Beruflich Dokumente
Kultur Dokumente
Diabetes - Complications
Diabetes Complications
Contents
1. Define the term diabetes mellitus, and indicate the common investigations
used in the diagnosis and monitoring of this condition.........................................4
Definition............................................................................................................ 4
Evaluation........................................................................................................... 4
Initial............................................................................................................... 4
Diabetic related complications........................................................................4
Gestational Diabetes Screening......................................................................5
Diagnosis............................................................................................................ 5
2. Distinguish between type1, type 2 and gestational diabetes on
epidemiological and clinical grounds.....................................................................6
3. Describe the role of insulin in carbohydrate and lipid metabolism. What broad
categories of insulins are available?......................................................................7
Glucose homeostasis.......................................................................................... 7
4. Describe the pathogenesis of the common forms of diabetes mellitus, and
outline the major risk factors for their development.............................................9
Diabetes Type 1.................................................................................................. 9
Genetic Susceptibility...................................................................................... 9
Environmental Factors..................................................................................... 9
Mechanisms of cell destruction....................................................................9
Type 2 DM......................................................................................................... 10
Insulin Resistance.......................................................................................... 10
5. Describe the biochemical basis of the major metabolic disturbances in
diabetes, including ketoacidosis and hyperglycaemic coma, and the likely
metabolic consequences of these conditions......................................................12
Diabetic Ketoacidosis........................................................................................ 12
Other Metabolic Disturbances..........................................................................13
6. Describe the macrovascular and microvascular complications of diabetes,
with emphasis on diabetic retinopathy and nephropathy. What pharmacotherapy
is indicated to slow down the progression of these complications, and why?......14
Macrovascular.................................................................................................. 14
Overall pathophysiology of complications of DM..............................................14
Diabetic Nephropathy....................................................................................... 14
Morphological Changes................................................................................. 15
Pathogenesis................................................................................................. 15
Diabetes - Complications
Diabetic Retinopathy........................................................................................ 15
Classification................................................................................................. 16
Pathophysiology............................................................................................ 16
Management................................................................................................. 16
7. Discuss the factors that may result in the development of a foot ulcer in an
individual with diabetes mellitus.........................................................................17
Diabetic Neuropathy......................................................................................... 17
Classifications................................................................................................ 17
Symptoms..................................................................................................... 17
Foot Ulcers.................................................................................................... 17
Pathophysiology of Foot Ulcers......................................................................18
Risk Classification............................................................................................. 18
Group 0......................................................................................................... 18
Group 1......................................................................................................... 18
Group 2......................................................................................................... 18
Group 3......................................................................................................... 18
8. List the microorganisms most commonly associated with foot ulcers in a
diabetic patient and outline the treatment strategy that you would recommend.
19
Microorganisms................................................................................................ 19
Antibiotics...................................................................................................... 19
9. Discuss the nature and pathogenesis of neurological lesions seen in longstanding diabetes mellitus................................................................................... 20
10. What pharmacotherapies are available for type 1 and type 2 diabetes?
Why do the treatments differ?.............................................................................21
Goals of Therapy.............................................................................................. 21
Diabetes Type 1................................................................................................ 21
Lifestyle......................................................................................................... 21
Glycaemic targets......................................................................................... 21
Insulin............................................................................................................ 21
Choice of insulin regimen..............................................................................22
Type 2 Diabetes................................................................................................ 22
Glucose Lowering Agents.............................................................................. 22
11. Explain the importance of ongoing monitoring of blood glucose levels in
diabetes............................................................................................................... 26
Glucocorticoids.................................................................................................... 27
Diabetes - Complications
Evaluation
Initial
Diabetes - Complications
Diagnosis
Diabetes - Complications
Type 1 Diabetes:
o Characterised by pancreatic cell destruction and absolute
deficiency of insulin
Type 2 diabetes
o Combination of peripheral resistance to insulin action and adequate
secretory response by pancreatic cells
o Most are overweight
o Two metabolic defects that characterise:
Decreased response of peripheral tissues to insulin
cell dysfunction that is manifested as inadequate insulin
secretion in face of insulin resistance and hyperglycaemia.
Diabetes - Complications
Glucose homeostasis
Diabetes - Complications
Fasting plasma glucose levels hence depend on hepatic
glucose output
After a meal, there is high insulin and low glucagon
Insulin promotes glucose uptake and utilisation in tissues
Skeletal muscle is major insulin-responsive site for
postprandial glucose utilisation, critical for preventing
hyperglycaemia and maintaining glucose homeostasis.
Glut-2
o Insulin independent glucose transporter in cells
Glucose undergoes oxidative metabolise to produce ATP
ATP inhibits inward K+ channel receptors on cell surface
This leads to membrane depolarisation, influx of Ca 2+ ions, and release of
stored insulin from cells.
Sulphonylurea binds to SUR1 receptor protein on K + channels and causes
blockage of K+ channel for depolarisation.
Other hormones and certain amino acids such as leucine and arginine also
stimulate insulin release
Diabetes - Complications
Genetic Susceptibility
Environmental Factors
Diabetes - Complications
Type 2 DM
Insulin Resistance
10
Diabetes - Complications
cell failure
o cells can exhaust capacity to adapt to long term demands of
peripheral insulin resistance
i.e. over-production of insulin exhausts the cells
o Hyperinsulinaemic state is compensation for peripheral resistance
which can last for years
Eventually cell compensation becomes inadequate, and
there is progression to hyperglycaemia.
Eventual cell failure
o Excess NEFAs leading to lipotoxicity can cause this.
o Agents like metformin improve AMPK activation and improve cell
function
11
Diabetes - Complications
Diabetic Ketoacidosis
Serious complication of T1DM but can also occur in T2DM, although not as
commonly.
Marked insulin deficiency
Release of adrenaline blocks residual insulin action, and stimulates
secretion of glucagon.
Insulin deficiency lipoprotein lipase breakdown of adipose stores
free fatty acids. Oxidation of fatty acids in liver ketone bodies.
Rate at which ketone bodies are produced may exceed utilisation by
peripheral tissues, leading to ketonaemia and ketoneuria.
If urinary excretion of ketones is compromised by dehydration, systemic
metabolic ketoacidosis results.
12
Diabetes - Complications
13
Diabetes - Complications
Atherosclerotic disease:
o CVD
AMI main cause of death
o Strokes (CVA cerebrovascular accident)
o Peripheral Vascular Disease
Can lead to gangrene
Hyaline arteriolosclerosis
o Amorphous hyaline thickening of arteriole walls
o Can occur without HTN.
Diabetic Nephropathy
14
Diabetes - Complications
Morphological Changes
Pathogenesis
15
Diabetes - Complications
Diabetic Retinopathy
Classification
Pathophysiology
16
Diabetes - Complications
Blood vessels can grow into anterior chamber of eye and cause
neovascular glaucoma.
Management
Laser treatment
Injection of corticosteroids/ anti-VEGF agents into eye
o Triamcinolone
Decreases macular oedema, increase in visual acuity
3 months every injection
o Bevacizumab (anti-VEGF)
Reduces diabetic macular oedema
Vitrectomy
o Done when theres a lot of blood in the vitreous
o Remove cloudy vitreous and replace with saline solution
o Done under local. Incision in sclera, eye patch for a few days
17
Diabetes - Complications
Symptoms
Foot Ulcers
Contributing factors:
o Diabetic neuropathy
o Abnormal foot biomechanics
o Peripheral vascular disease
18
Diabetes - Complications
Motor neuropathy:
o Imbalance between flexion and extension Deformity (hammer
toe, claw toe)
o Foot deformities due to abnormal weight bearing while walking
o Bony prominences, pressure points > ulcers
Altered metabolism
o Altered protein and lipid metabolism abnormal granulation tissue
formation
o Advanced glycation end products form on ECM with slow turnover
rate
o Alter the properties of collagen, laminin via cross linking on Type 1
collagen and elastin
Changes to fibroblast
o Fibroblasts from diabetic ulcers have decreased ECM protein
production and delayed wound contraction and impaired wound
healing.
Risk Classification
Group 0
No evidence of neuropathy
Group 1
Neuropathy present but no evidence of foot deformity or peripheral vascular
disease
Group 2
Neuropathy with evidence of deformity or peripheral vascular disease
Group 3
History of foot ulceration or lower extremity amputation
19
Diabetes - Complications
Antibiotics
First-line
Alternative
Mild-moderate
At least 5 days
amoxycillin+clavula
nate 875+125 mg
orally, 12-hourly
piperacillin+tazobac
tam 4+0.5 g IV, 8hourly
cephalexin 500 mg
orally, 6-hourly PLUS
metronidazole 400
mg orally, 12-hourly
ticarcillin+clavulanate
3+0.1 g IV, 6-hourly
Penicillin
hypersensitivity
ciprofloxacin 500 mg
orally, 12-hourly PLUS
clindamycin 600 mg
orally, 8-hourly.
ciprofloxacin 400 mg
IV, 12-hourly OR
ciprofloxacin 750 mg
orally, 12-hourly
PLUS clindamycin 900
mg IV, 8-hourly (slow
infusion required)
20
Diabetes - Complications
21
Diabetes - Complications
22
Diabetes - Complications
Diabetes Type 1
Lifestyle
Meals/ Diet
o Estimate how much carbs they are about to consume
o Patient should attempt to maintain consistent carbohydrate profile
daily
o Or patients could use carb : insulin ratios so they dont need to take
a fixed amount of carbs daily
Monitoring of blood glucose levels
o Self-testing done 4 7 times daily
Exercise
o Avoids weight gain
o Hypoglycaemia may occur after vigorous exercise
o Monitor blood glucose levels before during and after exercise
o Delay exercise if blood glucose >14mmol/L and ketones present
o If blood glucose <5.6mmol/L ingest carbs before
Glycaemic targets
Aim for HbA1C of <7%, set at 8% for older patients and those with
comorbidities or limited life expectancy
Insulin
23
Diabetes - Complications
rapid insulin prep via a pump is matter of patient prep and lifestyle.
Basal insulin
o Insulin Glargine
o NPH
o Detemir
Prandial insulin
o Regular
o Lispro
o Aspart
o Glulisine
Most newly diagnosed T1DM given total daily dose of 0.2 0.4 units of
insulin/kg/day, although most will ultimately require 0.6-0.7 units of
insulin/kg/day.
Approximately one half of total dose should be given as a basal insulin,
either once or twice daily.
o Remainder given as short or rapid acting insulin post/pre prandial.
Type 2 Diabetes
Lifestyle changes
o Exercise to promote insulin sensitivity and weight loss
24
Diabetes - Complications
25
Diabetes - Complications
DPP-IV inhibitors
Inhibit degradation action of DPP-IV on native GLP-1, enhancing the
incretin effect
DPP-IV usually expressed on cell surface of endothelial cells and some
lymphocytes
DDP-IV inhibitors promote insulin secretion in absence of hypoglycaemia
GLP-1 drugs (incretin) however produce greater GLP-1 action than DPP-IV
inhibitors
glucosidase inhibitors
Reduce postprandial hyperglycaemia, even with T1DM
Taken before each meal
Prevents cleavage of large oligosaccharides into simple sugars
Major side effects are diarrhoea, flatulence, abdo distension due to
increased delivery of oligosaccharides to intestinal gut
Thiazolidinediones aka glitazones
Bind to PPAR- nuclear receptor
PPAR- most expressed in adipocytes
PPAR- promotes adipocyte differentiation, reduced hepatic fat
accumulation and increased fatty acid storage.
Circulating insulin levels decrease, indicating reduction in insulin
resistance.
Rosiglitazone raises LDL, HDL, and triglycerides slightly
Proglitazone raises HDL to greater degree, and LDL a leser degree, but
lowers triglycerides.
Associated with weight gain, peripheral oedema and CHF
Contraindicated in patients with liver disease or CHF
Sodium-Glucose CO-Transporter 2 Inhibitors (SLGT2)
Lower blood glucose by inhibiting co-transporter in PCTs of kidney.
Inhibits glucose reabsorption and increased glucose excretion.
Limited clinical experience
Urinary/vaginal infections more common due to increased urinary glucose
Insulin Therapy
Insulin should be considered as initial therapy in T2DM with lean
individuals or those with severe weight loss, or in individuals with
underlying renal or hepatic disease
Usually initiated with single dose long acting insulin (0.3-0.4units/kg/day)
NPH, glargine or detemir
26
Diabetes - Complications
Choosing correct initial glucose lowering agent
Insulin secretagogues, biguanides, GLP-1 Receptor agonists, and
thiazolidinediones more effective than glucosidase inhibitors, DPP-IV
inhibitors and SLGT2 inhibitors.
Fast plasma glucose lowering: insulin secretagogues, GLP-1 Receptor
inhibitors, DPP-IV inhibitors, -glucosidase inhibitors and SLGT2
Slower (delayed by weeks): Biguanides, thiazolidinediones
Metformin usually given firs to meet glycaemic target or if max dose
reached, and then either insulin secretagogue or DPP-IV inhibitor used
27
Diabetes - Complications
28
Diabetes - Complications
29
Diabetes - Complications
Glucocorticoids