Pancreatic Hormones: Insulin and Glucagon
what are the characteristics of the glucagon receptor?
- G-protein - produces cAMP and Ca2+ - principally expressed in the liver and kidney, but found in lower amounts in the adipose tissue, heart, adrenal glands, GI track, and cerebral cortex. GLP receptor: - G-protein - increased Ca2+ and cAMP
how is glucose transported into cells?
- GLUT 1-4 transporters - contains 12 transmembrane - integral membrane protein - can have binding site for glucose on inside or outside of cell to aid in movement into or out of cell - when glucose is brought in, it is phosphorylated, has a negative charge, and cannot leave through the transporter
what are the molecular characteristics of glucagon and GLPs?
- all GLPs are produced from a single proglucagon gene but glucagon is made in the alpha cells of the pancreas while GLPs are produced in the intestines endocrine cells - glucagon is a single amino acid chain, highly conserved - no definable tertiary structure - aided by epinephrine (triggers glycogenolysis/lipolysis) and cortisol (stimulates GNG in liver) - increases cAMP, enzymes get phosphorylated and work in glycogenolysis and inhibits glycolysis
what are the characteristics of biosynthesis and secretion of glucagon and GLPs?
- both produced from a single proglucagon gene - only glucagon secreted from pancreas, GLPs in intestine - proglucagon gene expressed in intestine to give rise to oxyntomodulin (OXY), GLP-1 (extension of OXY) - OXY released postprandially, can pass through BBB proglucagon synthesized differently in intestine and pancreas PANCREAS: major products are glucagon and MPGF (major proglucagon fragment) INTESTINES: OXY, GLP-1/2
what are the major tissues that consume glucose? what do these tissues make during gluconeogenesis? what happens during glucose production?
- brain, RBC, WBC, muscle all consume (brain the most) - RBC, WBC, and muscle produce pyruvate and lactate; muscle produces alanine and glycogenic AA as well; adipose tissue produces glycerol AAs and glycerol go through gluconeogenesis to make glucose, are put into glycogen, and then can be broken down into glucose all in the liver
how is insulin secretion controlled/regulated?
- elevated levels of glucose, FFAs, and AA stimulate release - anticipatory signal: GI tract mobility and stimulation by PNS (ACh) - anticipatory signal: carbohydrate in GI causes release of GIP (gastric inhibitory peptide) which is an insulin secretagogue - GLP-1 from GI stimulates insulin and SST release from pancreas, inhibiting glucagon - calcium, cAMP, and DAG regulate insulin secretion AND are metabolic products of B cell - metabolism of glucose, FFAs, AAs within B cell close ATP-sensitive K+ channels that depolarize cell, lead to Ca influx and release of insulin - hypothalamic AVP and CRH are released during stress and there are receptors in the pancreas
what are hormones and NTs that can increase insulin? decrease?
- gastrin, secretin, CCK, and GIP increase - catecholamines inhibit secretion of insulin
what general factors lead to an increase in blood glucose levels?
- glucagon actions in the liver to stimulate glycogenolysis - epinephrine stimulation of glycogenolysis - cortisol stimulation of glycogenolysis - insulin antagonists, GH, cortisol - dietary intake of carbohydrates and proteins; mobilization from storage sites (glycogenolysis) - stimulation of insulin catabolism
how is insulin biosynthesized?
- in the pancreatic B cell -prepro synthesized in RER; pre is cleaved and disulfide bridges are added to yield pro - ribosomes make proinsulin converting enzymes (PECs) - PECs and proinsulin are enclosed in vesicles and packed in the golgi - clathrin coated vesicles pinch off from trans golgi and are rich in proinsulin - acidification of vesicles activates PECs that then form active insulin and C peptide - vesicles lose clathrin and mature into secretory granules full of insulin; stored until exocytosis - some is constitutive, but most is regulated secretory
what are the characteristics of the hepatopancreatic complex?
- includes liver, gall bladder, bile duct, pancreas, stomach, and duodenum - liver and pancreatic hormones fx to ensure homeostatic blood glucose - has endocrine (islet) and exocrine (acini) functions - each cell in the islets is surrounded by multiple blood vessels - arterial supply from splenic, hepatic, and mesenteric arteries - highly fenestrated capillaries - both endocrine and exocrine innervated by ANS (vagus nerve PNS increases insulin and decreases glucagon) EXOCRINE: - pancreatic juices controlled by reflex mechanisms after meal and GI hormones (secretin and CCK)
what general factors lead to a reduction in blood glucose levels?
- insulin - glucose uptake by peripheral tissues - glucosuria - exercise - stimulation of glucagon catabolism
Do the nervous and endocrine systems overlap in their functions? If so, explain. Provide an example using hormones and specific components of the nervous system. For example, do insulin and the parasympathetic branch of the autonomic nervous system function in unison to regulate blood glucose?
- insulin increases storage of glucose (anabolism) after a meal. explain how this is done - PNS: ??????????????????????????????????????????????????????
what are the characteristics of the insulin receptor?
- insulin primarily affects liver, muscle, and adipose tissue - has two A and two B subunits that are interlinked by disulfide bonds (similar to hormone) - 2 ligand-binding domains on A but they have negative cooper. - A subunits are outside of the membrane while B are inside - binding to A outside induces tyrosine kinase on the inside - generally lead to phosphorylation cascades - activation of 1/5 pathways (P1a, P1b, P2, P3, P4) AFTER BINDING: - receptor recycled but will be down regulated? - upregulates glucose transport via 12 TM GLUT4
what are the characteristics of type I diabetes?
- insulin-dependent - B cells in pancreas are partially or totally destroyed by autoimmune processes - no endogenous insulin secretion - require exogenous insulin TYPE A: - decreased insulin receptors TYPE B: - patients develop antibodies against parts of insulin receptor and block receptor binding
what are the molecular characteristics of insulin?
- large polypeptide/small protein - composed of two chains (A/B) that are joined by disulfide bridges - C peptide may bind GPCR and enhance neural, endothelial, and kidney functions - has sequence homology with relaxin, IGF-1, and NGF - can organize into a mononer, dimer, tetramer, or hexamer (monomer is active, hexamer is storage form)
what are the characteristics of type II diabetes?
- maturity-onset - relative lack of insulin - frequently associated with obesity - may have increased level of pancreatic production of insulin, skeletal muscle may be resistant to take up glucose (GLUT4), or pancreas has decreased B cell fx that then stimulates secretion of glucagon - only requires infrequent insulin supplementation
how does leptin affect the pancreatic hormones?
- peptide hormone, regulates body weight - produced primarily in white adipose tissue - leptin receptors are present in NPY neurons in the arcuate nucleus - orchestrates signals in the ventromedial nucleus to affect satiety overall affects hypothalamus which can affect the brainstem, autonomic outputs, and behavioral outputs
what are the characteristics of amylin and its actions?
- produced by by pancreatic B cells, cosecreted with insulin - slows gastric emptying (stomach) and promotes satiety (hypothalamus)
what are the characteristics of SST and its actions?
- produced by enteroendocrine D/gamma cells (specialized in the GI) - produced in gamma cells of endocrine pancreas - normally acts on pituitary to inhibit cAMP and GH secretion - inhibits pancreatic islet cells as well as intestine G cells, parietal cells of stomach, and eterochromaffin-like cells - protects against hyperglycemia
what are the characteristics of pancreatic polypeptide and its actions?
- stimulates gastric secretion of HCl and pepsin - secreted by F cells of pancreas - binds to a G-protein receptor that inhibits cAMP - inhibited gastric emptying and reduces food intake - regulated similar to glucagon
Insulin secretion is controlled by three different mechanisms (2 endocrine and 1 neural). Identify each and describe how they contribute to the secretion of insulin.
1) 2) anticipatory signaling: - GI track motility and stimulation by PNS secretes ACh to activate insulin secretion 3)
what is the stimulus secretion coupling of the beta cell in the pancreas?
1) glucose comes into cell 2) metabolism increases ATP 3) ATP-coupled K+ channel closes 4) dep. due to K+ channel closing 5) VDCC channel opens due to repolarization and Ca2+ influx 6) vesicles released due to Ca2+ 7) Ca2+ coupled K channels open 8) repolarization occurs 9) inhibition of VDCC channels
what are the intracellular responses after the binding of insulin to its receptor?
GENERAL: i) vascular constriction ii) vascular relaxation iii) stimulation of glucose uptake followed by glycogen synthesis in the liver, muscle, and adipose tissues iv) translocation of glucose transporters (GLUT4) to plasmalemma P1a: MAPK pathway - gene transcription, protein synthesis, cell growth and differentiation P1b: MAPK and EK-1 - vascular constriction by endothelin-1 (ET-1) P2: Akt and eNOS/NO - vascular dilation P3: Akt, aPKC/FOX01/GSK3 - glucose uptake, gluconeogenesis, glycogen synthesis in skeletal muscle, adipose, and liver P4: CAP-TCO - translocation of GLUT4
what are the biological actions of GLP-1 and GLP-2?
GLP-1: BRAIN/HYPOTHALAMUS: - increased sensation of satiety - diminished appetite ESOPHAGUS: - decreased gastric emptying STOMACH: - B cell proliferation - decreased apoptosis PANCREAS: - increased insulin and SST - decreased glucagon GLP-2: - increased blood flow, mucosal growth (intestine), nutrient transport - decreased apoptosis, gastric motility, and intestinal permeability
what happens after a meal?
IF BLOOD GLUCOSE HIGH - pancreatic B cells release insulin which binds receptors and increases GLUT transporters - glucose removed from blood and stored in muscle cells as glycogen - insulin inhibits gluconeogenesis WHEN BLOOD GLUCOSE LOW - pancreatic A cells release glucagon - glucagon promotes degradation of glycogen and release of glucose into blood
For the pancreas, identify the source of origin (cell/tissue), target tissue, its cognate receptor, the signal transduction pathway(s) linked to the receptor, biological outcome of ligand:receptor interaction, and mechanism(s) that regulate production/secretion of all the endocrine products.
INSULIN: GLUCAGON: OTHERS:
what are the effects of insulin and glucagon on the muscle?
INSULIN: - when insulin is low, stimulation of net protein catabolism - when insulin binds receptors, increased uptake of glucose and amino acids and associated protein synthesis GLUCAGON: - muscle does not have glucagon receptors, responsive to low insulin
what are the effects of insulin and glucagon on adipose tissue?
INSULIN: - stimulates storage of triglycerides GLYCOGEN: - mobilization of FFAs that can be delivered to heart and kidney (oxidative metabolism) or to liver
what are the effects of insulin and glucagon on the liver?
INSULIN: anabolic - elevated by increased glucose, FFAs, AAs - secreted from pancreas B cell - activates a phosphatase that leads to glycogen formation GLUCAGON: catabolic - elevated by decreased glucose - secreted from pancreas A cell - favors formation of active phosphorylase b kinase-kinase that leads to glucose formation
what are the main hormones secreted by the pancreas, where do they come from in the pancreas, and what are their functions?
ISLETS OF LANGERHAN 1) insulin: - BETA cells - stimulates anabolism by increasing the UPTAKE of glucose into stored glycogen 2) glucagon: - ALPHA cells - stimulates catabolism by increasing the RELEASE of glucose from storage 3) amylin: - BETA cells - slows gastric emptying and promotes satiety (prevents blood glucose spike) 4) SST: - delta cells - inhibits secretion of insulin, glucagon and PP 5) pancreatic peptide (PP) - F cells - stimulates secretion of gastric acid HCl by the parietal cells of the stomach 6) gastrins: - G cells - induce secretion of HCl by parietal cells adjacent to the antrum of the stomach
what are the actions of glucagon on the liver, muscle, adipose, pancreas, and brain?
LIVER: - inactivates glycogen synthetase and activates phosphorylase A (activates glycogenolysis) - increases activity of glucose 6Pase - enchances synthesis of glucose from pyruvate and lactate, as well as AAs (gluconeogenesis) MUSCLE: - does not contain glycogen receptors ADIPOSE: - in large doses, can stimulate lipolysis but normally no effect PANCREAS: - simulates insulin secretion, particularly after intestinal absorption of AAs BRAIN: - none
what are the actions of insulin on the liver, muscle, adipose tissue, and brain when there are sufficiency and deficient levels?
SUFFICIENT: - liver: NO EFFECT on glucose uptake, stimulates byosynthesis of hexokinase IV and activates glycogen synthetase, promotes glycolysis and formation of ATP - muscle: STIMULATION of glucose uptake, stimulates biosynthesis of hexokinase II and pyruvate kinase; stimulates glycolysis and formation of ATP, increases muscle glycogen levels and creatine phosphate - adipose: STIMULATION of glucose uptake, enhances glycolysis, makes glycerol phosphate available and enhances triglyceride synthesis. inhibits lipase activity - brain: no direct actions of insuli, brain is dependent on blood glucose DEFICIENT: - liver: uptake of FFAs and conversion to ketones - muscle: impaired blood glucose - adipose: decreases triglyceride synthesis due to lack of glycerol phosphate; stimulation of lipolysis and release of FFA int obloodstream - brain: none
what does the exocrine portion of the pancreas produce?
acini cells are exocrine enzymes for digestion - chymotrypsin - trypsin - amylase - lipase - bicarbonate
what are antagonists and agonists of glucagon?
antagonists: glucose and SST agonists: neuropeptides, hormones (epinephrine), amino acids (arginine, glutamine, alanine)
what is the innervation like in the pancreas?
both the islet cells and acinar cells are innervated by cholinergic AND adrenergic nerve fibers - stimulation of the PNS leads to insulin secretion and inhiibtion of glucagon secretion (ACh) - stimulation of SNS stimulates glucagon production and inhibits insulin secretion (NE)
what does the respiratory quotient tell you about the source of energy?
for glucose, with a RQ of 1, there is less energy expenditure to eliminate waste (oxygen and CO2 levels are similar); in others you need higher levels of O2 consumption?
what general factors affect blood glucose levels?
intestinal uptake, muscle activity, thermogenesis and response to external temp., presence of starvation, pregnancy and lactation, age, BMR
what are the general effects of insulin?
promotes storage of glucose, FFAs, and inhibits breakdown of glycogen and triglycerides - does this through blocking/reversing effects of other hormones - activates phosphatases that deactivate enzymes - reverses phosphorylation induced by caMP-dependent protein kinases
what are general responses (seconds, minutes, hours) after insulin binds to its receptor?
seconds: - binds receptor, RTK activity minutes: hexose transport, altered enzyme activity, gene regulation, recepteor internalization and down regulation hours: induction of DNA, RNA, protein and lipid synthesis, cell growth, down regulation of insulin receptor
