chapter 9 - endocrine pancreas Flashcards
what does pancreas secrete
insulin, glucagon, - regulate glucose, FA and AA metabolism
also somatostatin and pancreatic polypeptide
islets of langerhans
have 4 cell types:
beta - insulin
alpha - glucagon
delta - somatostatin
others secrete pancreatic polypeptide or other peptides
central core mostly beta, alpha around rim, delta interspersed between alpha and beta
ways cells of islet of langerhans communicate with each other (3)
1: gap junctions connect A to each other, B to each other, and A to B
2: recieve about 10% of total pancreatic blood flow - venous blood from one cell type bathes other cell types
3: innervated by adrenergic, cholinergic and peptidergic neurons
insulin
synthesized and secreted by beta cells
2 straight chains (A and B)
A linked to B by 2 disulfide bridges
A has third bridge
chromosome 11
location of gene that directs synthesis of insulin
member of superfamily of genes that encode related growth factors
proinsulin
made very early in biosynthetic process
shuttled to ER where disulfide bridges form
packaged into secretory granules on golgi - proteases cleave to make insulin
connecting peptide
part of proinsulin that is cleaved off
packaged with the insulin in the secretory granule
released in equilmolar quantities with insulin
basis for a test for beta-cell function in persons with type I diabetes mellitus
degradation of insulin
metabolized in liver and kidney by enzymes that break disulfide bonds
a and B chains released and excreted in urine
mechanism of insulin secretion
1: transport of glucose into the beta cell via Glut2 (via facilitated diffusion)
2: glucose phosphorylated to glucose-6-phosphate by glucokinase
3: glucose-6-phosphate is oxidized - generates ATP
4: ATP causes K+ channels in B-cell membrane to close
5: cell depolarized
6: depolarization opens V-G Ca2+ channels in membrane
7: Ca2+ flows into cell down electrochemical gradient
8: increased intracellular Ca2+ causees exocytosis of insulin-containing secretory granules
9: insulin secreted into pancreatic blood and delivered to systemic circulation - C peptide secreted in equilmolar amounts
stimulatory factors for insulin secretion
increased glucose concentration increased AA concentration increased FA and ketoacid concentration glucagon cortisol glucose-dependent insulinotropic peptide (GIP) potassium vagal stimulation; ACTH sulfonyleura drugs (eg tolbutamide, glyburide) obesity
inhibitory factors for insulin secretion
decreased blood glucose fasting exercise somatostatin alpha-adrenergic agonists diazoside
glucose dependent insulinotropic peptide (GIP)
secreted in response to oral glucose
GI hormone that has an independent stimulatory effect on insulin secretion (adding to the direct effect of glucose on beta cells)
IV glucose doesn’t have this indirect effect so doesn’t stimulate insulin secretion as much as oral glucose does
glucagon
activates a Gq portein coupled to phospholipase C => rise in intracellular Ca2+ => exocytosis of insulin
somatostatin
inhibits mechanism that glucagon stimulates
Gq protein coupled to phospholipase C => ris in intracelllular Ca2+/IP3
sulfonylurea drugs
used to treat type II (non-insulin dependent) diabetes mellitus
stimulate insulin release from beta cells by closing the ATP-dependent K+ channels, depolarizing cell, and mimicking the depolarization induced by glucose
insulin receptor structure
insulin receptor is a tetramer with two alpha and two beta subunits
alpha = extracellular
beta = across cell membrane
disulfide bond connects two alpha, each alpha connected to a beta by a disulfide bond
beta have tyrosine kinase activity
mechanism of action of insulin
1: insulin binds to alpha subunits => conformational change
2: activates tyrosine kinase in beta subunit
3: autophosphorylation with ATP
4: activated tyrosine kinase activates other enzymes/proteins
5: insulin-receptor complex is internalized by endocytosis
6: insulin receptor degraded, stored, or recycled
7: insulin down-regulates its receptor by decreasing rate of synthesis and increasing rate of degradation
8: insulin binds to elements in the nucleus, golgi, and ER
9: stimulates gene transcription
insulins actions on blood glucose concentration
hypoglycemic action
causes both decrease in blood glucose concentration and limits rise in blood glucose that occurs after eating carbs
does so by:
1: increases glucose transport into target cells such as muscle and adipose by directing the insertion of glut4 transporters => insulin enters cells and blood glucose level decreases
2: promotes formation of glycogen from glucose in liver and in muscle
3: inhibits glycogenolysis
4: inhibits gluconeogenesis by increasing production of fructose 2,6-biphosphate => increased phosphofructokinase activity - directs substates away from formation of glucose
actions of insulin on FA and ketoacid concentrations
inhibits mobilization and oxidation of fatty acids
increases storage of FA
overall decreases circulation levels of FA and ketoacids
in adipose: stimulates fat deposition
inhibits lipolysis
in liver: inhibits ketoacid formation
insulin effect on blood AA concentration
overall anabolic increases AA and protein uptake by tissues => decreased blood levels of AA increases protein synthesis inhibits protein degradation
insulin actions on K+ levels
increases activity of Na/K-ATPase => increased K+ uptake into cells
protects against increased K+ due to dietary uptake
hypothalamic satiety center
insulin appears to have direct effect
actions of insulin (list)
1: increases glucose uptake into cells => decreased blood glucose
2: increases glycogen formation
3: decreases glycogenolysis
4: increases protein synthesis => decreases blood AA
5: increases fat deposition => decreased blood FA
6: decreases lipolysis => decreased blood ketoacid
7: increases K+ uptake into cells => decreased blood K+
insulin-dependent diabetes mellitus (type I diabetes)
caused by destruction of beta cells
often result of an autoimmune process
beta cells dont’ secrete adequate insulin => carbohydrate, fat and protein metabolism disturbed
=>
1: increased blood glucose concentration from decreased uptake into cells, decreased glucose utilization, increased gluconeogenesis
2: increased blood FA and ketoacid concentrations due to increased lipolysis of fat, increased conversion of FA to ketoacids, and decreased utilization of ketoacids by tissues
3: increased blood AA concentrations due to increased breakdown of protein to AA
4: loss of lean body mass and loss of adipose tissue
5: diabetic ketoacidosis due to increased levels of ketoacids
6: osmotic diuresis, polyuria and thirst due to large amounts of nonreaborbed glucose in urine
polyuria => ECFV contraction and hypotension
7: shift of K+ out of cells => hyperkalemia
treatment = insulin replacement therapy
diabetic ketoacidosis (DKA)
metabolic acidosis due to increased levels of ketoacids in diabetes type I patients
non-insulin dependent diabetes mellitus (type II diabetes)
often associated with obesity
cuased by down-regulation of insulin receptors in target tissues and insulin resistance
insulin secreted normally, but at normal concentrations it can’t activate its receptors on muscle, liver, and adipose tissue
blood glucose concentration elevated in both fasting and postprandial states
treate with caloric restriction adn weight reduction, sulfonylurea drugs, which stimulate pancreatic insulin secretion, and with biguanide drugs (metformin) which up-regulated insulin receptors on target tissue
glucagon
synthesized by alpha cells on islets of langerhans
promotes mobilization and utilization of metabolic fuels
structure of glucagon
single, straight polypetide, 29 AA
member of family of peptides that includes secretin and gastric inhibitory peptide (GIP)
stimulatory factors of glucagon secretion
fasting decreased glucose concentration increased AA concentration, especially arginine cholecystokinin (CCK) beta-adrenergic agonists acetylcholine
inhibitory factors of glucagon secretion
insulin
somatostatin
increased FA and ketoacid concentration
cholecystokinin
stimulates glucagon secretion
secreted from GI tract when protein or fat is ingested, and during fasting and intense exercise
mechanism of action of glucagon
hormone binds to receptor coupled with adenylyl cyclase via Gs protein
second messenger is cAMP
activates protein kinases
glucagon on blood glucose concentrationd
increases blood glucose concentration by:
1: stimulating glycogenolysis
2: inhibits glycogen formation
3: increases gluconeogenesis by decreasing production of fructose 2,6-bisphosphate => decreased phosphofructoknase activity
glucagon on blood fatty acid and ketoacid concentration
increases lipolysis and inhibits FA syntehsis
also shunts substrates toward gluconeogenesis
ketoacids produced from FA
actions of glucagon (list)
1: increases glycogenolysis => increased blood glucose
2: increases gluconeogenesis
3: increases lipolysis => increased blood FA
4: increases ketoacid formation => increased blood ketoacid
somatostatin structure and production
14 AA
secreted by delta cells
GI counterpart has 28 AA
stimulated by ingestion of all forms of nutrients, several GI hormones, and by B-adrenergic agoinsts
inhibited by insulin via intraislet paracrine mechanism
actions of somatostatin
inhibits secretion of insulin and glucagon via paracrine actions on alpha and beta cells
modulates or limits the responses of insulin and glucagon to ingestion of food
