Module 1c: Endocrine Regulation of Organic Metabolism

INSULIN SIGNALING CASCADE

• Initial ligand-receptor interaction
  • Insulin binds to its tyrosine-kinase insulin receptor embedded in the plasma membrane.
  • Receptor autophosphorylation → recruitment & phosphorylation of IRS (Insulin-Receptor-Substrate) proteins.
• Core intracellular pathway
  • Phospho-IRS activates PI3K (phosphatidyl-inositol-3-kinase).
  • PI3K converts $PIP<em>2$ to $PIP</em>3$.
  • $PIP_3$ serves as a docking lipid for Akt/PKB (Protein-Kinase-B):
  – Akt is described as a “pleiotropic enzyme” because it co-ordinates many downstream metabolic effects in hepatocytes, skeletal muscle and adipocytes.
• Key Akt-dependent downstream branches
  • GLUT4 translocation → ↑ glucose import.
  • Activation of protein phosphatases → rapid (minutes) de-phosphorylation of rate-limiting enzymes:
  – Stimulates $\text{glycolysis}$ and $\text{glycogenesis}$.
  – Inhibits $\text{glycogenolysis}$, $\text{lipolysis}$, $\text{gluconeogenesis}$, $\text{ketogenesis}$.
  • mTORC1 pathway
  – Promotes $\text{protein synthesis}$, cell growth, & inhibits proteolysis/autophagy.
  • SREBP-1c activation
  – Drives transcription of lipogenic enzymes → ↑ $\text{lipogenesis}$ and ‘fed-state’ glycolytic enzymes.
  • FOXO1 inhibition (via phosphorylation & nuclear exclusion)
  – ↓ transcription of gluconeogenic genes & $VLDL$ export machinery.

INSULIN-REGULATED GLUCOSE UPTAKE

• Vesicular trafficking step
  • In the basal state, GLUT4 resides in intracellular vesicles.
  • Akt signaling triggers vesicle tethering, docking & fusion with the plasma membrane.
• Functional outcome
  • Facilitated diffusion of glucose down its concentration gradient into muscle & adipose tissue.
  • Entry of glucose provides substrate for:
  – $\text{Glycolysis}$ → $\text{C}<em>6\text{H}</em>{12}\text{O}<em>6 + 6 O</em>2 \rightarrow 6 CO<em>2 + 6 H</em>2O + ATP$.
  – $\text{Glycogen synthesis}$.
  – Triglyceride synthesis (via glycerol-3-phosphate production).

GLUT TRANSPORTERS

• GLUT1
  • Ubiquitous, high-affinity transporter → maintains basal glucose uptake.
  • Crucial for brain & erythrocyte energy supply.
• GLUT2
  • Low-affinity (high $K_m$) transporter → active when plasma glucose rises.
  • Major glucose flux route in liver, intestine, kidney; allows bidirectional transport.
• GLUT4
  • Restricted to skeletal & cardiac muscle + adipose tissue.
  • Insulin-dependent — resides intracellularly until stimulated.
  • Confocal microscopy (Watson et al., 2004) visualises vesicular redistribution upon insulin.

INSULIN ACTIONS DURING THE ABSORPTIVE (FED) STATE

• Trigger : ↑ blood glucose → β-cell sensing → ↑ plasma insulin.
• Target tissues & transport mechanisms
  • Muscle/fat: GLUT4-mediated facilitated diffusion of glucose.
  • Most cells: Active transport of amino acids enhanced.
• Anabolic effects promoted
  • ↑ Protein synthesis (ribosomal stimulation + mTORC1).
  • ↑ Glycogenesis (glycogen synthase de-phosphorylated).
  • ↑ Glycolysis → ATP generation.
  • ↑ Lipogenesis (acetyl-CoA carboxylase & fatty-acid synthase via SREBP-1c).
• Catabolic pathways inhibited
  • ↓ Gluconeogenesis, glycogenolysis, lipolysis, ketogenesis, proteolysis.

GLUCAGON OVERVIEW

• 29-amino-acid peptide discovered (Kimball & Murlin, 1923).
• Secreted by α-cells in pancreatic islets; plasma $t_{1/2} ≈ 5\text{ min}$ (rapid hepatic/renal degradation).
• Receptor: G-protein coupled 7-TM glucagon receptor → ↑ $cAMP$ → protein kinase A cascade.
• Clinical use: emergency treatment of severe hypoglycaemia.

GLUCAGON ACTIONS DURING THE POST-ABSORPTIVE (FASTED) STATE

• Trigger : ↓ blood glucose sensed by α-cells → ↑ plasma glucagon.
• Liver
  • ↑ Glycogenolysis (activates glycogen phosphorylase).
  • ↑ Gluconeogenesis (induces PEPCK, G-6-Pase).
• Adipose tissue
  • ↑ Lipolysis → ↑ plasma free fatty acids (FFAs).
  • FFAs oxidised by other tissues (glucose-sparing).
• Feedback : rising glucose & insulin inhibit further glucagon release.

AMINO ACIDS & GLUCAGON

• Protein-rich meals ↑ certain amino acids → stimulate BOTH insulin and glucagon.
• Resulting glucagon release prevents insulin-induced hypoglycaemia by driving hepatic glucose output.

GLUCOSE COUNTER-REGULATORY HORMONES

• When glucose drops, in addition to glucagon:
  • Epinephrine – rapid mobilisation of glycogen & lipolysis.
  • Cortisol – permissive, up-regulates gluconeogenic enzymes.
  • Growth hormone – chronic ↓ glucose uptake & ↑ lipolysis.
• Combined effects:
  • ↑ Glycogenolysis.
  • ↑ Gluconeogenesis.
  • ↑ Lipolysis.
  • ↓ Glucose uptake in muscle & adipose tissue.

KEY CONNECTIONS & IMPLICATIONS

• Homeostatic balance: Insulin = dominant “storage/anabolic” hormone; Glucagon & counter-regulators = safeguard against hypoglycaemia.
• Clinical relevance :
  • Diabetes Mellitus – insulin deficiency/resistance → pathway failure (↓ GLUT4 translocation, unchecked gluconeogenesis, ↑ lipolysis → ketoacidosis).
  • Glucagonoma – α-cell tumour → hyperglycaemia, wasting.
  • Therapeutics targeting PI3K/Akt/mTOR (oncology) can inadvertently perturb metabolic control.
• Ethical / philosophical reflection : Understanding hormonal control illuminates how multicellular organisms delegate nutrient allocation, mirroring broader principles of resource governance and systemic feedback regulation.