U1ii: Describe the physiology of Insulin

Definition

A polypeptide hormone

Structure

  • 1 α chain
  • 1 β chain
  • Linked by disulphide bridges
Disulphide Bridges

Synthesis & Storage

  • Synthesised & stored in β cells of Islets of Langerhans
  • Stored in granules
  • Require Ca2+ for exocytosis + release

Release

  • GLUT-2 = 1° sensor for glucose release
  • Glucose > 6mol/L stimulates majority of insulin release
  • Glucose enters via GLUT-2
  • Glucose phosphorylated by Glucokinase (maintains [ ] gradient)
  • Glucose metabolism in β cells produces ATP
  • ATP blocks K+ channel* (responsible for β cell RMP)
  • ∴ ↑ATP = depolarisation β cells
  • Voltage-dependent Ca2+ channel open
  • Ca2+ influx
  • Exocytosis on insulin
  • 2 phases:
    1. RAPID → stored insulin
    2. SLOW → stored & newly synthesised

* ATP-sensitive K channels are blocked by sulphonylureas

Control of Insulin Secretion

↑ Insulin

  • ↑ glucose
  • Glucagon
  • α – acids
  • β receptor stimulation
  • DRUGS:
    • β agonist
    • Sulphonylureas
    • Phosphodiesterase inhibitors
  • Cortisol, CCK, gastrin, secretin, gastric inhibiting peptide

↓ Insulin

  • ↓ glucose
  • Somatostatin
  • Fasting
  • α receptor stimulation (NA)
  • DRUGS:
    • β blockers
    • Thiazide diuretics
  • Leptin

Insulin Metabolism

  • Secreted into Portal System
  • t ½ 5 min
  • Liver + kidney remove from circulation by hydrolysis of disulphide bridges connecting a & b chains

Insulin Receptor

  • Belongs to large class of TYROSINE KINASE RECEPTOR
  • 2 a -chains + 2 b -chains held together by disulphide bridges (it is a transmembrane TK receptor)
  • a chains → extracellular, bind insulin
  • b chains → intracellular, intrinsic tyrosine kinase
  • Insulin binds a subunits
  • Activates TK
  • Autophosphorylation of receptor
  • Phosphorylates other proteins which produce 2nd, 3rd messengers with variety of effects

NOTE:

  • Insulin does NOT cross BBB/placenta
  • No effect on brain glucose uptake (its 1° substrate)
  • [Insulin] x 2 by 3rd trimester (insulin resistance 2° placental hormones)

Actions of Insulin

  • Major anabolic hormone

CHO Metabolism

    • ↑insulin → ↓glucose production, ↑glucose storage → ↓BSL
    • 4 Glucose Transporters:
      1. GLUT-1 → foetal tissue, RBC, BBB → basal glucose uptake
      2. GLUT-2 → hepatocytes, B cells, renal tubule cells
      3. GLUT-3 → neurons, placenta
      4. GLUT-4 → AT, skeletal m., cardiac m.
    • Muscle & AT
      • ↑glucose uptake by GLUT-4
      • ↑glycogen synthesis
      • ↓glycogenolysis
    • Hepatocytes
      • ↑glucokinase activity → phosphorylates glucose to promote diffusion gradient
      • ↑glycogenesis
      • ↓gluconeogenesis

* Hepatocyte membrane very permeable to glucose & does not need a transporter

Protein Metabolism

    • ↑α-acid transport intracellularly → ↑Pr storage
    • ↓gluconeogenesis from α-acids
    • ↓protein breakdown

Fat Metabolism

    • ↑glucose in hepatocytes
      • Once [glycogen] hits 6% → glycogen synthesis stops
      • Glucose → pyruvate → Acetyl CoA → FA substrate → ↑fat storage
    • Activates LIPOPROTEIN LIPASE → splits TAGS → FFA → AT → ↑fat storage
    • Inhibits HORMONE SENSITIVE LIPASE → ↓lipolysis
    • ↓ketogenesis 2° ↑glucose for fuel source