycaemic
agents (n = 234536). The conclusion reached was that exenatide
was not associated with an increased risk of pancreatitis when
compared with other antihyperglycaemic medications.12
Other retrospective cohort studies of a large medical and
pharmacy claims database of 786 656 patients have shown that
the incidence of acute pancreatitis in the non-diabetic group, the
diabetic group, the exenatide group and the sitagliptin group were
1.9, 5.6, 5.7 and 5.6 cases per 1 000 patient years, respectively. The
risk of acute pancreatitis was significantly higher in the combined
diabetic group than in the non-diabetic group.13
The risk of acute pancreatitis was similar in the exenatide versus
the diabetic control group, and the sitagliptin versus the diabetic
control group. No association was found between the use of
exenatide or sitagliptin and acute pancreatitis.12,13 Noel et al. also
examined the risk for pancreatitis in subjects with type 2 diabetes
and they reported a similar increased risk for acute pancreatitis
(4.22 cases per 1 000 patient years).14
Pancreas-related events after authorisation of DPP-4 inhibitors
have also raised early concerns about their possible association
with pancreatitis. Events of acute pancreatitis, including fatal
haemorrhagic or necrotising pancreatitis, have been reported in
patients receiving sitagliptin, vildagliptin or saxagliptin. In addition,
a casecontrol study suggests an association of sitagliptin with an
increased odds ratio of hospitalisation for acute pancreatitis.15-18
These findings need to be looked at with caution in the light
of data from randomised, controlled trials that did not verify an
association of sitagliptin with acute pancreatitis (n = 1 event per
4 709 patient years) compared with a control group (n = 4 events per
3 942 patient years).19 The incidence of acute or chronic pancreatitis
was similar however between patients receiving alogliptin and
those on placebo in a randomised control trial of 18 weeks.20,21
Linagliptin was associated with an increased number of cases
of pancreatitis compared to placebo. The study showed 11 cases
of pancreatitis among patients treated with linagliptin in a dataset
of 4 687 patients. There were 15.2 cases of pancreatitis per
10 000 patient-year exposure in patients treated with linagliptin as
opposed to 3.7 cases per 1 000 patient-year exposure in patients
receiving placebo.22,23 Furthermore, there were 11 reports of pancreatitis
out of 5 902 patients treated with allogliptin and five out of 5 183
patients in the control group during the drugs clinical programme.22
Conclusion
There are conflicting data surrounding the latest therapies for
diabetes mellitus, which include the GLP-1 mimetics and the DPP-4
antagonists, with some reports suggesting that there is a link
between incretin use and pancreatic adverse events. Others suggest
that there is no relationship between the two. Current evidence is
insufficient to define a causative relationship between the DPP-4
inhibitors and GLP-1 agonists and pancreatic adverse events. There
is a need for trials of sufficient size and duration with well-defined
parameters, as well as close pharmaco vigilance to evaluate their
REVIEW
effects on the durability of glycaemic control, the durability and

magnitude of weight regulation, their effects on cardiovascular
outcomes and long-term trials on safety.
Acknowledgement
Dr F Mahomed, head of Department of Internal Medicine, Greys
Hospital, assisted with this article.
References
1. Gautier JF, Choukem SP, Girard J. Physiology of incretins (GIP and GLP-I) and
abnormalities in type 2 diabetes. Diabetes Metab 2008; 34: S65S72.
2. Nauck AM, Vilsboll T, Gallwitz B, Garber A, Madsbad S. Incretin-based therapies,
viewpoints on the way to consensus. Diabetes care 2009; 32(2): S223S231.
3. Lamont BJ, Andrikopoulos S. Hope and fear for a new class of type 2 diabetes
drugs: Is there preclinical evidence that incretin-based therapies alter pancreatic
morphology? J Endocrinol 2014; 221(1): T43T61.
4. Butler AE, Campbell-Thompson M, Gurlo T, Dawson DW, Atkinson M, Butler
PC. Marked expansion of exocrine and endocrine pancreas with incretin therapy
in humans with increased exocrine pancreas dysplasia and the potential for
glucagon-producing neuroendocrine tumors. Diabetes 2013; 62: 25952604.
5. Cefalu WT. A critical analysis of the clinical use of incretin-based therapies.
Diabetes Care 2013; 36: 21262132.
6. Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler P. Pancreatitis, pancreatic
and thyroid cancer with glucagon like peptide I-based therapies. Gastroenterology
2011; 141: 150156.
7. Niels NCB, Molck AM, Lars MW, Lotte BK. The human GLP I analog liraglutide and
the pancreas. Evidence for the absence of structural pancreatic changes in three
species. Diabetes 2012; 61: 12431249.
8. Denker SP, Demarco PE. Exenatide (exendin-4)-induced pancreatitis. A case
report. Diabetes Care 2006; 29(2): 471.
9. Spranger J, Stammschulte UGT. GLP-I based therapies: The dilemma of uncertainty.
J Gastroenterol 2011; 141: 2023.
10. Vangoitsenhoven R, Mathieu C, Schueren B. GLP-I and cancer: friend or foe.
Endocrine Related Cancer 2012; 19: F77F88.
11. Phillips LK, Prins BJ. Update on incretin hormones. A New York Acad Sci 2012:
120.
12. Dore DD, Bloomgren GL, Wenten M, Hoffman C, Clifford CR, Quinn SG, et al. A
cohort study of acute pancreatitis in relation to exenatide use. Diabetes Obesity
Metab 2011; 13(6): 559566.
13. Garg R, Chen W, Pendergrass M. Acute pancreatitis in type 2 diabetes treated
with exenatide or sitagliptin, a retrospective observational pharmacy claims
analysis. Diabetes Care 2010; 33(11): 23492354.
14. Olansky L. Do incretin-based therapies cause acute pancreatitis. J Diabetes Sci
Technol 2010; 4(1): 228229.
15. Girgis C, Champion B. Vildagliptin induced acute pancreatitis. Endocrine Pract
2011; 17: e48e50.
16. Saraogi R, Mallik R, Ghosh S. Mid acute pancreatitis with vildagliptin use. Indian
J Endocrinol Metab 2012; 16: S480S482.
17. Kunjathaya P, Ramaswami P, Krishnamurthy A, Bhat N. Acute necrotizing
pancreatitis associated with vildagliptin. J Oncol Pract 2013; 14: 8184.
18. Singh S, Chang H, Richards T, Weiner J, Clark J, Segal J. Glucagon-like peptideI-based therapies and the risk of hospitalization for acute pancreatitis in type 2
diabetes mellitus: a population-based matched case-control study. J Am Med
Assoc Int Med 2013; 173: 534539.
19. Engel S, Williams HD, Golm G, Clay R, Machotka S, Kaufman K, et al. Sitagliptin:
review of preclinical and clinical data regarding the incidence of pancreatitis. Int J
Clin Pract 2010; 64: 984990.
20. Ligueros MS, Foley J, Schweizer A, Couturier A, Kothny W. An assessment of
adverse effects of vildagliptin versus comparators on the liver, spleen, the pancreas,
the immune system, the skin and in patients with impaired renal function from
a large pooled database of phase II and phase III clinical trials. Diabetes Obesity
Metab 2010; 12: 495509.
21. White W, Cannon C, Heller S, Nissen S, Bergenstal R, Bakris G, et al. Alogliptin
after acute coronary syndrome in patients with type 2 diabetes. New Engl J Med
2013; 369: 13271335.
22. Karagiannis T, Boura P, Tsapas A. Safety of dipeptidyl peptidase 4 inhibitors: a
perspective review. Ther Adv Drug Safety 2014; 5: 138146.
23. Linagliptin assessment report. Eur Med Agency (updated 20 September
2012, Cited 5 June 2014). Available from http://www.ema.europa.eu/docs/
en_GB/document_library/EPAR_-_public_assessment_report/human/000771/
WC500115748.pdf
101
REVIEW
The effects of systemic medication on diabetic retinopathy

Carl-Heinz Kruse
The incidence of diabetic retinopathy
Of all the complications of diabetes mellitus, diabetic retinopathy
(DR) is feared most by patients. These fears are well founded since
DR is the third leading cause of irreversible blindness in the world1
and the leading cause among working-age adults.2 As a matter
of fact, a diabetic patient is more likely to go blind in the next 14
years3 than die of a motor vehicle accident in his/her lifetime.4
The gold standard for the treatment of diabetic retinopathy has
until recently been laser therapy. This modality is useful for halting the
progress in both proliferative retinopathy as well as diabetic macular
oedema. Recently the use of intravitreal steroid (Triamcinolone) and
intravitreal anti-VEGF (Bevacizumab) have shown improved results
and have resulted in an overall improvement of vision over laser
therapy alone.
Despite these advances, some patients have relentless disease,
which sometimes inexorably leads to severe visual impairment
despite all treatment. The prevalence of self-rated visual impairment
among US adults with diabetes was almost 25%.5
The best management for DR remains prevention and the best
way to achieve this in a diabetic patient is meticulous control of
blood glucose levels.2 In recent studies, it has also been found
that other systemic drugs, often given for the treatment of other
conditions, can have deleterious or beneficial effects on the
initiation and progression of diabetic retinopathy. This article aims
to give a synopsis of the most relevant of these drugs.
Drugs for glucose control

Insulin
It is apparent that glycaemic medication would have the greatest
effect on the initiation and progression of DR. This effect is
particularly pronounced at the early stages of DR where good
glucose control has a stronger protective effect. Although strict
glucose control is almost always beneficial for DR, under certain
circumstances it can actually be harmful.
The Early Treatment Diabetes Retinopathy Study (ETDRS)6 clearly
showed that improving systemic glucose control reduces the risk of
progression to severe visual loss or vitrectomy at five years. Patients
with HbA1C levels above 12% had a 39% greater chance of a poor
outcome than those with HbA1c levels less than 8.3%.6
The exception to this rule is in patients with non-insulindependent diabetes mellitus (NIDDM), who improve their glycaemic
control by changing to aggressive insulin therapy.7 This effect was
Correspondence to: Dr Carl-Heinz Kruse

Department of Opthalmology, University of
KwaZulu-Natal, Durban
e-mail: ruraleye@gmail.com
102
particularly pronounced when the HbA1c levels where dropped by

more than 3%; 23% of these patients developed a progression
of retinopathy of three or more levels. This effect is termed early
worsening and occurs in the first two years after initiating insulin
therapy.
In most cases, this effect seems to be transient and strict glucose
control eventually gives better retinopathy results, especially after
the first three years.2,8 Early worsening is therefore not a reason not
to aggressively control glucose levels, but close monitoring of the
DR before and after initiation of insulin therapy is still warranted.
The introduction of antioxidant supplementation might attenuate
this transient insulin-induced worsening of DR.9
If the DR is severe, the intensive insulin therapy should be delayed
until laser panretinal photocoagulation has been completed. Rapid
development of proliferative DR has been reported in isolated cases
where extremely high doses of insulin were given.
Biguanides
Metformin not only has cardioprotective effects independent of
glucose control but also clinically inhibits inflammation-mediated
angiogenesis. The magnitude of this protective effect on DR is yet
to be elucidated.
Drugs for hypertension management

Controlling blood pressure is in itself a good method of reducing
the progression of DR.10 Keeping the blood pressure below 150/85
mmHg reduces the chances of deterioration of DR by two levels
in NIDDM by 34% over a nine-year period. A further decrease of
diastolic blood pressure to below 75 mmHg did not give added
benefit with regard to DR progression.11
Some antihypertensive drugs however seem to have an effect on
diabetic retinopathy independent of the antihypertensive effect.12
Blockage of the reninangiotensin system slows progression of
DR in insulin-dependent diabetes. Enalapril and losartan show a
65 and 70% reduction of a two-step progression of DR at five
years.13 Importantly, this effect is independent of the changes in
blood pressure and is therefore recommended in patients with both
diabetes and hypertension.
Candesartan not only slows progression but has been associated
with an overall regression of DR.14 This effect was seen in NIDDM
patients with mild to moderate retinopathy.
Drugs for lipid control

Lowering of serum lipid levels in diabetics with hyperlipidaemia
reduces the development of hard exudates and reduces the vision
loss from diabetic macular oedema.15 Once again, some of these
drugs show an additional advantage on DR independent of the
lipid-lowering effect.
Fenofibrate, a PPAR agonist, has been accepted in a number
of countries as an effective method to modulate and reduce
the progression of DR. Two large trials, the FIELD (Fenofibrate
Intervention and Event Lowering in Diabetes) and ACCORD
(Action to Control Cardiovascular Risk in Diabetes) studies, have
demonstrated its benefit in DR.16 These two trials together included

21 000 participants, of whom over 10 000 received fenofibrate.
Although these trials primarily looked at cardiovascular effects,
both had large retinopathy subsets.
The ACCORD study consistently showed benefit in reducing
progression of DR. The FIELD study showed that 40% fewer
patients taking fenofibrate had significant DR progression than the
control group after five years (10.2 vs 6.5%). Additionally, 30%
more patients in the control group required laser therapy than in
the fenofibrate group (3.6 vs 5.2%).16
Drugs for anaemia treatment

Erythropoietin is a potent ischaemia-induced angiogenic factor
during retinal angiogenesis in DR.17 Patients receiving erythropoietin
should have their retinopathy closely monitored, especially if in
combination with anaemia and kidney disease.
REVIEW
careful choice of systemic medication, especially for hypertension,

hyperlipidaemia, anaemia and cardiac complications management
can assist in decreasing irreversible loss of vision in diabetic
patients.
References
1.
2.
3.
4.
5.
6.
Drugs for cardiac complications management

Both salicylates and digoxin have the theoretical ability to be
advantageous in DR.
Salicylates
Aspirin-like substances may be useful in early DR to slow progression. As early as 1964, the effects of large doses of salicylates
on DR have been reported and recent studies show a positive effect
on DR in animals. Doses of 2 to 4 mg per day in humans could
delay the progression of DR. New advances in nanotechnology
imply that salicylates could be formulated as an eye drop for
topical use.18
One of the complications of proliferative diabetic retinopathy is
that of loss of vision due to vitreous haemorrhage. Systemic aspirin
has been proven not to increase this risk19 and neither does warfarin
nor heparin.20
Digoxin
Digoxin has been found to block hypoxia-induced expression
of multiple angiogenic genes and is also a powerful inhibitor of
neovascularisation of the retina and choroid layer.21 The FDA has
recently begun trials on a topical application.
Anti-angiogenic drugs and steroids

Both of these agents only improve DR (proliferative DR as well
as macular oedema) when injected intra-ocularly. Systemic
administration of both has a negligible effect and steroids can
make glycaemic control difficult, and potentially worsen DR.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
Conclusion
20.
Although good serum glucose control and regular fundoscopy are

most important for managing diabetic retinopathy, there are other
strategies we can use to modify the outcome of this disease. A
21.
Bourne RRA, et al. Causes of vision loss worldwide, 19902010: a systematic

analysis. Lancet Glob Health 2013; 1: e339e349.
Abbate M, Cravedi P, Iliev I, Remuzzi G, Ruggenenti P. Prevention and treatment of
diabetic retinopathy: evidence from clinical trials and perspectives. Curr Diabetes
Rev 2011; 7: 190200.
Moss SE, Klein R, Klein BEK. The 14-year incidence of visual loss in a diabetic
population. Ophthalmology 1998; 105: 9981003.
Lally S. NSC Releases 2014 edn of injury facts | EHS Works. NSC Releases 2014
edn Inj Facts EHS Works 2014. <http://ehsworks1.blogspot.com/2014/03/nscreleases-2014-edition-of-injury.html>
Saaddine JB, et al. Prevalence of self-rated visual impairment among adults with
diabetes. Am J Public Health 1999; 89: 12001205.
Davis, MD, et al. Risk factors for high-risk proliferative diabetic retinopathy and
severe visual loss: Early Treatment Diabetic Retinopathy Study Report #18. Invest
Ophthalmol Vis Sci 1998; 39: 233252.
Henricsson M, Janzon L, Groop L. Progression of Retinopathy after change of
treatment from oral antihyperglycemic agents to insulin in patients with NIDDM.
Diabetes Care 1995; 18: 15711576.
Diabetes Control and Complications Trial Research Group. Progression of
Retinopathy with Intensive versus Conventional Treatment in the Diabetes Control
and Complications Trial. Ophthalmology 1995; 102: 647661.
Wu H, et al. Supplementation with antioxidants attenuates transient worsening
of retinopathy in diabetes caused by acute intensive insulin therapy. Graefes Arch
Clin Exp Ophthalmol 2012; 250: 14531458.
Tight blood pressure control and risk of macrovascular and microvascular
complications in type 2 diabetes: UKPDS 38. Br Med J 1998; 317: 703713.
Estacio Ro, Jeffero BW, Gifford N, Schrier RW. Effect of blood pressure control
on diabetic microvascular complications in patients with hypertension and type 2
diabetes. Diabetes Care 2000; 23(Suppl 2): B5464.
Teuscher A, Schnell H, Wilson PW. Incidence of diabetic retinopathy and
relationship to baseline plasma glucose and blood pressure. Diabetes Care 1988;
11: 246251.
Mauer M, et al. Renal and retinal effects of enalapril and losartan in type 1
diabetes. N Engl J Med 2009; 361: 4051.
Sjlie AK, et al. Effect of candesartan on progression and regression of retinopathy
in type 2 diabetes (DIRECT-Protect 2): a randomised placebo-controlled trial.
Lancet 2008; 372: 13851393.
Chew EY, Klein ML, Ferris FL, III, et al. Association of elevated serum lipid levels
with retinal hard exudate in diabetic retinopathy: Early Treatment Diabetic
Retinopathy Study (ETDRS) report 22. Arch Ophthalmol 1996; 114: 10791084.
Wong TY, Sim R, Mitchell P. Fenofibrate a potential systemic treatment for
diabetic retinopathy? Am J Ophthalmol 2012; 154: 612.
Watanabe D, et al. Erythropoietin as a retinal angiogenic factor in proliferative
diabetic retinopathy. N Engl J Med 2005; 353, 782792 (2005).
Das S, Bellare JR, Banerjee R. Protein based nanoparticles as platforms for aspirin
delivery for ophthalmologic applications. Colloids Surf B Biointerfaces 2012;
93: 161168.
Early Treatment Diabetic Retinopathy Study Research Group. Effects of aspirin
treatment on diabetic retionopathy: ETDRS Report number 8. Ophthalmology
1991; 98: 757765.
Silva PS, Cavallerano JD, Sun JK, Aiello LM, Aiello LP. Effect of systemic medications
on onset and progression of diabetic retinopathy. Nat Rev Endocrinol 2010;
6: 494508.
Yoshida T, et al. Digoxin inhibits retinal ischemia-induced HIF-1 expression and
ocular neovascularization. FASEB J 2010; 24: 17591767.
103
REVIEW
An overview of the role of physiotherapy in managing

diabetes and diabetes-associated conditions
Heidi Shanahan
lthough physiotherapists usually encounter diabetes as a

secondary condition in patients during the evaluation and
treatment of movement, functional and musculoskeletal
disorders, physiotherapy is both a curative and preventative
discipline that employs a holistic approach to healthcare.
Physiotherapists in South Africa can utilise their knowledge
of therapeutic exercise and preventative care, so contributing to
addressing the challenges of non-communicable disease and
the increasing burden this is placing on healthcare resources.1
Involvement in primary healthcare embraces health promotion,
which encourages the patient to share responsibility for optimal
health outcomes and adopt beneficial behavioural changes and a
healthy lifestyle, and to better self-manage his/her condition.
Physiotherapists may encounter patients with impaired glucose
tolerance or insulin resistance (pre-diabetes), early diabetes with
no or minimal vascular changes, and more advanced disease
with several vascular complications, as well as complications that
include involvement of the musculoskeletal system. Some of these
musculoskeletal conditions are commonly seen by physiotherapists,
who may not be aware of the impact of diabetes on the condition.
Micro- and macrovascular complications affect several organs
including the muscle, skin, heart, brain and kidneys.
Even though conditions such as diabetic neuropathy, retinopathy,
nephropathy and cardiovascular and peripheral vascular diseases
may not be the reason for the physiotherapy intervention, it is
important for the physiotherapist to be aware of the underlying
vascular deficits when providing treatment for musculoskeletal
and movement disorders. In addition, physiotherapists can play
an important role in the care of people with diabetes because
interventions such as exercise prescription and promoting increased
physical activity can assist in alleviating symptoms, slow metabolic
progression to overt type 2 diabetes and reduce morbidity and
mortality associated with these complications.2
Musculoskeletal manifestations of diabetes

Assessment and management of the patient should include
questions regarding the presence of diabetes and glycaemic control,
and relevant patient education and exercise prescription, as well as
referral for review to other disciplines (e.g. dietitian, podiatrist) if
necessary.
Adhesive capsulitis
This is also known as frozen shoulder, and has been reported as having
greater incidence among patients with insulin-dependent diabetes,
Correspondence to: Heidi Shanahan
Physiotherapy Department, Greys Hospital, Pietermaritzburg
e-mail: heidi.shanahan@kznhealth.gov.za
104
with increased frequency of bilateral shoulder involvement.3,4

The condition is characterised by three phases: painful (pain is
dominant), adhesive (stiffness dominates), and resolution, which
may take two to three years to complete. Adhesive capsulitis is
considered to be a self-limiting condition, but many patients never
regain normal shoulder mobility.
Physiotherapy treatment of adhesive capsulitis aims to relieve
pain, maintain or improve active and passive range of motion
(ROM) and restore function. The modalities include exercise,
electrotherapy, mobilisation techniques and hydrotherapy.
Carette et al.5 concluded that a single intra-articular injection
of corticosteroid administered under fluoroscopy combined with
a simple home exercise programme was effective in improving
shoulder pain and disability in patients with adhesive capsulitis.
Adding supervised physiotherapy provided faster improvement
in shoulder range of motion. When used alone, supervised
physiotherapy was of limited efficacy.
Patients with greater disability levels, more co-morbidities, high
fear and anxiety levels, lower educational levels, and those who
have less social support may benefit more from formal supervised
physiotherapy.5,6 Patient education about the progression of
restricted motion and extended time to recovery is an important
aspect of treatment.
Carpal tunnel syndrome
The symptoms of parasthesia over the median nerves cutaneous
distribution may be caused by compression of the median nerve
in the carpal tunnel, by diabetic neuropathy, or a combination of
both.3 About 58% of patients with carpel tunnel syndrome have
diabetes, and it is more common in women than men.
Physiotherapy treatment of carpal tunnel syndrome with
ultrasound can provide satisfying short- to medium-term effects in
patients with mild to moderate idiopathic carpal tunnel syndrome.7
Digital flexor tendon-mobilising techniques have been shown to be
helpful in the management of pre- and postoperative carpal tunnel
patients.8
In addition, physiotherapists and occupational therapists can
offer advice on task modification and ergonomics, which will often
control mild or moderate symptoms of carpal tunnel syndrome.
The pressure in the carpal tunnel is lowest in neutral wrist flexion
extension range, with the pressure rising significantly as the wrist
is moved into flexion or extension. Splints that hold the wrist in the
neutral position are often helpful in controlling symptoms of mild
to moderate severity.8
Depuytrens contracture
This is palmar or digital thickening, tethering or contracture of
the hands. In patients with diabetes, the middle and ring finger
are more commonly affected, compared with the fifth finger in
patients without diabetes. Physiotherapy intervention comprises
a hand therapy programme with the aim of optimising ROM,
improving grip strength and maintaining or improving function.

Occupational therapy intervention may also include splinting to
assist with maintenance of ROM. In diabetics, the contractures are
usually mild and rarely require surgery.3
Flexor tenosynovitis
This has a higher incidence in diabetic patients and people with
impaired glucose tolerance. A corticosteroid injection into the
affected tendon sheath is often curative.3 Ultrasound over the
affected tendon may help to ease the symptoms.
Diffuse idiopathic skeletal hyperostosis (DISH)
This is also known as ankylosing hyperostosis and is characterised
by new bone formation, particularly in the thoracolumbar spine.
It occurs with greater frequency in the diabetic population than
in non-diabetics, and has a higher prevalence in type 1 compared
with type 2 diabetes. DISH is often asymptomatic and diagnosed
as an incidental radiographic finding. Physiotherapy treatment
would be symptomatic and include electrotherapy and exercise
programmes.3
Neuropathic (Charcots) joints
Limited joint mobility (diabetic cheiroarthropathy) and diabetic
amyotrophy are seen more often in type 1 diabetics. Charcots joints
occur as a result of diabetic peripheral neuropathy. The weightbearing joints are most commonly affected. The use of walking aids
and orthotics can reduce impact on the affected joints, assist with
reduction of pain when walking and improve mobility.
Diabetic cheiroarthropathy is characterised by thick, tight skin
mainly on the dorsum of the hand, and flexion deformities of the
metacarpophalangeal and interphalangeal joints. In the early stages,
slight pain and parasthesias develop, with pain increasing slowly.
3,9
Physiotherapy (and/or occupational therapy) intervention would
comprise a hand therapy programme with the aim of optimising
ROM, improving grip strength and maintaining or improving
function, as well as instruction on skin care.
Diabetic amyotrophy is characterised by muscle weakness and
wasting, and proximal lower limb muscle pain. The shoulder girdle
is less commonly affected. Most cases improve gradually with
stabilised glycaemic control.3
Effects of micro- and macrovascular complications

Diabetic peripheral neuropathy (DPN)
This is associated with both vascular and non-vascular mechanisms
of diabetes. Altered lower limb sensation and pain may be
encountered in the evaluation and treatment of balance and
movement disorders. When associated with impaired vascular
function, peripheral neuropathy can contribute to the development
of lower limb ulceration.2 Transcutaneous electrical nerve stimulation
(TENS), percutaneous electrical nerve stimulation (PENS) and
acupuncture have all been proposed as modalities that may relieve
the pain and discomfort associated with DPN. 10-13
Spinal cord involvement
This may occur at a subclinical stage of DPN, which suggests
that the metabolic insult of diabetes has a generalised effect
on the nervous system.14 Spinal cord involvement may be a reason
for poor responses to treatment modalities for pain associated
with DPN.
REVIEW
Cardiac autonomic neuropathy

This can include clinical abnormalities such as resting tachycardia,
exercise intolerance and slow heart rate recovery after exercise.2 The
patients perceived exertion should be used as a measure of effort for
exercise prescription, rather than relying on heart rate responses.
Diabetic retinopathy (DR)
DR is a leading cause of visual disability and blindness in people
with diabetes. The most significant factor in the development and
progression of DR appears to be hyperglycaemia.2 Vision loss has a
psychological impact as well as negatively impacting on diabetes
self-management skills. An intensive multidisciplinary rehabilitation
programme offering exercise training, instruction in diabetes selfmanagement techniques for the visually impaired, and group
support early in the course of vision loss may be of clinical benefit.15
Orientation and mobility (O&M) trainers are a scarce but valuable
resource for advising and training both the visually impaired patient
and their caregivers.
Diabetic nephropathy
This typically first manifests as microalbuminaria, which progresses
to renal failure and end-stage renal disease. Physiotherapy renal
rehabilitation programmes and exercise are recommended to
improve patient functional performance, exercise tolerance and
quality of life.16
Cardiovascular disease (CVD)
CVD risk factors are common in diabetes, but diabetes appears to
be an independent risk factor for CVD. Insulin resistance is also
linked with increased risk for CVD. Increased physical activity and
moderate to high levels of cardiorespiratory fitness is generally
recommended as an intervention, which assists with reduction and
control of central adiposity, dyslipidaemia, hyperglycaemia and
hypertension, so benefitting cardiovascular health and reducing
mortality.17,18
Cerebrovascular disease
Diabetes is an independent risk factor for stroke across all ages.
In the SASPI study of stroke prevalence in rural South Africans,
the risk factor associated with diabetes mellitus was 12%, after
hypertension (71%) and current alcohol use (20%).19 Diabetes
affects the cerebrovascular circulation by increasing the risk of
intracranial and extracranial atherosclerosis.
The challenges of accessing physiotherapy and occupational
therapy rehabilitation in rural areas and the lack of resources impact
negatively on the level of independent function that is achieved by
the stroke patient. Decreased functional abilities compounded by
cognitive disabilities associated with stroke can negatively impact
on diabetes self-care.
Peripheral vascular disease (PVD)
PVD is characterised by occlusion of the lower limb arteries, which
causes intermittent claudication and pain, especially with exercise
and activity. Severe disability and functional impairment is associated
with PVD and diabetes.
Exercise training in people with PVD has been shown to
be beneficial to improving walking distance and time, time to
claudication and pain, and quality of life. In addition, a person who
has better exercise tolerance and muscle power will be more likely
to achieve good functional outcomes post amputation.2
105
REVIEW
Physiotherapists frequently treat patients with diabetes-related

amputations. Rehabilitation may be challenging in the patient
with poor glycaemic control as wound healing may be delayed,
and vascular impairment, DN or ulceration of the intact limb affects
weight bearing and functional gait. The physiotherapist must be
aware of the condition of the wound and stump, as preparation of
the stump for prosthesis may damage fragile skin and subcutaneous
tissue. Resource limitations add to the challenges associated with
rehabilitation of amputees.
There are fewer than 800 medical orthotists and prosthetists
registered to practice in South Africa, of whom a minority practice in
the public health sector. Combined with financial restraints, this leads
to long waiting lists and delays in the provision of artificial limbs.
Considerations in the implementation of physical

activity and exercise
Barriers to participation in exercise are a factor in low activity levels.
Barriers to physical activity and exercise have been reported in
diabetic patients attending two urban clinics in Gauteng, including
both personal and environmental barriers such as health (e.g.
arthritis, foot problems, breathlessness, diabetes), laziness, socioeconomic circumstances (e.g. caring for dependants), perceived
adequate exercise (e.g. household chores, gardening), suitable
venue, safety, understanding the benefit of exercise.20,21
The physiotherapy departments at public health institutions are
well positioned to promote exercise in communities with limited
resources. Establishment of a diabetes exercise group would
offer the diabetic patient a safe venue, access to regular exercise
and information sessions, and a supportive environment that
promotes self-management. Those unable to attend supervised
exercise groups can be prescribed an exercise programme that they
implement unsupervised in their home setting.
Mshuqane et al. undertook a study at Bethlehem regional
hospital in the Free State, which allocated diabetic patients to
one of three groups, namely walking under supervision, cycling
under supervision or walking unsupervised (at home). Although
the study groups were small, all groups showed improvement in
serum glucose levels and exercise capacity over the three-month
study period.22
Patients who are unable or unwilling to take part in physical
activity of adequate duration, intensity and frequency may benefit
from participation in relaxation classes, which have been shown to
improve perception of health and general well-being, and reduce
stress and anxiety, which may have positive benefits for diabetes
self-management.23
Guidelines for implementation of effective and safe

exercise programmes
Pre-exercise evaluation
For moderate-intensity aerobic or resistance exercise, stress testing
is not routinely necessary. Previously sedentary patients with
multiple CVD risk factors should be assessed before an exercise
programme is prescribed, and the patients age, activity levels and
the presence of other conditions should be noted and considered
when developing an exercise programme.
Objective measures such as the six-minute walk test, resting
and recovery pulse rates, body mass index and the Borg scale
score (perceived exertion) should be recorded during the initial
assessment. These measures should be considered when structuring
106
personalised programmes and rates of progression of activity.

These baseline scores may be useful to measure future progress
and motivate the patient to continue with the programme.
Exercise prescription: type, duration and frequency
To improve glycaemic control, assist with weight maintenance and
reduce risk of CVD, the physical activity should be distributed over
at least three days/week, with no more than two consecutive days
without physical activity.17,18
At least 150 min/week of moderate-intensity aerobic physical
activity (5070% of maximum heart rate) and/or at least 90 min/
week of vigorous aerobic exercise (70% of maximum heart rate)
should be done. Resistance exercise should be done three times a
week, targeting all major muscle groups, progressing to three sets
of eight to 10 repetitions at a weight that cannot be lifted more
than eight to 10 times.17,18
Factors to consider during exercise prescription
Concerns have been expressed about the safety of high-intensity
resistance exercise in middle-aged and older people at risk of CVD.
The main concern is that the acute rise in blood pressure (BP)
associated with lifting a weight may provoke myocardial infarction,
stroke or retinal haemorrhage.18 However, as an acute rise in BP can
also be associated with aerobic exercise and activities of daily living,
CVD risk should not be regarded as a contra-indication.
Until the insulin-dependent patient knows his/her usual
glycaemic response to the activity, blood glucose levels should
be determined before, after, and several hours after completing
a session of physical activity in order to prevent hypoglycaemia.
If pre-exercise glucose levels are less than 6.6 mmol/l, additional
carbohydrate can be ingested. Doses of insulin can be reduced
before exercise sessions of physical activity, or both strategies can
be implemented. However these strategies must be personalised
and blood glucose levels monitored.17,18
Conclusion
Physiotherapists aim to restore normal function or minimise
dysfunction and pain and prevent recurring injuries and disabilities.
One of the core skills used by physiotherapists is exercise prescription,
which benefits many aspects of health. Physiotherapists are in a
position to impact on the prevention, control and management of
diabetes and diabetes-associated conditions.
References
1.
Frantz JM. Physiotherapy in the management of non-communicable diseases:

Facing the challenge. S Afr J Physiothery 2005; 61: 810.
2. Cade WT. Diabetes-related microvascular and macrovascular diseases in the
physical therapy setting. Phys Ther 2008; 88: 13221335.
3. Smith LL, Burnet SP, McNeil JD. Musculoskeletal manifestations of diabetes
mellitus. Br J Sports Med 2003; 37: 3035.
4. Pearsall AI. Adhesive capsulitis. eMedicine 2008. Accessed 20/05/2014.
5. Carette S, Moffet H, Tardif J, Bessette L, Morin F, Fremont P, et al. Intraarticular
corticosteroids, supervised physiotherapy, or a combination of the two in the
treatment of adhesive capsulitis of the shoulder. Arthritis Rheumatism 2003;
829838.
6. Kelley MJ, McClure PW, Leggin BG. Frozen shoulder: evidence and a proposed
model guiding rehabilitation. J Orthopaed Sports Phys Ther 2009; 39: 148.
7. Ebenbichler GR, Resch KL, Nicolakis P, Wiesinger GF, Uhl F, Ghanem A, Fialka V.
Ultrasound treatment for treating the carpal tunnel syndrome. Br Med J 1998;
316: 731735.
8. Burke FD, Ellis J, McKenna H, Bradley MJ. Primary care management of carpal
tunnel syndrome. Postgrad Med J 2003; 79: 433437.
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Hoffman S, Hislop M. Diabetes mellitis. In: Brukner P, Khan K (eds). Clinical Sports
Medicine, 3rd edn. Australia: McGraw-Hill, 2009: 841849.
Boulton AJ, Malik RA, Arezzo JC, Sosenko JM. Diabetic somatic neuropathies.
Diabetes Care 2004; 27: 14751486.
Pieber K, Herceg M. Electrotherapy for the treatment of painful diabetic peripheral
neuropathy: a review. J Rehabil Med 2010; 42: 289295.
Gersh MR, Wolf SL, Rao VR. Evaluation of transcutaneous electrical nerve
stimulation for pain relief in peripheral neuropathy, a clinical documentation. Phys
Ther 1980; 60: 4852.
National Institute for Health and Care Exellence (NICE) Guidelines. Percutaneous
electrical nerve stimulation for refractory neuropathic pain (IPG450). Issued March
2013.
Selvarajah D, Wilkinson ID, Emery CJ, Harris ND, Shaw PJ, Witte DR, et al. Early
involvement of the spinal cord in diabetic peripheral neuropathy. Diabetes Care
2006; 29: 26642669.
Bernbaum M, Albert SG, Duckro, PN. Psychosocial profiles in patients with visual
impairment due to diabetic retinopathy. Diabetes Care 1988; 11: 551557.
Gray PJ. Management of patients with chronic renal failure: role of physical
therapy. Phys Ther 1982; 62: 173176.
REVIEW
17. The 2012 SEMDSA guideline for the management of Type 2 diabetes. Physical
activity and type 2 diabetes mellitus. J Endocrin Metab Dis S Afr 2012; 17(suppl):
S18S19.
18. A consensus statement from the American Diabetes Association. Physical
activity/exercise and type 2 diabetes. Diabetes Care 2006; 29: 14331438.
19. Connor M, Bryer A. Stroke in South Africa. Cape Town: Medical Research
Council, 2006. http://www.mrc.ac.za/chronic/cdlchapter14.pdf (accessed 6
May, 2014).
20. Van Rooijen AJ, Rheeder P, Eales CJ, Molatoli HM. Barriers to and expectations
of performing physical activity in female subjects with type 2 diabetes. S Afr J
Physiother 2002; 311.
21. Nel C, Van Rooijen AJ, van der W, Viljoen I, Steenkamp EM, Mamadi S. Physical
activity levels in male and female diabetic patients at the Pretoria Academic
Hospital, South Africa. S Afr J Physiother 2007; 63: 26.
22. Mshuqane N, Cohen D, Kalk JK. Effects of an exercise programme on noninsulin dependant diabetes mellitus. S Afr J Physiother 2004; 60: 2630.
23. Van Rooijen AJ, Rheeder P, Eales CJ, Becker PJ. Effect of exercise versus relaxation
on health-related quality of life in black females with type 2 diabetes mellitus.
S Afr J Physiother 2005; 61: 714.
Effects of intensive glycaemic control on ischaemic heart disease
ow can three landmark trials of intensive versus standard

glucose-lowering strategies ADVANCE, ACCORD and
VADT raise more questions than they answer? This was the
conundrum a recent post hoc analysis of the studies looked to
address.
All three studies did not meet their primary objective of reducing cardiovascular events, despite achieving significantly lower
HbA1c levels; in the ACCORD study, the data-monitoring committee prematurely stopped the intensive-strategy arm due to an
excess rate of cardiovascular death. These results flew squarely
in the face of conventional wisdom that lowering HbA1c to
normal levels would improve cardiovascular outcomes, similar
to the clearly proven benefit of reducing microvascular complications. Each trial has subsequently published numerous analyses
that have tried, mostly unsuccessfully, to explain why mortality,
in particular, did not decrease, or in the case of ACCORD even
increased, with a more intensive glycaemic strategy.
What is interesting is that across these studies, there does
appear to be a consistent signal that improved glycaemic management may reduce coronary artery events. This observation
was first noted over a decade ago in the UKPDS study, in which
more intense glycaemic control reduced the rate of myocardial
infarction (MI).
The ACCORD investigators now report a consistent reduction
of about 1520% in non-fatal MI, unstable angina and coronary
revascularisation in the intensive-therapy arm. The benefit became
more apparent during the longer follow-up period, suggesting a
legacy effect. Interestingly, when controlling for achieved HbA1c
level, the benefit was attenuated, which implies that better glycaemic control may be causal in reducing ischaemic events.
It is important to remember that this is a post hoc analysis
and still cannot reconcile the higher rates of death in the intensive-strategy arm. But it raises the possibility that there may be
strategies that can both safely lower glucose and reduce cardiovascular events. How you improve glycaemic control may be as
important as the actual HbA1c target. The score of ongoing cardiovascular outcome trials of novel antihyperglycaemic agents
will likely provide further insight into this clinical dilemma.
The researchers assessed 10 251 adults aged 4079 years
with established type 2 diabetes, mean HbA1c concentration of
67 mmol/ml (8.3%) and risk factors for ischaemic heart disease enrolled in the ACCORD trial. Participants were assigned
to intensive or standard therapy [target HbA1c < 42 or 5363
mmol/ml (< 6.0 or 7.07.9%), respectively]. They assessed fatal
or non-fatal MI, coronary revascularisation, unstable angina and
new angina during active treatment (mean 3.7 years) plus a further mean of 1.2 years.
Raised glucose concentration is a modifiable risk factor for
ischaemic heart disease in middle-aged people with type 2 diabetes and other cardiovascular risk factors. MI was less frequent
in the intensive- than in the standard-therapy group during
active treatment [hazard ratio (HR) 0.80, 95% CI: 0.670.96; p
= 0.015] and overall (HR 0.84, 95% CI: 0.720.97; p = 0.02).
Findings were similar for combined MI, coronary revascularisation and unstable angina (active treatment HR 0.89, 95% CI:
0.790.99, overall HR 0.87; 95% C: 0.790.96) and for coronary
revascularisation alone (HR 0.84, 95% CI: 0.750.94) and unstable angina alone (HR 0.81, 95% CI: 0.670.97) during full follow
up. With lowest achieved HbA1c concentrations included as a
time-dependent covariate, all hazards became non-significant.
Source
Lancet, early online publication, 1 August 2014, doi:10.1016/S0140-6736(14)
60611-5.
http://www.diabetesincontrol.com/articles/53-/16753-effects-of-intensiveglycemic-control-on-ischemic-heart-disease.
107
REVIEW
Paediatric diabetes with a focus on the adolescent

Barnesh Dhada, David Blackbeard, Gayle Adams
oth type 1 and type 2 diabetes mellitus in children and

adolescents is increasing worldwide. While new cases are
diagnosed in South Africa annually, the true incidence is not
known.
The International Society for Paediatric and Adolescent Diabetes
(ISPAD) in conjunction with the International Diabetes Federation
(IDF) set out a comprehensive, evidence-based standard of
care guideline in 2011.1 The goal of diabetes care is to achieve
optimal glycaemic control in order to achieve good quality of life
by preventing and treating complications. However, successful
implementation of all aspects of care is complex.
In local operational research in a paediatric diabetes clinic at a
tertiary level in KwaZulu-Natal, we have identified the following
mediating variables that often play a positive and/or negative
role in patient care: self-efficacy of child and caregiver; family
functioning for support and supervision; psychosocial interventions
for the individual, family and group; a cohesive multidisciplinary
team (MDT) for consistency of care; material and socio-cultural
resources and support; and mental health and stress exposures for
the childcaregiver dyad.
We have found that working as an MDT to tease out the complexity
and use the expertise of each team member is an advantage, with
the patient at the heart of the teams efforts.2 In this situation,
diabetes education for patients and all MDT members remains vital
to empower all, especially the patients and their families.
The diagnosis of type 1 diabetes mellitus is based on clinical
features of weight loss, polyuria, polydipsia and glycosuria. The
majority of patients in our setting present for the first time with the
life-threatening early complication of diabetic ketoacidosis; many
having seen a doctor in the preceding weeks to months with the
classic clinical features. Without a high index of suspicion and simple
bedside diagnostic tests, a random blood glucose level indicating
hyperglycaemia and urine dipstix for ketonuria, this relatively easy
diagnosis is often missed.3
The underlying pathophysiology is a variable rate of autoimmune-based pancreatic islet beta-cell destruction, with deficient
insulin production leading to hyperglycaemia. The subsequent
dehydration and acidosis with ketone body formation from the
oxidation of fats to meet cellular energy needs complete the clinical
picture. Exogenous insulin administration and correction of the
dehydration and electrolyte disturbances are essential to break this
fatal cycle.
Correspondence to: Barnesh Dhada
Department of Paediatrics, Greys Hospital, Pietermaritzburg and Department
of Paediatrics and Child Health, University of KwaZulu-Natal, Durban
e-mail: Barnesh.Dhada@kznhealth.gov.za
David Blackbeard
Department of Clinical Psychology, Greys Hospital, Pietermaritzburg
Gayle Adams
Department of Dietetics, Greys Hospital, Pietermaritzburg
108
Type 2 diabetes mellitus, hyperglycaemia with peripheral insulin

resistance is increasing, especially among adolescents. Major risk
factors include a family history of type 2 diabetes, and the increasing
obesity/metabolic syndrome pandemic. Clinical features of insulin
resistance are obesity, acanthosis nigricans, dyslipidaemia, features
of ovarian hyperandrogenism, and non-alcoholic fatty liver.
However, the distinction between type 1 and 2 diabetes is
becoming more difficult, with pancreatic autoimmunity present
among those with typical type 2 features, and the absence of
autoimmunity and the presence of obesity in type 1 diabetes.
The concept of double diabetes4 has been coined to capture
this dilemma and it has implications for patient management,
complications and outcomes.
In the management of type 2 diabetes mellitus, the severity
of symptoms and signs at initial presentation determines the
need for insulin during stabilisation. Thereafter, therapy includes
dietary and lifestyle changes, exercise, weight management, and
oral hypoglycaemic agents (metformin and sulphonylurea), with
the need for insulin administration when these modalities fail to
maintain glycaemic targets.
There is controversy as to when insulin is initiated in these
patients and highlights again the multifactorial pathophysiology and
double diabetes phenomenon that makes individualised therapy
necessary. Co-morbidities such as hypertension, dyslipidaemia,
nephropathy albuminuria, and retinopathy need screening at
diagnosis and annually thereafter, for early detection and treatment
of micro- and macrovascular complications. As diabetes in children
and adolescents increases, the burden of ongoing care and
complications will be borne by the adult services in the future and
must be considered in resource allocation in South Africa.
Other types of diabetes include monogenic diabetes, with
several genetic abnormalities identified with a strong family history,
gestational diabetes during pregnancy, and diabetes secondary
to other factors such as drugs, chemicals, infections and other
diseases (cystic fibrosis, endocrinopathies, genetic syndromes and
disorders of the exocrine pancreas). While insulin is the mainstay of
therapy and is responsible for control and survival, other important
facets of therapy cannot be ignored. These are similar to HIV/AIDS
care with highly active antiretroviral therapy (HAART). A recent
review by Westwood et al., of transitional care in long-term health
conditions, while looking at a specific condition, makes reference
to the latest understanding of care in these conditions.5
Innovation in insulin therapy has allowed flexibility and improved
quality of life for many diabetic patients. These include the currently
available human insulin, the variable onset and duration of insulin
action, highlighted recently by the availability of insulin analogues
both ultra-short-acting and long-acting preparations, the delivery
systems for insulin, while still injectable, moving from syringes
and vials to pen sets and insulin pumps, and now even the bionic
pancreas as described by Russell et al.6 Furthermore, patients on
intensive insulin therapy with multiple daily injections of four or
more had better glycaemic control and long-term complications
than conventional twice-daily regimens with pre-mixed, bi-phasic
insulin combinations.7
Self-monitored blood glucose has also evolved with new

technology from colour-coded glucostix to glucometers with
downloadable memory and graphic data analysis, and now to
continuous glucose monitoring sensors that can give you a more
complete picture of glucose kinetics with more than 250 readings
a day. This has helped improve understanding around several
aspects, such as nocturnal hypoglycaemia, the ability to assess
glucose responses, and specific diets, activities, and more.
Objective monitoring of glycaemic control with three-monthly
HBA1c tests remains the standard of care. Comparisons between
clinical symptoms and signs, self-monitored blood glucose readings,
and HBA1c levels are an important aspect of ongoing, long-term
care, especially during adolescence. There are also several newer
oral hypoglycaemic agents on the market for adult care, with ISPAD
guidelines suggesting the use of metformin and sulphonylureas.
This is best done by a paediatric endocrinologist/diabetiologist. A
detailed discussion of these aspects of care is beyond the scope of
this review, but we would like to focus on diet and psychosocial
factors.
Dietetics and diabetes8

The involvement of a specialist paediatric dietician is important in
the comprehensive management of diabetes in both childhood and
adolescence. It is important that patients understand the relationship
between the food they eat and the insulin they require, and for the
MDT to understand the foods available to the patient. In South
Africa, the presence of both ends of the economic spectrum means
that MDTs have to be well prepared.
Prevention of obesity is a key strategy for optimal glycaemic
control, especially in type 2 diabetes. Furthermore, body image
issues among adolescents may play a large role in compliance,
as insulin can increase weight, while hyperglycaemia can cause
weight loss. While strict dietary control is desirable for optimal
glycaemic control, this must be approached with care and respect
for the adolescent patients needs, as disregarding them may
lead to rebellion and poor compliance. Matching insulin to food
intake may be taught as a strategy to overcome occasional dietary
indiscretions. Health professionals should be aware of the possibility
of eating disorders, however, this is rare in our setting.
Dietary recommendations need to be practical and achievable
and based on cultural beliefs and family traditions. Dietary advice
needs to be adapted to suit the economic availability of foods in the
household and focus on healthy eating for all, not just the diabetic
teen. Advice should include the amount, type and even distribution
of carbohydrates as part of a healthy balanced diet. Excessive
restriction of carbohydrates should be avoided. Insulin regimens can
be adapted to suit the dietary patterns of the adolescent, which can
often be erratic. Carbohydrate counting may be a complex concept
for some patients, however, adolescents and caregivers, even with
lower levels of education, can be taught the carbohydrate content
of foods using exchanges and the skill of balancing carbohydrates
throughout the day.
We have found that the majority of our diabetic patients have
a predominantly starch-based diet (maize meal and samp), limited
dietary diversity, and quantities vary with resources; adequate at the
beginning of the month but less or non-existent towards the end of
the month. In this situation, a fixed dose will result in erratic glucose
values, while adjusting the dose according to the carbohydrates on
the plate may produce better control.
REVIEW
A large portion of our children rely on a school feeding-scheme

meal, which is high in starch and fat and is often received at 10:00
rather than at lunch time. Health professionals need to be aware
of this and not withhold this vital meal, but rather adjust the
insulin regimen to allow for the meal. Active adolescents will need
additional dietary advice to support their sporting aspirations, while
maintaining blood glucose stability.
Child and adolescent diabetes: psychosocial factors

Adolescence is generally considered a time of change, with often
stressful adjustments for adolescents and their families in meeting
new developmental demands, such as neurocognitive, social or
physiological changes.9 It is well known that due to the physiological
changes of puberty, and social and developmental adjustments,
metabolic control is typically less effectively achieved in adolescence
than in other phases of the life span.10
Repeated incidents of hypoglycaemia, especially with early-onset
diabetes, is associated with significant cognitive impairments, which
in turn affect school performance and diabetes self-management.11
Neuro-maturational impulsivity during adolescence is a particular
challenge, especially given the normative social pressures for
independence, risk-taking and self-assertion at this stage.12
Researchers have identified a range of cognitive and emotional
factors affecting diabetes outcomes among adolescents. These
include negative affective experiences, such as health anxiety
and fears of complications, frustrations with the complexity of
diabetes self-care, the difficult task of balancing necessary self-care
behaviours with perceived independence, and peer acceptance.13
Studies show that although positive caregiver involvement is
consistently associated with better outcomes, for the adolescent with
diabetes there is a dilemma between the developmental needs, such
as independence and peer identification, and the need for ongoing
caregiver support. The kind of positive caregiver support required in
adolescence also differs from the close, supervising presence of the
caregiver with the child, to a collaborative, motivating involvement
between caregiver and adolescent; additionally depending on
cultural, contextual and social variations in parenting styles.14
From the age of 13 years onwards, individual self-management
and adherence plays an increasingly important role in positive
diabetes outcomes, with acquiring skills for active problem solving
being valuable for adolescent diabetes self-management. As selfmanagement increases, the role of caregivers also shifts towards
less direct supervision and support.15
Research into stress has identified the considerable demands
placed on the adolescent and caregiver in coping with the multiple
tasks required in diabetes self-management in addition to the burden
of adaptation to chronic disease. Secondary negative associations
with parenting stress, including lower family cohesion, higher
psychological maladjustment, and lower rates of school completion
are all multivariate contributors to negative diabetes outcomes.16
Levels of perceived stress among adolescents with diabetes are
associated with lower regimen adherence, psychological distress
and poor metabolic control, all of which highlight the importance
of stress management skills as part of support programmes.17
Unified goal setting between adolescent, caregiver and the health
provider team have been found to improve diabetes outcomes
among adolescents with diabetes.18
Recent studies from developed world settings have explored
the promising role of communication technology and the internet
109
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for supporting adolescents with diabetes through information and

behavioural reinforcement.19 The potential of such interventions
in resource- and technology-constrained contexts has not been
investigated, given that access and availability of communication
technology is not equitable across all contexts.
With much research on adolescent diabetes coming from the
developed world, less research has been done around the specific
challenges of adolescents with diabetes in developing world contexts.
Unique research from Ghana has revealed significant structural
barriers facing adolescents with diabetes in this resource-constrained
context. These included misdiagnosis or late diagnosis at primarycare level, stigmatising and unsupportive school environments,
affordability and accessibility constraints, lack of diabetes-specific
support systems and lack of accessible diabetes information.20
Again, from local research, common challenges identified by
both caregivers and patients were negative emotional experiences,
sustaining motivation for health compliance, and the physiological
changes in adolescence. Caregivers included emotional challenges
affecting the caregiver and practical issues of supervision,
whereas the child/adolescent patients listed peer relations, school
environments and family environments as significant psychosocial
challenges in diabetes management.2
Along with the physiological changes of puberty, adolescents
encounter a range of interpersonal adjustments and issues
of sexuality within cultural and social contexts. These include
negotiating love and friendships, variations in sexual activity, sexual
preference and risks of unplanned pregnancy. Few studies have
been done on sexuality and sex education for adolescents with
diabetes, yet this is a crucial domain of adolescent development, as
seen in recent research from Cuba.21
Defining diabetes outcomes is a difficult task, as objective
measures of metabolic control may tell only some of the story.
Researchers on youth diabetes outcomes have defined diabetes
outcomes as a multifaceted concept that can include measures of
psychological well-being, mastery of developmental tasks, optimal
metabolic control, and active participation in diabetes care. With
this in mind, key interventional strategies should also include early
detection and intervention for psychological distress, and support for
transition from paediatric to adult care systems, a central challenge
in late adolescence.22 Local research has suggested that optimal
outcomes may be achieved by supporting caregiver and adolescent
self-efficacy, a consistent and cohesive multidisciplinary treatment
team with patient-centered collaboration, supporting caregiver and
family functioning, supporting patient motivation, and appropriate
facilitation of health information to enhance health literacy.2
References
1.
110
Global IDF/ISPAD guideline for diabetes in childhood and adolescence 2011,

https://www.ispad.org/resource-type/idfispad-2011-global-guideline-diabeteschildhood-and-adolescence.
2. Dhada B, Blackbeard D. Using intervention mapping to develop a child diabetes

support intervention. Procedia Soc Behav Sci 2014; 113: 7483.
3. Reddy Y, Ganie Y, Pillay K. Characteristics of children presenting with newly diagnosed
type 1 diabetes. S Afr J CH 2013; 7(2): 4648. DOI:10.7196/SAJCH.500
4. Libman IM, Becker DJ. Coexistence of type 1 and type 2 diabetes mellitus: double
diabetes? Pediat Diabetes 2003: 4: 110113.
5. Westwood A, Langerak N, Fieggen G. Review: Transition from child- to adultorientated care for children with long-term health conditions: A process, not an
event. S Afr Med J 2014; 104( 4): 310313.
6. Russell SJ, El-Khatib FH, Sinha M, Magyar KL, McKeon K, Goergen LG, et al.
Outpatient glycaemic control with a bionic pancreas in type 1 diabetes. N Engl J
Med 19 June 2014. DOI: 10.1056/NEJMoa1314474.
7. Nathan DM, and the DCCT/EDIC Research Group. The Diabetes Control and
Complications Trial/ Epidemiology of Diabetes Interventions and Complications
Study at 30 years: Overview. Diabetes Care 2014; 37: 1 916; doi: 10. 2337/
dc13-2112 1935-5548.
8. Smart C, Aslander-van Vliet E, Waldron S, Swift P. Nutritional management.
Global IDF/ISPAD Guideline for Diabetes in Childhood and Adolescence 2011, ch
9: 6669.
9. Pilgrim NA, Blum RW. Adolescent mental and physical health in the Englishspeaking Caribbean. Rev Panam Salud Publica 2012; 32(1): 6269.
10. Moore SM, Hackworth NJ, Hamilton NJ, et al. Adolescents with type 1 diabetes:
parental perceptions of child health and family functioning and their relationship
to adolescent metabolic control. Health Qual Life Outcomes 2013; 11(1): e50.
11. Moosa FY, Segal D. Assessing maths literacy skills in type 1 diabetic children and
their caregivers. J Endocrin Metab Dis South Afr 2011; 16(3): 117160.
12. Cameron F. Teenagers with diabetes: management challenges. Austral Fam
Physician 2006; 35(6): 385390.
13. Herge WM, Streisand R, Chen R, et al. Family and youth factors associated with
health beliefs and health outcomes in youth with type 1 diabetes. J Ped Psychol
2012; 37(9): 980989.
14. Nordfeldt S, Angarne-Lindberg T, Nordwall M, et al. Parents of adolescents with
type 1 diabetes their views on information and communication needs and
internet use: a qualitative study. PLoS One 2013; 8(4): e62096. doi:10.1371/
journal.pone.0062096.
15. Mulvaney SM, Rothman RL, Osborn CY, et al. Self-management problem solving
for Adolescents with type 1 diabetes: intervention processes associated with an
internet program. Patient Educ Couns 2011; 85(2): 140142. doi:10.1016/j.
pec.2010.09.018.
16. Maas-van Schaaijk NM, Roeleveld-Versteegh ABC, van Baar AL. The interrelationships among paternal and maternal parenting stress, metabolic control,
and depressive symptoms in adolescents with type 1 diabetes mellitus. J Ped
Psychol 2012; 38(1) 3040.
17. Berlin KS, Rabideau EM, Hains AA. Empirically derived patterns of perceived
stress among youth with type 1 diabetes and relationships to metabolic control. J
Ped Psychol 2012; 37(9): 990998.
18. Boot M, Volkening, LK, Butler DA, et al. The impact of blood glucose and HbA1c
goals on glycaemic control in children and adolescents with type 1 diabetes.
Diabet Med 2013; 30(3): 333337. doi:10.1111/dme.12083.
19. Hanberger L, Ludvigsson J, Nordfeldt S. Use of a web 2.0 portal to improve
education and communication in young patients with families: randomized
controlled trial. J Med Internet Res 2013; 15(8): e175.
20. Kratzer J, Structural barriers to coping with type 1 diabetes mellitus in Ghana:
experiences of diabetic youth and their families. Ghana Med J 2012; 46(2): 3945.
21. Granela K, Cardoso Y, Gutirrez A, et al. Sex education for children and
adolescents with type 1 diabetes in Camagey Province, Cuba. MEDICC Rev
2013; 15(3): 3437.
22. Northam EA, Werthier GA, Lin A, et al. Psychosocial well-being and functional
outcomes in youth with type 1 diabetes 12 years after disease onset. Diabet Care
2010; 33: 14301437.
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A review of the literature on multidisciplinary interventions

in cardiac rehabilitation
Melisha Rabilal
Introduction
Cardiovascular disease (CVD) is a worldwide problem, with an
increased prevalence in sub-Saharan Africa. Rheumatic heart
disease, hypertension and cardiomyopathy are already prevalent,
and coronary heart disease is assuming growing significance. It is
vital that in developing countries, rehabilitative care be incorporated
into the existing healthcare system.1
Cardiac rehabilitation is a complex intervention that requires
the input of a multidisciplinary team of qualified and competent
professionals to encompass and deliver the recommended core
components. Cardiac rehabilitation can reduce morbidity and
mortality rates for patients with many types of cardiac disease, yet
is generally underutilised in South Africa.
Cardiac rehabilitation is cost effective, reduces mortality rates by
26% and improves quality of life for many. It can also help reduce
unplanned admissions and yield significant savings.2-4 The beneficial
effects of rehabilitation include a reduction in the rate of death
from cardiovascular disease, improved exercise tolerance, fewer
cardiac symptoms, improved serum lipid levels, decreased cigarette
smoking, improvement in psychosocial well-being and increased
likelihood of return to work.
The American Heart Association and American Association of
Cardiovascular and Pulmonary Rehabilitation (AACVPR) recognise
that all cardiac rehabilitation/secondary prevention programmes
should contain specific core components that aim to optimise
cardiovascular risk reduction, foster healthy behaviours and
compliance with these behaviours, reduce disability, and promote
an active lifestyle for patients with cardiovascular disease.5
In 1994, the American Heart Association stated that cardiac
rehabilitation programmes should consist of a multifaceted and
multidisciplinary approach to overall cardiovascular risk reduction,
and that programmes that comprise exercise training alone are not
considered cardiac rehabilitation.
The staff of a cardiac rehabilitation programme usually include
a medical doctor, physician, cardiologist trained in cardiac
rehabilitation, physiotherapist, exercise physiologist/biokineticist,
dietician, psychologist, and a cardiac-trained sister. Occupational
therapists and social workers may also be involved in the
programme. The importance of a mutlidisciplinary team approach
to cardiac rehabilitation has been stressed by Kellerman.6
Correspondence to: Melisha Rabilal

Physiotherapy Department, Greys Hospital,
Pietermaritzburg
e-mail: melisha.rabilal@gmail.com
Physiotherapy management of patients with coronary

artery disease: current practice in South Africa
The Association of Chartered Physiotherapists in Cardiac
Rehabilitation (ACPICR) and the British Association for Cardiac
Rehabilitation (BACR) describe the phases of cardiac rehabilitation
as follows:
Phase I: hospital in-patient period
Phase II : convalescent stage following discharge
Phase III: structured rehabilitation programme
Phase IV: long-term maintenance.
According to the ACPICR and BACR, physiotherapists play a
role in the physical activity component of all phases of cardiac
rehabilitation (many phase IV programmes however, are delivered
by appropriately trained BACR exercise instructors).
Internationally, physiotherapists treat patients with coronary
artery disease (CAD) in the acute stage following a coronary event
and/or following coronary artery bypass (CABG) surgery. These
patients are then subsequently followed up as out-patients during
cardiac rehabilitation in order to improve function and quality of life
and to delay the occurrence of subsequent coronary events.7-9
A study conducted recently in South Africa by Roos and van
Aswegen10 aimed at establishing the number of physiotherapists
working in the cardiopulmonary field of physiotherapy and involved
in the care and rehabilitation of patients with CAD. The current
physiotherapy interventions that are used in the management of
patients with CAD were examined. The clinical settings (acute
or out-patient care) in which patients with CAD regularly receive
physiotherapy interventions was determined.
The study determined the frequency of physiotherapy interventions
and follow up of patients with CAD. Also, explanations were
presented as to the reasons for non-involvement of physiotherapists
who work in a cardiopulmonary setting in rehabilitation of patients
with CAD in certain instances.
An observational, cross-sectional study was conducted with
questionnaires mailed to 50 regional and tertiary government
institutions and 137 electronic questionnaires were circulated. A total
of 187 questionnaires were sent out and 142 were returned (76%).
Results showed that 62% of the physiotherapists provided
care to patients with CAD (50 government physiotherapists and
38 private practitioners). Of the 38% who did not treat patients
with CAD, 38 were government physiotherapists and 16 private
practitioners. Care was mostly provided in a hospital setting (81%)
and out-patient phase III cardiac rehabilitation was lacking (11%).
In a study by Taylor et al.,11 a systematic review and meta-analysis
of randomised, controlled trials was undertaken with reference
to exercise-based rehabilitation for patients with coronary heart
disease. The purpose was to review the effectiveness of exercisebased cardiac rehabilitation in patients with coronary heart
disease.
Databases such as MEDLINE, EMBASE and the Cochrane Library
were searched up to March 2003. Trials with six or more months
111
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of follow up were included if they assessed the effects of exercise

training alone or in combination with psychological or educational
interventions.
In the results, 48 trials were included, with a total of 8 940
patients. Compared with usual care, cardiac rehabilitation was
associated with reduced all-cause mortality [odds ratio (OR): 0.80;
95% confidence interval (CI): 0.680.93] and cardiac mortality (OR:
0.74; 95% CI: 0.610.96); greater reductions in total cholesterol
level [weighted mean difference: 0.37 mmol/l ( 14.3 mg/dl); 95%
CI: 0.63 to 0.11 mmol/l (24.3 to 4.2 mg/dl)]; triglyceride level
[weighted mean difference: 0.23 mmol/dl (20.4 mg/dl); 95% CI:
0.39 to 0.07 mmol/l (34.5 to 6.2 mg/dl)], and systolic blood
pressure (weighted mean difference: 3.2 mmHg; 95% CI: 5.4 to
0.9 mmHg); and lower rates of self-reported smoking (OR: 0.64;
95% CI: 0.500.83). There were no significant differences in the
rates of non-fatal myocardial infarction and revascularisation, and
changes in high- and low-density lipoprotein cholesterol levels and
diastolic pressure.
Health-related quality of life improved to similar levels with
cardiac rehabilitation and usual care. The effect of cardiac
rehabilitation on total mortality was independent of diagnosis
of coronary heart disease, type of cardiac rehabilitation, length
of exercise intervention, length of follow up, and trial quality
and publication date. The review by Taylor et al.11 confirmed the
benefits of exercise-based cardiac rehabilitation within the context
of todays cardiovascular service provision.
In another study by Lawler et al.,12 a meta-analysis of randomised,
controlled trials (RCTs) was undertaken to (1) estimate the effect
of cardiac rehabililtation (CR) on cardiovascular outcomes, and
(2) examine the effect of CR programme characteristics on the
magnitude of CR benefits. The researchers systematically searched
MEDLINE as well as relevant bibliographies to identify all Englishlanguage RCTs examining the effects of exercise-based CR among
post-MI patients.
Data were aggregated using random-effects models. Stratified
analyses were conducted to examine the impact of RCT-level
characteristics on treatment benefits. Thirty-four RCTs were
identified (n = 6.111).
Overall, patients randomised to exercise-based CR had a lower
risk of re-infarction (OR: 0.53; 95% CI: 0.380.76), cardiac mortality
(OR: 0.64; 95% CI: 0.460.88), and all-cause mortality (OR: 0.74;
95% CI: 0.580.95). In stratified analyses, treatment effects were
consistent, regardless of study periods, duration of CR, or time
beyond the active intervention. Exercise-based CR had favourable
effects on cardiovascular risk factors, including smoking, blood
pressure, body weight and lipid profile.
The study by Lawler et al.12 concluded that exercise-based
cardiac rehabilitation is associated with reductions in mortality and
re-infarction rate post MI. The researchers state that their secondary
analyses suggest even shorter CR programmes may translate into
improved long-term outcomes, although these results need to be
confirmed in an RCT.
Nursing
A study by Jiang in the West China School of Nursing, Sichuan
University, indicates that a nurse-led cardiac rehabilitation
programme improved health behaviours and cardiac physiological
risk parameters.13 The aim of the study was to examine the effect
of a cardiac rehabilitation programme on health behaviours and
112
physiological risk parameters in patients with coronary heart disease

in Chengdu, China.
Epidemiological studies indicate a dose-, level- and durationdependant relationship exists between cardiac behavioural and
physiological risks and coronary heart disease incidence, as well as
subsequent cardiac morbidity and mortality.
Cardiac risk-factor modification has become the primary goal
of modern cardiac rehabilitation programmes. A randomised,
controlled trial was conducted. Coronary heart disease patients (n
= 167) who met the sampling criteria in two tertiary medical centres
in Chengdu, south-west China were randomly assigned to either
an intervention group (the cardiac rehabilitation programme) or
control group (the routine care). The change of health behaviours
(walking performance, step II diet adherence, medication adherence,
smoking cessation) and physiological risk parameters (serum
lipids, blood pressure, body weight) were assessed to evaluate the
programme effect.
Patients in the intervention group demonstrated a significantly
better performance in walking, step II diet adherence, and
medication adherence; a significantly greater reduction in serum
lipid levels including triglycerides, total cholesterol, and low-density
lipoprotein cholesterol; and significantly better control of systolic
and diastolic blood pressure at three months. The majority of these
positive impacts was maintained at six months. The effect of the
programme on smoking cessation, body weight, and serum highdensity lipoprotein levels was not confirmed.
The study concluded that a cardiac rehabilitation programme
led by a nurse can significantly improve the health behaviours and
cardiac physiological risk parameters in coronary heart disease
patients. Nurses can fill significant treatment gaps in the risk-factor
management of patients with coronary heart disease.
This study raises attention regarding the important role nurses
can play in cardiac rehabilitation and the unique way for nurses
to meet the rehabilitative care needs of coronary heart disease
patients. Furthermore, the hospitalhome bridging nature of the
programme also created a model for interfacing acute care and
community rehabilitative care.
Physician referral
A study by Smith et al. at McMaster University, Canada, explains
the role of automatic physician referral in predicting cardiac
rehabilitation enrolment.14 Despite the established benefits of
cardiac rehabilitation, evidence suggests referral to and subsequent
enrolment in cardiac rehabilitation following a coronary event
remains low (1025%). The aim of this study was to identify
predictors of attendance at cardiac rehabilitation intake and
subsequent enrolment in rehabilitation after CABG surgery within
the framework of an automatic referral system.
Researchers conducted a historical, prospective study of
patients who underwent CABG surgery between 1 April 1996
and 31 March 2000 and lived within the geographic referral
area of a multidisciplinary cardiac rehabilitation centre in southcentral Ontario, Canada. CABG surgery patients are automatically
referred for cardiac rehabilitation at the time of hospital discharge.
Consecutive health records of eligible patients were reviewed for
medical history, cardiac risk factor profiles, and evidence of cardiac
rehabilitation intake attendance and enrolment.
A total of 3 536 patients met the eligibility criteria. Patients
were predominantly male (79.1%), approximately 64 years of age,
living with a spouse or a partner, English-speaking, retired and

had multiple cardiac risk factors. Of the eligible patients, 2 121
(60%) attended the cardiac rehabilitation intake appointment. Of
the patients who attended intake, 1 463 (69%) enrolled in at least
one cardiac rehabilitation service, based on their risk-factor profile.
Selected cardiac rehabilitation services were exercise training (n
= 1287; 88%), nutritional counselling (n = 571; 39.0%), nursing
care (n = 546; 37.3%) and psychological intervention (n = 223;
15.2%).
The study concluded that an institutionalised, physician-endorsed
system of automatic referral to cardiac rehabilitation resulted in
higher rates of cardiac rehabilitation intake and enrolment following
CABG surgery than previously reported and should be adopted for
all cardiac populations.
Occupational therapy
In an article relating to occupational therapy and cardiac
rehabilitation, Torres asserted that occupational therapy in cardiac
rehabilitation is aimed at enabling the patient to return to work.15
Ergonomics in relation to dangerous tasks are taught to the patient
so that work may be done without risk. This is necessary because
there are differences between the work done in the effort tests and
the work done in an occupation- or work-related setting.
Therefore cardiac rehabilitation provides an efficient share in
coronary patient treatment and occupational therapy is a significant
complementary procedure. This indicates that occupational
therapists fulfil a role as part of the multidisciplinary team in a
cardiac rehabilitation programme.
Dietetics
A study by Holmes et al.16 was conducted in America to examine
the effectiveness of the registered dietician and education and
counselling on diet-related patient outcomes with general
education provided by the cardiac rehabilitation staff. The study also
evaluated the effectiveness of meat, eggs, dairy, fried foods, baked
goods, convenience foods, table fats and snacks. The MEDFICTS
dietary assessment questionnaire was used as an outcome measure
in cardiac rehabilitation.
Observational study data from 426 cardiac rehabilitation
patients discharged between January 1996 and February 2004
were examined. Groups were formed based on educational source:
(1) registered dietician, and (2) general education from cardiac
rehabilitation staff.
Baseline characteristics were compared between groups and
pre/post diet-related outcomes (lipid levels, waist circumference,
body mass index, MEDFICTS score) were compared within groups.
Controlling for baseline measures and lipid-lowering medication,
associations were examined between (1) registered dietician
education and diet-related outcomes, and (2) ending MEDFICTS
score and diet-related outcomes.
Mean age was 62 11 years, 30% of patients were female, and
28% were non-white. At baseline, the registered dietician group
(n = 359) had more dyslipidaemia (88 vs 76%), more obesity (47
vs 27%), a larger waist (40 6 vs 37 5 inches), a higher body
mass index (30 6 vs 27 5 kg/m2), a higher diet score (32 28
vs 19 19), and lower self-reported physical activity (7 12 vs 13
18 metabolic equivalent hours) (all p < 0.05) than the general
education group (n = 67).
Registered dietician education was associated with improved
REVIEW
levels of low-density lipoprotein (i = 0.13; p = 0.04) and triglycerides

(i = 0.48; p = 0.01), and MEDFICTS score (i = 0.18; p = 0.01).
Improvements in MEDFICTS scores were correlated with improved
total cholesterol and triglyceride levels, and waist measurements
(all i = 0.19; p = 0.04).
The study concluded that dietary education by a registered
dietician is associated with improved diet-related outcomes and
that the MEDFICTS score is a suitable outcome measure in cardiac
rehabilitation. This study affirms the role of the dietician as part of
the multidisciplinary team in cardiac rehabilitation.
Psychology
In a study by Yoshida in Sendai, Japan, physical and psychological
improvements were reported after phase II cardiac rehabilitation in
patients with myocardial infarction.17 A new four-week hospitalised
phase II cardiac rehabilitation programme was designed.
Twenty-nine patients (27 males, 2 females) with acute myocardial
infarction who enrolled in the programme were assessed. All
patients enrolled in this study had received coronary interventions.
The rehabilitation consisted of exercise training, education and
counselling. The physical and psychological status of the patients
before and just after the programme and at a six-month follow up
was evaluated.
The physical status was assessed by exercise tolerance measured
by the peak oxygen consumption and anaerobic threshold, frequency
of exercise, and serum concentrations of triglycerides, total
cholesterol, high-density lipoprotein cholesterol, and low-density
lipoprotein cholesterol. The psychological status was assessed by
the Spielberger state-trait anxiety inventory questionnaire (STA) and
the self-rating questionnaire for depression (SRQ-D). Thirty-four
patients (27 men, 7 women) with MI who did not participate in the
rehabilitation programme served as a control group.
After participation in the rehabilitation programme, exercise
tolerance and serum lipid profiles of the patients were improved
compared to six months after rehabilitation. The STA anxiety score
was improved significantly and the SRQ-D depression score tended
to be improved just after the rehabilitation programme. Regular
physical activity was continued even six months after the completion
of the programme.
The hospitalised phase II cardiac rehabilitation programme
improved the management of cardiac risk factors and the
psychological status in patients with MI. This comprehensive
programme may contribute to the secondary prevention of MI
as well as the recovery of physical and psychological activities.
Psychologists therefore form an integral component of the
multidisciplinary cardiac rehabilitation team. The articles cited
above describe the benefits of a multidiscipliary approach to a
cardiac rehabilitation.
An article by Yohannes et al.18 describes the benefits following
an investigation into the long-term benefits of a six-week
comprehensive cardiac rehabilitation programme on physical
activity, psychological well-being and quality of life in patients with
coronary heart disease. The researchers asserted that CR in the
short term improves exercise capacity and quality of life in patients
with cardiac disease. However, the long-term benefits of CR were
inconclusive.
A prospective CR programme with repeated-measures follow up
over 12 months was the design. A six-week out-patient cardiac
rehabilitation programme was conducted including 147 patients
113
REVIEW
with coronary heart disease. Patients completed the Physical

activity energy expenditure (seven-day recall activity), MacNew
heart disease health-related quality of life (MacNew) and Hospital
anxiety and depression scale (HADs) questionnaires at baseline, six
weeks, six months and 12 months.
One hundred and five (71%) patients (76 male) with a mean
age of 61.8 years (SD = 9.7) completed the four measurement
points. Analysis of variance revealed that total energy expenditure
[F (2.231) = 131, p < 0.001], HADs [F (2.237) = 19.3, p < 0.001],
depression score [F (2.235) = 21.06, p < 0.001], anxiety score
[F (2.237) = 17.02, p < 0.001) and MacNew [F (2.197) = 77.02,
p < 0.001] were all statistically significant over time. Bonferroni
pairwise follow up confirmed significant positive differences (p
< 0.05) between baseline values and all subsequent measures
over time. Depression was independently explained in 22% of
the variance in quality of life at six or 12 months. The energy
expenditure was significantly higher for men compared to women
[F (1.103) = 31, p < 0.001].
The researchers concluded that a six-week cardiac rehabilitation
programme is beneficial in improving quality of life, physical
activity status, and anxiety and depression levels. These benefits
were maintained at 12 months. Elevated levels of depression were
associated with impaired quality of life.
Yohannes et al.18 assert that all relevant healthcare staff should be
made aware of the benefits of cardiac rehabilitation and routinely
refer and encourage patients with cardiac disease to attend a cardiac
rehabilitation programme. The researchers indicate that depression
and anxiety intervention strategies should be incorporated into
cardiac rehabilitation programmes.
Conclusion
The AHA/AACVPR statement presents specific information
regarding evaluation, intervention and expected outcomes in
each of the core components of cardiac rehabilitation/secondary
prevention programmes. The outcomes of such programmes affirm
a multidisciplinary approach.
Training of all healthcare workers involved with cardiac patients and
the establishment of treatment protocols within a multidisciplinary
framework is imperative for the development of integrated, holistic
cardiac rehabilitation interventions in South Africa. Following
multidisciplinary liaison, the establishment of cardiac rehabilitation
protocols and the acquisition of human and equipment resources,
the implementation of cardiac rehabilitation programmes would
gain momentum.
114
References
1. Mathes P. Cardiovascular Prevention and Rehabilitation. London: Springer, 2007.
2. Heran BS, et al. Exercise based cardiac rehabilitation for coronary heart disease.
Cochrane Syst Rev 2011; 7. Art No CD 001800.DOI:10.1002/14651858.
CD00180.pub2.tinyurl.com/CR-heart-disease.
3. Lam G, et al. The effect of a comprehensive cardiac rehabilitation programme
on 60-day hospital readmissions after an acute myocardial infarction. J Am Coll
Cardiol 2011; 57: E597E597.
4. Davies EJ, et al. Exercise based rehabilitation for heart failure. Cochrane Syst Rev
2010; 4. Art No CD 003331.tinyurl.com/exercise-CR.
5. Balady GJ, Williams MA, Ades PA, Bittner V, Comross P, Foofy JM, et al. Core
components of cardiac rehabilitation/secondary prevention programmes A
scientific statement from the American Heart Association exercise, cardiac
rehabilitation, and prevention committee, the Council on Clinical Cardiology; the
councils on cardiovascular nursing, epidemiology and prevention, and nutrition,
physical activity, and metabolism; and the American Association of Cardiovascular
and Pulmonary Rehabilitation. Circulation 2007; 115: 26752682.
6. Kellerman JJ. Long-term comprehensive cardiac care the perspectives and tasks
of cardiac rehabilitation. Eur Heart J 1993; 14: 14411444.
7. Piotrowicz R, Wolszakiewicz J. Cardiac rehabilitation following myocardial
infarction. Cardiol J 2008; 15: 481487.
8. Martin AC. Current physiotherapy practice for post-operative cardiac patients. J
Assoc Chart Physiother Resp Care 2007; 39: 27312.
9. Tucker B, Jenkins S, Davies K, McGram R, Waddel J, King R, et al. The physiotherapy
management of patients undergoing coronary artery surgery: A questionnaire
survey. Australian J Physiother 1996; 42(2): 129137.
10. Roos R, van Aswegen H. Physiotherapy management of patients with coronary
artery disease: a report on current practice in South Africa. S Afr J Physiother
2011; 67(1) : 48.
11. Taylor RS, et al. Exercise-based rehabilitation for patients with coronary heart
disease: systematic review and meta-analysis of randomized controlled trials. Am
J Med 2004; 116: 682692.
12. Lawler PR, et al. Efficacy of exercise-based cardiac rehabilitation post-myocardial
infarction: a systematic review and meta-analysis of randomized controlled trials.
Am Heart J 2011; 162(4): 571584.
13. Jiang X, Sit JW, Wong TK. A nurse-led cardiac rehabilitation programme improves
health behaviours and cardiac physiological risk parameters: evidence from
Chengdu, China. J Clin Nurs 2007; 16(10): 18861897.
14. Smith KM, Harkness K, Arthur HM. Predicting cardiac rehabilitation enrolment:
the role of automatic physician referral. Eur J Cardiovasc Prevent Rehab 2006;
13(1): 6066.
15. Torres (Pastor) L, Sainz Hidalgo I, Guijarro Salcedo MC, Rena Sanchez M.
Occupational therapy in cardiac rehabilitation. Revista Espanola de cardiologica,
1995; 48(Suppl 1): 2832.
16. Holmes AL, Sanderson B, Maisiak R, Brown A, Bittner V. Dietician services
are associated with improved patient outcomes and the MEDFICTS dietary
assessment questionnaire is a suitable outcome measure in cardiac rehabilitation.
J Am Dietetic Assoc 2005; 105(10): 15331540.
17. Yoshida T, Kohzuki M, Yoshida K, Hiwatari M, Kamimoto M, Yamamoto C, et al.
Physical and psychological improvements after phase II cardiac rehabilitation in
patients with myocardial infarction. Nurs Health Sci 1999; 1(3): 163170.
18. Yohannes AM, et al. The long term benefits of cardiac rehabilitation on depression,
anxiety, physical activity and quality of life. J Clin Nurs 2010; 19(1920): 2806
2813.
REVIEW
The effects of medicinal plants on renal function and

blood pressure in diabetes mellitus
CT MUSABAYANE
Abstract
Diabetes mellitus is one of the most common chronic global
diseases affecting children and adolescents in both the developed and developing nations. The major types of diabetes
mellitus are type 1 and type 2, the former arising from inadequate production of insulin due to pancreatic -cell dysfunction, and the latter from reduced sensitivity to insulin in the
target tissues and/or inadequate insulin secretion. Sustained
hyperglycaemia is a common result of uncontrolled diabetes and, over time, can damage the heart, eyes, kidneys and
nerves, mainly through deteriorating blood vessels supplying the organs. Microvascular (retinopathy and nephropathy)
and macrovascular (atherosclerotic) disorders are the leading
causes of morbidity and mortality in diabetic patients. Therefore, emphasis on diabetes care and management is on optimal blood glucose control to avert these adverse outcomes.
Studies have demonstrated that diabetic nephropathy is
associated with increased cardiovascular mortality. In general,
about one in three patients with diabetes develops end-stage
renal disease (ESRD) which proceeds to diabetic nephropathy
(DN), the principal cause of significant morbidity and
mortality in diabetes. Hypertension, a wellestablished major
risk factor for cardiovascular disease contributes to ESRD in
diabetes. Clinical evidence suggests that there is no effective
treatment for diabetic nephropathy and prevention of the
progression of diabetic nephropathy. However, biomedical
evidence indicates that some plant extracts have beneficial
effects on certain processes associated with reduced renal
function in diabetes mellitus. On the other hand, other plant
extracts may be hazardous in diabetes, as reports indicate
impairment of renal function. This article outlines therapeutic
and pharmacological evidence supporting the potential of
some medicinal plants to control or compensate for diabetesassociated complications, with particular emphasis on kidney
function and hypertension.
Keywords: diabetes mellitus, diabetic nephropathy, medicinal
plants, hypertension
Diabetes mellitus is a global disease affecting both the developed
and developing nations. Epidemiological data suggest that at
least one in 20 deaths are attributable to diabetes and related
complications, a proportion which increases to at least one in 10
Correspondence to: CT Musabayane
Department of Human Physiology, Faculty of Medicine,
University of KwaZulu-Natal, Durban
e-mail: musabayanec@ukzn.ac.za
Previously published in Cardiovasc J Afr 2012; 23(8): 462
deaths in adults aged 35 to 64 years.1 The figure is considered to

be an underestimate since most individuals die from cardiovascular
and renal-related complications.2 World Health Organisation data
show that the age-standardised death rate for diabetics in South
Africa is 85 per 100 000. Death rates in other sub-Saharan African
countries range from 21 to 49 per 100 000, compared with 18 in
the USA and six per 100 000 in the UK.3
The principal causes of mortality in type 1 and 2 diabetes
patients are disorders grouped as microvascular (retinopathy and
nephropathy) and macrovascular (atherosclerotic) complications.4,5
Macrovascular diseases account for the majority of deaths in type
2 diabetes patients, and the presence of hypertension is associated
with a four- to five-fold increase in mortality.6 A causal relationship
between chronic hyperglycaemia and diabetic microvascular
disease, long inferred from various animal and clinical studies,7
has now been established by data from the Diabetes Control and
Complications Trial (DCCT) controlled clinical study.8
Conventional diabetes therapy using blood glucose-lowering
agents such as sulphonylureas, insulin therapy, -glucosidase
inhibitors, peroxisome proliferator gamma (PPAR-) agonists and
biguanides has limitations. For instance, insulin therapy does not
achieve glycaemic control in patients with insulin resistance, and
oral hypoglycaemic agents may lose their efficacy after prolonged
use. Previous studies elsewhere suggest that insulin is not only
ineffective in preventing type 1 diabetes in patients at risk of
developing this condition, but it can also cause cardiovascular
disease.9,10 Furthermore, conventional drugs are not easily accessible
to the general population in developing countries due to socioeconomic conditions.11,12 Hence there is an urgent need to find
affordable treatments that are effective in slowing the progression
of diabetic complications.
Traditional herbal medicine is used by many rural African
communities to treat a range of diseases, including diabetes.
Anecdotal evidence suggests that diabetic complications are less
common in rural populations, attributable to either the beneficial
effect of plant medicines or to the fact that other risk factors that
aggravate diabetes in the urban context are less prevalent in rural
situations. The World Health Organisation not only encourages the
use of plant medicines, but also recommended scientific evaluation
of the hypoglycaemic properties of plant extracts.13 Estimates
indicate that more than 70% of the worlds population uses
resources derived from traditional medicine to control diabetes.14
Medicinal-plant home remedies are used as crude extracts or
standard, enriched fractions in pharmaceutical preparations.
Research summarised in a recent review15 showed that several
southern African plant species used by rural communities
as traditional medicines had hypoglycaemic effects in
streptozotocininduced (STZ) diabetic rat. Furthermore, some
species had antihypertensive properties.16-19 The impact on the
kidney varies, with some species being reno-protective, whereas
others had a deleterious effect on kidney function. By identifying
the bio-active compound, oleanolic acid (OA), which confers reno
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protection,we have been able to demonstrate the effectiveness of

this agent in STZ diabetic rats.
The focus of this article is to evaluate current evidence on plant
extracts used for the management of hypertension and kidney disease
in diabetes. The beneficial as well as deleterious effects of medicinal
plants in both conditions are discussed based on reports on plants
frequently used in the southern Africa setting. Herein, a medicinal
plant is defined as any plant which provides health-promoting
characteristics, temporary relief or has curative properties.
Antihypertensive therapy and diabetic renal disease

Diabetic complications, which include damage to large and small
blood vessels, can lead to coronary heart disease, stroke and
hypertension, the latter being a well-established major risk factor for
cardiovascular disease that contributes to end-stage renal disease
(ESRD). Reduction of blood pressure (BP) is therefore an efficient way
of preventing or slowing the progression of ESRD. Conventionally,
reno-protection is achieved through reduction in BP with
antihypertensive regimens.20-23 Several studies however document
that antihypertensive treatment in diabetes not only improves the
quality of life,24-27 but also reduces renal complications.28
The major antihypertensive drug classes widely used include
thiazide diuretics, angiotensin converting enzyme (ACE) inhibitors,
angiotensin receptor blockers (ARBs), -blockers, central sympatholytic
agents, calcium channel antagonists and other vasodilators. However,
some antihypertensive agents, for example, thiazide diuretics and
-blockers deleteriously influence glycaemic control.29
To date, the most effective treatments for diabetic nephropathy
(DN) are the antihypertensive drugs, particularly those that target the
reninangiotensin system (RAS) such as ACE inhibitors, angiotensin-1
receptor antagonists, or their combination.25,30,31 Although these
treatments may retard the progressive decline in renal function in
diabetes, clinical trials suggest that there is no effective treatment
for DN.8
For these reasons, novel anti-diabetic therapeutic agents that
supplement, substitute or complement the existing modern
medications to ameliorate renal function in diabetes constitute
novel therapeutic strategies for diabetes. Evidence from biomedical
literature suggests that some plant extracts have protective effects
against cardiovascular disease in diabetes.32 The following sections
evaluate the therapeutic and pharmacological evidence for the use
of some of the medicinal plants and their bioactive phytochemicals
in cardio-renal related diabetic complications, as well as the
potential for nephrotoxicity from other plant extracts.
Natural plants for cardiovascular disease

Several plant extracts with potential therapeutic properties for the
treatment of hypertension and complications such as coronary
heart disease, angina, arrhythmias and congestive heart failure have
been identified.33-36 Traditional medicinal healers in southern Africa
have used Helichrysum ceres S Moore [Asteraceae] to treat kidney
and cardio-respiratory disorders.37 Recent laboratory studies suggest
that the hypotensive effects of H ceres leaf extract in anaesthetised
male Sprague-Dawley rats could in part be attributed to the
extracts natriuretic and diuretic properties.38 We reported that H
ceres ethanolic leaf extracts hypotensive effects were elicited in
part by the direct relaxant effects on cardiac and vascular smooth
muscles.39 The data suggested that lowering of blood pressure
was due to reduced peripheral resistance elicited by the extracts
116
vasodilatatory effects on the vascular smooth muscles, mediated

in part via the endothelium-derived factors (EDRF). This suggestion
was corroborated by the observations that H ceres leaf extract
elicited potent negative inotropic and chronotropic effects in vivo
and exhibited vasorelaxant effects in vascular tissue preparations.
We also reported that Ekebergia capensis Sparrm (Meliaceae)
leaf extract prevented the development of hypertension in weanling
genetically hypertensive Dahl salt-sensitive (DSS) rats, which
develop hypertension as they age.19 The in vivo reduction in blood
pressure by the extract occurred without significant alterations in
the heart rate, suggesting that the in vitro cardiovascular effects
of the extract significantly contributed to the hypotensive effects.
Indeed, studies showed that the hypotensive effect of E capensis
leaf extract was in part mediated via modulation of total peripheral
resistance of the vascular smooth muscles, as evidenced by the
extracts elicited dose-dependent vasorelaxations in endotheliumintact and endothelium-denuded aortic ring preparations. It should
be noted that lanoxin, one of the cardiac glycosides found in a
number of plants, has specific effects on the myocardium.
Kidney function changes in diabetes mellitus

Sustained hyperglycaemia is the main cause of the changes in
kidney function in diabetes mellitus. Hyperglycaemia leads to the
increased formation of advanced glycation end-products (AGEs),
oxidative stress, activation of the polyol pathway and hexosamine
flux, causing inflammation and renal damage.40 AGEs result in the
increased production of extracellular matrix proteins in endothelial
cells, mesangial cells and macrophages in the kidney.41 Additionally,
AGEs have been shown to reduce matrix protein flexibility through
cross-link formation of the extracellular matrix proteins, leading to
an abnormal interaction with other matrix components.41
Irrespective of all the other structural and functional changes,
the mesangial alterations appear to be the main cause of declining
renal function in experimental diabetic animal models.42 For
example, hyperfiltration, which occurs in the early stages of DN
has been attributed to increased mesangial production of vascular
permeability factors in response to stretching.43 The subsequent
decline in glomerular filtration rate (GFR) as nephropathy progresses
may be due to expansion of the mesangial matrix, which compresses
the glomerular capillaries, thereby reducing the filtration surface
area and impairing the mechanism that maintains the normal
glomerular capillary hydrostatic pressure.42
The fall in GFR also reduces the sodium load delivered to the
macula densa cells, resulting in enhanced tubulo-glomerular
feedback (TGF).44 In turn angiotensin II production increases due
to hyperactivation of the reninangiotensinaldosterone system,45
causing more reabsorption of sodium and an increase in systemic
blood pressure.
The accumulation of AGEs can be prevented by antioxidants such
as flavonoids or by preventing the glucose-dependent formation
of intermediate products (Amadori, Schiff bases or Milliard
products). Indeed, blocking or deleting AGEs receptor (RAGE) in
experimental animals reversed atherosclerosis.46 Amino guanidine
and pyridoxamine, AGEs formation inhibitors, had reno-protective
effects in diabetic animals.47,48 Furthermore, inhibition of AGEs effects
could be achieved through breaking of the AGEs cross links by drugs
such as alagebrium or inhibition of AGE signal transduction.48
Tanaka et al.49 reported that the biguanide metformin, the
only example of an approved antidiabetic from a herbal source,
REVIEW
French lilac (Galega officinalis) may be useful in the prevention of

the development of AGEs. The Panax quinquefolium (Linnaeus)
[Araliaceae] extracts, a phyto-oestrogen derived from Vitis vinifera
(Linnaeus) [Vitaceae] (resveratrol), curcumin from Curcuma longa
(Linnaeus) [Zingiberaceae] and glycosides from Stelechocarpus
cauliflorus (RE Fr) [Annonaceae] have also been reported to inhibit
formation of AGEs or RAGE.50-56
Diabetic nephropathy
Renal disease is a common and often severe complication of diabetes,
with the majority of patients with 18 years duration showing signs
of diabetic renal involvement.57 In general, about one in three
patients with type 1 or 2 diabetes develops ESRD which proceeds
to DN, the principal cause of significant morbidity and mortality in
diabetes.8 The onset of DN is associated with a progressive rate of
decline in renal function, urinary albumin excretion and glomerular
filtration rate. For purposes of this discussion, DN is used as a
generic term referring to any deleterious effect on kidney structure
and/or function caused by diabetes mellitus.
Management of diabetic nephropathy
World Health Organisation data report age-standardised death rate
for diabetics in South Africa is 85 per 100 000 compared with 18
in the USA and six per 100 000 in the UK.3 The principal reason for
the high mortality rates in South Africa is renal failure as a result of
DN. Some 30 to 40% of diabetics develop nephropathy, which is
the leading cause of ESRD.14
DN progresses through five well-defined stages.58 Stage 1 is an
increase in GFR, which progresses to the clinically silent stage 2, in
which hyperfiltration is associated with hypertrophy. Stage 3, or initial
nephropathy, is typified by microalbuminuria, modest increases in
blood pressure and a reduction in GFR. Stage 4 sees macroalbuminuria,
raised blood pressure and progressive reductions in GFR, leading to
stage 5 or ESRD when renal-replacement therapy is required.
ESRD is managed in developed countries by renal replacement
therapy (RRT), such as dialysis and transplantation. In developing
countries, however, kidney failure rates are double those in the
West because access to RRT is severely limited by its high cost to
patients.13 The figures are stark: 70% of patients in a Nigerian study
were able to afford dialysis for only one month, with less than 2%
having sufficient resources to remain on dialysis for more than 12
months.59 Access to RRT is virtually impossible for the rural poor.12
Current conventional diabetes therapy using blood glucoselowering medications has limitations in averting renal complications.
Progression towards ESRD may be slowed in part by strict control of
blood sugar levels and blood pressure, a reduction in dietary protein
intake and inhibition of the reninangiotensin system. Consequently,
drug developmental strategy should target these metabolic pathways
for the prevention of progression to ESRD, which proceeds to DN.
Many patients of sub-Saharan Africa however cannot afford these
expensive drugs. Hence there is an urgent need to find affordable
treatments which are effective in slowing the progression of DN.
Medicinal plants in the management of diabetic kidney
disease
Ethno-medicinal plants have traditionally been used for the
treatment of diabetes and its complications. In fact, current preclinical and clinical studies have demonstrated that many have
beneficial effects on some processes associated with reduced renal
Fig. 1. Oral glucose tolerance test in STZ-diabetic rats showing dose-related

reduction in plasma glucose levels following treatment with F thonningii bark
ethanolic extracts (FTE, 60240 mg/kg) comparable to that induced by metformin (500 mg/kg).17 Statistical comparison of the differences between the control and experimental group means was performed using one-way analysis of
variance (ANOVA) followed by Tukey-Kramer multiple comparison test. A value
of p < 0.05 was considered significant.
function in experimental animals.60-62 The active phytochemicals

responsible for their activities have also been identified.
Our research has established the therapeutic and pharmacological
properties of a number of ethno-botanical herbs traditionally used
in the management of diabetes mellitus by African communities.15
Observations indicate that some herbal extracts contain compounds
that could be effective in mild diabetes mellitus or in cases of impaired
glucose tolerance (Fig. 1). These are likely to have a positive impact
on glucose homeostasis in diabetic patients.
Investigations from our laboratory have also examined whether
herbal extracts could lower blood pressure or improve the impaired
renal and cardiovascular functions often seen in diabetes. The results
suggest that while some extracts such as Hypoxis hemerocallidea
corm aqueous extract (APE) had hypoglycaemic effects, they may
have deleterious effects on kidney function. Gondwe et al. found
that APE increased renal fluid output and electrolyte retention, and
reduced glomerular filtration rate,32 neither of which are desirable
in diabetes mellitus.
In contrast, other studies from our laboratories have shown
that Opuntia megacantha leaf extract, which had hypoglycaemic
effects, reversed the inability of the kidney to excrete Na+ in STZ
Fig. 2. Sub-chronic treatment with F thonningii bark ethanolic extracts (FTE)

every third day increased glomerular filtration rate in STZ-diabetic rats.63
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REVIEW
diabetes mellitus, suggesting that this plant may be beneficial.17

We undertook a systematic survey of medicinal plants used by
rural communities in South Africa and have identified several species
with beneficial effects in the prevention of renal complications in
diabetes mellitus. These effects were observed with both crude
extracts and bioactive compounds isolated from antidiabetic
plants. In particular, we showed that plants such as Sclerocarya
birrea [(A Rich) Hochst] [Anachardiaceae], Persea americana (Miller)
[Lauraceae], Ficus thonningii (Blume) [Moraceae] and Helichrysium
ceres had reno-protective effects (Fig. 2).17,32,38 Initial studies have
shown that extracts from these plants ameliorated renal dysfunction
in experimental diabetes.
Subsequently, we isolated oleanolic acid as the bioactive
compound and have shown that it possesses reno-protective effects
in experimental diabetes mellitus. Therefore S cordatumderived
oleanolic acid caused increased renal Na+ excretion in STZ-induced
diabetic rats, which was mediated by an improvement in glomerular
filtration rate (Fig. 3).63 Other active agents identified in these plants
include polysaccharides, flavonoids, xanthones and peptides.
There are various mechanisms by which reno-protection may be
achieved, including modulation of AGEs, of the polyol pathway, and
of the PKC pathway, and anti-oxidative properties. For example,
morroniside isolated from Corni fructus has shown reno-protection
in experimental diabetes through a reduction in the production of
AGEs.64 Additionally, some plants have been shown to cause an
Fig. 3. Sub-chronic treatment with oleanolic acid (OA, 60 mg/kg bid every third
day) increased glomerular filtration rate in STZ-diabetic rats.66
improvement in renal function in experimental diabetes mellitus

through inhibition of ET-1 and TGF-1 and the endothelin-1
receptor A (ETRA).65
Table 1. Partial survey of medicinal plants/plant extracts which affected the cardiovascular and kidney function in diabetes mellitus
Botanical species
Bioactive compounds Antidiabetic advantages Renal function advantages Cardiovascular advantages References
Allium sativum L (garlic)
phenols
insulin secretion
GFR
vasorelaxant,
67, 68
(Alliaceae)
flavonoids
hepatic glycogen
hypolipidaemic
Gongronema latifolium
flavonoids
hepatic glycogen
anti-oxidant
hypolipidaemic
69

saponins

polyphenols
Foeniculum vulgare L
phytoestrogens
glucose absorption
diuretic
vasorelaxant
70
(Apiaceae)
natriuretic
Opuntia megacantha
phenols, flavonoids
glucose absorption
GFR
vasorelaxant
71, 72, 73

(quercetin) taxifolin
Syzygium spp
phenylpropanoids
hepatic glycogen
GFR
vasorelaxant
63, 66, 74

flavonoids sesquiterpenes
insulin secretion

oleanolic acid rhamnetin
Sclerocarya birrea
flavonoids,
hepatic glucose
GFR
vasorelaxant
32, 75
[(A Rich) Hochst]
alkaloids, triterpenoids,
utilisation
[Anacardiaceae]
coumarins,
insulin secretion

ascorbic acid
Persea americana Mill
tannins, saponins
hepatic glycogen
GFR
vasorelaxant
32, 76, 77, 78
(Lauraceae) [Avocado]
flavonoids, alkaloids
insulin secretion
bradycardia

glycosides
hypolipidaemic
Hypoxis hemerocallidea
glycoside hypoxoside
insulin secretion
reno-toxic
cardiodepressant
79, 80

-sitosterol sterolins,
GFR
bradycardia

cytokinins
Ficus thonningii (Blume)
alkaloids anthraquinones
hepatic glycogen
GFR
cardiodepressant
17, 81
[Morarceae]
flavonoids saponins
vasorelaxant

tannins
bradycardia
Olea europaea L,
triterpenes, flavonoids,
insulin secretion
GFR
cardiodepressant
36, 82, 83, 84
(Oleaceae)
glycosides
glucose utilisation
antioxidant
vasorelaxant

bradycardia
Helichrysum ceres S
polyphenols, tannins,
unclear
diuretic
cardiodepressant
38, 39
Moore
triterpenes
natriuretic
vasorelaxant
[Asteraceae]
saponins
bradycardia

Ekebergia capensis
saponins
unclear
unclear
cardiodepressant
85
Sparrm
alkaloids
vasorelaxant
(Meliaceae)
flavonoids
bradycardia

tannins
118
Available evidence suggests that some herbal extracts interfere

with the concentrating and diluting mechanisms of tubular transport
processes in the proximal and distal tubules and/or on other
components of tubular cell membranes. Therefore we speculate
that oleanolic acid influences renal fluid and electrolyte handling
by altering the structural integrity and function of tubular epithelial
cells to affect reabsorption and secretion. Modification of risk factors
in diabetes has an impressive impact on morbidity and mortality in
diabetic patients. An overview of some of some medicinal plants
currently used in diabetic hypertension and kidney disease, together
with the possible mechanism(s) is summarised in Table 1.
Conclusion
We describe the therapeutic and pharmacological evidence in
support of some of the medicinal plant extracts used in the
management of hypertension and kidney disease in diabetes
mellitus. Some of these medicinal plant extracts are a potential
source of anti-diabetic drugs because of their therapeutic efficacy
and anti-diabetic mechanisms reported in experimental animals.
However, at present, the cellular/molecular mechanisms of action
of these plant extracts remain to be established.
Future research directed at the identification of active components
is the only viable option for supporting the efficacy claims for all
herbs. In the absence of such standardisation, health practitioners
and consumers alike should remain optimistic but wary. Research
funding to investigate potentially beneficial effects of medicinal
plants is critically important for optimal patient care and safety.
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REVIEW
The ADVANCE cardiovascular risk model and current

strategies for cardiovascular disease risk evaluation in
people with diabetes
Andre Pascal Kengne
Abstract
Purpose: To critically examine existing approaches to
cardiovascular disease (CVD) risk evaluation in people with
diabetes, and discuss the use of accurate and validated
absolute CVD risk tools as an appropriate basis for CVD
prevention in people with diabetes.
Methods: This was a narrative review using evidence from
the ADVANCE study and all relevant publications identified
via PubMed MEDLINE.
Results: There is sufficient evidence that diabetes does not
confer a CVD risk equivalent to that in non-diabetic people
with existing CVD in all circumstances. In people with
diabetes, CVD risk follows a gradient. Reliably capturing this
gradient depends on an adequate combination of several
risk factors. Many global CVD risk tools applicable to people
with diabetes have been developed. Those derived from
older cohorts are less accurate in contemporary populations
and many newer tools have not been tested. The ADVANCE
risk engine, recently developed from the large multinational
ADVANCE study, showed acceptable performance on the
ADVANCE population and largely outperformed the popular
Framingham risk equation when tested on the multinational
DIAB-HYCAR cohort of people with type 2 diabetes.
Conclusions: The high-risk status conferred by diabetes does
not preclude estimation of absolute CVD risk using tools
such as the ADVANCE risk engine and its use as the basis
for initiating and intensifying CVD preventative measures.
Adopting such an accurate and validated tool will likely
improve prescriptions and outcomes of diabetes care.
Keywords: diabetes mellitus, cardiovascular disease, risk evaluation,
ADVANCE, absolute risk
Cardiovascular disease (CVD), the leading global killer, is
multifactorial by nature. No single risk factor taken alone is able to
distinguish people who will go on to develop a cardiovascular event
from those who will not. This consideration forms the basis of the
contemporary multifactorial approaches to CVD risk evaluation and
reduction.
A key aim of CVD risk evaluation is to identify those in the
population whos health outcomes can be modified by performing
more medical tests, starting treatments to reduce the level of
Correspondence to: Andre Pascal Kengne
South African Medical Research Council, Tygerberg, Cape Town, South Africa
e-mail: andre.kengne@mrc.ac.za
risk factors or increasing the doses of prescribed riskreducing

therapies.1,2 Estimated risks are also used to educate patients about
their chances of experiencing a cardiovascular event within a given
time period (for example, five or 10 years).
Equipped with this knowledge, patients are more likely to be
motivated to adopt healthy lifestyle measures and/or to observe
prescribed risk-modifying treatments. These patients are also
more likely to regularly report back to their healthcare provider for
monitoring and adaptation of treatments, to lower and maintain
their risk factors at optimal levels.
Concerning CVD in people with diabetes, healthcare providers
who see these patients on a routine basis are interested in gauging
the chances of their patients developing any major CVD event over
a reasonable period of time (often five to 10 years), and not just
specific components such as stroke or myocardial infarction. These
busy healthcare providers are also interested in assessing the CVD
risk of their patients using accurate and validated global CVD riskevaluation tools.3-5
In the general population, efforts to develop reliable tools for
evaluating CVD risk based on a combination of several risk factors
have paralleled efforts to improve our understanding of the
determinants of CVD and more efficient ways to control them.6
These efforts were initially led by the Framingham investigators,
and more recently by investigators from other parts of the world.6,7
The first attempts to develop such tools from the Framingham
study date back to the year 1967.8 These first tools, however, did
not account for diabetes status or for any other indicator of chronic
hyperglycaemia.
Although many subsequent Framingham tools took diabetes
status into consideration, the uptake of the Framingham tools in
people with diabetes around the world has remained very limited,
resulting in the adoption of multivariable CVD tools in people with
diabetes to lag behind the general population. One reason was the
lack of trust among researchers on the validity of the Framingham
tools in people with diabetes, due to the relatively small number
of people with diabetes in the Framingham cohort, and the noninclusion of other indicators of exposure to chronic hyperglycaemia
in the Framingham tools.9
Another major reason was the publication in the late 1990s of
a study from Finland suggesting that people with diabetes but no
history of cardiovascular disease had a future risk of CVD similar
to the risk of non-diabetic people who have survived a CVD event
in the past.10 This study inspired the concept of diabetes as a CVD
risk equivalent, based on which people with diabetes should be
treated with cardiovascular risk-reducing therapies such as statins
or aspirin, without taking into consideration their absolute CVD
risk levels.
However, the concept of diabetes as a CVD risk equivalent has
been losing ground in recent years, with the accumulating evidence
challenging its validity in all circumstances,11 and supporting the
121
REVIEW
importance of absolute risk estimation in people with diabetes

as the appropriate basis for CVD risk-factor modification. Such
an approach is further supported by the gradual shift in the
management of diabetes mellitus from a glucocentric focus to an
intensive multifactorial strategy targeting reduction in the risk of
both macro- and microvascular complications of diabetes.12,13
The growing recognition of the importance of global CVD risk in
people with diabetes has generated interest among researchers to
develop tools with improved performance to estimate absolute risk
in people with diabetes, or to establish the validity of the existing
ones and refine their performance.7 The following development
is a discussion on the rationale and strategies for global CVD
risk estimation in people with diabetes, with emphasis on the
specificities and limitations of these strategies. The discussion is
largely inspired by new knowledge gained from CVD risk modelling
in the ADVANCE study.3,14
Overview of global cardiovascular risk assessment

Global cardiovascular risk assessment is based on the combination of
predictive information from several cardiovascular risk factors using
mathematical equations (also called models). In those models,
the coefficient of each included risk factor indicates its relative
contribution to the overall (global) CVD risk.2,15 A model can be
used to estimate the risk that a disease is present (diagnostic model)
or to estimate the risk that a particular disease or health event will
occur within a given time period (prognostic models). The focus of
the current article is on prognostic models.
Once developed, a cardiovascular risk model normally requires a
validation in both the sample population that was used to develop
the model (internal validation) and in independent populations
(external validation). Validation consists of testing whether the
prognostic model accurately estimates the risk of future events in
one or several populations.2,15
The performance of absolute cardiovascular risk models in
validation studies is commonly assessed in terms of discrimination,
calibration and, more recently, reclassification.2,15 Discrimination is
the ability of the model to distinguish people who go on to develop
a cardiovascular event and those who remain event free.2,15 For
example, for two individuals with diabetes with one developing
a cardiovascular event after 10 years of follow up and the other
remaining CVD free within that same time period, a discriminating
model will systematically assign, at the start of the follow up, a
higher absolute risk to the first subject compared to the second.
Discrimination is commonly assessed using the C-statistic,
which ranges from 0.5 (lack of discrimination) to 1.0 (perfect
discrimination).1,2,15 In general, a C-statistic of 0.7 or greater is
considered acceptable.
Calibration describes the agreement between estimated and
observed risks. It is assessed by comparing absolute risk estimates
from the model with the actual event rates in the test population.1,2,15
For illustration, a 10-year estimated absolute risk of CVD of 20%
for a patient indicates that, in a given group of patients with
similar characteristics, 20% will experience a cardiovascular
event within a 10-year period of follow up. The most commonly
reported measure of calibration is the Hosmer-Lemeshow statistic.
Estimates of calibration are sensitive to differences in background
levels of risk across populations. For example, if a given CVD risk
model is developed in a high-risk population but tested in a lowrisk population, the estimated absolute risks will be unreliably
122
high. Recalibration of the risk model by adjusting the baseline risk

estimates to fit the target population may help correcting the overor underestimation of risk.1,15
Global cardiovascular risk estimation in people with

diabetes
Global CVD risk has been estimated in people with diabetes using
essentially three main approaches.16 In the CVD riskequivalent
approach described above, the presence of diabetes mellitus is
considered to confer a 10-year absolute CVD risk of 20% or more,
which is approximately the 10-year CVD event rate observed
in non-diabetic individuals with a prior history of CVD. Such an
approach appears to be counter-intuitive as the CVD risk is not
uniformly distributed among people with diabetes. This is further
supported by many studies showing multivariable risk estimation
to be significantly better than classification of diabetes as a
cardiovascular risk equivalent.17,18
In the second approach, also termed step approach, unifying
CVD risk-estimation models are developed for both people with
diabetes and those without the condition. This approach assumes
that major risk factors for CVD are related to future occurrence of
CVD in a similar way, regardless of the status for diabetes mellitus.
Stated otherwise, everything else being equal, an individual with
diabetes will always have a higher risk of CVD (by a constant
amount) than the non-diabetic subject with the same level of other
risk factors (e.g. blood pressure or lipid levels). This has been the
basis for models such as the popular Framingham cardiovascular
absolute-risk models.16
In the last approach, also known as the interaction approach,
CVD risk models are constructed separately for people with and
without diabetes. This approach suggests that risk factors are related
to future CVD risk in different ways in people with and without
diabetes. This approach in people with diabetes was initially used
by the UKPDS investigators.9,19 Available studies largely suggest
that classical cardiovascular risk factors (including smoking, blood
pressure and lipid variables) and even some novel risk factors,16,20-23
affect the risk of CVD in similar ways in people with and without
diabetes with no evidence of interaction.
Some risk factors or characteristics are likely to be more frequent
in people with diabetes and may justify separate cardiovascular
risk models for people with diabetes. These diabetes-specific
characteristics include prescriptions of cardiovascular risk-reducing
therapies, which may differ in people with and without diabetes.
Additional specific factors are haemoglobin A1c (HbA1c) levels, urinary
albumin excretion rate and markers of microvascular complications
of diabetes in general (especially retinopathy). These have been
demonstrated to be associated with CVD risk and can contribute
useful information to predictions.24-29
Performance of popular CVD risk models and the

ADVANCE study
At the time the ADVANCE study was conducted, CVD riskprediction
models in the general population were dominated by models developed
from the Framingham Heart study, which for many could also be used
in people with diabetes.7 CVD risk models specific to people with
diabetes were also available, particularly those from the UKPDS study.7
However, the clinical utility and comparative performance of these
popular CVD risk models in contemporary populations with diabetes
in diverse settings were still to be established.
Therefore, one of the major initial steps was to conduct

extensive validation studies of the Framingham and UKPDS CVD
risk models, using the unique features of the ADVANCE cohort.3
These validation studies revealed that, in the cohort of ADVANCE
participants who had no known history of CVD at their enrolment
in the trial, the four-year absolute risk of cardiovascular events
and components was largely overestimated by the Framingham
Anderson,30 FraminghamDAgostino31 and UKPDS risk models.9,19
This overestimation was also observed in men and women,
Caucasians and non-Caucasians, and the double-placebo cohort
(i.e. those assigned to the placebo group in the blood pressurelowering arm and the standard-care group of the blood glucose
control arm).3
Discrimination of the Framingham and UKPDS risk models
in predicting CVD events in ADVANCE was poor for stroke, and
modest to acceptable for coronary heart disease and total CVD.
Recalibration substantially attenuated the magnitude of risk
overestimation by the Framingham and UKPDS risk models in
ADVANCE. Discrimination was unaffected as expected, indicating
the need for new CVD risk models with improved predictive accuracy
for people with diabetes, particularly those who are receiving many
contemporary cardiovascular riskreducing therapies.
Development of the ADVANCE cardiovascular risk

model
In developing a new model for risk prediction, it is critical to account
for the limitations of existing ones in order to improve performance.
The inclusion in ADVANCE of participants from many countries
provided the opportunity to account for the substantial variation
in the care of diabetes and CVD around the world. Available
models so far had been derived from homogenous populations.
The ADVANCE model targets total CVD and therefore captures the
interrelation between components of CVD such as CHD or stroke,
unlike many existing models that have focused specifically on these
components.
The complexity of the relationship between chronic hyperglycaemia
and cardiovascular risk has been less fully addressed in existing
models. Some improvement was achieved in the ADVANCE model
through integration of risk factors to capture both the exposure to
chronic hyperglycaemia prior to and after the clinical diagnosis of
diabetes. Statistical method is an important component of model
development. Trusted statistical methods were used to select the
potential risk factors and test their suitability for inclusion in the
ADVANCE risk model.14
Risk factors considered for inclusion in the ADVANCE model
were: age at clinical diagnosis of diabetes, duration of diagnosed
diabetes, gender, blood pressure (BP) indices [systolic BP, diastolic
BP, mean arterial (MAP) and pulse (PP) pressures], lipid variables
[total, high-density lipoprotein (HDL) and non-HDL cholesterol, ratio
of total:HDL cholesterol and triglycerides], body mass index (BMI),
waist circumference, waist-to-hip ratio, BP-lowering medication
(i.e. treated hypertension), statin use, current smoking, retinopathy,
atrial fibrillation (past or present), urinary albumin:creatinine ratio
(ACR), serum creatinine (Scr), HbA1c and fasting blood glucose
levels, and randomised treatments (BP lowering and glucose control
regimens).
Ten of these candidate risk factors were included in the final
ADVANCE risk model. Age at diabetes diagnosis and known
duration of diabetes were preferred to age at baseline to improve
REVIEW
the applicability of the ADVANCE risk model to other populations.

The beta coefficients and accompanying standard error for risk
factors in the ADVANCE risk model are shown in Table 1.14
Performance of the ADVANCE risk model

The applicability of the ADVANCE risk model14 was tested on the
same population used to develop the model (i.e. internal validation)
and on an independent external sample for which the DIABHYCAR cohort32 was used. In both internal and external validations,
the discrimination of the ADVANCE model was acceptable. In
comparison with existing total CVD models, the ADVANCE model
largely outperformed the FraminghamAnderson and Framingham
DAgostino models. The calibration of the ADVANCE model was
excellent in internal validation and good in external validation, with
only a modest risk underestimation. This is likely explained by the
difference in the levels of preventive therapies between ADVANCE
and DIABHYCAR population.
Interestingly, the agreement between predictions by the
ADVANCE models and the observed CVD events was consistent
across different cut-off points or predicted risk for CVD. For
comparison, the two Framingham equations overestimated the risk
of CVD in the DIAB-HYCAR cohort by 65% (Anderson equation)
and 99% (DAgostino equation). Using a cut-off point for fouryear predicted risk of 8% (which is approximately equivalent to
a 10-year predicted risk of 20% and above), the ADVANCE model
Table 1. BETA coefficients (95% confidence interval) and standard
errors for predictors in the advance CVD prediction model14
123
REVIEW
would reliably identify 22% of the ADVANCE participants and 39%

of the DIAB-HYCAR participants in whom 48% and 66% of CVD
events, respectively, occurred during follow up. Further intensifying
treatment in such groups on top of any baseline therapy could
achieve significant gain in terms of CVD risk reduction.
Dissemination of the ADVANCE risk model

To facilitate the uptake of the ADVANCE model in clinical practice,
a hand-held calculator and a risk-scoring chart (Fig. 1) have been
developed.14 Other tools from this model, including an online
calculator, are available on the website of the model to improve
its uptake.33 Extensive validations have been conducted to assure
that these tools provide estimates similar to those from the full
ADVANCE risk equation.
Performance of existing global risk tools for

cardiovascular risk estimation in diabetics
Two systematic reviews have examined the performance of CVD
risk-evaluation models applicable to people with diabetes.7,34 The
most recent and comprehensive review identified 45 CVD risk

models applicable to people with diabetes.7 Of these, 12 were
specifically developed for people with type 2 diabetes (including
the ADVANCE model) and 33 were developed in the general
population, accounting for diabetes as a risk factor. These models
vary greatly in their quality and the methodology used to develop
them.
Only about a third of the existing CVD risk tools applicable to
people with diabetes have been externally validated in a population
with diabetes. The discriminative ability of both diabetes-specific
CVD prediction models and general population prediction models
that use diabetes status as a predictor was generally acceptable to
good (i.e. C-statistic 0.70). The discrimination of prediction models
designed for the general population was moderate (C-statistic:
0.590.80) and their calibration generally poor.
The most commonly validated models were the general
population-based Framingham cardiovascular risk equations
and the diabetes-specific UKPDS risk engines. The Framingham
prediction models also showed a low-to-acceptable discrimination
and a poor calibration. Although the discriminative power of
As an illustration of the use of the risk-scoring chart, a male subject, diagnosed with diabetes three years previously at the age of 50 years, who has a pulse
pressure of 50 mmHg and is currently treated for hypertension, also has retinopathy, atrial fibrillation and microalbuminuria, an HbA1c level of 7% and a nonHDL cholesterol level of 3.3 mmol/l, will receive a total score of 13 points: 0 for gender, 3 for age at diagnosis, 1 for known duration, 1 for pulse pressure, 1 for
treated hypertension, 1 for retinopathy, 2 for atrial fibrillation, 2 for microabuminuria, and 1 for HbA1c and non-HDL cholesterol level each. A score of 13 points
is equivalent to a four-year estimated risk of 6.2%, which is similar to the risk estimated for the same patient using the full equation.
Fig. 1. Major cardiovascular disease points and four-year predicted risk by the ADVANCE model equation.14
124
UKPDS engines was acceptable, it had a poor calibration and a

tendency toward systematic overestimation of risk, particularly
in recent cohorts. The models with best external validity were
more contemporary but these had been validated in other patient
populations only once.7
Conclusion
The quest for the appropriate approaches to assess cardiovascular
risk and thus prevent vascular complications in individuals
with diabetes is a continuing pursuit. Diabetes mellitus is not a
cardiovascular risk equivalent in all circumstances. The CVD risk is
not uniformly distributed in individuals with diabetes, but rather
follows a gradient. Adequately capturing this gradient depends on
the combination of individual risk factors.
Global risk assessment appears to be the way forward for
managing CVD risk among people with diabetes. Both the ADVANCE
and subsequent studies have provided evidence that existing
popular models derived from older cohorts were less accurate for
cardiovascular risk evaluation in contemporary population with
diabetes.7 The recognition of this non-optimal performance and
other limitations of existing models have stimulated efforts to
develop new cardiovascular risk models (including the ADVANCE
model14) with improved predictive accuracy for people with
diabetes.
The ADVANCE model continues to enjoy the unique property
that it was developed from a contemporary multinational cohort of
people with diabetes, and has been successfully validated in another
recent multinational cohort of individuals with diabetes. Inclusion
of participants from developing countries in the ADVANCE cohort
highlights the potential of the ADVANCE risk model for assisting
cardiovascular risk-stratification efforts in many settings around the
world.
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RESEARCH ARTICLE
Prevalence and determinants of electrocardiographic

abnormalities in sub-Saharan African individuals with
type 2 diabetes
ANASTASE DZUDIE, SIMEON-PIERRE CHOUKEM, ABDOUL KADIR ADAM, ANDRE PASCAL KENGNE,
PATRICIA GOUKING, MESMIN DEHAYEM, FLICIT KAMDEM, MARIE SOLANGE DOUALLA,
HENRY ACHU JOKO, MARIELLE EPACKA EWANE LOBE, YVES MONKAM MBOUENDE, HENRY LUMA,
JEAN CLAUDE MBANYA, SAMUEL KINGUE
Abstract
Aim: This study assessed the prevalence and determinants
of electrocardiographic abnormalities in a group of type
2 diabetes patients recruited from two referral centres in
Cameroon.
Methods: A total of 420 patients (49% men) receiving chronic
diabetes care at the Douala General and Yaound Central
hospitals were included. Electrocardiographic abnormalities
were investigated, identified and related to potential
determinants, with logistic regressions.
Results: The mean age and median duration of diagnosis
were 56.7 years and four years, respectively. The main electrocardiographic aberrations (prevalence %) were: T-wave
abnormalities (20.9%), Cornell product left ventricular
Correspondence to: Anastase Dzudzie
Department of Internal Medicine, Buea Faculty of Health Sciences, and
Department of Internal Medicine, Douala General Hospital, Cameroon
e-mail: aitdzudie@yahoo.com
Department of Internal Medicine, Buea Faculty of Health Sciences, Cameroon
Simeon-Pierre Choukem
Flicit Kamden
Solange Doualla
Henry Achu Joko
Marielle Epacka Ewane Lobe
Yves Monkam Mbouende
Henry Luma
Universit des Montagnes, Bangangte, Cameroon
Abdoul Kadir Adam
Department of Medicine, University of Cape Town and
Medical Research Council, Cape Town, South Africa
Pascal Kengne
Diabetes and Endocrine Service, Yaound Central Hospital
and Faculty of Medicine, Cameroon
Patricia Gouking
Mesmin Dehayem
Jean Claude Mbanya
Department of Internal Medicine, Yaound Faculty of
Medicine, Cameroon
Solange Doualla
Henry Luma
Jean Claude Mbanya
Samuel Kingue
126
hypertrophy (16.4%), arrhythmia (16.2%), ischaemic heart

disease (13.6%), conduction defects (11.9%), QTc prolongation
(10.2%) and ectopic beats (4.8%). Blood pressure variables
were consistently associated with all electrocardiographic
abnormalities. Diabetes-specific factors were associated
with some abnormalities only.
Conclusions: Electrocardiographic aberrations in this population were dominated by repolarisation, conduction defects
and left ventricular hypertrophy, and were more related to
blood pressure than diabetes-specific factors.
Keywords: diabetes mellitus, sub-Saharan Africa, Cameroon,
ECG, cardiovascular disease
A major threat to the health of diabetes subjects is cardiovascular
disease (CVD), which currently accounts for about threequarters of
all deaths in diabetes patients in major populations and settings.1
Attempts to maintain cardiovascular health in diabetics include: (1)
routine prescription of medications with proven beneficial effects on
cardiovascular health, such as statins and aspirin; (2) investigation
and treatment of individuals with abnormal levels of modifiable
risk factors; (3) monitoring of individuals for infra-clinical changes,
which are indicators of future high risk for cardiovascular events, or
those with lessadvanced stages of diabetes, whose course could be
modified through early intervention.2
The electrocardiogram (ECG) is widely used for monitoring.3
ECG changes appear early in the course of diabetes, and usually
include alterations such as sinus tachycardia, QTc prolongation, QT
dispersion, changes in heart rate variability, STT changes, and left
ventricular hypertrophy. These changes and others, detected with
the use of a resting ECG, often together with an exercise ECG, are
used to detect silent ischaemia, assess prognosis and predict future
risk. Because the ECG is a non-invasive and relatively easy test to
perform, it is used in the series of investigations conducted as part
of the annual clinical evaluation of people with diabetes around
the world.3
The use of this modality however varies substantially, guided
essentially by the availability of ECG machines and the cost of such
investigations. As a result, the regional office of the International
Diabetes Federation (IDF) for Africa recommends ECG monitoring
in diabetes only at the secondary or tertiary level of the healthcare
system where facilities for performing an ECG are more readily
available.4
Therefore in sub-Saharan Africa, the majority of patients with
diabetes who receive care in primary healthcare facilities do not have
routine ECG screening. Failure to perform regular ECGs means that

opportunities to improve cardiovascular health in this population
are being missed. Furthermore, our knowledge of the major ECG
abnormalities and their determinants in this environment remains
very limited.
In this study we assessed the distribution of ECG aberrations and
investigated their potential determinants in a group of individuals
with type 2 diabetes who were receiving chronic care in two referral
hospitals in the two largest cities of Cameroon, Central Africa.
Methods
The out-patient sections of the Yaound Central Hospitals diabetes
and endocrine service, and the Douala General Hospitals (DGH)
internal medicine service and sub-specialties served as settings for
recruitment of participants for this study. The Yaound Central
Hospital (YCH) has been described in detail elsewhere.5,6 The DGH
internal medicine and sub-specialities service has an individualised,
dedicated endocrine section, which is the main referral centre for
endocrine diseases and diabetes in Douala, the second major city
of Cameroon (approximately 2.5 million people). Patients with
diabetes and its complications, residing in Douala and surrounding
regions were the most likely to receive care in our clinic during the
study period.
Overall, the healthcare system in Cameroon is organised into
primary, secondary and tertiary levels. Care at the primary level
is provided by nurses and general practitioners and is essentially
geared towards acute conditions. Secondary-level facilities provide
access to some form of specialist care. Tertiary-level facilities
(including YCH and DGH) serve as a referral hospital for primaryand secondary-level health facilities, and for routine consultations
and follow up, as in our study.
From January 2010, the Yaound health service has had three
endocrinologists and the Douala health service two. Patients with
diabetes who received chronic care in the two study clinics were
required to have an annual evaluation as part of their routine care.
In addition to a clinical consultation, this evaluation included: (1) an
assessment of diabetes control (fasting glucose and haemoglobin
A1c levels); (2) an assessment of chronic complications (eyes:
fundoscopy, kidney function: albuminuria, serum urea and creatinine
levels); (3) a cardiovascular work up including an assessment of lipid
profiles (total cholesterol, high-density lipoprotein cholesterol and
triglycerides) and a resting ECG.
Participants in this study were recruited from patients presenting
for these annual evaluations. The study was approved by the
administrative authorities of the two health facilities, and ethical
clearance was obtained from the Cameroon National Ethics
Committee.
Four hundred and twenty individuals with type 2 diabetes
receiving chronic care in the two study facilities were consecutively
enrolled over a two-year period from January 2008 to January
2010. Only the patients first consultation during this period was
considered, and no other exclusion criteria were applied. The type
of diabetes was based on the diagnosis of the attending physician.
In addition, patients had to be at least 30 years of age at the time
of their first diagnosis of diabetes.
Blood pressure (mmHg) was measured on the right arm with
the participant in a seated position, after 10 minutes rest, with an
Omron MX2 basic electronic device (Omron Healthcare Co, Ltd,
Kyoto, Japan) with the appropriate cuff size. The average of two
RESEARCH ARTICLE
measurements recorded five minutes apart was used in this study.

Body weight (kg) was measured in light clothing, using a SECA
scale, and height (m) was measured with a standard stadiometer.
The body mass index (BMI) for each patient was calculated as
weight/height2 (kg/m2). The waist circumference (cm) was measured
with a tape measure on the horizontal plane midway between the
lowest rib margin and upper edge of the iliac crest.
A 12-lead resting ECG was done on all subjects using the
Cardi Max Fx-7302. All ECG tracings were centrally interpreted
by the same investigator who is a cardiologist (AD) and did not
know the subjects backgrounds. Significant ECG findings such as
ST-segment elevation or depression, T-wave aberrations (inversion
or tall T wave), bundle branch block, left ventricular hypertrophy
(LVH), right and left atrial enlargement, arrhythmias and other
changes were noted.
LVH was defined according to three different criteria:
Cornell voltage-duration product [(RaVL + SV3) QRS complex
duration] > 2.623 mm ms in men and > 1.558.7 mm ms in
women,7
Cornell voltage (SV3 + RaVL > 24 mm in women and 28 mm in
men)
Sokolov-Lyon index (SV1 + RV5/6 > 35 mm).
Compared with echocardiography, the cut-off values for the Cornell
voltage duration product gave the best sensitivity with a specificity
of 95%.7
ECG measurements were done with a ruler on the resting ECG
tracings, and were expressed as the average of three determinations
on consecutive QRS complexes. R-wave amplitude in aVL and
S-wave depth in V3 were measured as the distance (mm) from the
isoelectric line of their zenith and nadir, respectively. QRS duration
was measured from the beginning to the end of the QRS complex.
QTc prolongation was defined as a QTc > 460 ms in both men and
women.
A diagnosis of ischaemic heart disease was made based on
the American Heart Association criteria. These criteria include
ECG features of significant ST-segment depression, defined as an
ST-segment depression > 1 mm in more than one lead, and T-wave
inversion. Myocardial infarction was defined as an ST-segment
elevation (convex upwards) > 0.08 s, associated with T-wave
inversion in multiple leads, and reciprocal ST-segment depression
in opposite leads.
Statistical analysis
Data were analysed using SPSS version 17 for Windows (SPSS,
Chicago, IL). Differences in means and proportions for participants
characteristics were assessed using analysis of variance and 2 tests
as applicable, and the influence of likely confounders was adjusted
for with logistic regressions models. A probability of p < 0.05 was
set as the threshold of statistical significance.
Results
Of the 420 patients recruited, 207 (49%) were men and 250 (56%)
were from the Yaound centre. The mean age was 56.7 years and
the median duration of diagnosed diabetes was four years (IQR
25th to 75th percentiles: 19).
As expected, anthropometric characteristics were different
between men and women. Diabetes control was also poorer in
men than in women (all p < 0.04), otherwise men were similar to
women with regard to many other characteristics, including history
127
RESEARCH ARTICLE
of diabetes, treatment and complications, and cardiovascular risk

profile (Table 1).
With few exceptions, participants characteristics were mostly
similar across the participating centres. The few exceptions related
to hip circumference (p < 0.001), diastolic blood pressure (p <
0.001), haemoglobin A1c level (p < 0.001), creatinine clearance rate
(p = 0.04), the use of ACE inhibitors (p = 0.01) and the presence of
neuropathy (p = 0.008).
The distribution of ECG abnormalities was: T-wave aberrations

(20.9%), left ventricular hypertrophy according to the Cornell
product criteria (16.4%), arrhythmia (16.2%), ischaemic heart
disease (13.6%), conduction defects (11.9%), QTc prolongation
(10.2%) and ectopic beats (4.8%). Unlike T-wave aberrations and
left ventricular hypertrophy, the prevalence of major aberrations was
similar in men and women (Table 2). The distribution of subtypes
of arrhythmia, conduction defects and T-wave aberrations is shown
in Fig. 1.
Table 1. Profile of the 420 men and women with type 2 diabetes
Variables
Number (%)
Age (years)
Median (range) known
duration of diabetes (years)
Parental history of diabetes
Smoking
Body mass index (kg/m2)
Waist circumference (cm)
Hip circumference (cm)
Waist-to-hip ratio
Men
n (%)
Women
n (%)
207 (49) 213 (51)

55.9 (9.83) 57.5 (9.96) 0.09
4 (09)
4 (18)
0.71
103 (49.7) 110 (51.6)
27 (13.1) 5 (2.3)
27.2 (4) 29.7 (6)
95.3 (10.8) 94.9 (12.92)
98.5 (10) 103.7 (12.9)
0.96 (0.08) 0.91 (0.11)
Total
n (%)
56.7 (9.92)
4 (19)
213 (50.7)
0.69
32 (7.6)
< 0.001 28.5 (5.2)
< 0.001 95.1 (11.9)
0.71 101.2 (11.8)
< 0.001 0.94 (0.10)
< 0.001 142.2 (25.3)
Hypertension and treatments

Systolic blood pressure
142.8 (23.6) 1
41.6 (26.91) 0.61 85.1 (13.2)
(mmHg)
Diastolic blood pressure
85.6 (12.2) 84.5 (14.15) 0.37 57.1 (18.2)
(mmHg)
Pulse pressure (mmHg)
57.2 (16.8) 57.1 (19.49) 0.95 211 (50.2)
Hypertension
97 (46.8) 114 (53.5%) 0.17 186 (44.3)
Any blood pressurelowering 83 (40.1) 103 (48.4) 0.09 139 (33.1)
medication
ACE inhibitors
70 (33.8) 69 (32.4)
0.84
5 (1.2)
ARA II antagonists
2 (1)
3 (1.4)
0.99 118 (28.1)
Diuretics
54 (26.1) 64 (30)
0.37
69 (16.4)
Calcium channel blockers
33 (15.9) 36 (16.9)
0.79
30 (7.1)
Beta-blockers
7 (3.4) 23 (10.8) 0.004 185 (49)
Lipid profile and lipid-modifying therapies
Total cholesterol (mg/dl)
187 (49) 184 (51)
0.57
47 (18)
HDL cholesterol (mg/dl)
47 (19)
48 (18)
0.52 101 (67141)
Median (range) triglycerides 99 (64142) 1
02 (68140) 0.62
35 (13.2)
(mg/dl)
Lipid modifying therapies
19 (9.2) 16 (7.5)
0.58
1 (0.2)
History of cardiovascular disease
Coronary heart disease
0 (0.0)
1 (0.5%)
Cerebrovascular diseases
6 (2.9)
9 (4.2%)
Lower limb occlusive
3 (1.4)
3 (1.4%)
vascular disease
Median (range) creatinine 91 (70113) 88(63108)
clearance (ml/min/1.73 m2)
0.32
15 (3.6)
0.46
6 (1.4)
0.97 89 (67111)
0.23
273 (66)
0.58
0.69
0.19
0.34
0.04
185 (44)
9 (2.1)
68 (16.2)
177 (81)
8.2 (2.3)
Diabetes treatment and control

Metformin
133 (64.7) 143 (67%)
Suphonamide
93 (45) 92 (43%)
Acarbose
2 (0.9)
7 (3.3%)
Insulin
37 (17.9) 31 (14.5%)
Fasting capillary glucose
185 (85) 169 (77)
(mg/dl)
Haemoglobin A1c (%)
8.5 (2.3) 7.9 (2.2)
0.03
Microvascular complications
Any diabetic retinopathy 38 (18.3%) 28 (13.1)
Any diabetic nephropathy 30 (14.5%) 37 (17.4)
Any diabetic neuropathy 52 (25.1%) 42 (19.7)
0.14
0.42
0.18
128
66 (15.7)
67 (15.9)
94 (22.4)
Fig. 1. Rhythm, conduction and T-wave changes in 420 men and women with
type 2 diabetes.
RESEARCH ARTICLE
Table 2. ECG changes in 420 men and women with type 2 diabetes

Variables
Number (%)
Arrhythmia
Conduction changes
Ectopic beats
T-waves changes
QTc prolongation
Ischaemic heart disease
Men
n (%)
207 (49)
31 (15)
28 (13.5)
10 (4.8)
53 (25.6)
18 (8.7)
34 (16.4)
Women
n (%)
p
213 (51)
37 (17.4)
0.51
22 (10.3)
0.37
10 (4.7)
0.99
35 (16.4)
0.02
25 (11.7)
0.34
23 (10.8)
0.12
Left ventricular hypertrophy by diagnostic criteria

Cornell product
14 (6.7)
55 (25,8) < 0.001
Sokolov index
17 (8.2)
7 (3.3)
0.03
Cornell index
12 (5.8)
5 (2.3)
0.09
Total
n (%)
420
68 (16.2)
50 (11.9)
20 (4.8)
88 (20.9)
43 (10.2)
57 (13.6)
69 (16.4)
24 (5.7)
17 (4.1)
The distribution of subtypes of conduction defects was

significantly different in men and women (p = 0.03). Significant
predictors of ECG abnormalities are shown in Table 3. Age variables
(age at diabetes diagnosis and duration of diagnosed diabetes), and
blood pressure variables were the common significant predictors of
ECG abnormalities.
The presence of diabetic nephropathy was significantly associated
with T-wave aberrations [OR: 0.45 (95% CI: 0.240.83)] and
ischaemic heart disease [OR: 0.47 (0.230.95)]; otherwise, diabetes
medications and markers of disease control were not associated
with the outcomes. Waist circumference was associated with a
3% (95% CI: 16%) higher risk of QTc prolongation, otherwise
no other marker of adiposity was associated with the outcomes.
Similarly, none of the lipid variables was significantly associated
with ECG abnormalities.
Discussion
This study revealed the high prevalence of ECG aberrations in this
population of individuals with a short duration of clinically overt type
2 diabetes. While some of these aberrations were benign, others
were potential indicators of the presence of serious conditions such
as ischaemic heart disease, or were associated with increased future
risk of fatal and non-fatal cardiovascular events. The minimal use of

preventive treatment for cardiovascular disease in this population
highlights the scope for improving cardiovascular health in people
with type 2 diabetes in this region.
Some aspects of ECG abnormalities in people with diabetes,
such as those relating to LVH,8 ischaemic heart disease9 or QTc
prolongation10 have been investigated in a few studies on diabetics
in Africa. To the best of our knowledge, however, there is no
recent study that has investigated the full spectrum of resting ECG
aberrations and potential determinants in people with diabetes in
this part of the world.
In accordance with a previous study in Tanzania,8 we found
a 16% prevalence of LVH in our study. Interestingly, blood
pressure variables were also the main determinants of LVH, with
approximately similar range of effects.8
That more than one in 10 participants in the current study
had ECG aberrations suggestive of ischaemic heart disease has
relevance in sub-Saharan Africa where cardiovascular diseases
are not considered a major priority health issue in people with
diabetes.11 In a previous study in the same region, using both resting
and exercise ECGs, a prevalence of 7.5% for cardiac ischaemia was
found; although this was based on a small sample size.12
Even after accounting for the uncertainties around the estimates
from this and other studies in sub-Saharan Africa,9 our findings
support a growing prevalence of ECG-diagnosed ischaemic heart
disease in diabetes patients in our region over time. This prevalence
was similar to that found in stroke survivors in Africa,13 and therefore
provides more evidence in support of the high cardiovascular risk of
diabetes patients in this part of the world.
It is possible that the prevalence of ECG-diagnosed cardiac
ischaemia was inflated in our study for at least two reasons: (1) in
the absence of a correlation between ECG aberrations and clinical
features, some of the observed ST-segment and T-wave changes
could have been variants of normal ECGs, as previously described
in blacks;14 (2) some of the repolarisation changes could have been
secondary to hypertension, which is very common in diabetes
patients in this region.5
In a cohort of black and white subjects with no known
Table 3. Odds ratio and 95% confidence intervals for predictors of ECG changes
Variables
Age at diabetes diagnosis (years)
Duration of diagnosed
diabetes (years)
Gender (men vs women)
Recruitment centre
(Yaound vs Douala)
Presence/history of nephropathy
Metformin use
Suphonylurea use
Insulin use
Waist circumference (cm)
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
Pulse pressure (mmHg)
Heart rate (beats/min)
Total cholesterol (mg/dl)
HDL cholesterol (mg/dl)
Arrhythmia
Conduction
T-wave changes
Long QTc
IHD
LVH
Ectopic beat
1.02 (0.991.04) 1.06 (1.021.09) *1.02 (0.991.04) 1.02 (0.991.06) 1.00 (0.971.03) 1.05 (1.021.08)* 1.06 (1.011.12)*
1.02 (0.971.06) 1.01 (0.961.07) 1.04 (1.001.08)* 1.08 (1.031.13)* 1.02 (0.981.07) 1.05 (1.001.10)* 1.04 (0.971.12)
1.16 (0.691.96) 0.66 (0.361.22) 0.55 (0.340.89)* 1.40 (0.732.68) 0.62 (0.351.09) 4.86 (2.549.25)* 0.84 (0.342.12)
0.89 (0.521.53)
0.69 (0.341.38)
1.06 (0.611.84)
0.87 (0.511.47)
0.60 (0.311.18)
0.98 (0.961.00)
1.00 (0.991.01)
1.00 (0.981.02)
1.01 (0.991.02)
1.01 (0.991.03)
0.60 (0.351.04)
0.66 (0.152.82)
0.89 (0.481.66)
0.76 (0.331.73)
0.87 (0.461.67)
0.90 (0.491.65)
3.26 (0.9611.09)
1.01 (0.981.03)
1.01 (1.001.03)*
1.01 (0.991.04)
1.02 (1.001.04)*
0.98 (0.961.01)
1.15 (0.632.10)
1.39 (0.296.51)
1.78 (1.102.87)
0.45 (0.240.83)*
1.04 (0.631.73)
0.71 (0.441.15)
1.06 (0.542.09)
0.98 (0.961.00)
1.01 (1.001.02)*
1.01 (0.991.03)
1.02 (1.001.03)
0.98 (0.961.00)*
1.55 (0.962.52)
2.23 (0.637.98)
1.05 (0.552.02) 1.28 (0.732.26) 3.79 (2.136.75)*

0.53 (0.251.15) 0.47 (0.230.95)* 0.66 (0.311.40)
1.86 (0.973.55) 0.85 (0.461.56)0.89 (0.481.64)
1.47 (0.762.86) 0.58 (0.331.02) 1.23 (0.691.20)
0.51 (0.261.11) 1.11 (0.502.47) 0.93 (0.402.17)
1.03 (1.011.06)* 1.00 (0.971.02) 1.02 (1.001.04)
1.02 (1.011.03)* 1.01 (0.991.02) 1.02 (1.011.03)
1.05 (1.021.07)* 1.01 (0.991.03) 1.01 (0.991.04)
1.02 (1.001.03) 1.01 (0.991.03) 1.03 (1.011.05)*
1.05 (1.031.08)* 0.99 (0.971.01) 0.99 (0.971.01)
1.22 (0.642.36) 1.27 (0.722.24) 1.24 (0.712.16)
1.03 (0.176.01) 3.82 (0.9215.96) 1.13 (0.242.39)
2.36 (0.935.95)
0.52 (0.171.66)
0.47 (0.151.46)
0.62 (0.251.57)
1.44 (0.316.75)
1.01 (0.971.04)
1.01 (0.991.02)
1.01 (0.981.05)
1.00 (0.981.03)
1.03 (0.971.04)
1.19 (0.482.97)
1.97 (0.1919.98)
*p < 0.05; IHD, ischaemic heart disease; LVH, left ventricular hypertrophy; all models are adjusted for gender, age and diabetes diagnosis, known duration of diabetes and
study centre
129
RESEARCH ARTICLE
cardiovascular disease who were participants of the Health, Aging,

and Body Composition study (Health ABC study), the presence of
major or minor ECG aberrations at baseline was associated with
coronary heart disease risk during follow up, independent of
classical cardiovascular risk factors.15 The findings of the Health
ABC study suggest that the presence of ECG aberrations, including
those used to diagnose cardiac ischaemia in our study, should be
given consideration as they may indicate an adverse underlying
cardiovascular risk profile.
Approximately 13% of participants in this study were on a
statin, preventive treatment widely recommended for routine use
in people with diabetes. No correlation was found between statin
use and ECG-diagnosed ischaemic heart disease. This suggests that
the use of statins in this population could be almost doubled by
using ECG criteria to diagnose for ischaemic heart disease. It was
shown in a recent study that the use of recommended preventive
therapies for cardiovascular disease risk reduction, based on global
risk evaluation, was limited in Africa in people with diabetes and
those without.16
Our study had some limitations. In the absence of follow up, we
were unable to establish any causal relationship between identified
predictors of cardiovascular risk and ECG aberrations. This was a
hospital-based study and therefore included participants who may
not have been typical of those in the community where the majority
of type 2 diabetes persons remain undiagnosed.17 While this could
have affected the prevalence of ECG changes found in our study,
it was less likely to have affected the direction of associations
described, and therefore would not have invalidated the major
findings from this study.
That ECGs were interpreted by an investigator who was unaware
of the clinical background of the patients, which could have
affected the prevalence of some of the outcomes. Indeed, using
such an approach resulted at best in a description of significant
changes, with no assumption about possible correlations between
coincident aberrations in the same patient.
Our study had some major advantages, including the considerable
sample size, which gave us reasonable statistical power to reliably
investigate the parameters. We were also able to investigate the
full spectrum of resting ECG aberrations, which no previous study
has achieved in Africa. The extensive data collection of both clinical
and biological profiles enabled a wide range of predictors to be
investigated for their possible link with prevalent ECG aberrations.
Conclusion
ECG aberrations are frequent in people with diabetes in sub-Saharan
Africa. While some may be benign, others are indicators of serious
130
underlying conditions or high future risk for cardiovascular disease.

These aberrations have the potential to improve cardiovascular
disease risk stratification and the implementation of preventative
strategies in people with diabetes in sub-Saharan Africa.
The growing prevalence of serious ECG aberrations over time
suggests the need for strategies to monitor such changes and
their determinants, so as to refine the cardiovascular preventative
strategies in sub-Saharan Africa. Elsewhere, dedicated diabetes
registries have successfully served these functions.
References
1. International Diabetes Federation. Diabetes Atlas. 4th edn. Brussels: IDF, 2009.
2. International Task Force for Prevention of Coronary Heart Disease, International
Atherosclerosis Society. Pocket Guide to Prevention of Coronary Heart Disease.
Munster: Born Bruckmeier Verlag GmbH, 2003.
3. International Diabetes Federation. Global Guidelines for Type 2 Diabetes. Brussels:
International Diabetes Federation, 2005.
4. IDF Africa Region Task Force on Type 2 Diabetes Clinical Practice Guidelines. Type
2 clinical practice guidelines for sub-Saharan Africa: IDF Afro Region, 2006.
5. Choukem SP, Kengne AP, Dehayem YM, Simo NL, Mbanya JC. Hypertension in
people with diabetes in sub-Saharan Africa: revealing the hidden face of the
iceberg. Diabetes Res Clin Pract 2007; 77: 293299.
6. Kengne AP, Djouogo CF, Dehayem MY, Fezeu L, Sobngwi E, Lekoubou A, et al.
Admission trends over 8 years for diabetic foot ulceration in a specialized diabetes
unit in Cameroon. Int J Low Extrem Wounds 2009; 8: 180186.
7. Norman JE, Jr., Levy D. Improved electrocardiographic detection of echocardiographic left ventricular hypertrophy: results of a correlated data base approach. J
Am Coll Cardiol 1995; 26: 10221029.
8. Lutale JJ, Thordarson H, Gulam-Abbas Z, Vetvik K, Gerdts E. Prevalence and
covariates of electrocardiographic left ventricular hypertrophy in diabetic patients
in Tanzania. Cardiovasc J Afr 2008; 19: 814.
9. Lester FT, Keen H. Macrovascular disease in middle-aged diabetic patients in
Addis Ababa, Ethiopia. Diabetologia 1988; 31: 361367.
10. Odusan O, Familoni OB, Raimi TH. Correlates of cardiac autonomic neuropathy
in Nigerian patients with type 2 diabetes mellitus. Afr J Med Med Sci 2008; 37:
315-320.
11. Kengne AP, Amoah AG, Mbanya JC. Cardiovascular complications of diabetes
mellitus in sub-Saharan Africa. Circulation 2005; 112: 35923601.
12. Mbanya JC, Sobngwi E, Mbanya DS, Ngu KB. Left ventricular mass and systolic
function in African diabetic patients: association with microalbuminuria. Diabetes
Metab 2001; 27: 378382.
13. Joubert J, McLean CA, Reid CM, Davel D, Pilloy W, Delport R, et al. Ischemic heart
disease in black South African stroke patients. Stroke 2000; 31: 12941298.
14. Brink AJ. The normal electrocardiogram in the adult South African Bantu. S Afr J
Lab Clin Med 1956; 2: 97123.
15. Auer R, Bauer DC, Marques-Vidal P, Butler J, Min LJ, Cornuz J, et al. Association
of major and minor ECG abnormalities with coronary heart disease events. J Am
Med Assoc 2012; 307: 14971505.
16. Kengne AP, Njamnshi AK, Mbanya JC. Cardiovascular risk reduction in diabetes
in sub-Saharan Africa: What should the priorities be in the absence of global risk
evaluation tools? Clin Med: Cardiol 2008; 2: 2531.
17. Mbanya JC, Kengne AP, Assah F. Diabetes care in Africa. Lancet 2006; 368: 1628
1629.
Diabetes Personality
Making a difference, one patient
at a time
S Afr J Diabetes Vasc Dis 2014;
11: 131132
r Hester Davel, a diabetes nurse educator at

the Centre for Diabetes and Endocrinology
(CDE) in Houghton, Johannesburg, has been
involved in diabetes education for 18 years. Her interest in chronic disease, and diabetes in particular,
began when she was working in a medical ward
and encountered a young boy with type 1 diabetes.
The other staff made sure he didnt have access to
sweets. At night, however, he used to steal sweets
from other patients while they were asleep, and
the next day his diabetes would be uncontrolled.
When I asked him why he did it, his answer was
that because his own sweets were always taken
away, Nobody gives me a choice.
Hester has a particular interest in type 1 diabetes patients, especially children, and much of her
work has focused on them. They tend to feel that
no one understands them. Often they feel deprived
of things, like sweets, that other children take for
granted. This makes them naturally rebellious. She
recalls being something of a rebel herself as a child
and is therefore able to relate.
Type 1 diabetes is hard work and as that boy
said, these young people are not given any choice
in the matter. It requires a demanding regimen of
constant testing and injecting, and patients dont
have the option to say, I dont want this! Hester
feels that her job as an educator is to walk the diabetes road beside her patients, not ahead of them
or behind them. Its important to listen to them
and hear what they want me to hear. I need to understand them in order to help them live well with
diabetes. Its not about me being prescriptive and
dictating what I think is good for them, without regard for their feelings.
So she works with patients to set goals that are

their own, rather than hers, and then facilitates their
making the difference in their lives that they want
for themselves. This is what she means by walking
beside them. If you walk ahead of your patient, it
means youre more interested in yourself than him/
her and more focused on what you think they need
to know and do. When you walk behind the patient,
it means youre not engaged enough and while
you might listen to them, you dont interact actively
enough to help them effect the changes they might
need to make.
Along with paediatric endocrinologist, Dr David
Segal, Hester was the driving force behind the establishment of regular camps for young diabetes
patients. The first one took place in 2005. I felt like
I was fulfilling my purpose on earth, because I had
always wanted to create a space for children with diabetes where they could play, laugh, sing, paint and
just have fun and be creative; a place where they
would not feel deprived in any way, and where they
would experience unconditional love and a sense of
complete safety. While not in the form of camps, she
is also currently focusing on creating an environment
of safety and understanding for those living with diabetes, family members, siblings and caretakers from
all walks of life.
Hester considers it a gift to be a diabetes nurse
educator and often uses the starfish fable to explain this. A little boy, who was walking along the
shore, picking up beached starfishes and throwing
them back in the sea, was stopped by a man who
asked him why he was doing this as he couldnt
save them all. The boy replied as he flung yet another starfish back into the water, Ive made a
131
DIABETES PERSONALITY
difference for that one! And thats what drives me, making a difference
one patient at a time.
Its important to see each patient as an individual and not only the
diabetes, she says. This requires genuine interest in who they are, the
whole person, and to help them see the light within. She knows shes
succeeding when a patient smiles when she enters a room or unexpectedly gives her a hug.
There is an emotional component to diabetes that Hester thinks is
often under-recognised. Diabetes patients and their families face many
challenges there are lots of ups and downs and a lot of pain. These
emotional aspects can sometimes seem overwhelming.
Hester understands this at a deeply personal level. Several years ago
she took Gareth in, a teenager with type 1 diabetes, becoming, as she
puts it, an instant mom. So I live with the reality every day myself. I
see his fears of hypoglycaemic episodes and of long-term complications and have experienced first-hand the challenges of dealing with
medical schemes to ensure that my pot of gold at the end of the
rainbow gets the best treatment possible. Today he is an awesome,
responsible young man who shares our vision of creating a better place
for those living with diabetes. He sees his diabetes as a gift rather than
a disadvantage.
Concluding, she underscores that its a great honour to work at the
CDE with a team of colleagues she considers mentors. I learn more and
more from them every day. And despite the challenges, I can honestly say
that there has never been a day when Ive hated my job. Ive never been
bored. I love what I do!
P Wagenaar
A single injection of FGF1 arrests type 2 diabetes in mice
n mice with diet-induced diabetes, the equivalent of type 2

diabetes in humans, a single injection of the protein FGF1 was
enough to restore blood glucose levels to a healthy range for
more than two days. The discovery by Salk scientists, published
recently in the journal Nature, could lead to a new generation of
safer, more effective diabetes drugs.
The team found that sustained treatment with the protein
doesnt merely keep blood glucose under control, it also
reverses insulin insensitivity, the underlying physiological cause
of diabetes. Equally exciting is that it doesnt result in the side
effects common to most current diabetes treatments.
Controlling glucose is a dominant problem in our society, says
Ronald M Evans, director of Salks Gene Expression Laboratory
and corresponding author of the article. And FGF1 offers a new
method to control glucose in a powerful and unexpected way.
Diabetes drugs currently on the market aim to boost insulin
levels and reverse insulin resistance by changing expression
levels of genes to lower glucose levels in the blood. But many of
these drugs, which increase the bodys production of insulin, can
cause glucose levels to dip too low and lead to life-threatening
hypoglycaemia, as well as other side effects.
In 2012, Evans and his colleagues discovered that FGF1, a
long-ignored growth factor, has a hidden function: it helps the
body respond to insulin. Unexpectedly, mice lacking FGF1 quickly
develop diabetes when placed on a high-fat diet, which suggests
that FGF1 plays a key role in managing blood glucose levels. This
led the researchers to wonder whether providing extra FGF1 to
diabetic mice could affect symptoms of the disease.
Evans team injected doses of FGF1 into obese mice with
diabetes to assess the proteins potential impact on metabolism.
The researchers were stunned by what happened: they found
that with a single dose, blood glucose levels quickly returned to
normal.
Many previous studies that had injected FGF1 showed no
effect on healthy mice, says Michael Downes, a senior staff
132
scientist and co-corresponding author of the study. However,

when we injected it into a diabetic mouse, we saw a dramatic
improvement in glucose levels.
Importantly, FGF1, even at high doses, did not cause glucose
to drop to dangerously low levels, a risk factor associated
with many glucose-lowering agents. Instead, the injections
restored the bodys own ability to regulate insulin and blood
sugar naturally, keeping glucose levels within a safe range and
effectively reversing the core symptoms of diabetes.
With FGF1, we really havent seen hypoglycaemia or other
common side effects, says Salk postdoctoral research fellow
Jae Myoung Suh, a member of Evans laboratory. It may be
that FGF1 leads to a more normal type of response compared
to other drugs because it metabolises quickly in the body and
targets certain cell types.
The mechanism of FGF1 still isnt fully understood; neither is
the mechanism of insulin resistance, but Evans group discovered
that the proteins ability to stimulate growth is independent
of its effect on glucose, bringing the protein a step closer to
therapeutic use.
There are many questions that emerge from this work and
the avenues for investigating FGF1 in diabetes and metabolism
are now wide open, Evans says. Identifying the signalling
pathways and receptors that FGF1 interacts with is one of the
first issues he would like to address. He is also planning human
trials of FGF1 with collaborators, but it will take time to finetune the protein into a therapeutic drug.
We want to move this to people by developing a new
generation of FGF1 variants that solely affect glucose and not
cell growth, he says. If we can find the perfect variation, I
think we will have found a new, very effective tool for glucose
control.
Source: http://medicalxpress.com/news/2014-07-diabetes-tracks-mice-side-effects.
html
Patient
information
leaflet
Ottilia Brown
Clinical Psychology Department,
e-mail: Ottilia.Brown@kznhealth.gov.za
S Afr J Diabetes Vasc Dis 2014;

11: 133136
Keep and Copy Series

PSYCHOLOGICAL CONSIDERATIONS IN
THE MANAGEMENT OF DIABETES
Diabetes is a complex non-communicable disease requiring lifelong management and
personal responsibility of the patient for every aspect of treatment. Inadequate metabolic
control in diabetic patients is well documented. This article focuses on psychology and
diabetes in terms of examining the role of psychology in management of the illness
throughout its course, and the negative influence of psychological presentations on
diabetes management. The article also highlights the prevalence of these presentations
and emphasises the importance of identifying and treating these conditions, as this can
significantly improve adherence and glycaemic control. In closing, some thoughts on the
way forward are discussed.
outh Africa faces a quadruple burden of diseases consisting of HIV and AIDS, other communicable diseases, non-communicable diseases, and violence and injuries. The consequence
of this is high levels of mortality.1 Non-communicable
diseases (NCDs) are the leading cause of mortality
globally, causing more deaths than all other causes
combined.
The Negotiated Service Delivery Agreement signed between the Minister of Health and the
President identified four strategic outputs for national
health, namely increasing life expectancy, decreasing maternal and child mortality, combating HIV and
AIDS and decreasing the burden of diseases from
tuberculosis, and strengthening health system effectiveness.2 Reducing mortality from NCDs is critical to
increasing life expectancy. Diabetes is classified as a
non-communicable chronic disease.
According to the World Health Organisation
(WHO),3 36 million people died globally from NCDs
in 2008, with 3% of these deaths being attributed
to diabetes. Premature deaths from NCDs are particularly high in poorer countries with around 80%
of such deaths occurring in low- and middle-income
countries. Globally, deaths due to NCDs are projected
to increase by 17% over the next 10 years, but the
greatest increase (24%) is expected in the African

region. By 2030 it is estimated that NCDs will contribute to 75% of global deaths.4
Accurate reporting on NCDs in South Africa is affected by inadequate surveillance and research and
hence there is a lack of recent data on the prevalence
of diabetes in South Africa.5 According to the WHO,6
NCDs accounted for 29% of deaths in South Africa
in 2008, with 3% of these deaths being attributed
to diabetes. Statistics South Africa attributed 40% of
deaths to NCDs in 2008, with 2% being attributed to
diabetes. While this prevalence may seem small in
relation to other NCDs, cardiovascular morbidity and
mortality related to diabetes is well documented,7
meaning that diabetes contributes to high NCD mortality in other ways.
Diabetes is a complex disease requiring multiple
treatment modalities, the bulk of which are reliant
on the patient taking primary responsibility for the
day-to-day management of the illness. Diabetes has
been recognised as one of the most emotionally
and behaviourally challenging and demanding
chronic illnesses.8 Both type 1 and type 2 diabetes
require treatment regimens that are complex,
including medication, self-monitoring and lifestyle
133
PATIENT INFORMATION LEAFLET
management (diet, exercise, coordination of food intake and exercise

to prevent hypoglycaemia).9 Adherence to these complex regimens is
paramount to delaying and/or preventing the onset of serious diabetes
complications, such as retinopathy, neuropathy and nephropathy.10
Research indicates that psychological factors such as depression,
anxiety, diabetes-specific distress, fear of hypoglycaemia, and eatingdisordered behaviours play a significant role in adherence to diabetes
regimens.11,12 In addition to adherence outcomes, research also indicates
that psychological factors can increase the risks of poor glycaemic control and diabetic keto-acidosis (DKA).13 The psychological aspects of diabetes are overwhelming and should be considered and included in the
treatment of diabetes in order to ensure the effective management of
the illness.14
DISEASE COURSE AND THE ROLE OF PSYCHOLOGY
The primary reasons for psychological referral of diabetic patients are
poor adherence to treatment regimen, poor adjustment to illness, stress
exacerbating medical symptoms and/or self-care, psychiatric presentations, and cognitive problems.15 The mental health of the diabetic patient
is an important consideration as the patient requires considerable motivation and ego strength to comply with the self-care demands of the
illness.8 Psychology has a significant role to play throughout the course
of the disease.
At diagnosis, patients are suddenly expected to make significant lifestyle changes and integrate complex treatment regimens into their lives.
Individuals diagnosed with type 2 diabetes are faced with challenges
pertaining to the fact that their nutrition and exercise habits are already
deeply entrenched.9 Patients inevitably respond differently to the diagnostic news, some may experience shock which may cause emotional
distress while others may respond indifferently or with relief as the reason for symptom presentation can now be explained.8
Following diagnosis, depending on the type of diabetes and stage
at diagnosis, a treatment regimen is prescribed. While adherence
can significantly delay the onset of diabetes-related complications,
it does not always translate into immediate good results, and positive
feedback may not be possible in the short term, causing the patient to
have to persist for long periods of time before benefitting from regimen
adherence. This delay in results, despite considerable efforts, may be
frustrating and even demotivating for patients. Patients can therefore
benefit from learning active, problem-focused, and pro-active coping
behaviours, which can be applied across settings and over a long period of time.8 Patients can further benefit from psychological interventions that identify barriers to adherence,16 and use this information to
develop new healthy behaviours, enhance existing healthy behaviours,
and eliminate unhealthy behaviours as they relate to improved glycaemic
control.17
134
PSYCHOLOGICAL PRESENTATIONS AND DIABETES

MANAGEMENT
Depression
Depression is twice as common in diabetic patients as the general
population.18,19 It has been associated with hyperglycaemia for type 1 and
type 2 diabetes.20 This co-morbidity is often under-diagnosed and undertreated in more than a quarter of the diabetic population.19,21 The clinical
relevance of this under-treatment is significant as depression has been
associated with decreased metabolic control,19 poor adherence to treatment regimens,22 diminished quality of life,19 and early mortality.23 Poor
glycaemic control can also exacerbate depression and diminish response
to anti-depressant therapy.19 In addition, the combination of depression
and diabetes has been shown to increase the risk of developing diabetes
complications such as cardiovascular disease.24
Anxiety
It has been reported that the prevalence of anxiety in diabetic patients is
30 to 40%.25 Anxiety has been related to poor glycaemic control, poorer
quality of life,25,26 and decreased self-care behaviours.27 A number of
explanations exist for this link. It has been postulated that sympathetic
nervous system responses to hyperglycaemia can produce anxiety symptoms. Further, endocrine abnormalities resulting from diabetes may be
aggravated by normal physiological stress responses. Lastly, anxiety may
be a response to the complexity of the illness and the associated treatment regimen, which may negatively affect coping ability.15 Regardless,
the negative effect of anxiety on adherence and quality of life makes this
condition clinically relevant in the effective management of diabetes.
Eating-disordered behaviour
Eating disorders and eating-disordered behaviour are a major concern
in managing diabetes.28 Eating problems that may be considered mild
in non-diabetic patients can have significant clinical consequences for
diabetic patients.29 In particular, insulin restriction to lose weight in type
1 diabetes patients increases risk for potentially life-threatening complications of diabetes, including higher HbA1c readings, more frequent
DKA episodes, higher risk for developing infections, more frequent use
of medical services, and increased risk of mortality.29,30 Insulin restriction
has also been related to earlier onset of diabetes-related complications,
retinopathy and neuropathy.31 Disordered eating behaviour is often well
hidden and therefore diabetes healthcare providers have to ask pertinent
questions to uncover this behaviour.28
Stress
The link between psychological stress and poor diabetes control is well
known.32 Stressful life events have been found to be concomitant with an
increased risk of the development of type 1 diabetes in children,33,34 as
well as type 2 diabetes in predisposed individuals.32 Psychological distress

and poor glycaemic control have been linked in patients with established
type 1 and type 2 diabetes.32,35 Stress elicits the release of counter-regulatory hormones, such as adrenaline and cortisol, which in turn results in
energy mobilisation, often resulting in elevated glucose levels. In addition,
stress can disrupt diabetes control by negatively affecting indispensable
self-care behaviours.36 Fortunately stress-management techniques can
play a significant role in long-term glycaemic control.32 Diabetic patients
can therefore benefit greatly from stress-management training.37
screening and appropriate referral becomes essential. The psychological

problems of depression, anxiety, eating-disordered behaviour and eating
disorders discussed in this article require comprehensive psychotherapeutic and psychopharmacological intervention. Screening for cognitive
decline and involving the family in diabetes management is essential to
ensure glycaemic control despite cognitive deficits. Addressing these
psychological presentations and recognising the role of psychology in
diabetes management can significantly improve glycaemic control and
delay and/or prevent diabetes complications.
Cognitive impairment
Diabetes is associated with a greater rate of decline in cognitive function
and a greater risk of cognitive decline.38,39 Findings with regard to the
contribution of co-morbid depression and diabetes to the development of
cognitive impairment have been mixed. While one study showed no significant relationship between depression and dementia,39 another study
with a cohort of 3 837 diabetic patients found that patients with major
depression and diabetes had an increased risk of the development of
dementia compared to those with diabetes alone.40
With regard to the aetiology of diabetes, cognitive deficits have been
associated with chronic hyperglycaemia and frequent, severe hypoglycaemic episodes.41 Cognitive deficits and decline will have a direct effect
on the patients ability to self-care. Family involvement becomes a crucial
part of diabetes care at this point. Screening and early detection are essential to ensure that adherence is not adversely affected.
References
THE WAY FORWARD

The clinical significance of identifying and appropriately treating psychological problems in diabetic patients is well documented. Psychosocial
adaptation is an important treatment outcome as it positively influences
quality of life and treatment efficacy.8 Given the adverse effect of the
presence of psychological conditions on diabetes management, a comprehensive approach to managing diabetes is required.
A multidisciplinary team comprising relevant medical and allied health
professionals would be ideal in order to tackle the physical and psychological complexities of diabetes.42 In addition, a patient-centred collaborative treatment approach that engages with and empowers the patient
to actively participate in his/her consultations and treatment and encourages open communication between patient and provider is highly recommended as a means of enlisting adherence.8 This open collaborative
communication should include discussions about barriers to adherence,
emotional responses to diabetes and psychological factors that affect
adherence and coping. Various authors have made a case for empowering patients, simply because every aspect of diabetes management is
dependent on the patient choosing to adhere.11,43
In cases where a multidisciplinary approach is not possible, effective
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Glucose control switch in the brain key to both types of diabetes
esearchers at Yale School of Medicine have pinpointed a

mechanism in part of the brain that is key to sensing glucose
levels in the blood, linking it to both type 1 and type 2 diabetes.
The findings were published in the July 28 issue of Proceedings of
the National Academies of Sciences.
Weve discovered that the prolyl endopeptidase enzyme, located
in a part of the hypothalamus known as the ventromedial nucleus,
sets a series of steps in motion that control glucose levels in the
blood, said lead author Sabrina Diano, professor in the Departments
of Obstetrics, Gynecology and Reproductive Sciences, Comparative
Medicine, and Neurobiology at Yale School of Medicine. Our
findings could eventually lead to new treatments for diabetes.
The ventromedial nucleus contains cells that are glucose
sensors. To understand the role of prolyl endopeptidase in this
part of the brain, the team used mice that were genetically
engineered with low levels of this enzyme. They found that in the
absence of this enzyme, mice had high levels of glucose in the
blood and became diabetic.
136
Diano and her team discovered that this enzyme is important

because it makes the neurons in this part of the brain sensitive
to glucose. The neurons sense the increase in glucose levels
and then tell the pancreas to release insulin, thus preventing
diabetes.
Because of the low levels of endopeptidase, the neurons
were no longer sensitive to increased glucose levels and could
not control the release of insulin from the pancreas, and the mice
developed diabetes, said Diano, who is also a member of the
Yale Program in Integrative Cell Signaling and Neurobiology of
Metabolism.
Diano said the next step in this research is to identify the
targets of this enzyme by understanding how the enzyme makes
the neurons sense changes in glucose levels. If we succeed in
doing this, we could be able to regulate the secretion of insulin,
and be able to prevent and treat type 2 diabetes, she said.
Source: http://medicalxpress.com/news/2014-07-glucose-brain-key-diabetes.html
Lipanthyl + Statin Better Outcome
THE MISSING
PIECE IN LIPID
MANAGEMENT 1
Combination fenobrate plus simvastatin

therapy in patients with mixed dyslipidaemias
Fenobrate plus simvastatin therapy signicantly improved ALL lipoprotein

abnormalities vs simvastatin alone (p < 0,001) 1
Change from baseline in lipid parameters 1

Fenofibrate + Simvastatin
Percentage change from baseline (%)
30
TG
TC
LDL-C
Simvastatin
HDL-C
non-HDL-C
Apo B
18,6
20
9,7
10
0
-10
-20
-20,0
-25,8
-31,2
-40
-50
-20,3
-26,3
-30
-43,0
-22,8
-26,1
-35,3
-32,6
p < 0,001
Adapted from Grundy SM, et al 1

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SAJDVD

The electronic version of

The South African Journal of Diabetes & Vascular Disease

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Incretins: harmful to the pancreas or not?

The effects of systemic medication on diabetic retinopathy

An overview of the role of physiotherapy in managing diabetes and

Paediatric diabetes with a focus on the adolescent

A review of the literature on multidisciplinary interventions in cardiac

The effects of medicinal plants on renal function and blood pressure in

The ADVANCE cardiovascular risk model and current strategies for

Prevalence and determinants of

Making a difference, one patient at a

Patient Information Leaflet

Psychological considerations in the

SA JOURNAL OF DIABETES & VASCULAR DISEASE

The role of allied health practitioners in diabetes care

his edition examines the important role of allied health

often overlooked in busy practices and hospitals in South Africa,

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REGISTRATION & ACCOMMODATION BOOKINGS OPEN

For more information:

at the SA Heart Association Congress

Bridging the Divide | 16 - 19 October 2014

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SA JOURNAL OF DIABETES & VASCULAR DISEASE

Incretins: harmful to the pancreas or not?

therapeutic agents, and non-diabetic control subjects. This study

VOLUME 11 NUMBER 3 SEPTEMBER 2014

SA JOURNAL OF DIABETES & VASCULAR DISEASE

treatments. It may suggest that the apparent increase in pancreatic

VOLUME 11 NUMBER 3 SEPTEMBER 2014

effects on the durability of glycaemic control, the durability and

SA JOURNAL OF DIABETES & VASCULAR DISEASE

The effects of systemic medication on diabetic retinopathy

Drugs for glucose control

Correspondence to: Dr Carl-Heinz Kruse

particularly pronounced when the HbA1c levels where dropped by

Drugs for hypertension management

Drugs for lipid control

VOLUME 11 NUMBER 3 SEPTEMBER 2014

SA JOURNAL OF DIABETES & VASCULAR DISEASE

demonstrated its benefit in DR.16 These two trials together included

Drugs for anaemia treatment

careful choice of systemic medication, especially for hypertension,

Drugs for cardiac complications management

Anti-angiogenic drugs and steroids

Although good serum glucose control and regular fundoscopy are

VOLUME 11 NUMBER 3 SEPTEMBER 2014

Bourne RRA, et al. Causes of vision loss worldwide, 19902010: a systematic

SA JOURNAL OF DIABETES & VASCULAR DISEASE