The Endocrine Pancreas

Question 1

Exocrine and endocrine functions

Answer 1

Formed of small clusters of glandular epithelial cells

98-99% of cells are clusters called acini- acini produce the digestive juices

Exocrine activity performed by acinar cells
-Manufacture and secrete fluid and digestive enzymes, called pancreatic juice, which is released into the gut

Endocrine activity performed by islet cells
-Manufacture and release several peptide hormones directly into portal vein

Question 2

Islets of Langherans

Answer 2

Heterogenous

Delta cell of the islets of langherans secrete somatostatin

Paracrine ‘crosstalk’ between alpha and beta cells is physiological, i.e. local insulin release inhibits glucagon

Alpha cell secretes glucogon

Beta cells secrete insulin

Question 3

Insulin

Answer 3

polypeptide, 51 amino acids
Reduces glucose output by liver, increases storage of glucose, fatty acids, amino acids

Has reciprocal action

Question 4

Glucagon

Answer 4

29 amino acid peptide
Mobilises (increases) glucose output, fatty acids and amino acids from stores

Has reciprocal action

Question 5

Somatostatin

Answer 5

Secreted from delta cells- inhibitor

Polypeptide- uncertain significance

Question 6

Insulin suppresses hepatic glucose output

Answer 6

Decrease in glycogenolysis
Decrease in gluconeogenisis

Increases glucose uptake into insulin sensitive tissues
- Muscle – glycogen, and protein synthesis
-Fat – fatty acid synthesis

Suppresses
-Lipolysis
-Breakdown of muscle (decreased ketogenesis)

Question 7

Glucagon- counter regulatory

Increase hepatic glucose output

Answer 7

Increase in glycogenolysis
Increase in gluconeogenisis

Reduces peripheral glucose uptake

Stimulates peripheral release of gluconeogenic precursors (glycerol, AAs)
-Lipolysis
-Muscle glycogenolysis and breakdown

Other counterregulatory hormones (adrenaline, cortisol, growth hormone have similar effects to glucagon and become relevant in certain disease states, including diabetes)

Question 8

Insulin secretion by the beta cell

Answer 8

Glucose equilibrates across the plasma membrane via the GLUT2 transporters. These are low affinity transporters so the uptake varies with the glucose concentration. Intracellular glucose concentration tracks the external supply.
Phosphorylated by glucokinase to glucose 6-phosphate
Rate of glycolysis is increased
Ultimately ATP is generated, this closes KATP channel, stopping efflux of K+, depolarising the membrane, allowing opening of voltage-dependent Ca2+ channels, allowing rapid influx of calcium
This triggers insulin exocytosis from primed secretory granules

Question 9

Insulin release- Proinsulin

Answer 9

Proinsulin contains the A and B chains of insulin (21 and 30 amino acid residues respectively), joined by the C peptide.

Disulfide bridges link a and B chains

Presence of C peptide implies endogenous insulin production

Insulin and C-peptide are stored together in secretory granules, and released in equimolar concentrations – important as helps to distinguish between endogenous and exogenous insulin

Question 10

Biphasic insulin release

Answer 10

B-cells sense rising glucose and aim to metabolise it

First phase response is rapid release of stored product

Second phase response is slower and as it is the release of newly synthesised hormone

Question 11

Insulin action in muscle and fat cells

Answer 11

Insulin binds to insulin receptor which causes GLUT4 vesicles to move to membrane

The GLUT4 insulin receptor is a high affinity large transmembrane glycoprotein,

By mechanisms not fully understood this causes exocytosis of GLUT4 vesicles, increasing glucose transporters in the cell membrane and rapid uptake of glucose

Question 12

Glucose homeostasis

Answer 12

Should remain constant

Liver glycogen is a short term glucose buffer

Table on 16

Glucose concentrations in portal venous blood can eaily reach 20mM after a meal.
Much of this removed by liver
Insulin allows peripheral muscle and adipose tissue to take up glucose from the circulation
Some of the surplus glucose is stored locally as glycogen, but it is mostly converted into fats

Question 13

Glucose sensing

Answer 13

Primary glucose sensors are in the pancreatic islets (beta cells)

Also in medulla, hypothalamus and carotid bodies

Inputs from eyes, nose, taste buds, gut all involved in
regulating food

Sensory cells in gut wall also stimulate insulin release from pancreas - incretins

Question 14

Incretins

Answer 14

Insulin response is greater following oral glucose than intravenous glucose despite similar plasma glucose concentrations

Gut hormones stimulating insulin release are called incretins, glucagon-like peptide (GLP-1) and glucose-dependent insulinotrophic peptide(GIP)

Question 15

Incretins role

Answer 15

Raise insulin by directly stimulating beta cells

Inhibits glucagon secretion by pancreas is alpha cells

Overall decrease in glucose being secreted in liver

Also slows down the rate at which gastric emptying occurs which is a major determinant of postprandial glycaemic excursion

Question 16

GLP1- Glucose dependant and short half life

Question 17

Regulation of CHO metabolism

Answer 17

In the fasting state, all glucose comes from liver
-Breakdown of glycogen
-Gluconeogenesis (utilises 3 carbon precursors to synthesise glucose including lactate, alanine and glycerol)

Glucose is delivered to insulin independent tissues, brain and red blood cells

Insulin levels are low

Muscle uses Free fatty acids for fuel

Some processes are very sensitive to insulin, even low insulin levels prevent unrestrained breakdown of fat to prevent all of fat to be broken down at once

After feeding (post prandial) - physiological need to dispose of a nutrient load

Rising glucose (5-10 min after eating) stimulates 5-10 fold increase in insulin secretion and suppresses glucagon

40% of ingested glucose goes to liver and 60% to periphery, mostly muscle

Ingested glucose helps to replenish glycogen stores both in liver and muscle

Excess glucose is converted into fats

High insulin and glucose levels suppress lipolysis and levels of non-esterified fatty acids (NEFA or FFA) fall

Question 18

Pathway

Answer 18

1) Low blood glucose (hypoglycaemia) stimulates release of glucagon

2) Glucagon acts on liver to:
-Convert glycogen into glucose
-Form glucose from lactic acid and amino acids

3) Glucose released from liver raises blood glucose to normal

4) If blood glucose continues to rise, hyperglycaemia inhibits release of glucagon

5) High blood glucose (hyperglycaemia) stimulates release of insulin

6) Insulin acts on various cells to:
-Accelerate facilitated diffusion of glucose into cells
-Speed conversion of glucose into glycogen
-Increase uptake of amino acids and increase protein synthesis
-Speed synthesis of fatty acids
-Slow glycogenolysis
-Slow gluconeogenesis
-Blood glucose levels fall
-If blood glucose continues to fall, hypoglycaemia inhibits release of insulin

7) Blood glucose levels fall

Question 19

Diabetes Melkite’s

Answer 19

A disorder of carbohydrate metabolism characterised by hyperglycaemia

Question 20

Insulin secretion by the beta cell

Answer 20

Glucose equilibrates across the plasma membrane via the GLUT2 transporters. These are low affinity transporters so the uptake varies with the glucose concentration.

Intracellular glucose concentration tracks the external supply.

Phosphorylated by glucokinase to glucose 6-phosphate

Rate of glycolysis is increased

Ultimately ATP is generated, this closes KATP channel, stopping efflux of K+, depolarising the membrane, allowing opening of voltage-dependent Ca2+ channels, allowing rapid influx of calcium

This triggers insulin exocytosis from primed secretory granules