INSULIN

DR NILESH KATE
MBBS,MD
ASSOCIATE 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.
IDDM
NIDDM
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
prandi
al 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.

INSULIN

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