Guyton Phys 78: Insulin, Glucagon, And Dm

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acini of pancreas

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secrete digestive juices into duodenum

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islet of Langerhans

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secrete insulin, glucogon directly into blood

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beta cells

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60% of islet cells, mainly in middle and secrete insulin and amylin

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alpha cells

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25% islet cells; secrete glucogon

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delta cells

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10% islet cells; secrete somatostatin

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PP cell

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present in smll numbers and secretes pancreatic polypeptide - unknown fxn

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composition of insulin

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2 polypeptide chains liked by disulfide linkages

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where is insulin synthesized in cells

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translation in ER to insulin preprohormone, cleaved in ER to proinsulin, further cleaved in golgi to form insulin

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half-life of insulin

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~6 minutes, mainly cleavered in ~10-15 minutes

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what degrades insulin

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insulinase mainly in liver, some in kidneys & muscle

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insulin receptor

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2 alpha extracellular and 2 beta transmembraneous units; tyrosine kinase

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what does the tyrosine kinase activate in insulin receptors

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insulin-receptor substrates; different IRS for different tissues

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overall effects of insulin

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1) within seconds of release, 80% body's cells increase glucose uptake 2) cells become more permeable to aas, K+, phosphate ions 3) slower effects 10-15 mins change intracellular enzyme activity via phosphorylation 4) much slower effects (hours/days) via translation of mRNA

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What is believed to result in increased glucose uptake with insulin

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translocation of multiple intracelluar vesicles to the cell membranes

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when does muscle use glucose for energy

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moderate/heavy exercise and a few hours after meals (in presence of high insulin concentrations)

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what do muscle cells do with glucose if it is not ready to be used

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stored as glycogen up to 2-3% concentration

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how much can insulin increase the rate of transport of glucose into the resting cell membrane

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at least 15 fold

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mechanism that insulin causes glucose uptake and storage in the liver (3 steps)

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1) inactivates liver phosphorylase 2) enhanced uptake of glucose via increased glucokinase 3) increases glycogen synthesis via glycogen synthase

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what does phosphorylase do

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principle enzyme that causes liver glycogen to split into glucose

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fxn of glucokinase

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one of the enzymes that causes initial phosphorylation of glucose after it diffuses into liver cells

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why is glucose phosphorylated inside liver cells

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prevents diffusion out of cell

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fxn of glycogen synthase

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polymerizstion of monosaccharide units to form the glycogen molecules

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how much glycogen can be stored in the liver

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almost 100 g (5-6 % liver mass)

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what causes liver release of glucose

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1) decreased insulin 2) glucose uptake stopped 3) phosphorylase activated 4) glucose phosphatase activated

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what perccent of glucose in a meal is stored in the liver and released later

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~60%

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what does insulin cause with excess glucose

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conversion of excess to fatty acids, package as triglycerides in vLDLs and transported to adipose tissue and deposited as fat

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how does insulin reduce gluconeogenesis

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decrease release of aas frommuscle and other extrahepatic tissues

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when do symptoms of hypoglycemic shock dvlp

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20-50 mg/100 ml glucose level

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symptoms of hypoglycemic shock

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nervous irritability that leads to fainting, seizures, and even coma

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how does insulin promote deposition of fat in cells

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glucose in adipose cells provides substrate for glycerol portion of mat molecule

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factors that lead to increased fatty acid synthesis in liver

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1) insulin increases glucose transport into liver cells 2) excess citric acid activates acetyl CoA carboxylase 3) insulin activates lipoprotein lipase in adipose tissue

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What occurs to excess glucose that forms fat in the liver

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split into pyruvate in glycolytic pathway and converted to acetyl CoA

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What is the fxn of acetyl-CoA carboxylase

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acetyl CoA to malonyl CoA-first step in fatty acid synthesis

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two other important effects of insulin on fat storage in adipose cells

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1) inhibits hormone-sensitive lipase 2) promotes glucose transport through cell membrane

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what occurs with fatty acids from liver when insulin not available

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blocked from adipose cells since there isn't a glycerol substrate to store excess fat

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what promotes the dvlpmnt of atherosclerosis in people with serious diabetes

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excess fatty acids cause increase in liver phospohlipids and cholesterol which are released into plasma

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why is excessive acetoacetic acid produced with insulin lack

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excess fatty acids cause carnitine transport mechanism into mitochondria to be increasingly activated; B-oxidation releases excess acetyl-CoA, a lot of which is condensed to acetoacetic acid and released into blood

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what occurs to acetoacidic acid in blood

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transported to peripheral cells where it is converted to acetyl-CoA and used for energy

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how else does insulin affect acetoacetic acid levels

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decreases peripheral tissues utilization

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what can some of the excess acetoacidic acid be converted to in insulin absence

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B-hydroxybutyric acid and acetone

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what aa does insulin strongly cause transport into cells

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valine, leucine, isoleucine, tyrosine, phenylalanine

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ribosome dependence on insulin

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in absence ribosomes stop working as if insulin opperates an on/off switch

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one of most serious effects of diabetes mellitus

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protein wasting due to degradation of proteins to aas

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how do pancreatic B-cells detect glucose levels in blood

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glucose phosphoylated to glucose-6-phosphate by glucokinase which is responsible for sensing and adjustment of insulin secretion

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what does glucose-6-phosphate do

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oxidized to ATP which inhibits ATP-sensitive K+ channels; closure of channels depolarizes membrane opening voltage-gated Ca2+ channels

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what does Ca2+ influx cause in B-cells

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stimulated fusion of docked insulin-containing vesicles with cell membrane and exocytosis

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what hormones inhibit exocytosis of insulin

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somatostatin and norepi

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how do sulfonylurea drugs stimulate insulin secretion

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binding to ATP-sensitive K+ channels and blocking activity

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what else plays a role in insulin secretion

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blood aas and other factors

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normal fasting level of blood glucose

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80-90 mg/100 ml

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two stages of insulin secretion with sudden increase in glucose concentration

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1) plasma insulin increases 10 fold in 3-5 minutes (decreaseshalf to normal within 5-10 minutes) 2) at 15 mintutes insulin secretion rises and reaches plateau in 2-3 hours generally greater than initial phase

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what aas can cause insulin secretion

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arginine and lysine are most potent, especially when glucose levels are elevated

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what GI hormones cause moderate increase in insulin secretion

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gastrin, secretin, cholecystokinin, and gastric inhibitory peptide; 'anticipatory' increase

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other hormones that directly increase insulin secretion

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glucagon, GH, cortisol, and some in estrogen and progesterone

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when is diabetes common

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sustained pharmacologic doses of some hormones, giants, acromegalic people

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GH and cortisol

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secreted in response to hypoglycemia, promote fat utilization; require many hours for max expression

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epinephrine

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increase plasma glucose and fatty acid concentration

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effect of 1 ug/kg glucagon

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elevate glucose 20 mg/100 ml in about 20 minutes

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major effects of glucagon on glucose metabolism

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1) breakdown of liver glycogen 2) increased gluconeogenesis in liver

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how does glucagon increase glycogen breakdown in liver step 1

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activates adenylyl cyclase in hepatic cell membrane

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how does glucagon increase glycogen breakdown in liver step 2

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formation of cyclic adenosine monophosphate

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how does glucagon increase glycogen breakdown in liver step 3

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protein kinase regulator protein activated which activates protein kinase

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how does glucagon increase glycogen breakdown in liver step 4

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phosphorylase b kinase activated and converts phosphylase b into phosphorylase a

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how does glucagon increase glycogen breakdown in liver step 5

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promotes degradation of glycogen into glucose-1-phosphate

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how does glucagon increase glycogen breakdown in liver step 6

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dephophorylated and glucose released into liver cells

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what can glucagon cause in high concentrations

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1) enhance strength of heart 2) increases blood flow in some tissues, especially kidneys 3) enhances bile secretion 4) inhibits gastric acid secretion

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most important factor in glucagon secretion

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blood glucose levels

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when do insulin and glucagon act together

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high concentration of aas (like after high protein meal); glucagon causes aas to be converted into glucose

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what may cause glucagon increased secretion during heavy exercise

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increased aa circulation or B-adrenergic stimulation

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somatostatin half-life, stimulation causes,

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half-life 3 minutes; stimulated by ingestion of food

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what are the effects of somatostatin

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1) increase blood glucose 2) increase aas 3) increase fatty acids 4) increased concentrations of several GI hormones released from upper GI tract in response to food intake

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what does somatostatin inhibit

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1) local islets of langerhans (depresses insulin and glucagon secretion) 2) decrease stomach, duodenum, and gallbladder motility 3) decreases secretion and absorption in GI tract

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what is somatostatin the same chemical substance as

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GH inhibitory hormone secreted by hypothalamus and suppresses anterior pituitary gland GH secretion

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blood glucose concentration the first hour after a meal

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120-140 mg/100ml

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what is the immediate effect in severe hypoglycemia and what occurs after hours/days

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hypothalamus stimulates sympathetic nervous system; GH and cortisol secreted

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where is glucose the only nutrient that can normally be used

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brain, retina, germinal epithelium of gonads

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why is it important blood glucose not raise to high

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1) osmotic P 2) loss in urine 3) osmotic diuresis in kidneys 4) damage tissues, especially blood vessels long-term

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when is glucose lost in urine

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above ~180mg/100ml

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what develops and amplified effects in diabetes

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hypertension secondary to renal injury, atherosclerosis secondary to abnormal lipid metabolism

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what pH causes acidotic coma and can cause death within hours

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~7.0

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possible reason for insulin resistance in obese

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fewer insulin receptors, especially in skeletal muscle, liver, and adipose tissue; abnormalities of signaling pathways that link receptor acitvation wit cellular effects

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what may cause the impaired singaling in insulin resistance

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toxic effects of lipid accumulation secondary to weight gain

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major consequence of metabolic syndrome

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cardiovascular disease

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polycystic ovary syndrome and insulin

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increases in ovarian androgens - causes insulin resistance in 80% of cases; affects 6% of women in reproductive life

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drugs that increase insulin sensitivity

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thiazolidinediones and metformin