Lecture 9 Flashcards
Structure of pancreas:
Pancreatic cells are found in clusters called acini. Acini are made up of millions of islets of Langerhans. Each islet has 2500 cells.
Secretory products of pancreatic islet cell types:
Alpha: glucagon
Beta: insulin
Delta: somatostatin
F: pancreatic polypeptide
Neural innervation of pancreatic islets:
Cholinergic to stimulate insulin secretion.
Alpha adrenergic to inhibit.
Beta adrenergic to stimulate.
% of pancreatic islet cell types:
Alpha: 20%
Beta: 70%
Delta: 7%
F: 3%
Biosynthesis of insulin:
B cells make mRNA.
Ribosomes synthesize preproinsulin.
ER folds preproinsulin into proinsulin and gives it disulfide bonds.
Trans-Golgi packages proinsulin into secretory granules.
Proteases cleave proinsulin to insulin.
Glucose transporters:
GLUT1 - RBCs and endothelial cells
GLUT2 - renal tubular cells, hepatic cells, pancreatic beta cells
GLUT4 - adipose, skeletal muscle, cardiac tissue
Regulation of insulin release by beta cell:
Glucose enters via GLUT2. Increased glucose metabolism increases ATP concentration. ATP inhibits out K+ channels. Depolarization activates Ca2+ channel. Increased Ca2+ leads to exocytosis of insulin.
Composition of insulin secretion:
5% proinsulin, equimolar C-peptide and insulin.
Factors that stimulate insulin release:
Increased glucose, AA, fatty acids, ketoacid.
Glucagon, growth hormone, cortisol, ACh, gastric inhibitory peptide.
Obesity.
Drugs that inhibits ATP-dependent K+ channels.
Factors that inhibit insulin release:
Decreased glucose.
Fasting, exercise.
Somatostatin.
Alpha-adrenergic agonists.
Insulin response to oral vs IV glucose:
Greater response to oral because of GIP’s independent stimulatory effect.
What kind of receptor is a insulin receptor? (2)
Catalytic: triggers enzymatic activity on cytoplasmic side when bound.
RTK: phosphorylates tyrosine on itself and others.
Insulin receptor structure:
Heterotetramer with two extracellular alpha chains and two membrane-spanning beta chains.
Where does insulin bind on insulin receptors?
Cysteine-rich region of alpha chains.
Factors determining number of insulin receptors on a cell:
Receptor synthesis
Endocytosis of receptors
Endocytosis by degradation
Factors determining insulin’s ability to act on a target cell:
Number of receptors
Receptors’ insulin affinity
Receptors’ ability to transduce insulin signal
Mechanisms of insulin signal transmission:
SH2 domain proteins bind and (P)ate tyrosines on insulin receptor on lipids. Insulin receptor (P)ates and activates other proteins. Insulin receptor (P)ates insulin-receptor substrates (IRS).
IRS: what are they? what they do?
Docking proteins for SH2 domains. Use PIP3 cascade to insert GLUT4 into membrane, and enhance glycogen synthesis. Use MAPK to activate glycogen synthase.
IRS: different kinds
1, 2, 3, 4.
IRS-1: skeletal muscle.
IRS-2: hepatic insulin action, supporting pancreatic beta cells.
IRS-3 and 4: redundant.
Lipoprotein lipase is a big weirdo:
Breaks down lipids and also enhances reuptake of lipids.
Insulin effect in liver: (3)
Promotes glycogenesis.
Promotes lipogenesis.
Promotes protein metabolism.
Insulin effect in muscle: (4)
Stimulates uptake of glucose (GLUT4).
Slightly promotes glycogenesis.
Promotes glucose breakdown.
Promotes protein synthesis (skeletal).
Insulin effect in adipose tissue: (4)
Stimulates uptake of glucose (GLUT4).
Stimulates glucose breakdown.
Promotes triglyceride formation.
Promotes lipoprotein lipase synthesis.
Hypoglycemia: manifestations
Early: Palpitations, tachycardia, diaphoresis, anxiety, hyperventilation, shakiness, weakness, hunger, nausea.
Prolonged/severe: confusion, unusual behaviour, hallucinations, seizures, focal neurologic deficits, coma.
