insulin
TRANSCRIPT
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.
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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.
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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.
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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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Biosynthesis.
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Mechanism of insulin secretion.
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Mechanism of insulin secretion.
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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.
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Regulation of secretion. Role of exogenous nutrients. Role of gastrointestinal & other hormones. Role of sympathetic & parasympathetic
nervous system.
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Role of exogenous nutrients.
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ROLE OF BLOOD GLUCOSE.EFFECT OF BSL ON INSULIN BIPHASIC INSULIN
SECRETION
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Role of Amino Acids Induces secretion of insulin, particularly
after protein rich meal. Most potent – Arginine & Lysine. Moderate – Leucine, Alanine.
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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.
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Role of sympathetic & parasympathetic nervous system. Sympathetic .
Rise in blood sugar level.
So insulin release decreased
Glucagon release increased.
Parasympathetic . Insulin secretion
increased.
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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.
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Circulation & Degradation. Circulates unbound to any carrier protein. Half life – 5-18 min. Metabolic clearance rate – 1000 ml/min. “Insulinase” -- Degrade , break disulphide
chains
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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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STEPS IN MECHANISM OF ACTION.
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STEPS IN MECHANISM OF ACTION.
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Actions of Insulin. Metabolic effect. Ion transport. Role in cell growth & development.
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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.
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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)
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Carbohydrate metabolism In Adipose tissue.
Increase Glucose uptake (translocating Glut-4)
Storage as Triglycerides.
Converted to FA.
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Lipid metabolism Increases Lipogenesis. Decrease Lypolysis. Reducing ketogenesis.
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Protein metabolism. Stimulate protein
synthesis. By increasing transport
into cell. Translation of
messenger RNA. Transcription.
Inhibit protein degradation. Inhibit proteolysis.
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Ion transport. Increases.
K,PO4, Mg uptake
So insulin effect causes – Hypokalemia,
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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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Applied aspects. Diabetes mellitus. Hypoglycemia.
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Diabetes mellitus. Diabetes – A clinical syndrome of
hyperglycemia due to deficiency of Insulin.
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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.
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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.
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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.
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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
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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.
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Clinical features Cardinal symptoms –
Polyuria, Polyphagia, polydipsia, wt loss.
Biochemical – Hyperglycemia, Glycosuria, ketosis, ketonuria, Ketoacidosis.
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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.
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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)
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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
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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.
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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.
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Hypoglycemia. Blood Glucose level
below 45 mg %.
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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.
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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
Thank You