Glucagon and Insulin

Question 1

metabolic reserves in a 70kg man

Answer 1

• plasma/ECF glucose-20 g would last 1 hour
• glycogen-100g in liver, 200g in muscle, enough for part of one day
• protein- 10-12 kg, mostly in skeletal muscle, about 1/2 available for energy needs before death from starvation due to respiratory muscle failure
• fat-10kg mostly in adipose tissue- lasts 40 days with water

Question 2

blood glucose homeostasis

Answer 2

• insulin, glucagon, norepi, epi, cortisol, GI hormones, somatostatin
• blood glucose to brain, liver, heart, muscle, adipose tissue
• 80-100 mg/dl
• brain relies almost exclusively on circulating glucose to meet energy demands
• consumes more than 20% of oxygen supply

Question 3

islet of langerhans

Answer 3

• constitute approximately 1-2% of the mass of the pancreas
• highly vascularized and receives SNS and PNS inputs
• beta cells secrete insulin, 60% of islets
• alpha cells secrete glucagon from periphery of islets, 25%
• delta cells secrete somatostatin, in periphery
• F cells secrete pancreatic polypeptide, periphery- inhibits gallbladder contraction and pancreatic exocrine secretion

Question 4

post translational processing of glucagon

Answer 4

• GRPP, glucagon, glicentin, GLP1, IP2, GLP2
• glucagon most understood
• circulates unbound and has a half life of 3-4 min
• degraded in the liver and kidney, with little excreted in the urine

Question 5

glucagon 1

Answer 5

• 29 aa, MW 3500 D
• 160 aa pro-glucagon
• packaged and stored in membrane bound granules and secreted like other peptide hormones

Question 6

stimulators of glucagon secretion

Answer 6

• hypoglycemia (less than 50)- most important
• increase in arginine and alanine (indicative of protein degradation)
• exercise- liver supplies glucose to muscle
• stress- during healing after surgery

Question 7

inhibitors of glucagon secretion

Answer 7

• somatostatin- paracrine that inhibits release of insulin and glucagon as well as gastrin, gastric acid secretion, and all gut hormones
• insulin
• hyperglycemia (above 200)

Question 8

effects of glucagon in liver

Answer 8

• binds to Gs and increases cAMP and PKA
• catabolic hormone
• glucagon rises during food deprivation
• mobilizes glycogen, fat, protein to increase blood glucose
• counter regulatory hormone released in times of stress
• glycogenolysis, gluconeogenesis, and increases lipolysis

Question 9

processing of pro-insulin

Answer 9

• proinsulin and endopeptidase (trypsin like) secreted together
• C-peptide has no known activity, but level in blood quantitates endogenous insulin production
• 51 aa with MW 6000D
• preproinsulin-proinsulin-golgi and processed to storage granules-proinsulin cleaved to C peptide
• used recombinant human insulin to prevent reactions today
• half life of 5-8 minutes, degraded by insulinase in the liver, kidney and other tissues

Question 10

control of insulin secretion

Answer 10

• glucose stimulates release of insulin

- if you perfuse pancreas, jump in insulin and then slow rise due to increased synthesis of insulin

Question 11

insulin secretion by beta cells

Answer 11

1. glucose enters the cell via GLUT2 transporter
2. increased glucose influx stimulates glucose metabolism, leading to an increase in ATP or ATP:ADP ratio
3. the increased ATP inhibits ATP sensitive K channel
4. Inhibition of K channel causes Vm to depolarize
5. the depolarization activates a voltage gated Ca channel
6. the channel causes Ca influx, which induces CICR
7. elevated Ca leads to exocytosis and release of insulin

• insulin also increased by glucagon/B adrenergic agonists and Gs/ PKA
• galactose and mannose and certain aa can also stimulate fusion of vesicles
• CCK and Ach-stim Gq and PLC and PKC and therefore insulin
• inhibited by somatostatin/alpha-adrenergic by binding to Gq and decreasing cAMP and PKA

Question 12

why is insulin increased by glucagon

Answer 12

• glucagon signals starvation so we need increased blood glucose, but we want some insulin out so that protein degradation doesn’t happen in the muscles to become a source of glucose
• major target organ of glucagon is liver but insulin has a large effect on skeletal muscle

Question 13

response of insulin after feeding

Answer 13

• cephalic phase-gastric acid secretion and small rise in plasma insulin mediated by vagus nerve
• intestinal phase-glucose absorption and rise is plasma glucose is primary stimulus for insulin secretion
• incretins provide an advance notice of feeding and stimulate insulin secretion, oral glucose yields more insulin than IV does
• CCK and GIP enhance insulin
• GLP-1 similarly increases insulin during feeding

Question 14

stimulators of insulin secretion

Answer 14

• inc serum glucose, aa, free FA, ketone bodies
• GIP, glucagon, gastrin, CCK, secretin, VIP, epi (B-receptor)
• PNS

Question 15

inhibitors of insulin secretion

Answer 15

• dec glucose, aa, free FA

- somatostatin, epi via alpha

Question 16

response of catecholamines and insulin during exercise

Answer 16

• circulating epi stimulates insulin secretion via B receptor
• local autonomic stim via alpha dominates
• net result is to suppress insulin secretion and to precent hypoglycemia caused by excessive uptake of glucose by muscle
• reduced insulin also permits the liver to supply glucose to muscle, and adipose tissue to supply FA to muscle

Question 17

anabolic action of insulin on liver

Answer 17

• stimulates glucose uptake and decreases output
• stimulates formation of glycogen and inhibits glycogenolysis
• promotes glycolysis and lipogenesis
• decreases fat oxidation, gluconeogenesis, and ketogenesis
• promotes protein synthesis and inhibits protein breakdown and the urea cycle
• glu enters through non-insulin sensitized channel- just increase of glucose in blood

Question 18

anabolic action of insulin on muscle

Answer 18

• taken up by GLUT 4, which increases in the OM in response to insulin binding to a receptor
• promotes glycogenesis and glycolysis, aa uptake and protein synthesis and decreases proteolysis

Question 19

anabolic action of insulin on adipocyte

Answer 19

• glut 4 transporter again thats added in response to insulin receptor
• synthesize more fat
• increases glycolysis and a-glycerophosphate- inc esterification of fats
• decreases lipolysis
• stimulates lipoprotein lipase-moves to surface endo cells where it releases FA from chylomicrons and VLDLD to go back into the cell for lipid synthesis

Question 20

glucose tolerance test

Answer 20

-normal subject shows increase in insulin to response in glucose, diabetic does not

Question 21

diseases involving abnormal levels of insulin and glucagon

Answer 21

• insulin deficiency-type I diabetes
• insulinemia-elevated levels of insulin in blood
• glucagon deficiency very very rare
• glucagnoma-high levels of glucagon in blood-hyperglycemia

Question 22

control of appetite

Answer 22

• lateral hypothalamus
• NTS
• leptin, insulin, ghrelin, CCK, GLP1, PYY

Question 23

orixigenic factors

Answer 23

• nt that stimulate feeding

- neuropeptide Y

Question 24

anorexigenic factors

Answer 24

• nt that inhibit feeding

- corticotropin releasing hormone, GLP1, alpha MSG, cocaine

Question 25

satiation signals

Answer 25

• satiation signals secreted in response to food ingestion
• single meal time frame
• GI distension triggers vagal afferents that suppresses hunger center
• CCK, GLP1, glicentin, GLP2, glucagon, peptide tyrosine-tyrosine
• CCK diffuses locally in a paracrine fashion to stimulate CCK1 receptors on branches of vagal sensory nerves
• message that ingested fat and protein is being processes and will soon be absorbed is conveyed to the NTS and relayed to the hypothalamus
• ghrelin is secreted from oxyntic glands of stomach- only GI hormone to increase food intake-increase before meals and decrease after
• works with arcuate nucleus

Question 26

adiposity signals

Answer 26

• leptin and insulin-hormones secretion in proportion in the amount of fat in the body
• leptin from white adipocytes
• both hormones cross the blood brain barrier and gain access to the hypothalamus to influence energy homeostasis
• neurons sensitive to insulin and leptin receive a signal proportional to amt of fat in the body
• leptin and insulin stimulate proopopmelanocortin neurons to produce alpha melanocyte stimulating hormone, which binds on receptors on other hypothalamic neurons and elsewhere to reduce food intake
• leptin and insulin inhibit agouti-related peptide and NPY containing neurons in the ARC-similar projections as POMC

Question 27

meal onset

Answer 27

• controlled by social, cultural and environmental factors
• low leptin levels, hypoglycemia, hypoinsulinemia, and conditions of negative energy balance all enhance NPY/AgRP expression in ARC
• activate orexin and MCH expression to increase urge of food intake

-satiation signals activate vagus nerve and pass info to NTS