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