DIABETES MELLITUS

Dr. Ashok Kumar J

Department of Biochemistry

Management and Science University

Malaysia

Islet cell structure

cell : glucagon cell : insulincell : somatostatin

cell

cell

cell

Type 1 Type 2

Heterogeneous group of syndromes characterized

by an elevated plasma glucose caused by

relative or absolute deficiency of INSULIN

Diabetes Mellitus

Classification of Diabetes Mellitus

by Etiology

Type 1 -cell destructioncomplete 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

(frequent urination)

Polydipsia (Excessive

thirst)

Polyphagia (Excessive

hunger)

Polyuria

Uptake of glucose by the extra-hepatic

tissues is decreased

Hyperglycemia

Glucose is osmotically active

Urine volume is increased

Polyuria

PolydipsiaExcess loss of water

Osmolality of blood

increases

Stimulates thirst center in

hypothalamusOther Symptoms:Polyphagia

recurrent infection

Diabetes Mellitus

Type 1 Type 2

Age of onset Usually during

childhood or puberty

Symptoms develop

rapidly

Frequently after

the age of 35

Symptoms

develop

gradually

Nutritional

status at the

time of disease

onset

Frequently

undernourished

Obesity usually

present

Type 1 Type 2

Prevalence 10% of the

diagnosed

cases

90% of the

diagnoses cases

Genetic

predisposition

Moderate Very strong

Defect or

deficiency

cells are destroyed

Insulin resistance

combined with

inability of cells to produce appropriate

quantities of insulin

Type 1 Type 2

Frequency of

Ketosis

Common Rare

Plasma insulin Low to absent High early in

disease; low in

disease of long

duration

Acute

complications

Ketoacidosis Hyperosmolar

state

Type 1 Type 2

Treatment

with oral

hypoglycemic

drugs

Unresponsive Responsive

Treatment Insulin is

always

necessary

Diet, exercise, oral

hypoglycemic

drugs; insulin may

or may not be

necessary

Type 1

Absolute deficiency of insulin

Autoimmune attack on the cells of pancreas

cell destruction requires both a stimulus from the environment (such as viral infection)

Type 2 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

Symptoms appear abruptly when 80 to 90%

of the cells are destroyed

Among the monozygotic twins

if one sibling develops type 1 diabetes mellitus

chance of the other twin developing diabetes mellitus

is only 30 to 50%

but

incase of type 2 diabetes mellitus both individuals

develop disease

Insulin resistance

Decrease ability of the target tissue to

respond properly to normal circulating

concentration of insulin

Insulin resistance and obesity:

Most common cause

In the absence of defect in the cells function, nondiabetic obese individuals compensate for

insulin resistance with elevated levels of insulin

Most of the individuals with obesity and insulin resistance

do not become diabetic

Insulin secretion is higher in obese subjects than it is

in lean individuals

Insulin resistance

Hyperinsulinemia

Impaired glucose tolerance

Decline of beta cell function

Type 2 diabetes

Genetics,

Obesity,

Sedentary lifestyle

Aging

+

Genetis

Glucose toxiity

Free fatty acids

+

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

Triglyceride

Fatty Acids

Glycerol

Albumin

adipose

tissue

Fatty

Acids

liver

Fatty Acids

Fatty

Acids

albumin

Acetyl Co A

-oxidation

Energy for the Brain and

Extrahepatic tissues

TCA

Cycle

Hormone

Sensitive

Lipase

Glucagon

Epinephrine

Glucocortic-

oids

+

1

3

2

Fatty Acids

mitochondria

Dr. Ashok Kumar;Professor;

Department of Biochemistry

Ketone

Bodies

21

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

Hyperglycemia

Neuropathy

Peripheral Autonomic

Biology of

Microvascular Complications

Retinopathy

Cataract

Glaucoma

Nephropathy

Microalbuminuria Gross albuminuria

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 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 bodymay 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)