DIABETES_ LECTURE

PROF. DR. DOINA CATRINOIU

 Diabetes Mellitus
One of the most common non-
communicable diseases
Fourth leading cause of death in most
developed countries
More than 194 million people with
diabetes worldwide
Incidence of diabetes is increasing
estimated to rise to 333 million by 2025
To more than double in Africa, the Eastern
Mediterranean and Middle East, and South-East Asia
To rise by 50% in North America, 20% in Europe,
85% in South and Central Americas and 75% in the
Western Pacific
: International Diabetes Federation website
 Types of Diabetes Mellitus
Type 1 diabetes (insulin-dependent
diabetes)
mainly in childhood/early adult life
10-20% of cases
Type 2 diabetes (non-insulin-dependent
diabetes)
usually develops in the middle-age/elderly
incidence increasing at a younger age
80-90% of cases
At least 50% of all people with
diabetes are unaware of their
condition : International Diabetes Federation website
 CLASSIFICATION OF DIABETES
Impaired glucose tolerance without
diabetes (IGT)
Primary diabetes mellitus
Insulin dependent (IDDM or Type 1)
Noninsulin dependent (NIDDM or Type 2)
Malnutrition-related diabetes mellitus
(MRDM)
Secondary diabetes mellitus
Pancreatic disease
Endocrine disorders
Drug therapy
Inherited disorders
 SynthesisSecretia
of insulin de insulina
Synthesis of insulin

Proinsulin (86aa) Insulin (21 + 30aa)

NH2 HOOC NH2 - chain
S S S S

S S S S

HOOC HOOC NH2 - chain

S S S S

C - peptide (35aa)
ESR10-08 ESR10-0
 Basal-bolus therapy attempts to re-
create physiological insulin secretion
Rapid-acting insulin
Predicted plasma insulin concentration

Basal insulin

Total
profile (mU/l)

Time of day
 Diabetes is defined biochemically
by the following criteria
A fasting venous plasma glucose
level greater than 7.8 mmol/litre
(126 mg/dl) on more than one
occasion;

or A 2-hour (plus one other)

venous plasma glucose level in
excess of 11.1 mmol/litre (200
mg/dl) in a formal 75 g oral
glucose tolerance test (GTT).
 Clinical features of diabetes at
diagnosis
Type 1 Type 2
Polyuria and thirst ++ +
Weakness or fatigue ++ +
Polyphagia with weight loss++
Recurrent blurred vision + ++
Vulvovaginitis or pruritus + ++
Peripheral neuropathy + ++
Nocturnal enuresis ++
Often asymptomatic ++
 A diagnostic algorithm for diabetes
mellitus

Blood glucose > 200 mg/dl

Classical
Symptoms* + Blood glucose 100 -200 mg/dl

DIABETES

A Fasting plasma glucose

S > 126 mg/dl
Y
2-h Plasma glucose after
M Fasting plasma glucose "OGTT" > 200 mg/dl
P 109-125 mg/dl and/or
T Fasting plasma glucose >
126 mg/dl
O
postprandial plasma
M glucose > 200mg/dl
A
T Blood glucose > 200 mg/dl
I "occasionally"
C
 INVESTIGATIONS

Blood glucose is the key to diagnosis in

diabetes.
Glycosylated haemoglobin and other
proteins: measurement of these proteins
reflects the degree of diabetic control in
the previous 4-6 weeks and is of value in
long-term management and control .
 INVESTIGATIONS

Urine testing for glucose-glucose will

be found in the urine only when it rises
above the renal threshold (usually about
10 mmol/l
Urine testing for ketone bodies the
presence of ketones suggests loss of
control.
Proteinuria is a reflection of the
development of renal complications and
is an early indicator of diabetic renal
disease Multiple test strips allow rapid
testing for all these substancesin urine.
 INVESTIGATIONS

Proteinuria is a reflection of the

development of renal complications and
is an early indicator of diabetic renal
disease Multiple test strips allow rapid
testing for all these substancesin urine.
Microalbuminuria is a very sensitive
marker of early and potentially reversible
renal impairment; it is the term given to
the presence of protein below the level of
detection with the stick methods, that is
200 mg/litre.
 INVESTIGATIONS
Serum electrolytes, blood gases,
osmolality and anion gap are all of
value in metabolic crises if there is
loss of water, sodium and potassium
and acidosis is developing, or if there
is a hyperosmolar state.
Lipid profile: elevations in serum
cholesterol are common, and
elevation of serum triglycerides is a
reflection of poor glycaemic control,
which usually reverts to normal when
euglycaemia is achieved.
 PRESENTING FEATURES OF DIABETES
Acute: the typical presentation of the young
patient with IDDM; features include polyuria,
polydipsia and weight loss of short duration,
often associated with, or apparently
precipitated by, a viral infection;visual
disturbance or impairment of the conscious
level associated with severe ketoacidosis
Chronic: the typical presentation of a patient
with NIDDM; the symptoms have usually been
present for some months and often include
weight loss, thirst, excess urine volume, genital
and skin infections
 PRESENTING FEATURES OF DIABETES

Coincidental discovery: routine

screening for urine or blood glucose as
part of a pre-employment medical, during
pregnancy or in local campaigns
Complications: visual disturbance or
overt retinopathy, neuropathy,
nephropathy or after major thrombotic
events such as premature stroke or
myocardial infarction
 PRESENTING FEATURES OF DIABETES
Drug-related diabetes may develop in
patients on long-term steroids or thiazide
diuretics
Disease-related as in acromegaly,
Cushing's syndrome,
phaeochromocytoma, thyrotoxicosis,
pancreatitis, haemochromatosis, cystic
fibrosis, carcinoma or surgical removal of
the pancreas
Gestational: pregnancy may unmask
diabetes in a woman who is predisposed.
A full history and clinical examination are
essential to detect any of the causative
diseases and document the consequences.
PRESENTING FEATURES OF DIABETES

Patients with type 2 diabetes may

or may not have characteristic
features. The presence of obesity
or a strongly positive family
history for mild diabetes
suggests a high risk for the
development of type 2 diabetes.
DM Kendall et al. Eur J Intern Med 20, ( 2009) S329S339
Prin amabilitatea Prof. Dr. N. Hncu
Treatmentul DZ tip 2: inlocuirea deficitului
Obesitate IGT Diabet [necontrolat]

Postprandial
Glicemia
(mg/dl)
126
Fasting

insulinorezistenta
Functia
-celulara
(%)
100
Insulin Level

-20 -10 0 10 20 30
Diabetes duration (years)
Adapted from IDC, Minneapolis
 The Progression from CV Risk Factors to
Endothelial Injury and Clinical Events

LDL-C BP Risk factors Diabetes Smoking Heart failure

Oxidative stress

Endothelial dysfunction

NO Local mediators Tissue ACE-Ang II

Endothelium Growth factors Proteolysis

PAI-1 VCAM
matrix
ICAM cytokines

Thrombosis Inflammation Vasoconstriction Vascular lesion Plaque rupture

and remodelling

Clinical endpoints

NO Nitric oxide
Gibbons GH, Dzau VJ. N Engl J Med 1994;330;1431-1438.
 The Metabolic Syndrome and
Associated CVD Risk Factors
Hypertension

Abdominal obesity
Atherosclerosis
Hyperinsulinaemia
Insulin
Diabetes
Resistance
Hypercoagulability
Endothelial
Dyslipidaemia
high TGs
Dysfunction
small dense LDL
low HDL-C

Deedwania PC. Am J Med 1998;105(1A);1S-3S.

 NCEP ATP III: The Metabolic
Syndrome
Recommends a diagnosis when 3 of these risk factors are present

Risk Factor Defining Level

Abdominal obesity
(Waist circumference)
Men >102 cm (>40 in)
Women >88 cm (>35 in)
TG 150 mg/dL (1.7
HDL-C mmol/L)
Men <40 mg/dL (1.0
Women mmol/L)
Blood pressure <50 mg/dL
130/85 mm(1.3
Hg
mmol/L)
Fasting glucose 110 mg/dL (6.0
mmol/L)
NCEP, Adult Treatment Panel III, 2001. JAMA 2001:285;2486-2497.
WHO: The Metabolic Syndrome

A working definition is glucose intolerance, IGT or

diabetes mellitus and/or insulin resistance together
with two or more of the following:
Raised arterial pressure 160/90 mmHg
Raised plasma triglycerides (1.7 mmol/L, 150
mg/dL) and/or low HDL-C (men <0.9 mmol/L,
35 mg/dL; women <1.0 mmol/L, 39 mg/dL)
Central obesity
Microalbuminuria (UAER 20 g/min or
albumin: creatinine ratio 20 mg/g)

Alberti KGMM for the WHO. Diabet Med 1998:15;539-553.

 TREATMENT
Type 1 diabetes ONLY INSULIN is a
replacement therapy

Type 2 diabetes ORAL DRUGS+/-

INSULIN THERAPY
Human insulins do not closely match the
endogenous insulin response

Adapted from: Polonsky et al. J Clin Invest 1988;81:4428

Insulin analogues address the limitations of
human insulin

Adapted from: Polonsky et al. J Clin Invest 1988;81:4428

 Strategy for engineering analogue safety: the
importance of molecular design
The following important factors are always
considered when developing new insulin
analogues:
IGF-1 receptor affinity relative to human IR
affinity should not be higher than for human
insulin
Insulin dissociation/off-rate from the IR should
be similar to that of human insulin
The mitogenic/metabolic potency ratio should
IGF-1, insulin-like growth factor 1; IR, insulin receptor
not exceed 1
Potential sites for modification of
insulin

Kaarsholm and Ludvigsen. Receptor 1995;5:18

Molecular modifications of insulin
analogues

Kaarsholm and Ludvigsen. Receptor 1995;5:18

Pires and Chacra. Arq Bras Endocrinol Metabol 2008;52:26878
The structure of insulin detemir
monomer

Whittingham. Biochemistry 1997;36:2826

 Defining glucose variability
Hypoglycaemic events
Postprandial glucose excursions
Minor fluctuations in blood glucose levels

Monnier and Colette. Diabetes Care 2008;31(Suppl.2):S1504

 Nonglycemic effects of oral therapy
Cardiovascular Sulfonil Rapid- Metfor Thiazolidindi -
risk factor urea acting min ones glucosida
insulin se
secretago inhibitors
gues

Insulin resistance 0 0 0
Hyperinsulinemia 0 0
LDL chol levels 0 0 or 0 0
LDL particle pattern 0 0 ? Large buoyant 0
HDL chol levels 0 0 0 0
Triglycerides 0 0 0
LP (a) 0 0 0
PAI-1 0 0 0
Endothelial function 0 0 0
Body weight 0
Visceral adiposity ? 0 or 0

Modified fromHE Lebovitz, Endocrinol clin North Am, 2001, 30: 909-933
 Potential down-sides of pharmacological
treatment modalities in patients with T2DM
Potential problem Avoid or reconsider
Unwanted weight gain Sulphonylureas, glinides,
glitazones, insulin

Gastrointestinal symptoms Biguanides, alpha-glucosidase

inhibitors

Sulphonylureas, glinides,
Hypoglycemia
insulin

Impaired kidney function

Biguanides, sulphonylureas

Impaired liver function

Glinides, glitazones, biguanides,
alpha-glucosidase

Impaired cardio-pulmonary Biguanides, glitazones

function

ESC, EASD Guidelines, 2007

 Suggested policy for the selection of glucose-
lowering therapy according to the glucometabolic
situation

Post-prandial alpha-glucosidase inhibitors, short-

hyperglycemia acting SU, glinides, short-acting regular
insulin or insulin analogs

Fasting hyperglycemia Biguanides, long-acting SU, glitazones,

long-acting insulin or insulin analogs

Insulin resistance Biguanides, glitazones, alpha-

glucosidase inhibitors

Insulin deficiency SU, glinides, insulin

ESC, EASD Guidelines, 2007

 Revisit T2DM treatment strategies:
the evolving HbA1c position

Persistent HbA1c >7%

ACTION

Realistic target:
lowest HbA1c possible without
unacceptable hypoglycaemia

Healthy individual HbA1c 46%

Achieving and maintaining HbA1c at target may require

incremental and combination therapies
Treat-to-target concept

Adapted from Rosenstock J, Riddle MC. Chapter 9: Insulin therapy in type 2 diabetes. In: Cefalu
WT, Gerich JE, LeRoith D (eds). The CADRE Handbook of Diabetes Management. New York:
Medical Information Press; 2004:14568.
 Summary of antidiabetic interventions as
monotherapy
Interventions Expected Advantages Disadvantages
decrease
in A1c
(%)
Step 1: initial
Lifestyle to decrease weight 1-2 Low cost, many Fails for most in first year
and increase activity benefits GI side effects, rare lactic
Metformin 1.5 Weight neutral, acidosis
inexpensive
Step 2: additional therapy Injections, monitoring,
Insulin 1.5-2.5 No dose limit, hypoglycemia, weight gain
inexpensive,
improved lipid profile
Sulphonylureas 1.5 Inexpensive Weight gain, hypoglycemia
TZDs 0.5-1.4 Improved lipid Fluid retention, weight
profile gain, expensive
Other drugs
-glucosidase inhibitors 0.5-0.8 Weight neutral Frequent GI side effects,
expensive
Exenatide 0.5-1.0 Weight loss Injections, frequent GI side
effects, expensive, little
experience
Glinides 1-1.5 Short duration 3x/ day dosing, expensive
Pramlintide 0.5-1.0 Weight loss Injections, frequent GI side
effects, expensive, little
experience

A consensus statement from ADA and EASD. Diabetologia, 2006, 49: 1711-21
Strategii si algoritmuri
Algorithm for the metabolic management of T2DM
Diagnosis

Lifestyle intervention + metformin

HbA1C7
%

Add basal insulin Add sulfonylurea Add glitazone

-most efective -least expensive -no hypoglycamia

HbA1C7% HbA1C7% HbA1C7%

Intensify insulin Add glitazone Add basal insulin Add sulfonylurea

HbA1C7% HbA1C7%

Add basal or intensify insulin

Intensive insulin + metformin +/- glitazone

A consensus statement from ADA and EASD. Diabetologia, 2006, 49: 1711-21
 Management of hyperglycemia in type 2 diabetes
How do I establish and sustain glycemic control?

Lifestyle change: an

Q A
option?
Is metformin still the
first line drug?
&
Which drugs after
metformin?
Sulphonylureas, TZDs
or insulin?
And then? Three oral agents,
insulin as add-on or insulin alone?
What is the evidence for the
proposed algorithm?
Will new drugs be able to halt
the decline of beta-cell function?

RJ Heine et al. BMJ, 9 december 2006, 333: 1200-1204

 Contraindications can damage your healthis
metformin a case in point?
Standard contraindications to the use of metformin should be relaxed,
and that the benefits of reducing the number of patients excluded from
using it would by far outweigh the potential risks
propose removal of the following contraindications from the list:
1. old age
2. chronic renal insufficiency (as long as GFR>40 ml/min)
3. chronic heart failure (NYHA stages I and II)
4. discontinuation of metformin therapy 2 days before surgery
and i.v. contrast medium administration
A clear re-definition of metformin contraindications will enable more
physicians to prescribe within the guidelines
The main effect of revising these contraindications and precautions will
be to bring the official guidelines into harmony with day-to-day clinical
practice

A Holstein, M. Stumwoll. Doiabetologia, 2005, 48:2454-59

 Insulin

Oral agents
SIOFOR 1000

Chacra RA et al. Diabetes, Obesity, Metab, 2005, 7: 148-160

 GLP-1
SNC
Stomac
Cord Neuroprotecie
Apetitul
Cardioprotecie

Funcia cardiac
Evacuarea
Intestinul coninutului gastric

GLP-1
Ficat
Pancreas
Producia de
glucoz

Sensibilitate
Muchi la insulin Secreia de insulin

esut Secreia de glucagon

Sinteza de insulin
adipos
Proliferarea beta-celular
Preluarea i stocarea Apoptoza celulelor beta
glucozei

Baggio LL, Drucker DJ. Gastroenterology. 2007;132:2131-2157 Reprodus cu permisiune Elsevier 2007.
Efects ofGLP-1 in healthy
subjects

Eliberare de
insulin

Insulin
54
Exenatid is not inactivated by
DPP-4

Eliberare de
insulin

Insulin
55
The basal/bolus insulin concept

Basal insulin
Suppresses glucose production between
meals and overnight
40% to 50% of daily needs

Bolus insulin (mealtime)

Limits hyperglycaemia after meals
Immediate rise and sharp peak at 1 hour
10% to 20% of total daily insulin
requirement at each meal
Acute complications of
diabetes
Ketoacidosis
 Diabetic ketoacidosis (DKA)
is a potentially life-threatening
complication in patients with dm
It happens predominantly in those with
type1, but it can occur in those with type2
under certain circumstances.
results from a shortage of insulin; in
response the body switches to burning FFA
and producing acidic ketonic bodies that
cause most of the symptoms and
complications
 Causes
intercurrent illness
poor compliance with insulin therapy.
Vomiting, dehydration, deep gasping
breathing, confusion and occasionally
coma are typical symptoms.
DKA is diagnosed with blood and urine
tests; it is distinguished from other, rarer
forms of ketoacidosis by the presence of
high blood sugar levels.
 DKA is a medical emergency, and
without treatment it can lead to
death.
was first described in 1886; until the
introduction of insulin therapy in the
1920s it was almost universally fatal.
It now carries a mortality of less
than 5% with adequate and timely
treatment
 Signs and simptoms

nausea and vomiting,

pronounced thirst,
excessive urine production
abdominal pain that may be severe.
 Signs and simptoms

hyperglycemia (high blood sugar levels).

In severe DKA, breathing becomes labored
and of a deep, gasping character (a state
referred to as "Kussmaul respiration").
The abdomen may be tender to the point
that an acute abdomen may be suspected,
such as acute pancreatitis, appendicitis or
gastrointestinal perforation
Coffee ground vomiting (vomiting of
altered blood) occurs in a minority of
patients; this tends to originate from
erosion of the esophagus or gastric
mucosa.
 In severe DKA, there may be confusion,
lethargy, stupor or even coma (a marked
decrease in the level of consciousness).
On physical examination there is usually
clinical evidence of dehydration, such as a
dry mouth and decreased skin turgor.
The dehydration is profound enough to
cause a decrease in the circulating blood
volume, tachycardia (a fast heart rate)
and low blood pressure
 Often, a "ketotic" odor is present,
described as "fruity", often compared to
the smell of pear drops whose scent is a
ketone.
If Kussmaul respiration is present, this is
reflected in an increased respiratory rate.
Small children with DKA are relatively
prone to cerebral edema, which may
cause headache, coma, loss of the
pupillary light reflex, and progress to
death.
It occurs in 0.71.0% of children with
DKA, and has been described in young
adults, but is overall very rare in adults.
It carries a 20% mortality.
 Cause

intercurrent illness (pneumonia, influenza,

gastroenteritis, a urinary tract infection),
pregnancy,
inadequate insulin administration (e.g.
defective insulin pen device),
myocardial infarction (heart attack),
stroke
use of cocaine.
eating disorder, or may be using
insufficient insulin for fear that it will
cause weight gain
In 5% of cases, no cause for the DKA
 Mechanism
arises because of a lack of insulin in the
body.
The lack of insulin and corresponding
elevation of glucagon leads to increased
release of glucose by the liver (a process
that is normally suppressed by insulin)
from glycogen and through
gluconeogenesis.
High glucose levels spill over into the
urine, taking water and solutes (such as
sodium and potassium) along with it in a
process known as osmotic diuresis.
Ketones, too, participate in osmotic
diuresis and lead to further electrolyte
losses. This leads to polyuria, dehydration,
 Mechanism

The absence of insulin also leads to the

release of free fatty acids from adipose
tissue, which are converted, again in the
liver, into ketone bodies (acetoacetate and
-hydroxybutyrate).
-Hydroxybutyrate can serve as an energy
source in absence of insulin-mediated
glucose delivery, and is a protective
mechanism in case of starvation.
The ketone bodies, however, have a low
ph and therefore turn the blood acidic
(metabolic acidosis).
 Mechanism
The body initially buffers the change with
the bicarbonate buffering system, but this
system is quickly overwhelmed and other
mechanisms must work to compensate for
the acidosis.
One such mechanism is hyperventilation
to lower the blood carbon dioxide levels
(respiratory alkalosis). This
hyperventilation, in its extreme form, may
be observed as Kussmaul respiration.
In various situations such as infection,
insulin demands rise but are not matched
by the failing pancreas.
Blood sugars rise, dehydration ensues,
and resistance to the normal effects of
 Mechanism
the average adult DKA patient has a total
body water shortage of about 6 liters (or
100 mL/kg),
substantial shortages in sodium,
potassium, chloride, phosphate,
magnesium and calcium.
Glucose levels exceed 13.8 mmol/L or
250 mg/dL1
-hydroxybutyrate, despite chemically not
actually being a ketone, is the principal
"ketone body" in diabetic ketoacidosis.
In type 2 diabetes, insulin production is
present but is insufficient to meet the
 Mechanism
The clinical state of DKA is
associated, in addition to the above,
with the release of various
counterregulatory hormones such as
glucagon and adrenaline as well as
cytokines, the latter of which leads
to increased markers of
inflammation, even in the absence of
infection.
Complications -cerebral edema, which is the most
dangerous DKA complication

is the result from overvigorous fluid

replacement
dehydration,
acidosis
low carbon dioxide levels
the increased level of inflammation and
coagulation may, together with these
factors, lead to decreased blood flow to
parts of the brain, which then swells up
once fluid replacement has been
commenced
The swelling of brain tissue leads to raised
 Invvestigations
hyperglycemia (high blood sugars),
ketones in the blood or on urinalysis
acidosis
Arterial blood gas measurement is usually
performed to demonstrate the acidosis;
this requires taking a blood sample from
an artery. Subsequent measurements (to
ensure treatment is effective), may be
taken from a normal blood test taken from
a vein, as there is little difference between
the arterial and the venous pH
 urea and creatinine (measures of kidney
function, which may be impaired in DKA
as a result of dehydration) and
electrolytes.
markers of infection (complete blood
count, C-reactive protein)
acute pancreatitis (amylase and lipase)
chest radiography
urinalysis
computed tomography if cerebral edema is
suspected, may be performed to assess
its severity and to exclude other causes
such as stroke.
 Criteria
Diabetic ketoacidosis is distinguished from other diabetic
emergencies by the presence of large amounts of ketones
in blood and urine, and marked metabolic acidosis.
Hyperosmolar hyperglycemic state (HHS, sometimes
labeled "hyperosmolar non-ketotic state" or HONK) is much
more common in type 2 diabetes and features increased
plasma osmolarity (above 320 mosm/kg) due to profound
dehydration and concentration of the blood; mild acidosis
and ketonemia may occur in this state, but not to the
extent observed in DKA.
There is a degree of overlap between DKA and HHS, as in
DKA the osmolarity may also be increased, but in most
situations it is possible to classify a case into either DKA or
HHS.
2006 ADA statement (for adults) categorizes DKA
into one of three stages of severity:

Mild- blood pH mildly decreased to

between 7.25 and 7.30 (normal 7.35
7.45); serum bicarbonate decreased to
1518 mmol/l (normal above 20); the
patient is alert
Moderate-pH 7.007.25, bicarbonate 10
15, mild drowsiness may be present
Severe-pH below7.00, bicarbonate
below10,stupor or coma
 Prevention
Attacks of DKA can be prevented in known
diabetics to an extent by adherence to
"sick day rules"; these are clear-cut
instructions to patients on how to treat
themselves when unwell.
include advice on how much extra insulin
to take when sugar levels appear
uncontrolled,
an easily digestible diet rich in salt and
carbohydrates, means to suppress fever
and treat infection,
recommendations when to call for medical
help
 Management
The main aims in the treatment of diabetic
ketoacidosis are:
replacing the lost fluids and electrolytes

suppressing the high blood sugars and

ketone production with insulin.

admission to an intensive care unit or

similar high-dependency area or ward for

close observation may be necessary.
 Fluid replecement

The amount of fluid depends on the

estimated degree of dehydration.
1. If dehydration is so severe as to cause
shock (severely decreased blood
pressure with insufficient blood supply to
the body's organs), or a depressed level
of consciousness, rapid infusion of saline
(1 liter for adults, 10 ml/kg in repeated
doses for children)
2. Slower rehydration based on calculated
water and sodium shortage may be
possible if the dehydration is moderate,
and again saline is the recommended
 Insulin

Some guidelines recommend

1. a bolus (initial large dose) of insulin of
0.1 unit of insulin per kilogram of body
weight. This can be administered
immediately after the potassium level is
known to be higher than 3.3 mmol/l; if
the level is any lower, administering
insulin could lead to a dangerously low
potassium level
2. Other guidelines recommend delaying
the initiation of insulin until fluids have
been administered
 Insulin
insulin is given at 0.1 unit/kg per hour to
reduce the blood sugars and suppress
ketone production.
guidelines differ as to which dose to use
when blood sugar levels start falling;
some recommend reducing the dose of
insulin once glucose falls below
16.6 mmol/l (300 mg/dl)
other recommend infusing glucose in
addition to saline to allow for ongoing
infusion of higher doses of insulin
 Potassium
potassium levels can fluctuate severely during
the treatment of DKA, because insulin decreases
potassium levels in the blood by redistributing it
into cells.
a large part of the shifted extracellular potassium
would have been lost in urine because of osmotic
diuresis.
increases the risk of dangerous irregularities in
the heart rate.
continuous observation of the heart rate is
recomended, as well as repeated measurement of
the potassium levels and addition of potassium to
the intravenous fluids once levels fall below
5.3 mmol/l.
If potassium levels fall below 3.3 mmol/l, insulin
 Bicarbonat

The administration of sodium bicarbonate

solution to rapidly improve the acid levels
in the blood is controversial.
There is little evidence that it improves
outcomes beyond standard therapy, and
indeed some evidence that while it may
improve the acidity of the blood, it may
actually worsen acidity inside the body's
cells and increase the risk of certain
complications.
Its use is therefore disscouraged, although
some guidelines recommend it for
extreme acidosis (pH<6.9), and smaller
 Complications-Cerebral edema
Cerebral edema, if associated with coma,
often necessitates admission to intensive
care, artificial ventilation, and close
observation.
The administration of fluids is slowed.
The ideal treatment of cerebral edema in
DKA is not established, but intravenous
mannitol and hypertonic saline (3%) are
used, as in some other forms of cerebral
edema,in an attempt to reduce the
swelling.
Resolution of DKA is defined as general
improvement in the symptoms, such as

1. the ability to tolerate oral nutrition and fluids,

2. normalization of blood acidity (pH>7.3)
3. and absence of ketones in blood (<1 mmol/l) or
urine.
Once this has been achieved, insulin may be
switched to the usual subcutaneously
administred regimen, one hour after which the
intravenous administration can be discontinued
In patients with type 2 diabetes, determination
of antibodies against glutamic acid
decarboxylase and islet cells may aid in the
decision whether to continue insulin
 Hypoglycemia
Also called low blood glucose or low blood sugar,
occurs when blood glucose drops below normal
levels.
Carbohydrates are the main dietary source of
glucose. Rice, potatoes, bread, tortillas, cereal,
milk, fruit, and sweets are all carbohydrate-rich
foods.
After a meal, glucose is absorbed into the
bloodstream and carried to the body's cells.
Insulin helps the cells use glucose for energy. If a
person takes in more glucose than the body
needs at the time, the body stores the extra
glucose in the liver and muscles in a form called
glycogen.
The body can use glycogen for energy between
 Glucagon
When blood glucose begins to fall,
glucagon signals the liver to break down
glycogen and release glucose into the
bloodstream. Blood glucose will then rise
toward a normal level.
In some people with diabetes, this
glucagon response to hypoglycemia is
impaired and other hormones such as
epinephrine, also called adrenaline, may
raise the blood glucose level.
 Hypoglycemia can happen suddenly. It is
usually mild and can be treated quickly
and easily by eating or drinking a small
amount of glucose-rich food. If left
untreated, hypoglycemia can get worse
and cause confusion, clumsiness, or
fainting.
Severe hypoglycemia can lead to seizures,
coma, and even death.
In adults and children older than 10 years,
hypoglycemia is uncommon except as a
side effect of diabetes treatment.
Hypoglycemia can also result, however,
from other medications or diseases,
hormone or enzyme deficiencies, or
tumors.
 Hypoglycemia
intense hunger,
dizzy spells,
headaches,
irregular heartbeat and pulse,
pale skin,
profuse sweating
anxiety attacks
 Nocturnal hypoglycaemia
Hypoglycemia can also happen during
sleep. Some signs of hypoglycemia
during sleep include
1. crying out or having nightmares
2. finding pajamas or sheets damp from
perspiration
3. feeling tired, irritable, or confused after
waking up
 Reactive hypoglycemia -Fasting hypoglycemia

* Diabetes - hypos or hypoglycemic conditions

are caused by the treatments for diabetes rather
than diabetes itself.
* Pregnancy
* Fasting - Often extreme dieting or lengthy
periods without food bring about hyepoglycemic
symptoms.
* Strenuous exercise
* Alcoholism
* Insulinoma
* Hereditary enzyme deficiencies
* Hormone deficiencies
* Liver disease
* Hereditary fructose intolerance
* Galactosemia
* Growth hormone deficiency
* IGF-II producing tumors
 occur as a side effect of various
medications given to diabetics, usually
intended to treat high blood sugar by
lowering the bodys blood glucose levels.
Hypoglycemia happens when the medicine
intended to regulate blood sugar lowers
the bodys glucose levels too much
(probably as a result of wrong dosage or
improper administration)
Results in the bodys natural glucose-
regulating functions kicking in, forcing the
liver to release its glucose stores and for
other parts of the body such as the
hormones and the nervous system to
adjust to the changes, all of these are
happening too fast resulting in irregular
external effects.
 Hypoglycemia in diabetes may also occur
after taking too much insulin compared to
the amount of your carbohydrates intake,

Problems relating to a diabetics eating

habits can also cause hypoglycemia
attacks.
Referred to as Reactive Hypoglycemia, a
person who tends to miss meals, or does
not eat enough, or eats much later than
usual, may develop hypoglycemia.
It can also result from drinking alcohol on
an empty stomach, or eating a meal with
too much simple sugar (candies,
chocolates, pastries that have icing, and
snacks that contain dried sugar).
 How can hypoglycemia be prevented?

Their diabetes medications.

A health care provider can explain which
diabetes medications can cause
hypoglycemia and explain how and when
to take medications.
For good diabetes management, people
with diabetes should take diabetes
medications in the recommended doses at
the recommended times.
In some cases, health care providers may
suggest that patients learn how to adjust
medications to match changes in their
schedule or routine.
 Their meal plan. A registered dietitian can help
design a meal plan that fits one's personal
preferences and lifestyle. They should eat regular
meals, have enough food at each meal, and try
not to skip meals or snacks. Snacks are
particularly important for some people before
going to sleep or exercising.
Their daily activity. To help prevent
hypoglycemia caused by physical activity, health
care providers may advise
1. checking blood glucose before sports, exercise, or
other physical activity and having a snack if the
level is below 100 milligrams per deciliter
(mg/dL)
2. adjusting medication before physical activity
3. checking blood glucose at regular intervals during
extended periods of physical activity and having
snacks as needed
 Their use of alcoholic beverages.
Drinking alcoholic beverages, especially on
an empty stomach, can cause
hypoglycemia, even a day or two later.
Heavy drinking can be particularly
dangerous for people taking insulin or
medications that increase insulin
production. Alcoholic beverages should
always be consumed with a snack or meal
at the same time.
Their diabetes management plan.
Intensive diabetes management-keeping
blood glucose as close to the normal range
as possible to prevent long-term
complications-can increase the risk of
When people think their blood glucose is too low,
they should check the blood glucose level of a
blood sample using a meter. If the level is below
70 mg/dL, foods should be consumed right away
to raise blood glucose:
3 or 4 glucose tablets

1 serving of glucose gel-the amount equal to 15

grams of carbohydrate
1/2 cup, or 4 ounces, of any fruit juice

1/2 cup, or 4 ounces, of a regular-not diet-soft

drink
1 cup, or 8 ounces, of milk

5 or 6 pieces of hard candy

1 tablespoon of sugar or honey

The next step is to recheck blood glucose in 15

minutes to make sure it is 70 mg/dL or above. If
it's still too low, another serving of a quick-fix
 Severe hypoglycemia

very low blood glucose-can cause a person

to pass out and can even be life
threatening.
is more likely to occur in people with type
1 diabetes.
Another person can help someone who
has passed out by giving an injection of
glucagon. Glucagon will rapidly bring the
blood glucose level back to normal and
help the person regain consciousness.
Hypertonic glucose in i.v.perfusion
Never give oral glucose when the person
is uncouncious
 Hypoglycemia Unawareness
Some people with diabetes do not have early
warning signs of low blood glucose, a condition
called hypoglycemia unawareness. This condition
occurs most often in people with type 1 diabetes,
but it can also occur in people with type 2
diabetes.
People with hypoglycemia unawareness may need
to check their blood glucose level more often so
they know when hypoglycemia is about to occur.
They also may need a change in their
medications, meal plan, or physical activity
routine.
Hypoglycemia unawareness develops when
frequent episodes of hypoglycemia lead to
changes in how the body reacts to low blood
glucose levels. The body stops releasing the
hormone epinephrine and other stress hormones
when blood glucose drops too low.
 Epinephrine causes early warning
symptoms of hypoglycemia such as
shakiness, sweating, anxiety, and hunger.
Without the release of epinephrine and the
symptoms it causes, a person may not
realize that hypoglycemia is occurring and
may not take action to treat it.
A vicious cycle can occur in which frequent
hypoglycemia leads to hypoglycemia
unawareness and HAAF, which in turn
leads to even more severe and dangerous
hypoglycemia.
Health care providers may therefore
advise people who have had severe
hypoglycemia to aim for higher-than-usual
blood glucose targets for short-term
 Take home messages
When people with diabetes think their
blood glucose level is low, they should
check it and treat the problem right away.
To treat hypoglycemia, people should have
a serving of a quick-fix food, wait 15
minutes, and check their blood glucose
again. They should repeat the treatment
until their blood glucose is 70 mg/dL or
above.
People at risk for hypoglycemia should
keep quick-fix foods in the car, at work-
anywhere they spend time.
People at risk for hypoglycemia should be
careful when driving. They should check
their blood glucose frequently and snack
 Nonketotic hyperosmolar coma

is a type of diabetic coma associated

with a high mortality seen in
diabetes mellitus type 2.
 Signs and simptoms
The increasing hemoconcentration and
volume depletion may result in:
Hypervyscosity and increased risk of

thrombosis
Disordered mental functioning

Neurologic signs including focal signs such

as sensory or motor impairments or focal

seizures or motor abnormalities, including
flaccidity, depressed reflexes, tremors or
fasciculations
 Pathophysiology
is usually precipitated by an infection,
myocardial infarction, stroke or another
acute illness.
A relative insulin deficiency leads to a
serum glucose that is usually higher than
33 mmol/l (600 mg/dl), and a resulting
serum osmolarity that is greater than 320
mOsm.
This leads to polyuria (excessive urination,
an osmotic diuresis), which, in turn, leads
to volume depletion and
hemoconcentration that causes a further
increase in blood glucose level.
 Management
Begins with reestablishing tissue perfusion using
intravenous fluids. People with HHS can be
dehydrated by 8 to 12 l Attempts to correct this
usually take place over 24 hrs with initial rates of
normal saline or glucose 5% often in the range of
1 l/hr for the first few hours.
Severe potassium deficits, usually range around
350 mEq in a 70 kg person. This is generally
replaced at a rate 10 mEq per hour as long as
there is urinary output.
Insulin is given to reduce blood glucose
concentration; however, as it also causes the
movement of potassium into cells, serum
potassium levels must be sufficiently high or
dangerous hypokalemia may result. Once
potassium levels have been verified to be greater
Lactic acidosis-is a physiological condition
characterized by
low pH in body tissues and blood
(acidosis) Lactic acidosis is characterized
by lactate levels >5 mmol/L and serum pH
<7.35.
buildup of lactate especially D-lactate, and
is considered a distinct form of metabolic
acidosis.
The condition typically occurs when cells
receive too little oxygen (hypoxia), for
example, during vigorous exercise. In this
situation, impaired cellular respiration
leads to lower pH levels. Simultaneously,
cells are forced to metabolize glucose
anaerobically, which leads to lactate
formation. Therefore, elevated lactate is
 Pathophysiology
Most cells in the body normally
metabolize glucose to form water
and carbon dioxide in a two-step
process.
First, glucose is broken down to
pyruvate through glycolysis.
Then, mitochondria oxidize the
pyruvate into water and carbon
dioxide by means of the Krebs cycle
and oxidative phosphorylation. This
second step requires oxygen. The
net result is ATP, the energy carrier
 Pathophysiology
If oxygen supply is inadequate (hypoxia),
the mitochondria are unable to continue
ATP synthesis at a rate sufficient to supply
the cell with the required ATP.
In this situation, glycolysis is increased to
provide additional ATP, and the excess
pyruvate produced is converted into
lactate and released from the cell into the
bloodstream, where it accumulates over
time.
Signs and symptoms of lactic acidosis i
Nausea
Vomiting
Hyperventilation
Abdominal pain
Lethargy
Anemia
Hypotension
Tachycardia
 Therapy

Same like in hyperosmolar coma

More alkalin substance for severe
acidosis
 Polineuropathy

Diabetic neuropathies are neuropathic

disorders that are associated with diabetes
mellitus. result from diabetic
microvascular injury involving small blood
vessels that supply nerves (vasa
nervorum) in addition to macrovascular
conditions that can culminate in diabetic
neuropathy.
common conditions which may be
associated with diabetic neuropathy
include third nerve palsy;
mononeuropathy; mononeuropathy
multiplex; diabetic amyotrophy; a painful
polyneuropathy; autonomic neuropathy;
 Signs and symtoms

affects all peripheral nerves including pain fibers,

motor neurons and the autonomic nervous
system.
It can affect all organs and systems, as all are
innervated.
There are several distinct syndromes based upon
the organ systems and members affected, but
these are by no means exclusive.
A patient can have sensorimotor and autonomic
neuropathy or any other combination.
Symptoms vary depending on the nerve(s)
affected and may include symptoms other than
those listed. Symptoms usually develop gradually
 Symptoms
Numbness and tingling of extremities
Dysesthesia (abnormal sensation to
a body part
Diarrhea
Erectile dysfunction
Urinary incontinence (loss of bladder
control)
 Pathophysiology-1.Microangiopathy

Vascular and neural diseases are closely

related and intertwined.
The first pathological change in the
microvasculature is vasoconstriction.
capillary basement membrane thickening
and endothelial hyperplasia, which
contribute to diminished oxygen tension
and hypoxia.
Neuronal ischemia is a well-established
characteristic of diabetic neuropathy.
 Pathophysiology2.Advanced glycation end
product
Elevated intracellular levels of
glucose cause a non-enzymatic
covalent bonding with proteins,
which alters their structure and
inhibits their function.
Some of these glycosylated proteins
have been implicated in the
pathology of diabetic neuropathy and
other long term complications of
diabetes.
 Pathophysiology - 3.Protein kinase C

PKC is implicated in the pathology of

diabetic neuropathy.
Increased levels of glucose cause an
increase in intracellular
diacylglycerol, which activates PKC.
PKC inhibitors will increase nerve
conduction velocity by increasing
neuronal blood flow.
 Pathophysiology-4.Polyol pathway

Also called the sorbitol/aldose reductase pathway,

the polyol pathway may be implicated in diabetic
complications that result in microvascular
damage to nervous tissue, and also to the retina
and kidney.
Glucose is a highly reactive compound, and it
must be metabolized or it will find tissues in the
body to react with.
Increased glucose levels activates this alternative
biochemical pathway, which in turn causes a
decrease in glutathione and an increase in
reactive oxygen radicals.
The pathway is dependent on the enzyme aldose
reductase.
 Sensoriomotor polyneuropathy

Longer nerve fibers are affected to a greater

degree than shorter ones, because nerve
conduction velocity is slowed in proportion to a
nerve's length.
Dysesthesia and night time pain. The pain can
feel like burning, pricking sensation, achy or dull.
Pins and needles sensation is common.
Loss of proprioception, the sense of where a limb
is in space, is affected early.
Multiple fractures of the knee, ankle or foot, and
develop a Charcot joint.
Loss of motor function results in dorsiflexion,
contractures of the toes, loss of the interosseous
muscle function and leads to contraction of the
 Authonomic nervous system
is composed of nerves serving the heart,
lungs, blood vessels, bone, adipose tissue,
sweat glands, gastrointestinal system and
genitourinary system.
orthostatic hypotension, or fainting when
standing up.
loss of the usual change in heart rate seen
with normal breathing. These two findings
suggest autonomic neuropathy.
 Treatment
tricyclic antidepressants (TCAs), serotonin
reuptake inhibitors (SSRIs) and antiepileptic
drugs (AEDs). A systematic review concluded
that "tricyclic antidepressants and traditional
anticonvulsants are better for short term pain
relief than newer generation anticonvulsants.
A combination of these medication (gabapentin +
nortriptyline) may also be superior to a single
agent.
The only two drugs approved by the FDA for
diabetic peripheral neuropathy are the
antidepressant duloxetine and the anticonvulsant
pregabalin.
 Other therapies
-lipoic acid, and anti-oxidant that is a
non-prescription dietary supplement once-
daily oral doses of 600 mg to 1800 mg
Methylcobalamin, a specific form of
Vitamin B-12 found in spinal fluid, has
been studied and shown to have
significant effect, taken orally or injected,
in treating and improving diabetic
neuropathy.
Sativex, a cannabis based medicine has
not been found to be effective
 Diabetic nephropathy

known as Kimmelstiel-Wilson
syndrome, or nodular diabetic
glomerulosclerosis and intercapillary
glomerulonephritis, is a progressive
kidney disease caused by angiopathy of
capillaries in the kidney glomeruli.
It is characterized by nephrotic syndrome
and diffuse glomerulosclerosis.
It is due to longstanding diabetes mellitus,
and is a prime indication for dialysis in
many Western countries.
 Pathophysiology

The earliest detectable change in the

course of diabetic nephropathy is a
thickening in the glomerulus.
the kidney may leak more serum albumin
(plasma protein) than normal in the urine
(albuminuria),
As diabetic nephropathy progresses,
increasing numbers of glomeruli are
destroyed by progressive nodular
glomerulosclerosis. Urine albumin
increases to the point that it may be
detected by ordinary urinalysis
techniques. A kidney biopsy generally
clearly shows diabetic nephropathy.
 Signs
Kidney failure provoked by glomerulosclerosis
leads to fluid filtration deficits and other disorders
of kidney function.
Increase in blood pressure (hypertension) and
fluid retention in the body plus a reduced plasma
oncotic pressure causes edema
Other complications may be arteriosclerosis of
the renal artery and proteinuria.
Throughout its early course, diabetic nephropathy
has no symptoms. They develop in late stages
and may be a result of excretion of high amounts
of protein in the urine or due to renal failure:
 Treatment

slow the progression of kidney

damage and control related
complications.
ACE inhibitor drugs, which usually
reduces proteinuria levels and slows
the progression of diabetic
nephropathy.
angiotensin receptor blockers
(ARBs), have a similar benefit.
 Diabetic Arteriopathy

In diabetic population the incidence

of arteriopathy is 14% after 2 years
of diabetes,15% after 10 years and
45% after 20 years.
In particular ischemic ulcers and
gangrene are present in about 10%
of old diabetic people
 Characteristics
In addition to atherosclerotic changes,
the vessels of diabetic patients are
characterized by increased amounts of
connective tissue,such as fibronectin,
collagen, and glycoproteins, as well as
increased amounts of calcium in the
medial layer of the arterial wall, a
constellation named diabetic
macroangiopathy.
These changes lead to a loss of elasticity
of the arterial wall.
 Diabetes rethinopathy
It is an ocular manifestation of systemic
disease which affects up to 80% of all
patients who have had diabetes for 10
years or more.1 Despite these intimidating
statistics, research indicates that at least
90% of these new cases could be reduced
if there was proper and vigilant treatment
and monitoring of the eyes.2 The longer a
person has diabetes, the higher his or her
chances of developing diabetic
retinopathy.3
 Often has no early warning signs.
Macular edema which may cause vision loss more
rapidly, may not have any warning signs for some
time.
As new blood vessels form at the back of the eye
as a part of proliferative diabetic retinopathy
(PDR), they can bleed (ocular hemorrhage) and
blur vision.
In most cases, it will leave just a few specks of
blood, or spots, floating in a person's visual field,
though the spots often go away after a few
hours.
These spots are often followed within a few days
or weeks by a much greater leakage of blood,
which blurs vision.
It may take the blood anywhere from a few days
Pathogenesis-is the result of microvascular
retinal changes. -
Hyperglycemia-induced intramural
pericyte death and thickening of the
basement membrane lead to
incompetence of the vascular walls.
These damages change the formation of
the blood-retinal barrier and also make
the retinal blood vessels become more
permeable.4
The pericyte death is caused when
"hyperglycemia persistently activates
protein kinase mitogen-activated protein
kinase
This signaling cascade leads to PDGF
receptor- dephosphorylation and a
reduction in downstream signaling from
 Pathogenesis
As the disease progresses, severe
nonproliferative diabetic retinopathy enters an
advanced, or proliferative, stage when blood
vessels proliferate
The lack of oxygen in the retina causes fragile,
new, blood vessels to grow along the retina and
in the clear, gel-like vitreous humour that fills the
inside of the eye.
Fibrovascular proliferation can also cause
tractional retinal detachment. The new blood
vessels can also grow into the angle of the
anterior chamber of the eye and cause
neovascular glaucoma.
Nonproliferative diabetic retinopathy shows up as
cotton wool spots, or microvascular abnormalities
or as superficial retinal hemorrhages. Even so,
 Eye examination
Visual acuity test: This test uses an eye
chart to measure how well a person sees
at various distances
Pupil dilation: The eye care professional
places drops into the eye to widen the
pupil.
Ophthalmoscopy

(1) looks through a slit lamp biomicroscope

with a special magnifying lens that
provides a narrow view of the retina,
(2) wearing a headset (indirect
ophthalmoscope) with a bright light, looks
through a special magnifying glass and
gains a wide view of the retina. Hand-held
ophthalmoscopy is insufficient to rule
 Management

laser surgery,
injection of corticosteroids or Anti-
VEGF into the eye,
vitrctomy.