184. Intermediary Metabolism

Question 1

Insulin

• source
• synthesis
• regulation of secretion
• effects
• stimulation for ins secretion
• what inhibits ins secretion

Answer 1

Source: pancreatic beta islet cells
Synthesis: pre-proinsulin polypeptide cleaved to ins (A + B chain) and C-peptide (longer half life than ins - better measurement of ins)
Regulation: beta cells have GLUT2 (no ins needed)
glu metabolized to ATP = closes K(ATP) channel = depolarizes membrane = activates V-gated Ca channel = Ca influx = Ca-dependent Ca release from ER = fusion of pre-stored ins vesicles to plasma membrane = ins and c-peptide release (FAST = prestored)

Effects: Lower BG, promotes anabolism through increased glu uptake in myocytes/adipocytes, increased hepatic glu uptake by decreasing glycogenolysis and increasing hepatic glycogen synthesis (creates diffusion gradient increasing glu uptake), decreasing glucagon secretion, stim of lipogenesis and protein synthesis (ANABOLISM)

Stim for secretion: hyperglycemia (GLU - MAJOR STIM), GLP-1/GIP, glucagon

Inhibits ins secretion: inflammatory cytokines, NE (critically ill or post-surgery pts have huge rises in glucose)

Question 2

Describe Insulin Signaling pathway - how does insulin binding lead to its various effects?

Answer 2

Ins binds RTK homodimers

1. Activate Cbl = trafficking of premade GLUT4 vesicles to plasma membrane (ins-dependent glu uptake)
2. Activate IRS = activates PI3K and RAS
   2a. Active PI3K: increases glycogen synthesis in liver and muscle (liver: store glu and release when fasting - bloodstream reservoir; muscle: store glu and release in muscle use), increase glu metabolism, glycogen, protein and lipid synthesis (raise glycolysis, glycogen synthesis, decrease glycogenolysis, gluconeogenesis, FA metabolism, increase FA synthesis)
   2b. Active RAS: cell growth and differentiation: ANABOLIC (increased protein synthesis and lipogenesis= esp important in 1st year of life)

Question 3

Glucagon

• source
• mechanism of action
• effects
• what inhibits glucagon secretion?
• what stimulates glucagon secretion?

Answer 3

Source = pancreatic alpha-cells in islets of Langerhans
Action: GPCR
Effects: oppose ins (increase glycogenolysis, increase gluconeogenesis (from lactate, glycerol, AA), increase FA metabolism (ketone body production))
Inhibited by: high GLU, ins. (counterhormone)
Stimulation for glucagon secretion: low BG

Question 4

GLP-1 and GIP

• source
• mechanism of action
• how is it metabolized
• effects

Answer 4

Source: L-cells of jejunum, secreted due to FEEDING
Acts through GPCR
Metabolized by DPP4
Effects: enhance glu-stimulated Ins secretion from beta cells (increases cAMP - still needs glu to enhance release, does not promote hypoglycemia)
decrease glucagon
delay gastric emptying (more time to metabolize glu)
induce satiety

Question 5

Leptin

• source
• mechanism of action
• effect
• effect of leptin resistance or inactivating mutations in leptin secretion/signaling

Answer 5

Source = adipocytes (more fat mass = more leptin)
Action: cytokine activated cell membrane receptor (JAK-STAT)
Effect: induces satiety (in hypothalamus)
Poor leptin signaling = hyperphagia, obesity

Question 6

Ghrelin

• source
• stimulation for secretion
• mechanism of action
• effects
• when do levels increase

Answer 6

Source: epsilon cells of islets of langerhans and gastric cells
Stim: FASTING STATE
Acts through GPCR
Effects: induce hunger, decrease EE
Levels increase prior to meals/feedings

Question 7

What are the differences in hormones and metabolism in the fasting vs. fed states?

Answer 7

FASTING

• catabolic metabolism
• energy depletion
• increased appetite
• HIGH: ghrelin, gluca
• LOW: insulin, leptin, GLP-1/GIP

FED

• anabolic metabolism
• energy storage
• decreased appetite
• HIGH: insulin, leptin, GLP-1/GIP
• LOW: ghrelin, glucagon