Jawaharlal Nehru Technological University Hyderabad B.Pharmacy II BIOCHEMISTRY Previous Question Paper (September-2021 - R17)

Blood glucose levels are tightly regulated within a narrow range (70–110 mg/dL) through the coordinated action of several hormones that act primarily on the liver, skeletal muscle, and adipose tissue.

Insulin: Secreted by the β-cells of the pancreas in response to high blood glucose, insulin is the primary hypoglycemic hormone. It promotes glucose uptake into cells (especially muscle and adipose tissue via GLUT4 translocation), stimulates glycogenesis (glycogen synthesis), enhances glycolysis, and promotes lipogenesis while inhibiting gluconeogenesis and glycogenolysis.

Glucagon: Secreted by the α-cells of the pancreas during hypoglycemia, it acts as a hyperglycemic hormone. It stimulates glycogenolysis and gluconeogenesis in the liver to release glucose into the bloodstream.

Other Regulatory Hormones: Epinephrine (adrenaline) stimulates rapid glycogenolysis in muscle and liver during stress. Glucocorticoids (e.g., cortisol) increase blood glucose by promoting gluconeogenesis and decreasing peripheral glucose utilization. Growth Hormone and Thyroxine also exert hyperglycemic effects by antagonizing insulin action and stimulating glycogenolysis.

Disorders of glucose metabolism primarily manifest as deviations from normal glycemic control:

1. Diabetes Mellitus: A chronic metabolic disorder characterized by hyperglycemia due to absolute or relative insulin deficiency. Type 1 is an autoimmune destruction of β-cells, while Type 2 is characterized by insulin resistance and progressive β-cell dysfunction. It leads to polyuria, polydipsia, and long-term complications like neuropathy and retinopathy.
2. Hypoglycemia: Characterized by abnormally low blood glucose levels, often resulting from insulin overdose, insulinoma, or severe starvation. It presents with tremors, sweating, confusion, and in severe cases, coma.
3. Glycogen Storage Diseases (GSDs): Genetic disorders caused by deficiencies in enzymes involved in glycogen synthesis or degradation (e.g., Von Gierke disease due to glucose-6-phosphatase deficiency), leading to abnormal accumulation of glycogen in tissues and severe fasting hypoglycemia.
4. Galactosemia and Fructosuria: Inborn errors of metabolism involving the inability to properly metabolize galactose or fructose, leading to accumulation of toxic intermediates and systemic complications like cataracts or liver damage.

The Citric Acid Cycle (also known as the Krebs cycle or TCA cycle) is the final common pathway for the oxidation of carbohydrates, lipids, and proteins. It occurs in the mitochondrial matrix.

The reactions are as follows:

1. Condensation: Acetyl-CoA (2C) reacts with Oxaloacetate (4C) in the presence of citrate synthase to form Citrate (6C).
2. Isomerization: Citrate is converted to Isocitrate via the intermediate cis-aconitate by the enzyme aconitase.
3. Oxidative Decarboxylation: Isocitrate is oxidized to α-Ketoglutarate by isocitrate dehydrogenase, releasing CO2 and reducing NAD+ to NADH.
4. Second Oxidative Decarboxylation: α-Ketoglutarate is converted to Succinyl-CoA by the α-ketoglutarate dehydrogenase complex, releasing CO2 and producing another NADH.
5. Substrate-level Phosphorylation: Succinyl-CoA is converted to Succinate by succinyl-CoA synthetase, coupled with the phosphorylation of GDP to GTP (or ADP to ATP).
6. Dehydrogenation: Succinate is oxidized to Fumarate by succinate dehydrogenase, reducing FAD to FADH2.
7. Hydration: Fumarate is hydrated to form L-Malate by the enzyme fumarase.
8. Regeneration: L-Malate is oxidized to Oxaloacetate by malate dehydrogenase, producing the final NADH, allowing the cycle to restart.

The net reaction per acetyl-CoA is: Acetyl-CoA + 3NAD+ + FAD + GDP + Pi + 2H2O → 2CO2 + 3NADH + 3H+ + FADH2 + GTP + CoA.

Significance:

• Acts as the primary source of energy by generating high-energy electron carriers (NADH and FADH2) for the electron transport chain.
• Provides precursors for biosynthetic pathways, such as the synthesis of amino acids (via α-ketoglutarate and oxaloacetate), heme (via succinyl-CoA), and fatty acids (via citrate).
• Maintains metabolic homeostasis by linking carbohydrate, lipid, and protein metabolism.