1. The Pancreatic Islets

2. Morphology of the Endocrine Pancreas
The human pancreas contains 1 to 2 million islets of Langerhans which range in size from about 50 to about 500 mm
Collectively the islets make up only 1 to 2% of the pancreatic mass
They are highly vascular
The islets are richly innervated with both sympathetic and parasympathetic fibers that terminate on or near the secretory cells

3. Islets of Langerhans
Histologically, the islets consist of three major cell types
Beta cells, which synthesize and secrete insulin, make up about 60% of a typical islet
Alpha cells are the source of glucagon and comprise perhaps as much as 30% of islet tissue
Delta cells, which are considerably less abundant, produce somatostatin
F cells , which secrete pancreatic polypeptide, may also appear in the exocrine part of the pancreas. A fifth cell type that secretes ghrelin

4. Glucagon
Glucagon is a simple unbranched peptide chain that consists of 29 amino acids
Glucagon is packaged, stored in membrane-bound granules, and secreted by exocytosis like other peptide hormones
It circulates without binding to carrier proteins and has a half-life in blood of about 5 minutes
Glucagon degradation:
25% is destroyed during passage through the liver
The kidney is another important site of degradation
and a considerable fraction of circulating glucagon is destroyed by plasma peptidases

5. Physiological Actions of Glucagon
The physiological role of glucagon is to stimulate hepatic production and secretion of glucose and to a lesser extent, ketone bodies (which are derived from fatty acids)
Glucagon stimulates the liver to release glucose and produces a rapid increase in blood glucose concentration
Glucose that is released from the liver is obtained from:
breakdown of stored glycogen (glycogenolysis)
and new synthesis (gluconeogenesis)

6. Physiological Actions of Glucagon
All the effects of glucagon appear to be mediated by cAMP
cAMP results in:
phosphorylation of enzymes,
which increase or decrease their activity,
or phosphorylation of transcription factors
CREB (cAMP response element-binding protein) which usually increases transcription of target genes

7. Glucose Production
Increase in hepatic glycogenolysis and gluconeogenesis leading to increase glucose production and release into the blood
Increase in lipolysis and mobilization of fatty acids (from triglycerides), resulting in increased levels of circulating ketoacids
Regulation is achieved both by:
modulating the activity of enzymes already present in cells
requires only seconds
By cofactors
phosphorylation and dephosphorylation
and by increasing or decreasing rates of enzyme synthesis and therefore the amounts of enzyme molecules
requires minutes or even hours

8. Regulation of Glucagon Secretion
The concentration of glucose in blood is the most important determinant of glucagon secretion in normal individuals
When the plasma glucose concentration exceeds 200 mg/dL, glucagon secretion is maximally inhibited
Inhibitory effects of glucose are proportionately less at lower concentrations
and disappear when its concentration falls below 50 mg/dL
Alpha cells can respond to fluctuations in blood glucose with either an increase or a decrease in glucagon output

9. Regulation of Glucagon Secretion
Alternatively, changes in glucagon secretion may be controlled by insulin released from adjacent beta cells
They have well documented capacity to monitor blood glucose concentrations
Insulin inhibits glucagon secretion
A quick decline in insulin secretion in response to hypoglycemia may trigger glucagon release
In persons suffering from insulin deficiency glucagon secretion is disturbed
and may be elevated despite high blood glucose concentrations,
or may fail to increase in response to hypoglycemia
Food in the small intestine stimulates secretion of the incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP)
CCK: cholecystokinin
GIP: glucose-dependent insulinotropic peptide
FFA: free fatty acids
GLP-1: Glucagon-like peptide-1

10. Insulin
Insulin (51 amino acids) is composed of two unbranched peptide chains joined together by two disulfide bridges
Processing of the single-chain proinsulin molecule to form the two chained mature insulin takes place in the secretory granules
A 31-residue peptide, called the connecting peptide (C peptide), is excised
No physiological role for the C peptide has yet been established yet
Amylin (storage granule protein) may contribute to the amyloid that accumulates in and around beta cells in states of insulin hypersecretion and may contribute to islet pathology

11. Insulin
Insulin is cleared rapidly from the circulation with a half-life of four to six minutes
The first step in insulin degradation is receptor-mediated internalization by an endosomic mechanism
The liver is the principal site of insulin degradation

12. Physiological Actions of Insulin
Insulin is the only hormone with the ability to directly lower the blood glucose level
Promote the storage of chemical energy derived from food in the form of glycogen, proteins and lipids
While suppressing the mobilization of stored nutrients
The major target organs for insulin action are consequently:
the liver, muscles and adipose tissue, i.e. organs that are specialized for energy storage

13. The Principal Effects of Insulin
Stimulation of glycogen synthesis in skeletal muscle, liver and adipose tissue
Increase in hepatic glucose phosphorylation and a decrease in glucose dephosphorylation
Increase in glucose metabolism (glycolysis) with a simultaneous decrease in liver gluconeogenesis

14. Effects of insulin deficiency
Hyperglycemia
Blood glucose in diabetics may be 300 to 400 mg/dL
Glycosuria (excretion of glucose in urine)
If blood glucose level exceeds about 180 mg/dl
Polyuria
excessive production of urine
Polydipsia
stimulates thirst
Polyphagia
appetite is increased
Weight loss

15. Regulation of insulin secretion
Physiological role is promotion of fuel storage
insulin secretion is greatest immediately after eating
and decreases during between-meal periods
Coordination of insulin secretion with nutritional state as well as with fluctuating demands for energy production is achieved through stimulation of beta cells by:
metabolites, hormones, and neural signals
Secretory activity of beta cells is also enhanced by growth hormone and prolactin by mechanisms that are not yet understood.
Excessive secretion of growth hormone or cortisol decreases tissue sensitivity to insulin and provokes compensatory increases in both basal and stimulated secretion.
VIP: neuropeptide
GIP: glucose-dependent insulinotropic peptide
GLP-1: Glucagon-like peptide-1

16. Triggering of insulin secretion by glucose
“ Resting ” beta cell (blood glucose < 100 mg/dl)
ADP/ATP ratio is high enough so that ATP sensitive potassium channels (K-ATP) are open
Voltage-sensitive calcium channels (VSCC) and calcium sensitive potassium channels (CSKC ) are closed
Beta cell response to increased blood glucose
Increased entry and metabolism of glucose decreases the ratio of ADP/ATP
K-ATP channels close
Voltage-sensitive calcium channels (VSCC) are activated; calcium enters and stimulates insulin secretion

17. Beta Cell Response to Increased Blood Glucose
Influx of calcium:
inhibits voltage-sensitive calcium channels
and activates calcium-sensitive potassium channels
thereby allowing the cell membrane to repolarize and calcium channels to close
Calcium is extruded by membrane calcium ATPase
Persistence of high glucose results in repeated spiking of electrical discharges and oscillation of intracellular calcium concentrations

18. Somatostatin
Physiological importance of pancreatic somatostatin is not understood
Its major role may be as a paracrine regulator of insulin and glucagon secretion