Hormonal Regulation of Metabolism & Starvation Adaptations OVERARCHING THEME Maintaining [glucose] b l o o d \text{[glucose]}_{blood} [glucose] b l oo d 3.9 – 6.7 mmol⋅L − 1 3.9–6.7\,\text{mmol·L}^{-1} 3.9–6.7 mmol⋅L − 1 Control relies on a classic negative-feedback loop in which deviations in glucose are sensed by pancreatic islets, triggering hormone release that drives compensatory metabolic pathways until the set point is re-established. 1 Homeostasis Basics Definition Homeostasis = the dynamic process by which physiological variables are kept within limits compatible with life despite external or internal change. Mechanistic outline Sensor → Integrator → Effector scheme: Error → Islets → Hormone → Metabolic Pathway → − Error \text{Error} \to \text{Islets} \to \text{Hormone} \to \text{Metabolic Pathway} \to -\text{Error} Error → Islets → Hormone → Metabolic Pathway → − Error Importance Prevents neuro-glycopenia, protects proteins from being catabolised and sustains osmotic balance. 2 Pancreatic Control of Blood Glucose Islet architecture β \beta β ↑ [ glucose ] \uparrow\,[\text{glucose}] ↑ [ glucose ] α \alpha α ↓ [ glucose ] \downarrow\,[\text{glucose}] ↓ [ glucose ] Hormonal interplay Insulin and glucagon act as functional antagonists yet cooperate to hold glucose steady. Time-scale: minutes (hormone secretion) → seconds (enzyme phosphorylation) → hours (gene expression). 3 Insulin: Cellular & Molecular Actions Trigger: post-prandial hyperglycaemia. Receptor = tyrosine-kinase dimer → autophosphorylation → phosphorylation cascade. Major metabolic outcomes ↑ GLUT4 translocation in muscle/adipose → ↑ glucose uptake. ↑ Glycogen synthesis in liver & muscle via dual control: Activates glycogen synthase (GS) by de-phosphorylation. Inhibits glycogen phosphorylase (GP) by de-phosphorylation. Promotes glycolysis & lipogenesis, suppresses gluconeogenesis & lipolysis. Key enzyme logic Only one direction active at a time (avoids futile cycling). Representative reaction Glycogen < e m > n + UDP-Glucose → GS Glycogen < / e m > n + 1 + UDP \text{Glycogen}<em>{n} + \text{UDP-Glucose} \xrightarrow{\text{GS}} \text{Glycogen}</em>{n+1} + \text{UDP} Glycogen < e m > n + UDP-Glucose GS Glycogen < / e m > n + 1 + UDP 4 Glucagon & Epinephrine During Hypoglycaemia Released when fasting, exercise or stress lower glucose. Receptors coupled to G s G_s G s Effects Inhibits glycogen synthase (via phosphorylation). Activates glycogen phosphorylase kinase → phosphorylase a → glycogenolysis. Stimulates hepatic gluconeogenesis & adipose lipolysis; spares glucose for brain. Epinephrine adds rapid muscle glycogenolysis for “fight-or-flight”. 5 Phosphorylation as a Regulatory Switch Adds PO 4 3 − \text{PO}_4^{3-} PO 4 3 − Alters electrostatic landscape → conformational change → functional change. Three typical consequences Enzyme activation, inhibition, or modified cellular localisation. Reversible: kinases add, phosphatases (e.g. 6 Predictive Applications ↑ Insulin → ↑ glycogenesis, ↓ glycogenolysis, ↓ blood glucose. ↑ Glucagon/Epi → ↑ glycogenolysis, ↑ gluconeogenesis, ↑ blood glucose. Failure of either limb → dysglycaemia (e.g. 7 Review / Self-Test Concepts Explain why insulin and glucagon form a negative feedback loop. Predict hepatic enzyme activity after a carbohydrate-rich meal versus during an overnight fast. Why are futile cycles (simultaneous synthesis & breakdown) energetically disadvantageous? 1 Physiological Context & Stages Starvation = prolonged (> 24 h) nutrient deprivation. Four chronological fuel phases Glycogenolysis (0–24 h). Gluconeogenesis (+ lipolysis begins) (1–3 days). Lipolysis dominant → hepatic ketogenesis (3–20 days). Protein catabolism rises sharply once fat exhausted → organ failure → death. Hormonal milieu ↓ Insulin, ↑ Glucagon, ↑ Cortisol, ↑ Growth Hormone, ↑ Catecholamines. 2 Body Energy Reserves (Approx.) Carbohydrate (glycogen) ≈ 2 000 kcal 2\,000\,\text{kcal} 2 000 kcal Triacylglycerol (adipose) ≈ 135 000 kcal 135\,000\,\text{kcal} 135 000 kcal Mobilisable protein ≈ 24 000 kcal 24\,000\,\text{kcal} 24 000 kcal Example exercise (slide table): dividing kcal by 1 600 kcal⋅day − 1 1\,600\,\text{kcal·day}^{-1} 1 600 kcal⋅day − 1 3 Organ-Specific Fuel Preferences Brain Normally strictly glucose (≈ 120 g⋅day − 1 120\,\text{g·day}^{-1} 120 g⋅day − 1 Switches to ketone bodies (acetoacetate, β-hydroxybutyrate) after ≈ 3 days, lowering glucose demand by ≈ 2 3 \frac{2}{3} 3 2 Muscle Uses its own glycogen early; later prefers fatty acids and ketones, sparing glucose. Liver Central hub: glycogenolysis, gluconeogenesis, β-oxidation, ketogenesis. Heart Highly oxidative; thrives on fatty acids and ketones throughout. Adipose Lipolysis releases fatty acids + glycerol (gluconeogenic precursor). Gluconeogenesis Substrates: lactate (Cori cycle), glycerol, glucogenic amino acids. Requires bypass of three irreversible glycolytic steps: Pyruvate → Pyruvate carboxylase + PEPCK PEP → ⋯ → Glucose \text{Pyruvate} \xrightarrow{\text{Pyruvate carboxylase} + \text{PEPCK}} \text{PEP} \to \dots \to \text{Glucose} Pyruvate Pyruvate carboxylase + PEPCK PEP → ⋯ → Glucose Lipolysis Hormone-sensitive lipase in adipose hydrolyses TAG → 3 fatty acids + glycerol. Ketogenesis When acetyl-CoA from β-oxidation exceeds TCA capacity: 2 Acetyl-CoA → Acetoacetate ⇆ β -Hydroxybutyrate + Acetone 2\,\text{Acetyl-CoA} \to \text{Acetoacetate} \leftrightarrows \beta\text{-Hydroxybutyrate} + \text{Acetone} 2 Acetyl-CoA → Acetoacetate ⇆ β -Hydroxybutyrate + Acetone Ketones are water-soluble, cross the BBB and spare muscle protein. 5 Clinical Perspective: Ketosis vs Ketoacidosis Nutritional ketosis: 0.5 – 3 mmol⋅L − 1 0.5–3\,\text{mmol·L}^{-1} 0.5–3 mmol⋅L − 1 Ketoacidosis: > 10 mmol⋅L − 1 10\,\text{mmol·L}^{-1} 10 mmol⋅L − 1 7.3 7.3 7.3 Symptoms: fruity breath (acetone), Kussmaul breathing, mental status change; treat with insulin, fluids, electrolytes. 6 Case Study – David Blaine’s 44-Day Fast Observations Lost ≈ 24.5 kg 24.5\,\text{kg} 24.5 kg Reported “pear-drop” taste → acetone. Plasma graphs show ↓ glucose, ↑ free fatty acids, ↑ ketones. Biochemical explanation Glycogen used up within first day. Gluconeogenesis maintained minimal glucose using amino acids & glycerol. Lipolysis supplied acetyl-CoA → ketones fuelled brain, allowing protein sparing. Weight loss mainly adipose + some lean mass; re-feeding required medical supervision to avoid re-feeding syndrome. 7 Integrated Survival Strategy Hierarchical substrate use: Glycogen → Fat → Protein \text{Glycogen} \to \text{Fat} \to \text{Protein} Glycogen → Fat → Protein Hormones orchestrate enzyme ensembles through phosphorylation/de-phosphorylation. Gluconeogenesis and ketogenesis jointly protect critical organs and extend lifespan during nutrient absence. 8 Self-Assessment & Ethical Reflection Predict metabolic profile (hormones, substrates) after 2 days vs 20 days of fasting. Discuss risks/benefits of ketogenic diets; where is the line between adaptation and pathology? Consider humanitarian crises where starvation is involuntary—understand biochemistry to guide medical relief.