Flashcards in hormonal regulation of glucose Deck (32)
· Describe the hormone secreting cells of the pancreas
pancreatic islet cells- Beta cells: secrete insulin. Alpha cells: secrete glucagon. Delta cells: secrete somatostatin. PP cells: secrete pancreatic polypeptide
· Describe structure of insulin
Insulin is derived from pro-insulin by cleavage of ‘connecting peptide’ (the C-peptide) leaving the A and B chains joined by disulfide bonds
what is C peptide used for
secreted into blood with insulin. Recombinant insulins, used to treat diabetes, do not contain C-peptide, so you can measure C-peptide in the blood of a person with diabetes who is taking insulin to see if their beta cells are making insulin
biphasic response to increased glucose
high glucose for <20 mins causes rapid surge of insulin followed by decline, then a sustained rise that stays high as long as glucose is high. First phase due to vesicles already docked at plasma membrane, second phase due to recruitment of cytoplasmic vesicles to docked position
Types of stimuli for insulin secretion
Initiators: glucose, amino acids and drugs stimulate insulin release on their own. Potentiators: glucagon, incretin peptides (glucagon-like peptide 1) and acetylcholine increase insulin secretion only in presence of glucose.
Inhibitors of insulin secretion
The drug diazoxide, somatostatin (paracrine) and alpha-adrenergic agents. Long term fatty acid exposure and longstanding hyperglycemia (glucose toxicity). Epinephrine bnds alpha adrenergic receptors on beta cells
· Describe the cellular mechanisms leading to the secretion of insulin in response to an increase in serum glucose
glucose enters beta cell in pancreas via GLUT-2 > metabolized to ATP via glycolysis and TCA cycle > closure of ATP regulated K channels > beta cell depolarization > opening of voltage dependent calcium channels > Ca causes exocytosis of insulin.
action of sulfonylureas
directly block ATP regulated K channels in beta cells
nervous system and insulin release
Stimulation of the splanchnic nerves inhibits insulin secretion as the catecholamines liberated interact with α-receptors on the β-cell. Stimulation of the vagal nerve with attendant release of acetylcholine increases insulin secretion. This results in a modest increase in insulin with the sight or first taste of food the so called ‘cephalic phase’ of insulin release.
How does chronic high blood glucose affect insulin
It leads to to islet cell hypertrophy allowing the pancreas to respond appropriately in individuals with insulin resistance. This process is not sufficient to maintain normal glucose levels in people who get type 2 diabetes.
Alloxan and streptozotocin
destroy the islet cells and are used to create experimental diabetes
what kind of receptor is the insulin receptor
EGF family- two alpha and two beta chains. Insulin binds the alpha chain. The beta chains have inherent tyrosine kinase activity which increases when insulin binds
· Describe the general mechanisms for insulin signaling within target cells
insulin binds receptor > activated receptor auto-phosphorylates tyrosines of cytoplasmic insulin receptor substrates > insulin receptor substrates (IRS) now act as docking sites for various SH2 domain proteins > insulin signaling progresses down a metabolic or mitogenic pathway
· List the actions of insulin on Muscle, Liver and Adipose tissue
liver: stimulates glycogen synthesis, fat synthesis and reduces gluconeogenesis, but does NOT increase glucose uptake b/c GLUT-2 is NOT insulin responsive. Skeletal muscle: stimulates glucose uptake via GLUT-2, increases glycogen synthesis. Adipose tissue: stimulates glucose uptake and fat synthesis, inhibits fat breakdown
metabolic pathway of insulin
results in glucose uptake into cells-Insulin stimulates phosphorylation of IRS-1 which in turn stimulates PI3K which in turn causes rapid translocation to the plasma membrane and activation/translocation of Glut-4 transporters to cell membrane. Also activates glycogen synthase.
Mitogenic pathway of insulin
Involves MAP kinase and results in gene expression/ cell growth
· Describe in general what insulin resistance is
reduced insulin action- it takes a higher concentration of insulin to get the same levels of peripheral glucose disposal or reductions in liver glucose production. In response, beta cells secrete more insulin to maintain normal glucose levels but if person cant make more insulin, blood glucose rises and they develop type 2 diabetes
what causes insulin resistance
Genetic/lifestyle factors change metabolism such that phosphorylatin of serine and threonine residues on insuling signaling molecules makes signaling along these pathways less effective.
· Describe the incretin effect
Incretin effect: insulin secretion is stimulated more when glucose is taken orally rather than infused intravenously. This is due to two intestinal insulin-stimulating hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)
What is GLP-1 produced from
product of glucagon gene- in L cells of intestinal mucosa pro-glucagon is cleaved to release GLP-1 and 2
what stimulates GLP-1 release
nutrients in lumen of gut
insulin secretion, inhibits glucagon secretion, inhibits GI secretion and motility, inibits appetite and food intake
downsides to GLP-1 as therapeutic agent
very short half life
where is glucagon produced
alpha cells of pancreatic islets- primary target is liver
increased glycogenolysis and gluconeogenesis in liver- increases glucose output by liver to provide source of glucose in fasing state. Also increases breakdown of triglycerides in adipose and generation of ketones in liver.
regulation of glucagon secretion
Glucagon is secreted in response to hypoglycemia and inhibited by hyperglycemia (requires insulin mediated transport of glucose into alpha cells).
NE and epi Increase blood glucose by increasing glycogenolysis, gluconeogenesis and ketogenesis, and decreasing glycolysis and glycogen formation.
States situations where catecholamines are elevated
Insulin induced hypoglycemia, medical illness, surgical stress, prolonged exercise, diabetic ketoacidosis
Cortisol effect on blood glucose
Increases blood glucose- increases supply of amino acids available as substrates for gluconeogenesis (promotes protein breakdown), inibits insulin action via insulin resistance, potentiates actions of glucagon and catecholamines