Download - Diabetes mellitus Biochemistry By Dr. Ashok KUmar Jeppu

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DIABETES MELLITUS

Dr. Ashok Kumar J

Department of Biochemistry

Management and Science University

Malaysia

Islet cell structure

α cell : glucagon

β cell : insulin

δcell : somatostatin

α cell

β cell

δcell

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 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

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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

β cells are

destroyed

Insulin resistance

combined with

inability of βcells 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 βcells of pancreas

Βcell 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 βcells 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 βcells 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 ketosisDiabetic 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 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 1 (insulin-dependent) diabetes mellitus. David

immediately started taking injectable 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

The Miracle

of Insulin

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 lot of water

(polydipsia)?

4. David takes his insulin parenterally (by

subcutaneous injection). Why can’t he

take insulin orally?

Ans: Insulin is destroyed by the proteolytic

enzymes of GIT if given 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.

1. Name ketone bodies.

2. How did insulin deficiency lead to the

finding of ketones in blood and urine?

3. What are the long term complications of

diabetes mellitus

4. What is the biochemical basis behind

cataract developed I diabetic patients

• Thank you