insulin

DR NILESH KATE

MBBS,MDASSOCIATE PROF

ESIC MEDICAL COLLEGE, GULBARGA. DEPT. OF PHYSIOLOGY

INSULIN.

OBJECTIVES Endocrine Pancreas Structure & synthesis. Secretion. Regulation of secretion. Plasma levels, circulation,

degradation. Mechanism of action. Actions of insulin. Applied aspects.

Saturday, March 14, 2015

Endocrine pancreas. Functional anatomy. Islets of Langerhans. (1

million) Cellular structure

(2500) Alpha (20%) – Glucagon Beta (60-70%) – Insulin. Delta (10%) – Somatostatin. PP cells – Pancreatic

peptide.


Endocrine pancreas. Gap junctions – link

between cells. Vascular arrangements.

– arteriole to capillaries to venules. Bath each cell with insulin for local effect.

Strategic location -- for local effect on exocrine part of pancreas.


Insulin. Firsts to its credits.

1st hormone to be isolated, purified, crystallized & synthesized.

1st protein to possess hormonal activity. 1st protein sequence for amino acids to determine the

structure. 1st protein estimated by RIA (Radio Immuno Assay) 1st protein synthesized by Recombinant DNA

technology.


Structure Protein (51 AA) 2 polypeptide chain

A (21 AA) B (30 AA) Connected by interchain

disulphide linkage to A7-B7,A20-B19, & A6-11.

IF 2 chains break apart functional activity lost.


Biosynthesis.


Mechanism of insulin secretion.


Mechanism of insulin secretion.

By Glucagon. By stimulator G protein

via cyclic AMP.

By Somatostatin. By inhibitor G protein

via cyclic AMP.

By Acetylcholine. By G protein linked

Phospholipase C by producing

Phospahtidyl Inositol & Diacyl Glycerol.


Regulation of secretion. Role of exogenous nutrients. Role of gastrointestinal & other hormones. Role of sympathetic & parasympathetic

nervous system.


Role of exogenous nutrients.


ROLE OF BLOOD GLUCOSE.EFFECT OF BSL ON INSULIN BIPHASIC INSULIN

SECRETION


Role of Amino Acids Induces secretion of insulin, particularly

after protein rich meal. Most potent – Arginine & Lysine. Moderate – Leucine, Alanine.


Role of Gastrointestinal & other Hormones.

GIT Hormones – enhances

Other hormones – Growth hormone, cortisol, glucagon, progesterone & estrogen.

Burning out –Prolonged secretion of other hormone causes use of Islets of Langerhans leads to DM.


Role of sympathetic & parasympathetic nervous system. Sympathetic .

Rise in blood sugar level.

So insulin release decreased

Glucagon release increased.

Parasympathetic . Insulin secretion

increased.


Plasma levels. Basal level – 10 μU/ml. After meal –

Increases 3 -10 times. After 30 -60 min.

Daily Secretion 0.5 -1.25 units/hr. Peripheral delivery 30

units. Without 1st pass

metabolism secretion – 2.5 units/hr.


Circulation & Degradation. Circulates unbound to any carrier protein. Half life – 5-18 min. Metabolic clearance rate – 1000 ml/min. “Insulinase” -- Degrade , break disulphide

chains


Mechanism of action. Insulin receptors.(2-3

L) Protein kinase

receptors. Structure.

Alpha (α) – outer surface.

Beta (β) – across plasma membrane, have tyrosine kinase domain.


STEPS IN MECHANISM OF ACTION.


Actions of Insulin. Metabolic effect. Ion transport. Role in cell growth & development.


Metabolic effect. Carbohydrate

metabolism.(Decreases blood Glucose levels.) Increase glucose uptake Promote Glucose

utilization. – Glycolysis & Glycogen formation.

Decrease Glucose production. – Gluconeogenesis & Glycogenolysis.

Insulin Dependent uptake – muscles, adipose tissue, WBC & mammary glands.

Insulin Independent – nervous tissue, kidney, RBC, retina, blood vessels, intestinal mucosa.


Carbohydrate metabolism In liver.

Increase glucose uptake – by increasing Glucokinase.

Glycogen synthesis – by Glycogen synthase enzyme.

Glycolysis – by phosphofructokinase & pyruvate kinase.

Decrease Glycogenolysis & Gluconeogenesis.

In muscles. Increase Glucose

uptake (Glut -4) Increase Glycolysis.

(Pyruvate Dehydrogenase)

Increase Glycogen synthesis. (Glycogen synthase)


Carbohydrate metabolism In Adipose tissue.

Increase Glucose uptake (translocating Glut-4)

Storage as Triglycerides.

Converted to FA.


Lipid metabolism Increases Lipogenesis. Decrease Lypolysis. Reducing ketogenesis.


Protein metabolism. Stimulate protein

synthesis. By increasing transport

into cell. Translation of

messenger RNA. Transcription.

Inhibit protein degradation. Inhibit proteolysis.


Ion transport. Increases.

K,PO4, Mg uptake

So insulin effect causes – Hypokalemia,


Role in cell growth & development.

Anabolic action. Direct stimulatory effect

on macromolecules. – cartilage & bone

Stimulation of other growth factors. – Somatomedins (IGF 1&2), Epidermal growth factor (EGF), Nerve growth factor (NGF), Relaxin.


Applied aspects. Diabetes mellitus. Hypoglycemia.


Diabetes mellitus. Diabetes – A clinical syndrome of

hyperglycemia due to deficiency of Insulin.


TYPES . PRIMARY DM – cause not known.

IDDMNIDDM

SECONDARY DM – due to Pathological conditions, pancreatitis, cystic fibrosis, Acromegaly, Cushing syndrome etc.

STAGES.•PRE-DIABETICS or Potential diabetics. – Genetic predisposition.•Latent diabetics or chemical diabetics – normal F& PP BSL but increased after stress.• Clinical diabetics – C/F without complications.• Complicated diabetics.

IDDM & NIDDM.FEATURES IDDM NIDDM

DEFECT β cell destruction.– insulin def.

Resistance of target tissue.

Prevalence 10-20 % 80-90%

Age of onset < 40 yrs > 40 yrs.

Body wt Low High

Gene focus Chromosome 6 Chromosome 1

Family history Mild/moderate Strong.

Acute complication Ketoacidosis Hyperosmolar coma.

Plasma insulin Decreased or absent Normal

Ketonuria Present Absent

Treatment Insulin Oral hypoglymic.

Mortality High Low.


Pathophysiology of DM. Hyperglycemia. –

Due to decreased peripheral utilization. Increased hepatic output of glucose.

Hypertriglyceridaemia, ketosis . Less utilization turns it to FFA Excess FFA leads to formation of TG & Ketoacidosis.

Protein catabolism. Insulin --- Anabolic hormone. Promote protein synthesis & inhibit proteolysis.


Hyperglycemia. Glycosuria. –

Glucose in urine above 180 mg/100ml. Polyuria (osmotic diuresis), loss of electrolyte, cellular

dehydration, polydipsia, increased caloric loss, Polyphagia, loss of body weight.

Impaired Phagocytic function. Hyperosmolar effect. (above 375 mOsm/kg) Glycosylation of proteins.

Hemoglobin (HbA1c ) Tissue proteins – Diabetic Nephropathy, D. Neuropathy,

D. Retinopathy.


Hypertriglyceridaemia, Ketosis .

Hypertriglyceridaemia – glucose converted to FFA

FFA to TG. Increase secretion of

VLDL & chylomicrons. Leads to

Hypercholesterolemia.

Ketosis . Cellular dehydration. Ketoacidosis.

Dyspnoea, Kussmaul breathing.

Breath acetone smell. Electrolyte loss Hypovolaemia &

hypotension. Coma & death


Protein catabolism. Protein catabolism increased & anabolism

suppressed. Protein depletion. Muscle wasting. Negative nitrogen balance. Released large amount of amino acids

Used for energy production. Substrate for enhanced gluconeogenesis.


Clinical features Cardinal symptoms –

Polyuria, Polyphagia, polydipsia, wt loss.

Biochemical – Hyperglycemia, Glycosuria, ketosis, ketonuria, Ketoacidosis.


Complications. Predisposition to

infection. – Phagocytic function, protein depletion

Acute complication – ketotic coma, Non-ketotic Hyperosmolar coma.

Chronic complication.– atherosclerosis., Hyperlipidemia, hypercholesterolemia,

Microangiopathy – D. retinopathy, nephropathy, neuropathy.


Diagnosis. Urine examination for Glycosuria. – exclude

renal Glycosuria. Urine examination for ketone bodies. – other

causes starvation, fasting, high fat diet, repeated vomiting.

Blood glucose levels – fasting (70-120 mg%) & postprandial (120-180mg%)

Glucose tolerance tests (GTT)


Glucose tolerance tests (GTT)

Prior test normal carbohydrate diet for 3 days.

Early morning fasting BSL & urine taken.

75 mg glucose dissolve in 300 ml of water given orally.

BSL & urine tested ½ hrly for next 3 hrs.

Plasma glucose conc. (mg%)NORMAL IMPAIRED

GLUCOSE TOLERAAN

CE

DM

Fasting level.

< 110 110-126

≥ 126.

Peak post

prandial level.

< 140 >140-< 200

≥ 200


Management of Diabetes Mellitus.

Goals of therapy. Maintain blood glucose to normal. Maintain ideal body weight. Symptoms free. Retard or prevent complications.

Treatment modalities. Dietary management. Oral hypoglycemic agents. Insulin along with dietary management.


Treatment modalities. Dietary management.

Low energy wt reducing diet (for obese NIDDM)

Wt maintenance diet (Non obese NIDDM) Frequent small meals.

Oral hypoglycemic agents. Sulphonylurea Biguanides.

Insulin along with dietary management. For IDDM. For new Ketoacidosis. Emergencies with IDDM & NIDDM.


Hypoglycemia. Blood Glucose level

below 45 mg %.


Types & causes of Hypoglycemia.

Hypoglycemia in non- diabetics. Postprandial hypoglycemia.

(Reactive) Post-absorption or fasting

hypoglycemia. – insulin secreting tumors leading to hyperinsulinaemia.

Hepatic failure. Due to alcohol intake. – due

to decreased Gluconeogenesis.

Hypoglycemia in Diabetics. Overdose of anti-

diabetic drugs. No intake. Mismatch between

insulin & food habits. Alcohol intake.


Hypoglycemia signs & symptoms.

CNS Neuroglycopenic symptoms –

tremors, hallucinations, extreme nervousness, convulsions, drowsiness.

CVS Palpitation, tachycardia,

arrhythmias

GIT – Nausea & vomiting. SKIN– sweating,

hypothermia.


Thank You

insulin

Health & Medicine

mechanism of insulin

actions of insulin

insulin receptors

regulation of secretion

prolonged secretion

role of blood glucose

role of gastrointestinal

mechanism of action