Diabetes Pathophysiology & Drugs Flashcards
How is insulin synthesised?
Synthesised as proinsulin. Enzymes cleave off the connecting C-peptide to release active insulin, composed of two peptide chains (A and B). These two chains are connected by disulphide bonds.
What is the significance of C-peptide?
Indicates endogenous synthesis of insulin because insulin itself has a short half life
How does glucose trigger insulin release?
Increased levels of glucose bind to GLUT2 (a low affinity [km15-20] transporter and enter the pancreatic beta cells
The glucose goes through the glycolytic pathway to produce ATP.
Increased ATP causes ATP-dependent potassium channel to close, leading to depolarisation.
The cell depolarisation causes a voltage-sensitive calcium channel to open, allowing calcium to enter the cell
Calcium entry prompts the exocytosis of insulin
Apart from glucose, what other factors regulate insulin release?
Amino acids such as leucine and arginine trigger insulin release
Parasympathetic release of AcH acts via the phospholipase C-IP3 pathway to increase intracellular calcium in beta cells, stimulating insulin release
Adrenaline suppresses insulin release
What is the structure of the insulin receptor?
2 heterodimers - an extracellular alpha subunit and a transmembrane beta-subunit containing the enzyme tyrosine kinase.
Binding of insulin to the alpha subunit results in autophosphorylation and activation of the tyrosine kinase in the beta-subunit
How does insulin signal within a cell?
- When insulin receptor binds insulin, the activated receptor phosphorylates the IRS-1 protein
- IRS-1 activates PI-3-Kinase, which catalyses the addition of a phosphate group to the membrane lipid PIP2, thereby converting it to PIP3. PTEN can convert PIP3 back to PIP2
- PIP3 binds Akt
- Akt catalyses phosphorylation of key proteins leading to increase in glycogen synthase and recruitment of GLUT4 to the membrane
Describe the types of glucose transporters
- GLUT1: All mammalian tissues (km=1, for basal glucose uptake)
- GLUT2: Liver & Pancreatic beta cells (km=15-20)
- GLUT3: all mammalian tissues (km=1, basal glucose uptake)
- GLUT4: Muscle and Fat Cells (km=5, insulin dependent)
- GLUT5: small intestine (primarily a fructose transporter)
What are the metabolic actions of insulin on cells?
Liver: Glycolysis, Glycogen Synthesis, Fatty Acid Synthesis, Protein Synthesis
Muscle: Increase GLUT4 expression, protein synthesis, glycogen synthesis, glycolysis
Adipose Tissue: Increase GLUT4 expression, Fatty Acid Synthesis (Increase LPL), Glycogen Synthesis
How is insulin cleared?
- 50% cleared during first pass
- Kidney is a major site of insulin clearance from systemic circulation, removing 50% of peripheral insulin via glomerular filtration and proximal tubular reabsorption and degradation
- Exogenous insulin is mainly cleared by the kidneys
What are the principles of treatment for T1 diabetes patients?
- Insulin Therapy
- Basal Insulin
- Prandial Insulin
What is the mechanism of action of rapid acting insulin?
Substitution or addition of amino acids resulting in changes to charge and/or conformation of insulin molecule at physiological pH
Weakening the propensity for insulin to self associate, allowing rapid absorption from subcutaneous tissue at time of injection
What is the onset of action of rapid acting insulins and what is the significance of that?
- Lispro - 15-30min, Aspart - 12-18min, Glulisine - 12-30min
Significance: Can be injected just before meals
What is the duration of action of rapid acting insulins and what is the significance of that?
- Lispro - 2-4h; Aspart - 3-5h; Glulisine - 3-5h
Significance: Shorter duration of action means lower incidence of hypoglycemia
What is the mechanism of action of short-acting insulin (Regular Human Insulin)?
Structurally similar to endogenous human insulin, consists of dissolved zinc-insulin crystals which self aggregate in the subcutaneous tissue, resulting in a delayed onset of action of 30-60min
What is the onset of action for regular human insulin? what is the significance?
30-60min. Inject 20-30min before food
