LF129 8: Receptor Enzymes

Overview of Insulin and Its Mechanism

  • Insulin Receptor (IR): A key receptor with intrinsic enzyme activity crucial for metabolizing glucose and signaling pathways for growth.

Classes of Receptors

  • Intrinsic Enzyme Activity: Some receptors can act as enzymes themselves (e.g., insulin receptor).
  • Linked to Protein Kinases: Receptors that initiate signaling through protein kinases.
  • Coupled via G Proteins: Receptors that interact with G proteins.
  • Intracellular Receptors: Receptors located inside the cell that mediate responses to lipophilic signals.
  • Ion Channel Receptors: Receptors that form ion channels in membranes.

Blood Glucose Regulation

  • Normal Levels: Approximately 4.5 mM; spikes occur post-meal.
  • Hormones Involved:
    • Insulin: Decreases blood sugar levels.
    • Glucagon: Increases blood sugar levels.
    • Epinephrine: Raises blood sugar levels (stress response).
    • Cortisol: Raises blood sugar levels (long-term stress response).

Structure and Activation of Insulin Receptor

  • Formation:

    • IR is synthesized as a single protein from one gene.
    • Undergoes processing to form α and β subunits in the endoplasmic reticulum and Golgi complex before reaching the plasma membrane.

  • Activation: Insulin binding induces conformational changes, causing autophosphorylation which activates IR.

Signal Transduction Pathway

  • First Step: Activated IR phosphorylates insulin receptor substrate-1 (IRS-1).
  • Adaptor Proteins: Grb2 and Sos bind IRS-1 and facilitate further signaling.
    • Sos as a Guanine Nucleotide Exchange Factor (GEF) converts Ras from inactive GDP-bound to active GTP-bound state.
MAPK Cascade Activation
  • Ras activation leads to the recruitment of Raf kinase, further activating the MAPK cascade, involving:
    • Raf → activates MEK → activates ERK.
    • Resulting in the modulation of gene expression and cellular responses.

Protein Kinase B (PKB/Akt) Activation

  • IRS-1 also activates PI-3K, which then converts PIP2 to second messenger PIP3.
  • PIP3 activates PKB (Akt), involved in glucose metabolism and cellular growth signaling pathways.

Cellular Responses to Insulin

  • Immediate Effects (minutes):

    • Enhanced glucose uptake in muscle and fat cells.
    • Changes in enzyme activities without new protein synthesis.

  • Delayed Effects (hours):

    • Increased expression of enzymes for glycogen synthesis in the liver and fat storage.
    • Changes in gene expression involved in cell growth.

Diabetes Mellitus

  • Types:

    • Type I (IDDM): Insulin production deficiency, usually early onset, treated with insulin injections.
    • Type II (NIDDM): Insulin resistance, often linked to obesity and late onset.

  • Symptoms:

    • Excessive thirst, frequent urination, high blood glucose levels in urine.

Insulin Signaling in Diabetes

  • In Type II diabetes, impaired PKB activity reduces glucose uptake via GLUT4 transporters and impacts glycogen synthesis leading to sustained high blood sugar levels.

  • Lifestyle interventions such as diet changes and physical activity can restore insulin sensitivity over time, reducing symptoms and complications associated with Type II diabetes.

Conclusion

  • Insulin serves dual functions: as a growth factor through MAPK signaling and a glucose regulator using the PI3K/AKT pathway.
  • Chronic high blood sugar may lead to desensitization of insulin signals and can be addressed via intensive management strategies.