DIABETES MELLITUS

Dr. Ashok Kumar J

 Islet cell structure
α cell : glucagon
β cell : insulin
δcell : somatostatin

δcell

α cell

β cell
 Diabetes Mellitus

Heterogeneous group of syndromes characterized

by an elevated plasma glucose caused by
relative or absolute deficiency of INSULIN

Type I Type II
 Classification of Diabetes Mellitus
by Etiology
Type 1 -cell destruction—complete lack of
insulin
Type 2 -cell dysfunction and insulin
resistance

Gestational -cell dysfunction and insulin

resistance during pregnancy

Other specific types • Genetic defects of -cell function

• Exocrine pancreatic diseases
• Endocrinopathies
• Drug- or chemical-induced
• Other rare forms
11
Diabetes Mellitus
 Polyuria
Uptake of glucose by
the extra-hepatic
tissues is decreased

Hyperglycemia

Glucose is osmotically active

Urine volume is increased
Polyuria
 Polydipsia

Other Symptoms:
Polyphagia
recurrent infection
 Diabetes Mellitus

Type I Type II
Age of onset Usually during Frequently after
childhood or puberty the age of 35
Symptoms develop Symptoms
rapidly develop
gradually
Nutritional Frequently Obesity usually
status at the undernourished present
time of disease
onset
 Type I Type II

Prevalence 10% of the 90% of the

diagnosed diagnoses cases
cases
Genetic Moderate Very strong
predisposition
Defect or β cells are Insulin resistance
deficiency destroyed combined with
inability of βcells to
produce appropriate
quantities of insulin
 Type I Type II

Frequency of Common Rare

Ketosis
Plasma insulin Low to absent High early in
disease; low in
disease of long
duration
Acute Ketoacidosis Hyperosmolar
complications state
 Type I Type II

Treatment Unresponsive Responsive

with oral
hypoglycemic
drugs
Treatment Insulin is Diet, exercise, oral
always hypoglycemic
necessary drugs; insulin may
or may not be
necessary
 Type I
Absolute deficiency of insulin
Autoimmune attack on the βcells of pancreas

Βcell destruction requires both a stimulus from

the environment (such as viral infection)
and
A genetic determinant that allows the βcell to be
recognized as ‘nonself’
 Type II Diabetes mellitus
• Most common form of the disease

• Often detected by routine screening tests

• Symptoms of polyuria and polydipsia of several

weeks duration

• Polyphagia may be present but less common

 Among the monozygotic twins
if one sibling develops type I diabetes mellitus
chance of the other twin developing diabetes mellitus
is only 30 to 50%
but
incase of type II diabetes mellitus both individuals
develop disease

Symptoms appear abruptly when 80 to 90%

of the βcells are destroyed
 Insulin resistance
Decrease ability of the target tissue to
respond properly to normal circulating
concentration of insulin

Insulin resistance and obesity:

Most common cause
Most of the individuals with obesity and
insulin resistance
do not become diabetic

In the absence of defect in the βcells function,

nondiabetic obese individuals compensate for
insulin resistance with elevated levels of insulin

Insulin secretion is higher

in obese subjects than it is
in lean individuals
 +
Insulin resistance
Genetics,
Obesity,
Sedentary lifestyle
Aging
Hyperinsulinemia

Impaired glucose tolerance

Genetis
+
Glucose toxiity
Decline of beta cell function
Free fatty acids

Type 2 diabetes
 Metabolic changes
• Due to deficiency of insulin
• Profoundly affect three tissues
Liver
Muscle
Adipose tissue
Hyperglycemia and ketoacidosis
•Elevated levels of blood glucose and ketones are
hallmarks of untreated diabetes mellitus
Hyperglycemia and ketoacidosis
Increased hepatic production and diminished
peripheral utilization of glucose –
hyperglycemia

Increased mobilization of fatty acids – ketone

body production and ketosis
Diabetic ketoacidosis occurs in
25 to 40% of those newly
diagnosed type I cases
 adipose liver
tissue
Fatty Fatty Acids
Triglyceride Acids
albumin
2 mitochondria

Glucagon
1 Fatty Acids
Epinephrine Hormone
Glucocortic-
oids
Sensitive
Lipase Albumin -oxidation 3
+ Acetyl Co A
Glycerol
TCA
Cycle
Fatty Acids Fatty
Acids Ketone
Bodies

Dr. Ashok Kumar;Professor; Energy for the Brain and 21

Department of Biochemistry Extrahepatic tissues
 American Diabetes Association
Criteria for diabetic ketoacidosis
GLUCOSE > 250 mg/dl
ANION GAP > 10 mEq/L
BICARBONATE < 18 mEq/ L
pH < 7.3
Urine ketone bodies +ve
 Biology of
Microvascular Complications
Hyperglycemia

Retinopathy Nephropathy Neuropathy

Cataract – Microalbuminuria – Peripheral
Glaucoma – Gross albuminuria – Autonomic

Blindness Kidney failure Amputation

Death and/or disability

 Retinopathy
RETINA

NORMAL DIABETES
 Cataract

Glucose

Sorbitol

Osmotic damage of the tissue

Opacity of the lens of the eye

(CATARAT)
Diabetic Foot
 Hypertriglyceridemia

Hypercholesterolemiaemia
 Laboratory investigation
• Blood Glucose level
• Complete lipid profile
• Blood urea and creatinine
• Microalbuminuria
• Glycated hemoglobin (HbA1c)
 Diagnosis
Oral glucose tolerance test

Test done to assess the ability of

an individual to handle excess
amount of glucose
 Preparation of the patient
• Performed at least 3 days of unrestricted
diet (>150gm carbohydrate/day) and usual
physical activity.
• Reasonable carbohydrate containing meal
(30 to 40 grams) to be consumed on the
evening before the test
• Overnight fasting (8 to 12 hours)
• Smoking is not permitted during the test
 Test procedure
• Collect the fasting blood and Urine sample
• Weigh 75 g of anhydrous glucose or 82.5
gms of glucose monohydrate
• For children 1.75gms of glucose per kg
body weight
• Dissolve glucose in about 200 ml of water
• Ask the patient to drink this glucose
solution
• After giving the glucose load collect blood
and urine sample every half an hour for
about 2 ½ Hour
• Estimate the glucose present in the blood
sample and analyze the urine sample to
detect the presence of glucose
Interpretation
 Diagnostic Criteria for Diabetes Mellitus

1. If the fasting plasma glucose is more than

126 mg/dl, on more than one occasion.
2. Or, if 2 hr post-glucose load value of OGTT is
more than 200 mg/dl (even at one occasion).
3. Or, if both fasting and 2 hr values are above
these levels, on the same occasion.
4. If the random plasma glucose level is more than
200 mg/dl, on more than one occasion.
Diagnosis should not be based on a single
random test alone; it should be repeated.
OGTT Graph
 Glycated Hemoglobin

• When there is hyperglycemia, proteins in the body

may undergo glycation
• When glucose is attached to hemoglobin,
glucose is not removed from hemoglobin.
[ remains inside the erythrocyte, throughout the
life span of RBCs (120 days)]
• HbA1c - where glucose is attached to the N-
terminal valine of beta chain of hemoglobin
• Hb A1c level
reveals the mean glucose level over the
previous 10-12 weeks

Used for monitoring the response to treatment

1.Normal Level of is 5.5% ( very good control)
2.Adequate control 7%
3.Inadequate control 8%
4.Very poor control 9%

The estimation should be done at least every 3

months in all diabetic patients
Used for Diagnosis of diabetes mellitus
HbA1c level more than 6.5% at any occasion
person can be considered diabetic

(Recommendations of Associaation of clinical

chemistry and American Diabetes Association)
 Fructoseamine
• Glycated albumin
• Half life of albumin is 20 days
• It reflects the glycemic control over the
past 2 to 3 weeks
 Microalbumin
(Presence of albumin in the urine 30 to 300mg/dl)

Kimmelsteil –Wilson syndrome

• Complication of diabetes resulting from
nephrosclerosis
• Characterized by proteinuria and renal
failure
• Glycation of basement membrane protein
may be the cause for nephropathy
 CASE 1
Hyperglycemia: Type I Diabetes Mellitus

David Mandel was diagnosed with type I (insulin-dependent)

diabetes mellitus when he was 12 years old . At the time of his
diagnosis, David was in middle school.
He was constantly thirsty and was urinating every 30 to 40 min.
Furthermore, despite a voracious appetite, he seemed to be
losing weight.
David’s parents panicked because they knew that these were
classic symptoms of diabetes mellitus. They took David to see
his pediatrician immediately.
The pediatrician performed a physical examination and ordered
laboratory tests
Height 5 ft, 3 in
Weight 100 lb (decreased 5 lb from his annual
checkup 2 months earlier)
Fasting plasma glucose 320 mg/dL (normal, 70–110
mg/dL)
Plasma ketones + (normal, none)
Urinary glucose + (normal, none)
Urinary ketones + (normal, none)
All of the findings were consistent with a diagnosis of type I
(insulin-dependent) diabetes mellitus. David immediately
started taking injectable insulin.

The Miracle
of Insulin

He excelled in high school and won a scholarship to the

state university, where he is currently a premedical student
and is planning a career in pediatric endocrinology. He has
periodic checkups with his endocrinologist, who closely
monitors his renal function
Questions

1. How did insulin deficiency lead to an increase in

David’s blood glucose concentration?

2. Why did David have glucose in his urine

(glucosuria)?

3. Why did David have increased urine production

(polyuria)? Why was he drinking so much
(polydipsia)?
4. David takes his insulin parenterally (by
subcutaneous injection). Why can’t he
take insulin orally?

5. The endocrinologist closely monitors

David’s renal function. What is the major
nephrologic complication of type I diabetes
mellitus?
6.What is Glycated hemoglobin ?

7. What is the normal level of Glycated hemoglobin ?

8. What is the significance of glycated hemoglobin

estimation ?
 Case 2
The following plasma values of a 21 year old male
diabetic who presented with diabetic ketoacidosis.
He was treated immediately with intravenous
normal saline and an insulin infusion of
appropriately of 2.0 units / hour. After 2 hours,
when the plasma potassium fell to 3.0 mmol/L KCL
was added to the infusion
 On admis.. 6 Hrs after 16 Hrs Normal
Treat after Tret
Na 132 142 138 132- 144
K 6.5 3.6 4.1 3.2 – 4.8
Cl 89 110 108 98 – 108
HCO3 6 10 24 23 – 33
Creatinine 0.30 0.27 0.13 0.06 – 0.12
Anion gap 43 26 10 7 – 17
Glucose 63 26 6.6 3.5 – 6.4
3-hydroxyl 14.2 7.6 0.45 <0.20
butyrate
Aceto - 52 4.3 0,41 <0.02
- acetate
PO4 3.5 1.85 0.20 0.65 – 1.25
1. Name ketone bodies.

2. How did insulin deficiency lead to the

finding of ketones in blood and urine?

3. Why potassium level decreased during

treatment ?

4. Why insulin and glucose infusion is given

during treatment of diabetic ketosis ?
• Thank you
 Symptoms of diabetes mellitus
1. Excessive thirst (=> polydipsia)
2. Frequent urination (polyuria)
3. Excretion of large amounts of glucose in the urine
(glucosuria)
4. Excessive but incomplete oxidation of FAs in the liver
Overproduction of ketonebodies (ketosis)
– Acetone, B-hydroxybutyrate
– Increase of ketonebodies in the blood (ketoanemia)
– Increase of ketonebodies in the urine (ketouria)
5. Lowering of blood pH (ketoacidosis)
R9224
 Biology of
Microvascular Complications
Hyperglycemia
Eye Kidney Nerves

Retinopathy Nephropathy Neuropathy

Cataract – Microalbuminuria – Peripheral
Glaucoma – Gross albuminuria – Autonomic

Blindness Kidney failure Amputation

Death and/or disability

 Biology of
Macrovascular Complications
Small artery Coronary
arterioscleros artery
is atherosclerosi
s

www.urmc.rochester.edu/neuroslides
www.urmc.rochester.edu/neuroslides
 Biology of
Macrovascular Complications
Metabolic injury to large
vessels

Heart Brain Extremities

Coronary artery disease Cerebrovascular disease Peripheral vascular

– Coronary syndrome – TIA disease
– MI – CVA – Ulceration
– CHF – Cognitive impairment – Gangrene
– Amputation
 Two Mechanisms of Tissue Injury
by Hyperglycemia

Glycation Hyperglycemia Sorbitol

pathway pathway

Advanced glycation
Glycated proteins Sorbitol and fructose
end products (AGEs)
(eg, A1C)

Altered function Receptor-mediated Osmotic Oxidative

or turnover cytokine effects effects effects

Brownlee M. Metabolism. 2000;49(suppl 1):9-13; Greene DA et al. N Engl J Med.

1987;316:599-606; Sheetz MJ, King GL. JAMA. 2002;288:2579-2588 4
Sorbitol pathway
• Increased fructose leads to: osmotic
changes; non-enzymic fructosylation
and AGE (via 3-deoxyglucasone)
• Decreased NADPH/NADP+ leads to:
alteration in redox state(decreased
ability to deal with oxidative stress);
increased activity of pentose phosphate
shunt (PPP)
• Increased NADH/NAD+ leads to:
increased activity of PPP
• Increased triose phosphate
intermediates leads to increased second
messenger diacylglycerol (DAG) and,
thus, Protein Kinase C activity.
• Increase PKC activity leads to a wide
variety of changes (see later)
• Arachidonate in DAG may be a substrate
for the synthesis of eicosanoids
including prostaglandins, prostacyclins,
AGE
• Maillard reaction
‘browning’ of food
described in 1912
• Non-enzymatic
glycation of amines
AGE
Free radicals in DM - ‘Oxidative
stress’
• Increased production e.g. by auto-
oxidation of glucose, superoxide
production from mitochondrial oxidation of
NADH to NAD+
• Decreased clearance via action of
catalase or glutathione peroxidase.
Regeneration of reduced glutathione
requires NADPH, levels of which are
decreased (in tissues containing aldose
reductase)