PANCREAS

Dr Parvathy S
• Exocrine pancreas : acini

• Endocrine pancreas : Islets of Langerhans.

• 1 million islet cells : 1 - 2% pancreatic tissue.

 Islet cells

• Beta cells (About 3/4th) : — INSULIN, C peptide, Amylin.

• Alpha cells (20%). :— GLUCAGON.
• Delta cells (10%). :— SOMATOSTATIN
• F cells :— PANCREATIC POLYPEPTIDE
INSULIN
• 1st hormone isolated from animal sources.

• 1st hormone to have its structure determined.

• 1st hormone measured by RIA.

• 1st hormone to be synthesised by

recombinant DNA TECHNOLOGY.
BANTING & BEST
Nobel Prize - 1924.
 Structure of insulin

• Polypeptide hormone; 2 chains : A chain & B chain.

• A : 21 AA; B : 30 AA.
• Linked : disulphide linkages.
 Synthesis

• Insulin gene : chromosome 11.

• PREPROINSULIN - precursor.
• PROINSULIN + signal peptide.
• Endoplasmic reticulum -> Golgi bodies.
• Secretory granules -> INSULIN + C peptide.
• Stimulation :- secretory granules release : Insulin & C
peptide.

• C peptide assay : test for β cell function.

• DM patients receiving exogenous insulin injection.

• Metabolism - liver & kidney.

• Enzyme : insulinase.

• t1/2 : 5 minutes.
MECHANISM OF ACTION
 INSULIN RECEPTOR

• Tetramer : 4 subunits.
• 2 alpha subunits : extracellular
• 2 beta subunits : transmembrane.
 Insulin binds to α subunit

Autophosphorylation of β subunits

Activation of tyrosine kinase

Phosphorylation of IRS

Genetic effects
Mobilisation of
glucose transporters
Muscle cells
Adipose cells Increase in Phosphorylation of
Membrane permeability Metabolic Enzymes
(AA, K , PO4)
+
Actions of insulin
• Metabolic actions

• Action on cell membrane : ion transport.

• Role in growth & development.

 Metabolic effects

• Hormone of abundance.

• Target organs : liver, muscle & adipose tissue.

• Promotes glucose uptake : muscles, adipose tissue.

• Non-insulin dependant glucose transport : nervous tissue,

kidney, RBC, retina.
• Effect on carbohydrate metabolism :

• Increase glucose uptake : glucose transporters (GLUT4).

• Increase glucose utilisation : Glycolysis, Glycogen synthesis.

• Decrease glucose production : inhibits Gluconeogenesis,

Glycogenolysis.
• Effect on lipid metabolism :
• Lipogenesis : hepatic synthesis of fats & cholesterol.

• Adipose tissue : activates lipoprotein lipase enzyme.

• Inhibits hormone sensitive lipase.

• Reduce ketogenesis.

• Increased utilisation of LDL & VLDL :- triglyceride

synthesis.
• Effect on protein metabolism : ANABOLIC hormone.

• Increase protein synthesis

• Increased AA uptake.

• Decreased AA utilisation (gluconeogenesis)

• Increase mRNA translation.

• Decrease proteolysis.
 ACTIONS ON MEMBRANE
• Increases K +transport into skeletal muscle cells &
hepatocytes.

• Other ions : PO4- , Mg 2 +

• Renal reabsorption of K ,
+ PO4 ,
- Na+ increases.
 Role in growth
• Direct action :
• Anabolic action.
• Synergistic action with GH.

• Indirect action : stimulates synthesis of Somatomedins

(IGF -1, IGF-2).
Stimuli for secretion
• BLOOD GLUCOSE Level.

• Daily secretion of insulin = 40 units/day.

• Normal plasma insulin level = 0.70 μU/mL.

• Amino acids : Arginine, Lysine (potentiating action).

• GI hormones : gastrin, secretin, CCK, GLP-1, GIP.

• INCRETINs : enhance rate of insulin release from beta

cells.
• GLP-1 : Glucagon like Peptide-1
• GIP : Glucose-dependent Insulinotropic Peptide.
Regulation of insulin
secretion
 Biphasic response
• On rise in blood glucose levels;
• Immediate pulse of Insulin
• 10 fold increase in 3-5 min
• release of stored insulin.
• Second phase -
• 15 min later;
• slower prolonged rise :
• synthesis of new insulin molecules.
 NSILA

• Non Suppressible Insulin-Like Activity.

• Present after pancreatectomy, anti-insulin antibodies.
• Mediated by IGF-I & IGF-II.
GLUCAGON
 Glucagon

• Alpha islet cells.

• Hormone of Starvation.
 Structure & synthesis

• Single straight chain; 29 AA.

• Preproglucagon - precursor form.
• Stored in dense granules of α islet cells.
 MECHANISM of action

• Cell membrane GPCR receptor.

• cAMP pathway.
 Actions of glucagon

• Mobilization & utilisation of stored nutrients.

• Goal : maintain blood glucose levels in starvation.
• Target organ : liver.
 Metabolic actions

• Major effects :
• Stimulate Glycogenolysis (inhibit glycogen synthesis)
• Increase Gluconeogenesis
• Both increase blood glucose level : Hyperglycaemic
hormone.
• Other effects :

• Lipid metabolism -
• Activates hormone sensitive lipase :- increase lipolysis.
• Increase Fatty acid release -> energy production.
• Increase ketogenesis.

• Increase amino acid uptake by liver - lower plasma levels.

 Other actions

• Increase cardiac force of contraction (large dose).

• Stimulate secretion of growth hormone, insulin,
somatostatin.
• Enhance bile & decrease gastric acid secretion.
• CNS - regulation of appetite.
 Regulation of secretion

• Blood glucose level decrease : most potent factor.

• Amino acids: arginine, alanine.
• Cholecystokinin
• Fasting
• Intense Exercise
• Inhibitory factors
• High blood glucose
• Free fatty acids
• Keto acids.
Somatostatin
 Pancreatic somatostatin

• Delta cells of pancreas

• 14 AA polypeptide.
• t 1/2 : 3 min.
• Stimuli :
• All nutrients (glucose, fatty acids, amino acids)
• GI hormones
• Glucagon
• β agonists
 Actions

• Inhibits secretion :- insulin & glucagon.

• Decrease motility of stomach, duodenum, gall bladder.
• Decrease secretion & absorption in GIT.
PANCREATIC POLYPEPTIDE
 Actions

• Linear polypeptide - 36 AAs :- F cells.

• Related to Polypeptide YY (git) & neuropeptide Y (brain).
• Stimuli : protein meal, fasting, exercise, hypoglycaemia.
• Action : slows absorption.
APPLIED PHYSIOLOGY
• DIABETES MELLITUS

• HYPOGLYCEMIA
DIABETES MELLITUS
 Definition
• Syndrome of impaired carbohydrate, fat & protein
metabolism.

• Due to :
• Lack of insulin secretion
• Decreased sensitivity of tissues to insulin.
 Types

• Type 1/ insulin-dependant DM (IDDM) : insulin

de ciency.

• Type 2/ Non-insulin-dependant DM (NIDDM) : insulin

resistance.
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 Type I dm

• Cause : autoimmune/ viral infection mediated

destruction of β cells.
• JUVENILE DM - age of onset before 40.
• Rapid onset.
• Symptoms appear : >80% of β cells are destroyed.
 Type ii dm
• Cause : down regulation/ insensitivity of insulin
receptors.
• More common
• Associated with obesity.
• Age of onset - 50 to 60 yr : ADULT ONSET
DIABETES.
 LACK of insulin effects

• Decreased peripheral glucose uptake.

• Increased glucose release into plasma (Gluconeogenesis,
Glycogenolysis).
• Increased lipolysis.
• Increased protein breakdown.
• Increased Glucagon release.
• STARVATION IN THE MIDST OF PLENTY.
• Renal Glycosuria.
• Urinary loss of Na & K.
 Signs & symptoms

• Cardinal symptom triad :

• POLYURIA
• POLYDIPSIA
• POLYPHAGIA
WHY POLYURIA?
Hyperglycaemia

Increased renal glucose ltration

Glucosuria

Increased urine osmolarity

OSMOTIC DIURESIS
Increased tubular water secretion

Frequent urination;
increased urine volume.
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 WHY POLYDIPSIA?
Excess water loss in urine

Cellular dehydration

Reduced ECF volume

Increased ECF osmolarity

Stimulation of Hypothalamic Thirst Centre

Increased thirst
 WHY POLYPHAGIA?
Lack of insulin

Cellular entry of glucose prevented

Glucoreceptors in
Hypothalamus

Inhibition of Satiety Centre Stimulation of Feeding centre

Increased hunger
• Other symptoms :
• Protein depletion & muscle weakness.
• Weight loss.
• Hyperlipidemia.
• Ketoacidosis.
 Complications

• Excess glucose :- converted to SORBITOL.

• Deposition in eyes (lens) :- Cataract.

• Non-enzymatic glycosylation of proteins (hemoglobin,
albumin, collagen)

• Diabetic Nephropathy;
• Diabetic Retinopathy;
• Diabetic Neuropathy.
• Increased plasma free fatty acids :- ketone body synthesis.
• Acetyl CoA, Acetoacetic acid, β hydroxy butyric acid
• Diabetic Ketoacidosis.
• Kussmaul breathing.
• Acidic urine :- H, Na, K loss in urine.
• Severe cellular Dehydration :- Hypotension.
• Coma in DM :

• KETOACIDOTIC COMA (due to acidosis)

• HYPEROSMOLAR COMA (due to cerebral
cellular dehydration)
• Lack of insulin :- increased plasma cholesterol.
• Increased LDL, VLDL.
• ATHEROSCLEROSIS,
• HYPERTENSION &
• CAD.
 Diagnosis

• Normal fasting blood glucose : 70 - 110 mg/dl.

• 1. FBS > 126mg/dl; PPBS > 200 mg/dl.
• 2. OGTT (oral glucose tolerance test).
• 3. HbA1C (plasma glycated hemoglobin)
 Treatment

• Insulin : treatment of choice in IDDM.

• Oral Hypoglycaemia Agents (OHA) : NIDDM.
• SULPHONYL UREAS : glipizide, tolbutamide.
• BIGUANIDES : metformin.
• Lifestyle modi cations (diet, exercise).
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 HYPOGLYCEMIA

• Reduction in blood glucose level below normal range

(70-110 mg/dL).
• CAUSES
• Overdose of insulin/oral hypoglycaemic drugs in
diabetics.
• Insulinomas.
• Severe exercise in Diabetics on insulin.
• SIGNS & SYMPTOMS
• Fatigue, irritability, confusion.
• Headache, anxiety, tachycardia, sweating.
• Persistent cases : coma & death.
• TREATMENT
• Glucose replacement - oral.
• IV Dextrose.
 METABOLIC SYNDROME/
syndrome x
• Cluster of
• Obesity (abdominal fat accumulation)
• Insulin resistance
• Fasting hyperglycaemia
• Lipid abnormalities (increased TG & reduced HDL)
• Hypertension.
 Theories

• Role of white adipose tissue as endocrine organ.

• Hormones : LEPTIN, ADIPONECTIN, RESISTIN.
• Leptin & Adiponectin : decrease insulin resistance.
• Resistin : increase insulin resistance.
• Leptin : satiety hormone.
• Mutation :- obesity.
• Role of stress :
• Stress induces release of CRH, ACTH & Cortisol
release.
• Allostasis : process of maintaining homeostasis.
• Chronic stress :- sustained hypercortisolemia.
• Hyperglycaemia, increased visceral fat, hypertension,
hyperlipidemia, change in immune response.
• Psychiatry & Metabolic Syndrome
• Major Depressive Disorder
• Schizophrenia
• Anxiety Disorder
• Bipolar Disorder
• PTSD.
Previous questions
• The most abundant cell type in the islets of Langerhans is
……………………
• Describe the mechanism of action of insulin and its functions. Add a
note on clinical signs and symptoms of diabetes mellitus. Explain
glucose tolerance test curve.
• Mention all the hormones that promote growth of the human body and
write brie y on each.
• Metabolic effects of insulin
• Functions of glucagon
• Physiological actions of glucagon on carbohydrate metabolism
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• Physiological basis :
• Polyphagia of diabetes mellitus.
• Presence of insulin is needed for glucose entry into the
skeletal muscle.
• Liver plays a major role to produce hyperglycaemia in
diabetes mellitus.
• Hypoglycaemic action of insulin
• Polyuria in diabetes mellitus
• A 50 years old diabetic was brought to the hospital complaining of severe
breathlessness. His breath had a fruity odour and the respiratory rate was
30 per minute. His blood sugar was 375mg% and plasma pH was 7.2.
Answer the following questions based on your knowledge in physiology:
• What is the most likely clinical diagnosis of his condition?
• What is the most important medication that should be administered
immediately?
• Name two abnormal substances that might be present in his urine.
• Explain the physiological actions of the hormone involved and its
regulation.
•
A 50 years old person complaints of increased appetite, increased
thirst & increased frequency of urination. The blood glucose was
found to be 180 mg/dl. Answer the following questions based on
your knowledge in physiology :
• What is the probable diagnosis.
• Which hormone is affected?
• What are the physiological effects of this hormone in the body.
• Enumerate the other hormones involved in the regulation of
blood glucose.
•