Insulin

INSULIN

Peptide hormone secreted by pancreatic beta cells
Promotes anabolic (synthetic pathways): energy requiring
Binds receptor tyrosine kinases (liver, muscle, adipose tissue, etc.)

PANCREAS

Islets of Langerhans (1-2% of pancreatic beta cells)

Beta cell: secretes insulin
Alpha cell: secretes glucagon (opposes insulin)

INSULIN SYNTHESIS AND STRUCTURE

Components of insulin

N-terminal signal peptide: targets preproinsulin to endoplasmic reticulum
B chain: portion of final hormone
C peptide: marker of endogenously synthesized insulin
A chain: portion of final hormone
Two disulfide bonds: 1 within A chain, another between B and A chains

Synthesis

Signal peptide cleaved from preproinsulin in ER of beta cells to form proinsulin
C peptide cleaved from proinsulin in Golgi apparatus
Two products: C peptide and insulin

C peptide

Longer half-life than insulin: marker of insulin synthesis and secretion

Insulin

Half-life ~ 6 min.

INSULIN SECRETION

Pancreatic beta cell surface

Voltage-dependent Ca2+ channel (closed)
ATP-sensitive K+ channel (open): K+ flows down concentration gradient out of cell
GLUT2: tissue-specific glucose transporter (beta cells and liver cells)

Steps of secretion

1. Eat carbohydrate rich meal: plasma glucose is high 2. Glucose enters beta cell via GLUT2 3. Glucokinase phosphorylates/sequesters glucose in cell (glucose --> glucose 6P)

Glucokinase: tissue specific (beta cells and liver cells), high Km and high Vmax

4. Glycolysis: Glucose 6P --> ATP 5. ATP binds K+ channel and closes it: depolarizes membrane & activates Ca2+ channel 6. Ca2+ influx promotes exocytosis and release of insulin secretory granules

Pancreatic beta cells: most important glucose-sensing cells

GLUT2: high Km, only bind glucose when plasma glucose is high
Glucokinase: High Km, high Vmax & no product inhibition (can continue trapping glucose even when intracellular glucose concen. rise)

INSULIN MECHANISM OF ACTION

Key insulin-sensitive tissues: liver, muscle & adipose tissue

1. Insulin binds receptor tyrosine kinase: activates intracellular RTK beta subunits 2. Autophosphorylation: activated RTK phosphorylates other intracellular proteins 3. Initiates signaling cascade 4. Muscle & adipose: signaling cascade mobilizes GLUT4 transporters from intracellular storage to cell surface

Increases glucose absorption
Seconds after insulin binding
Does not occur in hepatocytes

5. Activates anabolic enzymes: glycogen, protein and lipid synthesis (~minutes/hours)

Promotes glucose storage when glucose is abundant

6. Inhibits catabolic enzymes: glycogen & lipid breakdown (~minutes/hours) 7. Inhibits gluconeogenesis(~minutes/hours) 8. Long-term response: transcriptional control (~hours/days)

Insulin

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