Diabetes Mellitus

Diabetes Mellitus

Dr. Rohini C.Sane

• Diabetes Mellitus : Insulin deficiency or decreased response of target organs to insulin results in this disease

BIOCHEMICAL ASPECTS OF INSULIN

YEAR INVENTION NOBLE LOREATE

1869 Alpha &Beta cells of Pancreas Langerhans

1922 Isolation of pure form Banting

1926 Crystallization Abel

1954 Amino acid sequence Sanger

1962 Humulin—insulin synthesized by

recombinant DNA technology

Pancreatic cells secreting Hormones

Pancreatic cells Hormone secreted

Alpha glucagon

Beta insulin

D Somatostatin

F Pancreatic polypeptide

BIOCHEMICAL ASPECTS OF INSULIN

Synthesis by Beta pancreatic cells

Gene located on Chromosome 11

Synthesis Pre-pro insulin form(153 AA),MW 11500,Single

polypeptide chain

Pro-insulin 86AA

Insulin51 AA (Di-peptide)+ C –Peptide

Molecular weight 5734

Total number of amino acids present in molecule 51

Polypeptide chains (alpha chain ,beta chain ) 2

Total number of amino acids in Alpha chain 21

Total number of amino acids in Beta chain 30

Interchange di-sulphide bridges Location:(6 AA of alpha 7 AA of beta )&

(11 AA of alpha 10AA of beta)

Storage form in beta pancreatic cells Zn complex of insulin—secretion by exocytosis

Poly peptide hormone synthesized in precursor from Pre pro insulin.

Pre pro insulin ( molecular weight 11500 )

Pro insulin ( molecular weight 9000 )

Insulin ( molecular weight 5734 )

Major metabolic effect of Insulin on cells is removal of sugar, amino acids , & fatty acids for anabolic use .

Diabetes Mellitus is syndrome ( a complex group of metabolic symptoms ) in which there is accumulation of Glucose ,fatty acids, ketone bodies & amino acids in blood for the want of Insulin.

Symptoms of Diabetes Mellitus

• Polyuria –frequency & volume urine increases (5-6lts /day) This leads to dehydration .Cause of Polyuria is high concentration of glucose in urine-called as Glycosuria

• Polydipsia –increased Thirst

• Polyphagia –increased appetite/ hunger

• Yet there is Loss of body weight (utilization of body protein, mobilization of fat )

• slow healing of wounds

• Insulin can drastically cure Diabetes.

Biochemistry of Diabetes Mellitus

• Blood glucose is too high due to deficiency of available insulin,(decrease production ,decrease action ,increase in counter hormone )

• In absence of Insulin ,glucose cannot freely enter muscle ,and adipose cells ( Insulin is not necessary for uptake of Glucose by Liver & brain cells leads to Hyperglycemia

• Hyperglycemia Blood glucose >130mg/dl (1HR after 100gm of glucose in DM )

• Insulin secretion—non /inadequate—>Diabetes Mellitus

• No glucose weakness ,tiredness

• Utilization of proteins –blood urea increases

• Ketosis –increase in fatty acid oxidation—increased Acetyl CoA increased cholesterol

• KETO ACIDOSIS Beta Hydroxy Butyric acid , Acetoacetic acid decrease in plasma bicarbonate -loss of sodium diabetic coma

• Insulin production by pancreas –normal but requirement increases due to obesity Diabetes Mellitus

Biochemical changes due to decrease insulin levels

Hyperglycemia :

1. Decrease glucose uptake decrease glycolysis

2. Tissue protein degradation muscle wasting increase plasma Glucogenic amino acids

3. Glycogenolysis increases &glycogen synthesis decreases

4. Gluconeogenesis increase ( low insulin/glucagon ratio )

GLYCOSURIA

Major metabolic alterations in Diabetes Mellitus –Lipid metabolism

• LIPOLYSIS –Diabetes Mellitus ,increase in plasma free fatty acids concentration

• Increased lipolysis in adipose tissue high plasma fatty acids. This is the major source of energy in diabetic patients.

• Thus Respiratory Quotient is 0.8 ( RQ =CO ₂ produced / Oxygen consumed )

• Hypercholesterolemia(increase Acetyl CoA by beta oxidation in liver not further oxidized in TCA cycle for want of Oxaloacetate which is normally is formed from carbohydrate )

• increase under utilized Acetyl CoA HEPATIC KETOGENESIS KETONEMIA( large amount of ketone bodies in blood )

• KETOACIDOSIS( two ketone bodies beta hydroxy Butyric acids , Aceto acetic acids are strong acids ),

• KETONURIA( excretion of ketone bodies in urine )

• Increase in free fatty acids increase in TG synthesis ,Hyper-Triglyceridemia increase in VLDL

• Hyperlipedemia (HMP shunt increases increase in NADPH & fatty acid synthesis

• Enzyme lipoprotein lipase low increase of Triacylglycerol Increase in VLDL chylomicrons concentration increases

• Secretion of VLDL, increase in chylomicrons

Major metabolic alterations in Diabetes Mellitus –Protein metabolism

• Increased protein catabolism liberates amino acids which by gluconeogenesis form glucose .

• This is also lost from body .

• Nitrogen is lost as urea.

Complications of Diabetes Mellitus

1. Atherosclerosis

2. Retinopathy

3. Nephropathy

4. Neuropathy

5. Micro-vascular changes Glycation of proteins

6. Coma & Death ( untreated diabetic )

Diabetic retinopathy

Diabetes Neuropathy

ATHEROSCLEROSIS

DIAGNOSTIC CRITERIA FOR DIABETIS MELLITUS

NORMAL INDIVIDUAL CRITERIA FOR DIAGNOSIS OF DM

FASTING <110 mg/dl (<6.1 mmol / lt ) >126 mg/dl (> 7.0 mmol / lt )

1 hr after 1gm /Kg Glucose

intake

< 160 mg/dl (<9 mmol /lt ) Not specified

2 hr after 1gm /Kg Glucose

intake

< 140 mg/dl (<7.8 mmol/lt ) >200 mg/dl (> 11.7 mmol / lt )

A decreased tolerance is seen in diabetes Mellitus in oral Glucose Tolerance test .( GTT )

CRITERIA INSULIN DEPENDENT DM

IDDM –TYPE I

INSULIN DEPENDENT DM

NIDDM –TYPE II

Onset Juvenile onset Elderly onset ( maturity onset )

Undetected for years

Prevalence 10-20% of Diabetic population 80-90% of diabetic population

Age of onset Childhood <20yrs Predominantly adults >40yrs

Remain undetected for long ,slow

development

Body weight Normal or low ( thin & wasted in appearance ) Obese(overeating /underactivity)

Genetic disposition Mild /moderate Very strong

Increase resistance to insulin activity

Decrease receptors on insulin target cells

( Down- regulation-lack of sensitivity to

Insulin)

Biochemical defect Insulin deficiency due to destruction of beta

Pancreatic cells

Impairment in production of insulin by

beta cells & resistance of target cell to

insulin

CRITERIA INSULIN DEPENDENT DM

IDDM –TYPE I

INSULIN DEPENDENT DM

NIDDM -TYPEII

Plasma insulin Decreased /absent Normal or increased

Auto antibodies Frequently found/drug induced Rare

Ketosis Very common Rare

Acute complications Ketoacidosis Hyper osmolar coma

Clinical duration of symptoms Weeks Months/ years

Oral hypoglycemic drugs Not useful Suitable for treatment

Administration of insulin Continuous administration of Insulin

always required

Usually not necessary

Biochemical indices of Diabetes Mellitus• Blood glucose estimation

• Urine glucose

• Glycated haemoglobin post transcription (non enzymatic sugar)-addition of sugar to Hb Valine of Beta chain of Hb

• Rate of synthesis of Hb A1 C α blood glucose

• Remains in RBC for 120days therefore indicates blood glucose over 120days

• Normal concentration of Hb A1 C 3-5% of total Hb

• Monitoring of Diabetic control

• Risk of retinopathy /renal complication increases with increase elevated Glycated Hb

• False positive with Thalassemia patients as HbF elution along with Hb A1C

• Low Hb A1 C with hemolytic anemia eg HbS, HbC (retention in HPLC column )

Biochemical indices of Diabetes Mellitus

Estimation of blood glucose by glucometer

*

*

*

*slight variation in values based on a technique employed *

MANAGEMENT OF DIABETES MELLITUS

DIETARY MANAGEMENT

1. Balanced diet

2. Low calorie intake

3. Low carbohydrate /complex sugars/starch

4. low saturated fat intake

5. High protein diet

6. Fiber rich food

7. Adequate PUFA

8. Supplementation of minerals /vitamins

EXERCISE

HYPOGLYCEMIC DRUGS –SULFONYL UREAS eg Tolbutamide /Glibenclamide (increase in insulin secretion in TypeIIDM ) &

BIGUANIDES eg Phenoformin (decrease glucose by increased uptake/ absorption & increased in glucose excretion )

INSULINSHORT ACTING -6hrs unmodified

LONG ACTING –several hours modified absorbed on protamine

Genetic engineering


FOOD RICH IN MINRALS ,VITAMINS & FIBERS


Exercise- Walking/ swimming for 30 minutes



Diabetic bracelet


Insulin synthesized by genetic engineering

now available for treatment of DM

Genetic Engineering –future treatment for DM

Gene therapy for Type I DM ?

Health & Medicine

Diabetes Mellitus