ENDOCRINE PANCREAS

Dr.Gomathi Sivakumar MD.,

Senior Assistant Professor of Physiology,
Govt. Kilpauk Medical College.
1 million islets per pancreas

Major cell types in islets:

-cells(20%) - glucagon
-cells (60-70%) – insulin
Delta cells(10%) – somatostatin
F or PP cells - pançreatic polypeptide
Paracrine control system in pancreas
Insulin
Best and Banting in 1921
 Insulin

51 amino acids

2 polypeptide chains
(A = 21, B = 30)

3 disulphide bridges:
rigid structure

Preproinsulin(108) to proinsulin (86) and C

peptide
Chromosome 11 has insulin gene
Mechanism of insulin secretion
Regulation of insulin secretion

 Substrate control
 Hormonal control
 Neural control
 Substrate control

1.Blood glucose – most important

2.Amino acids – arginine, leucine, lysine
3.Keto acids
Biphasic insulin secretion
 Hormonal control
 Incretin effect
greater insulin secretion occurs when glucose is given
orally rather than intravenously.
GI hormones like GIP, gastrin, secretin and CCK
Which are released after Food increases insulin
secretion.
 Growth hormone, cortisol and glucagon increase
insulin secretion. Prolonged secretion of these
hormones causes burning out of islets and cause
insulin deficiency.
 Catecholamines decrease insulin secretion.
 Neural control
 Sympathetic stimulation(alpha
receptor stimulation) decreases
insulin secretion.

 Vagal stimulation increases

insulin secretion
Role of cAMP

 cAMP increases insulin secretion by increasing

intracellular calcium
 Phosphodiesterase enzyme degrades cAMP.
 Phosphodiesterase inhibitors like theophylline
and oral hypoglycemic agents increase insulin
secretion.
Transport and metabolism
 Water soluble- carried dissolved in plasma – no special
transport proteins.

 interact with cell surface receptors on target cells.

Metabolised by
 Hepatic glutathione insulin transhydrogenase and inulinase
present in various organs
 Half life is 5 to 10 min
Mechanism of insulin action
 Insulin receptor

 Cell membrane receptor

 Intrinsic tyrosine kinase activity
Mechanism of
actions of insulin
 1.Translocation of glucose transporters to the plasma
membrane
 2.Activation or deactivation of enzymes of
carbohydrate, protein and fat metabolism.
 3.Modulation of gene expression
 4.Synthesis of proteins including enzymes of
metabolism.
Actions of insulin
 Actions of insulin

 1. Metabolic effects
 2.Effects on ion transport
 3.Roll in cell growth and development
 Metabolic effects
Signal of feeding.

Target tissues:
liver, adipose
skeletal muscle

Affects metabolism of:

carbohydrates, lipids
proteins

Actions are anabolic

Hormone of abundance
Hormone of energy storage
Carbohydrate metabolism

 Increases cellular uptake of glucose.

Insulin independent glucose entry in brain(exceptventromedial nucleus of
hypothalamus), RBC, git and kidney tubules
 Increases peripheral utilisation of glucose
 Increases glycolysis
 Increases glycogen synthesis
 Decreases gluconeogenesis
 Decreases glycogenolysis

Decreases blood glucose

Fat metabolism

 Increases the synthesis of triglycerides

 Decreases lipolysis
 Increases uptake of ketone bodies in muscle
Protein metabolism

 Promotes amino acid uptake into cells ,

especially in skeletal muscle
 Promotes protein synthesis
 Inhibits protein lysis
 Effects on ion transport

 Increases potassium, phosphate and magnesium ions

uptake into cells
Roll in cell growth and
development
 Anabolic action of insulin is as important as
growth hormone for promotion of normal growth
 Stimulates the synthesis of macromolecules in
tissues like bone and cartilage.
Glucagon
29 amino acids

1 polypeptide

Alpha cells
preproglucagon-proglucagon-glucagon n

Stored in granules and released by exocytosis

Transported in plasma as unbound form. Half life is 6 min.
Degraded mainly in liver and kidney.
 Regulation of Glucagon secretion

Increased by Decreased by

 Decreased blood glucose  Hyperglycemia

 Protein meal  Free fatty acids, ketone bod
 GI hormones:CCK,Gastrin, GIP  Secretin
 Sympathetic stimulation-beta receptors
 Alpha adrenergic stimulatio
 Cortisol, acetylcholine, theophylline  Insulin, somatostatin.
Mechanism of glucagon action
 Cell membrane receptor
 G protein coupled receptor
 Second messenger is cAMP
Actions of glucagon
Signal of fasting.

Target tissues:
liver, adipose

Affects metabolism of:

carbohydrates, lipids

Actions are catabolic

 Increases glycogenolysis in liver- immediate
and profound effect
 Decreases glycogen synthesis
 Increases gluconeogenesis- slow but more
sustained rise blood glucose which lasts for
hours and days
 Powerful lipolytic hormone.
 Promotes ketone bodies formation
 Increases amino acid uptake by liver-for
gluconeogenesis
 Calorigenic effect- due to increased hepatic
deamination of amino acids. Requires
glucocorticoids and T4
 In large doses , glucagon increases force of
contraction of heart via cAMP
 Stimulates secretion of growth hormone,
insulin and pancreatic somatostatin
Glucose homeostasis
APPLIED ASPECTS
What happens to metabolism when insulin or glucagon
levels are abnormal?

Insulin
 High – hypoglycaemia.
 Low – diabetes.

Glucagon
 High – no significant effect.
 Low – no significant effect.
  Normal blood glucose

Capillary blood glucose is slightly higher than venous blood.

Hypoglycaemia

Blood glucose low

Uptake of glucose by glucose-dependent tissues not adequate to maintain

tissue function.

CNS very sensitive:

Impaired vision, slurred speech, staggered walk
Mood change – aggressive
Confusion, coma, death

Stress response (release of adrenaline):

Pale
Sweating – clammy
Diabetes Mellitus

Metabolic disorder

Characterised by:
 chronic hyperglycaemia (prolonged elevation of blood glucose)
 leading to long-term clinical complications

Caused by:
 Insulin deficiency – failure to secrete adequate amounts of
insulin from -cells.
and/or
 Insulin resistance – tissues become insensitive to insulin.
Classification of Diabetes

Two major types recognised clinically

Type 1 – absolute insulin deficiency (loss of -cells).

Type 2 – relative insulin deficiency and/or insulin resistanc

Also Gestational Diabetes (only occurs during pregnancy)

 Chronic complications of hyperglycaemia

Chronic - microvascular disease:

 eye disease including retinopathy.
 kidney (nephropathy).
 peripheral nervous system (neuropathy).

Chronic - macrovascular disease:

 coronary artery disease.
 stroke.
 poor peripheral circulation (feet).
 Microvascular complications of diabetes
Tissues affected - peripheral nerve, eye, kidney.

Uptake of glucose into these tissues:

 does not require insulin.
 determined by extracellular [glucose].

During hyperglycaemia  intracellular [glucose]:

 High glucose concentrations can promote the nonenzymatic
formation of advanced glycosylated end products (AGEs) and
cause altered protein structure and formation.
 High glucose levels increase the flux of sugar molecules
through the polyol pathway, which causes sorbitol
accumulation in cells and osmotic stress.
 High glucose levels can stimulate free radical production and
reactive oxygen species formation.
Glycosylated (glycated) haemoglobin

As erythrocytes age - gradual conversion of haemoglobin (HbA) to a

series of glycosylated forms (HbA1).

Major component of HbA1 is HbA1c – glucose added to the N-terminal

valine of the -chain.

Amount of HbA1c correlates with the average blood glucose

concentration over the previous 2 - 3 months.

In non-diabetic subjects HbA1c = ~5% of the total HbA.

In diabetic patients HbA1c give a good indication of blood glucose

control.
Macrovascular complications
Atherosclerosis
• Chronic inflammation and injury to the
endothelium
• Subendothelial accumulation of oxidized
lipids from LDL particles
• Monocyte infiltration of the arterial wall
and differentiation into foam cells(lipid
laden macrophages)
• Attraction of T-lymphocytes and Tcell-
inducd smooth muscle proliferation in
the arterial walls and collagen
accumulation
Treatment

 Oral hypoglycemic agents

 Insulin