Glucose Homeostasis (2)

Question 1

Insulin discovery, structure,

Answer 1

-Banting & Best demonstrated link btw insulin and diabetes

structure: hexamer surrounding zinc
- highly conserved 51 a.a.
- A & B chain connected via disulfide
- proinsulin has C-peptide, gets chopped

Question 2

regulation insulin secretion

Answer 2

release is stimulated by glucose in []-dependent way
btw 4-8 mM glucose = exponential insulin secretion

• 1st (rapid) and 2nd (slower) phase
• secreted in oscillatory way

secretion is 98% regulated

• insulin has v short half life (last 4 min in blood)
• clearance at liver/kidney

release stimulates by food intake (via PSNS and GI hormones), blood a.a. concentration, and blood glucose
- glucose, a.a., FA stimulate insulin secretion

inhibited by SNS (and epinephrine)

Question 3

intracellular mechanisms of insulin secretion by beta cells

Answer 3

1. glucose enters beta cells through GLUT
2. glucose phosphorylated to glucose-6 phosphate. metabolized to produce ATP (glycolysis)
3. increased ATP/ADP ratio = closure K+ channels, membrane depolarization, opening VGCa2+C
4. increased intracellular Ca2+=exocytosis insulin

dense-core insulin granules fuse with PM, release insulin via exocytosis
1st phase: corresponds with fusion of “docked” granules
2nd phase: mobilization of reserve

Question 4

insulin receptor

Answer 4

glycoprotein: 2 EC alpha subunits, 2 spanning beta units. alpha and beta joined by disulfide bonds
- Kinase, phosphorylates scaffold protein

Question 5

glucagon structure, synthesis

Answer 5

• single chain polypeptide, 29 a.a.
• synthesized as large precursor “proglucagon”
• processed to mature by prohormone convertase 2 in alpha cells

Question 6

glucagon receptor

Answer 6

GPCR

- glucagon binding = activation AC = increase cAMP via PKA = increase glycogenolysis

Question 7

regulation glucagon secretion

Answer 7

1. nutrients: low glucose, a.a. stimulate
   high glucose inhibits
   FA inhibit
2. hormonal- GIP, CCK stimulate
   GLP, somatostatin inhibit
3. neural- activation SNS and PSNS stimulate

Question 8

role glucagon in glucose regulation

Answer 8

major site action = liver

• increases gluconeogenesis (from a.a., FA)
• increase glycogenolysis
• decrease glycogen synthesis
• increases ketogenesis
• decreases hepatic protein synthesis
• increase protein catabolism

Question 9

insulin storage

Answer 9

• stored in dense granules in beta cell

Question 10

short and long-term effects of increased insulin

Answer 10

immediate- glucose transport
min-hour- metabolix enzymes
hours-days-cell differentiation/growth

biological effects: increase protein, lipid, glycogen synthesis, stimulate GLUT containing vesicles to go to PM

Question 11

short and long-term effects of increased insulin

Answer 11

immediate- glucose transport
min-hour- metabolic enzymes
hours-days-cell differentiation/growth

biological effects: increase protein, lipid, glycogen synthesis, stimulate GLUT containing vesicles to go to PM