Flashcards in Unit 6 - Insulin and Glucagon Deck (42)
Metabolic reserves in 70 kg man
what is the most important storage in case of starvation/
plasma/ECF glucose: 20 grams; would last an hour
glycogen: 100 g in liver, 200 in muscle; would last part of a day
protein: 10-12 kg, mostly in skeletal muscle; about half is available for energy before death from starvation due to respiratory muscle failure
fat: 10 kg in adipose tissue; lasts ~40 days with water
-most important E reserve in case of starvation
at what level is plasma glucose regulated at? what regulates it? which are anabolic and catabolic?
80-100 mg/dL (4-5 mmol/L)
-down-regulated by insulin only (anabolic)
-up-regulated by glucagon, NE, E, cortisol, GI hormones (catabolic)
how much glucose and O2 does the brain use?
relies exclusively on circulating glucose to meet E needs
-consumes more than 20% of O2 supply
-stores little glycogen, and cannot oxidize FA or AA, but can use ketone bodies if starving
-vulnerable to hypoglycemia, quickly making coma and death
what do the following islet of Langerhans cells do:
a: glucagon made and secreted at periphery (25% of IoL)
b: insulin, proinsulin, and c-peptide made and secreted at center (60% of IoL)
d: somatostatin made and secreted, dispersed in periphery
F: pancreatic polypeptide (GI hormone) made and secreted, dispersed in periperhy
what does pancreatic polypeptide do?
inhibits GB contraction and pancreatic exocrine secretion
post-translational processing of glucagon
proglucagon processed differently in pancreas and intestine
-IoL alpha cells: becomes GRPP, glucagon, and major proglucagon fragment
-L cells: becomes glicentin, GLP-1/2, IP-2 (glucagon-like peptide and inhibitory peptide)
how is glucagon packaged, stored, and circulated?
packaged and stored in membrane bound granules, and secreted like other peptide hormones
-circulates unbound with half-life of 3-4 minutes
-degraded in liver (80%) and kidney, with little in urine
what are stimulators of glucagon secretion?
1. hypoglycemia (<50 mg/dL blood glucose); most important
2. increased arg and ala (indicates PRO degradation)
3. exercise (liver supplies glucose to muscle)
4. stress (during healing after surgery)
what are inhibitors of glucagon secretion?
1. somatostatin (paracrine that inhibits release of insulin and glucagon, along with gastrin, gastric acid secretion, and all gut hormones)
2. insulin (antagonist to glucagon)
3. hyperglycemia (above 200 mg/dL); max inhibition
which organ has the most glucagon receptors?
what are the effects of glucagon in the liver?
catabolic hormone that activates AC, increases cAMP, which activates PKA to phosphorylate key enzymes in glycolysis and gluconeogenesis
-increases glycogenolysis, gluconeogenesis, and lipolysis
-decreases glycolysis, glycogen synthesis, and lipid formation
what are counter-regulatory hormones?
glucagon, catecholamines, growth hormones, and cortisol
-released in times of stress (exercise, illness, etc.)
-keeps blood glucose levels high enough to support brain metabolism
proinsulin processing, storage, and secretion
packaged in Golgi, and processed during sorting to storage granules that contain endopeptidase with trypsin-like activity
-proinsulin and endopeptidase are secreted together with Zn to join the 6 insulin molecules into hexamers
-cleaved into insulin and C-peptide
what is the clinical use of C-peptide?
no known biological activity, but level in blood is used to quantitate endogenous insulin production in patients getting exogenous insulin
-this works because insulin is used by liver, muscles, and other organs, so you cannot measure it directly
--since C-peptide isn't used by anything, it is a good marker to see how much insulin was made
what is recombinant human insulin used for? crystalline zinc insulin?
rHI: avoid antibody reactions
CZnI: basic pharmaceutical preparation used to treat DM
insulin half life and degradation
half life of 5-8 minutes
-degraded by insulinase in liver, kidney, and other tissues
how do insulin levels differ with glucose ingestion VS glucose IVs?
ingestion: fast component (early phase) of insulin release occurs within 10 minutes of ingestion, and peaks 30-40 minutes later
IV: first peak is release of stored insulin, and falls in 10 minutes
-if peak maintained, then insulin will gradually rise during next hour (late phase) reflecting newly formed insulin
mechanism of insulin secretion by beta cells
1. glucose enters cell via GLUT2 transporter, mediating facilitated diffusion into cell
2. increased influx stimulates glucose metabolism, causing increase in [ATP], inhibiting ATP-sensitive K+ channel
3. inhibition of K+ channel causes depolarization, which activates voltage-gated Ca++ channel
4. activation of Ca++ channel promotes Ca++ influx, increasing intracellular Ca++ and Ca++ release
5. increased intracellular Ca++ causes release of insulin from secretory granules
stimulators of insulin secretion
-increased serum glucose, AA, FFA (ketoacids), ketones
inhibitors of insulin secretion
-decreased glucose, AA, FFA
what is the response of insulin after feeding during:
cephalic: gastric acid secretion and small rise in plasma insulin mediated by vagus nerve
-PNS: even if chew and spit out, has insulin secretion that quickly stops
intestinal: glucose absorption and rise in plasma glucose is primary stimulus for insulin secretion
what are incretins?
intestine generated hormones that provide advance notice of feeding and stimulate insulin secretion
-this means that oral glucose yields more insulin than IV glucose
-CCK and GIP both enhance insulin secretion, with GLP-1 increasing during feeding
response of catecholamines and insulin during exercise
circulating epinephrine stimulates insulin secretion via beta receptor on pancreatic beta cell
-local autonomic adrenergic innervation releasing NE acts via alpha recceptor and predominates
-net result is to suppress insulin secretion and prevent hypoglycemia caused by excessive uptake of glucose by muscle
-reduced insulin allows liver to supply glucose to muscle, and adipose tissue to supply FA to muscle
what is the anabolic action of insulin on liver?
glucose enters via GLUT 2, noninsulin sensitive transporter in membrane
-stimulates glucose uptake, glycogen formation, glycolysis, lipogenesis, PRO synthesis
-inhibits glycogenolysis, fat oxidation, gluconeogenesis, ketogenesis, PRO breakdown
what is the anabolic action of insulin on muscle?
insulin causes GLUT 4, insulin sensitive transporter, to externalize from vesicles within
-stimulates glucose and AA intake, glycolysis, glycogenesis, lipogenesis, FA synthesis, PRO synthesis
-inhibits glycogenolysis, proteolysis
what is the anabolic action of insulin on adipocyte?
insulin causes GLUT4 to externalize to get glucose
-increases glycolysis to make alpha-glycerophosphate to increase esterification of fats
-increased synthesis of lipoprotein lipase, which moves to surface of endothelial cells to release FA from chylomicrons and VLDL
glucose tolerance test
normal: plasma glucose rises slowly, and insulin rises sharply and high, then glucose drops somewhat slowly, and insulin quickly
diabetic: insulin barely increases, while glucose drops quickly and tapers off very slowly
elevated levels of insulin in blood
-from insulin shots or insulinoma (beta-cell tumor)
is glucagon deficiency common?
no, it is very, very rare
-genetically not found, but rarely spontaneous