Regulation of Blood Glucose: Fed–Fasting Physiology & Hormonal Control

Physiological Importance of Circulating Glucose

Glucose is the universal metabolic fuel for most human cells, with the brain being uniquely dependent on it.

• Brain tissue cannot polymerise glucose into glycogen; therefore it relies on a constant external supply.
• Alternative brain fuels (used only when glucose is scarce): free fatty acids (FFAs) and ketone bodies. Neither is metabolically preferable, and prolonged reliance on either is a stress signal.

Consequences of Dysregulated Glucose

• Hypoglycaemia ("too low")
  • Rapid neuronal energy failure → confusion, seizure, coma → death.
• Hyperglycaemia ("too high")
  • Direct osmotic/neural toxicity.
  • Systemic vascular, renal and retinal damage, typified in uncontrolled type-2 diabetes.

The Pancreas: Endocrine Control Centre

• Exocrine bulk (digestive enzymes) embeds ≈1–2 million islets of Langerhans (≈1 % of organ mass).
• Each islet houses:
  • β-cells → insulin.
  • α-cells → glucagon.

Normal Blood-Glucose Window

Homeostatic set-point is extremely narrow:

(3\,\text{mmol·L}^{-1} \le [\text{glucose}]_{blood} \le 7\text{–}8\,\text{mmol·L}^{-1})

Deviation is corrected by complementary hormone release:

• Rising glucose → insulin.
• Falling glucose → glucagon.

Fed vs. Fasting States

Tissue-Specific Handling of Glucose

1. Skeletal Muscle

• Largest glucose sink.
• Insulin inserts GLUT (primarily GLUT-4) transporters into sarcolemma → ↑ glucose influx.
• Pathways
  • Fed: glucose → glycogen (glycogenesis).
  • Fasting: glycogen → glucose-6-P → glycolysis → ATP + lactate (anaerobic) or CO₂ (aerobic).
  • Prolonged starvation: proteolysis → amino acids → liver for gluconeogenesis.

2. Adipose (Fat) Tissue

• Fed: insulin-stimulated GLUT-4 uptake + circulating FFAs → re-esterified into triglycerides (large lipid droplets).
• Fasting: hormone-sensitive lipase hydrolyses triglycerides → FFAs + glycerol.
  • FFAs supply peripheral tissues & hepatic ketogenesis.
  • Glycerol travels to liver for gluconeogenesis.

3. Liver

• Fed: GLUT-2 (insulin-independent) uptake; insulin drives glycogenesis.
• Fasting: glucagon triggers
  • Glycogenolysis (glycogen → glucose-1-P → glucose).
  • Gluconeogenesis using lactate, amino acids, glycerol.
• Exports products via same GLUT-2 transporter:
  • Glucose to bloodstream (brain fuel).
  • Ketone bodies from β-oxidised FFAs (alternative brain fuel when prolonged fasting).

Integrated Fed-State Map

Gut → blood glucose ↑ → β-cells secrete insulin →

• Muscle: GLUT-4 insertion → glycogenesis.
• Liver: glycogenesis ± lipogenesis.
• Adipose: triglyceride synthesis.
  Net effect: clamp glucose in the \le7\,\text{mmol·L}^{-1} range.

Integrated Fasting-State Map

[Glucose] ↓ → α-cells secrete glucagon →

• Liver: glycogenolysis + gluconeogenesis → glucose output.
  • Substrates supplied by
  • Muscle: lactate & amino acids.
  • Adipose: glycerol.
• Adipose: FFAs fuel peripheral tissues; hepatic FFAs → ketones.
  Net effect: maintain \ge3\,\text{mmol·L}^{-1}.

Molecular Actions of the Hormones

Insulin (anabolic / storage)

• Receptor tyrosine kinase → signalling cascade (PI3K–AKT).
• Muscle & Fat: translocation of GLUT-4 vesicles to plasma membrane (↑ V_max for glucose uptake).
• Liver: not transporter-regulated; instead insulin activates glycogen synthase & suppresses glycogen phosphorylase.

Glucagon (catabolic / mobilising)

• G_s protein-coupled receptor mostly on hepatocytes.
• cAMP ↑ → PKA activation →
  • Activates glycogen phosphorylase.
  • Induces phosphoenolpyruvate carboxykinase → gluconeogenesis.
• Negligible direct effect on muscle or adipose GLUT transporters.

Ethical & Clinical Implications

• Tight glycaemic control is life-saving in type-1 diabetes (exogenous insulin) and disease-modifying in type-2 diabetes (lifestyle ± drugs enhancing insulin sensitivity or limiting hepatic gluconeogenesis).
• Understanding tissue cross-talk informs anti-diabetic therapies (e.g., metformin targets hepatic glucose output; SGLT2 inhibitors increase renal loss).
• Prolonged fasting / eating disorders: muscle wasting and ketosis arise from the described pathways.

Numerical / Biochemical Highlights

• Brain glucose utilisation ≈ 120\,\text{g·day}^{-1} in adults.
• Glycogen storage capacity: liver ≈ $100\,\text{g}$, muscle ≈ $300\text{–}400\,\text{g}$ (varies by mass & training).
• Hormone thresholds: insulin peaks within ≈ $30\,\text{min}$ post-prandially; glucagon spikes when glucose < \sim4.4\,\text{mmol·L}^{-1}.

Links to Other Lectures / Pathways

• Detailed glycolysis, gluconeogenesis, and glycogen metabolism pathways will be covered in subsequent biochemistry sessions.
• β-oxidation and ketogenesis mechanisms elaborated in lipid metabolism lecture.