Insulin, Glucagon, GLP1 and Counter Regulatory Hormones

Question 1

Describe the hormone secreting cells of the pancreas, including number, cell types, blood supply, and innervation

Answer 1

Number: ~1,000,000 (1-2% of total pancreatic cells)

Cell types: 
B-cells - secrete insulin, 60% of total
a-cells - secrete glucagon, 25% of total
d-cells - secrete somatostatin, 
PP-cells - secrete pancreatic polypeptide

Blood supply:
Fenestrated capillaries supply blood to the islets and drain the the Portal Vein. Hormones are secreted into the blood supply and are transported directly to the liver, thus the liver receives a higher hormone concentration than other tissues.

Innervation:
Autonomic - Sympathetic and Parasympathetic, mainly cholinergic

Question 2

β-cells

Answer 2

60% of islet cells
Secrete insulin
Central core of islet

Question 3

α-cells

Answer 3

25% of islet cells
Secrete glucagon
Sit next to beta cells

Question 4

delta cells

Answer 4

secrete somastatin

Question 5

PP cells

Answer 5

secrete pancreatic polypeptide

Question 6

Structure of insulin

Answer 6

Derived from pro-insulin by cleavage of ‘connecting peptide’ (the C-peptide) leaving the A and B chains joined by disulfide bonds

Question 7

Stimuli leading to insulin release

Answer 7

Initiators (cause insulin release on their own) and potentiators (increase insulin release only in presence of glucose)

Initiators: glucose, amino acids and drugs such as sulfonylureas. (e.g. glipizide and glyburide)

Potentiators: glucagon, incretin peptides such as glucagon like peptide-1 (GLP-1, discussed below), and acetylcholine

Question 8

Cellular mechanisms leading to the secretion of insulin in response to an increase in serum glucose

Answer 8

Glucose is taken up by the β-cell through GLUT 2 transporters, metabolized via glycolysis by glucokinase and the TCA cycle. This results in the production of ATP.

Metabolism of glucose depolarizes the ß-cell by closing ATP-regulated potassium channels.

Depolarization leads to opening of voltage-dependent calcium channels in the plasma membrane. The attendant rise in intracellular calcium brings about exocytosis.

Question 9

Mechanisms for insulin signaling within target cells for metabolic and mitogenic actions

What are the key intermediates for the two most important insulin pathways?

Answer 9

β-chain of the insulin receptor has an inherent tyrosine kinase activity whose activity is dramatically increased upon insulin binding.

Signaling occurs both via auto-phosphorylation of the receptor and other substrates of the receptor.

Activation of the insulin receptor results in phosphorylation of multiple tyrosine residues no the receptor.

The phosphorylated form of IRS now acts as a docking site for various SH2 domain proteins.

Progresses down two main pathways:
1. metabolic effects such as glucose uptake into cells (PI3K and AKT)

2. results in other effects importantly the mitogenic effects (MAP kinase)

Question 10

Actions of insulin on Muscle

Answer 10

Stimulates glucose uptake by stimulating the Glut-4 glucose transporter

Increases glycogen synthesis

Question 11

Actions of insulin on liver

Answer 11

Stimulates glycogen synthesis
Stimulates fat synthesis
Reduces gluconeogenesis

Does not increase glucose uptake in liver because that’s mediated by Glut-2 glucose transporters, which are not insulin responsive

Question 12

Actions of insulin on adipose tissue

Answer 12

Stimulates glucose uptake and fat synthesis

Inhibits fat breakdown

Question 13

Insulin resistance

Answer 13

Insulin action is reduced

Takes a higher concentration of insulin to get the same effects

Initially results in higher levels of insulin in the blood of affected individuals and can lead to type 2 diabetes.

It’s currently thought that genetic and lifestyle factors combine to change cellular metabolism making signaling along the affected pathways less effective

Question 14

Incretin effect

Answer 14

When glucose is taken orally, insulin secretion is stimulated much more than it is when glucose is infused intravenously.

Responsible for 50 to 70% of the insulin response to oral glucose ingestion

Caused mainly by the two intestinal insulin-stimulating hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).

Question 15

Effects of GLP-1

Answer 15

Increases insulin secretion WHEN glucose present only

Inhibits glucagon secretion

Inhibits GI secretion and motility

Inhibits appetite and food intake

When used as a medication it will not cause hypoglycemia

Question 16

Effects catecholamines

Answer 16

Increase blood glucose concentrations

Increase glycogenolysis, gluconeogenesis and ketogenesis

Decrease glycolysis and glycogen formation

Augment and prolong the increase in blood glucose by inhibiting insulin secretion and producing insulin resistance in skeletal muscle by stimulating glycogenolysis.

Question 17

Biphasic insulin release

Answer 17

Exposure of islet cells to high glucose concentrations for 20 minutes or longer results in a rapid surge of insulin followed by a decline and then a rise that is sustained as long as glucose remains high.

The first phase is thought to be the result of secretion by vesicles already “docked” at the plasma membrane.

The second phase probably involves recruitment of cytoplasmic vesicles to the “docked” position.

Question 18

Inhibitors of insulin release

Answer 18

diazoxide, somatostatin, alpha-adrenergic agents, fatty acids (long-term), and longstanding hyperglycemia

Question 19

Glucagon

Answer 19

Glucagon interacts with a G-protein coupled cell surface receptor that, when activated by glucagon binding, increases cellular levels of cAMP. When the glucagon levels rise in the portal circulation it results in increases in glycogenolysis and gluconeogenesis in the liver.

Increases glucose output by the liver

Increases breakdown of triglyceride in adipose tissue (lipolysis) and the generation of ketones by the liver

Question 20

Effects of cortisol

Answer 20

Increases in blood glucose levels

Increased release in response to stress.

SLOW effect

Increases the supply of amino acids available as substrates for gluconeogenesis by promoting protein breakdown in muscle.

Inhibits insulin action by producing insulin resistance at a cellular level through mechanisms like those described with insulin resistance.

Potentiates the physiological actions of glucagon and catecholamines.

Question 21

Effects of growth hormone

Answer 21

Increases blood glucose levels

Increased in response to hypoglycemia as well as other forms of stress

Promotion of lipolysis and stimulation of protein synthesis

Promote utilization of lipids rather than proteins during long term energy deprivation

Has anti-insulin effects and decreases insulin-senstitivity

Question 22

Describe the structure of insulin

Answer 22

Pro-insulin consists of A, B and C chains. The A and B chains are connected by disulfide bonds, and the C peptide is connected by peptide bonds to both A and B.

Insulin is derived from this by cleavage of the C chain from both A and B chains, leaving them attached only by 2 disulfide bonds.

Question 23

How is insulin synthesized and secreted?

Answer 23

Pre-pro-insulin is created in the ER of the b-cells and then packed in vesicles by the golgi as pro-insulin. The C-peptide is cleaved inside the secretory vesicles and insulin crystallizes around zinc atoms. The entire vesicle is exocytosed and the low extracellular concentration of insulin induces the breakdown of the crystal structure and dispersal of the insulin. C-peptide is also released from the vesicle and is detectable in the blood. This provides a useful test to determine if a patient is producing his/her own insulin (+ C-peptide) or is totally reliant on exogenous insulin (- C-peptide)