INSULIN

INSULIN

1. DR NILESH KATE
MBBS,MD
ASSOCIATE PROF
ESIC MEDICAL COLLEGE, GULBARGA.
DEPT. OF PHYSIOLOGY
INSULIN.

2. 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

3. 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.
Saturday, March 14, 2015

4. 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.
Saturday, March 14, 2015

5. Insulin.
Firsts to its credits.
1
st
hormone to be isolated, purified, crystallized &
synthesized.
1
st
protein to possess hormonal activity.
1
st
protein sequence for amino acids to determine the
structure.
1
st
protein estimated by RIA (Radio Immuno Assay)
1
st
protein synthesized by Recombinant DNA
technology.
Saturday, March 14, 2015

6. 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.
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7. Biosynthesis.
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8. Mechanism of insulin
secretion.
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9. Mechanism of insulin
secretion.
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10. 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.
Saturday, March 14, 2015

11. Regulation of secretion.
Role of exogenous nutrients.
Role of gastrointestinal & other hormones.
Role of sympathetic & parasympathetic
nervous system.
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12. Role of exogenous nutrients.
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13. ROLE OF BLOOD GLUCOSE.
EFFECT OF BSL ON INSULIN BIPHASIC INSULIN
SECRETION
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14. Role of Amino Acids
Induces secretion of insulin, particularly
after protein rich meal.
Most potent – Arginine & Lysine.
Moderate – Leucine, Alanine.
Saturday, March 14, 2015

15. 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.
Saturday, March 14, 2015

16. Role of sympathetic &
parasympathetic nervous system.
Sympathetic .
Rise in blood sugar
level.
So insulin release
decreased
Glucagon release
increased.
Parasympathetic .
Insulin secretion
increased.
Saturday, March 14, 2015

17. 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.
Saturday, March 14, 2015

18. Circulation & Degradation.
Circulates unbound to any carrier protein.
Half life – 5-18 min.
Metabolic clearance rate – 1000 ml/min.
“Insulinase” -- Degrade , break disulphide
chains
Saturday, March 14, 2015

19. 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.
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20. STEPS IN MECHANISM OF
ACTION.
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21. STEPS IN MECHANISM OF
ACTION.
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22. Actions of Insulin.
Metabolic effect.
Ion transport.
Role in cell growth & development.
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23. 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.
Saturday, March 14, 2015

24. 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)
Saturday, March 14, 2015

25. Carbohydrate metabolism
In Adipose tissue.
Increase Glucose
uptake (translocating
Glut-4)
Storage as
Triglycerides.
Converted to FA.
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26. Lipid metabolism
Increases Lipogenesis.
Decrease Lypolysis.
Reducing ketogenesis.
Saturday, March 14, 2015

27. Protein metabolism.
Stimulate protein
synthesis.
By increasing transport
into cell.
Translation of
messenger RNA.
Transcription.
Inhibit protein
degradation.
Inhibit proteolysis.
Saturday, March 14, 2015

28. Ion transport.
Increases.
K,PO4, Mg uptake
So insulin effect
causes – Hypokalemia,
Saturday, March 14, 2015

29. 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.
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30. Applied aspects.
Diabetes mellitus.
Hypoglycemia.
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31. Diabetes mellitus.
Diabetes – A clinical syndrome of
hyperglycemia due to deficiency of Insulin.
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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.

32. 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.
Saturday, March 14, 2015

33. 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.
Saturday, March 14, 2015

34. 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 (HbA
1c
)
Tissue proteins – Diabetic Nephropathy, D. Neuropathy,
D. Retinopathy.
Saturday, March 14, 2015

35. 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
Saturday, March 14, 2015

36. 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.
Saturday, March 14, 2015

37. Clinical features
Cardinal symptoms –
Polyuria, Polyphagia,
polydipsia, wt loss.
Biochemical –
Hyperglycemia,
Glycosuria, ketosis,
ketonuria,
Ketoacidosis.
Saturday, March 14, 2015

38. 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.
Saturday, March 14, 2015

39. 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)
Saturday, March 14, 2015

40. 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
Saturday, March 14, 2015

41. 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.
Saturday, March 14, 2015

42. 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.
Saturday, March 14, 2015

43. Hypoglycemia.
Blood Glucose level
below 45 mg %.
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44. 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.
Saturday, March 14, 2015

45. Hypoglycemia signs &
symptoms.
CNS
Neuroglycopenic symptoms –
tremors, hallucinations,
extreme nervousness,
convulsions, drowsiness.
CVS
Palpitation, tachycardia,
arrhythmias
GIT – Nausea & vomiting.
SKIN– sweating,
hypothermia.
Saturday, March 14, 2015

46. Thank
You