Insulin, Glucagon, GLP1 and Counter Regulatory Hormones Flashcards
Describe the hormone secreting cells of the pancreas, including number, cell types, blood supply, and innervation
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
β-cells
60% of islet cells
Secrete insulin
Central core of islet
α-cells
25% of islet cells
Secrete glucagon
Sit next to beta cells
delta cells
secrete somastatin
PP cells
secrete pancreatic polypeptide
Structure of insulin
Derived from pro-insulin by cleavage of ‘connecting peptide’ (the C-peptide) leaving the A and B chains joined by disulfide bonds
Stimuli leading to insulin release
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
Cellular mechanisms leading to the secretion of insulin in response to an increase in serum glucose
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.
Mechanisms for insulin signaling within target cells for metabolic and mitogenic actions
What are the key intermediates for the two most important insulin pathways?
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)
- results in other effects importantly the mitogenic effects (MAP kinase)
Actions of insulin on Muscle
Stimulates glucose uptake by stimulating the Glut-4 glucose transporter
Increases glycogen synthesis
Actions of insulin on liver
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
Actions of insulin on adipose tissue
Stimulates glucose uptake and fat synthesis
Inhibits fat breakdown
Insulin resistance
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
Incretin effect
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).
Effects of GLP-1
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
Effects catecholamines
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.
Biphasic insulin release
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.
Inhibitors of insulin release
diazoxide, somatostatin, alpha-adrenergic agents, fatty acids (long-term), and longstanding hyperglycemia
Glucagon
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
Effects of cortisol
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.
Effects of growth hormone
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
Describe the structure of insulin
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.
How is insulin synthesized and secreted?
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)
