Insulin Secretion Mechanism Quiz

GLP-1 and Insulin

• GLP-1 stimulates insulin secretion, suppresses glucagon secretion, slows gastric emptying, reduces food intake, increases β cell mass, maintains β cell function, improves insulin sensitivity, and enhances glucose disposal.
• The glucose-lowering effects of GLP-1 are preserved in type 2 diabetics.
• However, native GLP-1 is rapidly degraded by dipeptidyl peptidase-IV (DPP-IV) after parenteral administration.
• GLP-1 receptor (GLP-1R) agonists and DPP-IV inhibitors have shown promising results in clinical trials for the treatment of type 2 diabetes.

Mechanism of Insulin Action

• Insulin binds to specific high-affinity membrane receptors with tyrosine kinase activity.
• Phosphorylation cascade results in the translocation of Glut-4 (and some Glut-1) transport proteins into the plasma membrane.
• It induces the transcription of several genes resulting in increased glucose catabolism and inhibits the transcription of genes involved in gluconeogenesis.
• Insulin promotes the uptake of K+ into cells.

Action of Insulin on Various Tissues

• Liver: ↓ glucose production, ↑ glucose transport, ↑ glycolysis
• Muscle: ↑ glucose transport, ↑ glycolysis
• Adipose: ↓ glucose production, ↑ glucose transport, ↑ lipogenesis, ↑ lipoprotein lipase activity, ↑ TG synthesis, ↑ glycogen deposition, ↓ intracellular lipolysis, ↑ protein synthesis

Insulin Therapy

• The goal of insulin therapy is to mimic the normal basal, prandial, and post-prandial secretion of insulin.
• Short-acting forms are usually combined with longer-acting preparations to achieve this effect.
• Rapid Onset and Ultrashort-acting Preparations:
  • Regular insulin: short-acting, soluble, crystalline zinc insulin, usually given subcutaneously, rapidly lowers glucose levels.
  • Lispro, Aspart & Glulisine preparations: classified as ultrashort-acting forms with an onset more rapid than regular insulin and a shorter duration.
• Intermediate–acting Insulin Preparations:
  • Lente insulin: amorphous precipitate of insulin with zinc ion combined with 70% ultralente insulin, onset is slower but more sustained than regular insulin.
  • Isophane NPH insulin: suspension of crystalline zinc insulin combined with protamine (a polypeptide), conjugation with protamine delays its onset of action and prolongs its effectiveness.

Type 2 Diabetes Treatment

• Classes of Oral Hypoglycemic Drugs:
  • Sulfonylureas
  • Biguanides
  • Thiazolidinediones
  • Alpha-glucosidase inhibitors
  • Meglitinides
• Sulfonylureas:
  • Stimulate release of insulin from pancreatic islet cells
  • Increase sensitivity of insulin receptors on target cells
  • Most common adverse effect is hypoglycemia
• Alpha-Glucosidase Inhibitors:
  • Acarbose and miglitol: delay carbohydrate digestion by competitively inhibiting α-glucosidase
  • Pharmacokinetics: Acarbose is poorly absorbed, remaining in the intestinal lumen; Miglitol is absorbed and excreted by the kidney
  • Adverse Effects: GUESS (flatulence, diarrhea, cramping)

Metformin

• Enters the cell through transporters such as SLC22A1
• Inhibits mitochondrial complex I, resulting in reduced ATP levels and an accumulation of AMP
• Activates AMPK, which suppresses fat metabolism and possibly also contributes to the reduced gluconeogenic gene expression