MBBS Stage 1: Liver and Gluconeogenesis

Glucose: Importance and Sources

• Glucose is the preferred fuel source for all tissues, with some tissues having a continuous dependence on glucose.
• The normal physiological circulating glucose concentration is 3.9-6.2 mM, with an average fasting concentration of 4.4-5 mM for most adults.
• If blood glucose concentration drops to 2.5 mM or less, coma and death can result, while prolonged elevated levels can lead to dehydration, wasting of body tissue, and eventually death.

Roles of Glucose

• Glucose is a source of energy, producing 2 ATP through glycolysis and 31 ATP through the citric acid cycle.
• Glucose is a source of NADPH, needed for synthetic reactions, fatty acid synthesis, and drug metabolism.
• Glucose is a source of pentose sugars for synthetic reactions, such as nucleotide and DNA synthesis.
• Glucose is a source of carbon for other sugars and glycoconjugates.

Advantages and Disadvantages of Glucose as a Metabolic Fuel

• Advantages: water-soluble, can cross the blood-brain barrier, and can be oxidized anaerobically.
• Disadvantages: relatively low yield of ATP per mole compared to fatty acids, osmotically active, and can directly damage cells or lead to toxic by-products in high concentrations.

Glucose Metabolism in Different Tissues

• Skeletal muscle: glycolysis for anaerobic muscle contraction, glycolysis/TCA cycle for energy production, and glycogen synthesis/degradation for energy storage.
• Heart/brain: glycolysis/TCA cycle for energy production.
• Adipose tissue: glycolysis for glycerol production and TAG synthesis.
• Erythrocytes: glycolysis for energy production, and pentose phosphate pathway for NADPH production.

Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency

• X-linked hereditary disorder affecting over 400 million people worldwide, particularly in African, Middle Eastern, and South Asian populations.
• Triggers for hemolytic anemia in G6PD-deficient individuals include favism, resulting from the ingestion of fava beans.

Glucose Metabolism in the Liver

• Glycolysis/TCA cycle for acetyl-CoA production.
• Pentose phosphate pathway for NADPH and pentose sugar production.
• Glycogen synthesis/degradation for glucose storage and release.
• Gluconeogenesis for glucose production from non-carbohydrate sources.

Gluconeogenesis

• Occurs in the liver during carbohydrate deprivation, synthesizing glucose from non-carbohydrate sources such as lactate, glycerol, and glucogenic amino acids.
• Not simply the reversal of glycolysis, requiring bypassing of three irreversible reactions in glycolysis.

Regulation of Gluconeogenesis

• Mobilization of substrate from fat breakdown and muscle protein breakdown.
• Activation of enzymes, including G6Pase, F1,6bisPase, and PEPCK, and pyruvate carboxylase by acetyl-CoA.

Blood Glucose Maintenance

• Insulin, glucagon, and adrenaline (and to a lesser extent cortisol) signal and coordinate the activities of the liver, adipose tissue, and muscle tissue to maintain physiological blood glucose concentrations.
• Insulin promotes synthesis and storage, while glucagon promotes degradation of stored fuel.

Insulin and Glucagon

• Insulin: anabolic hormone promoting synthesis and storage, with effects on liver, muscle, and adipose tissue metabolism.
• Glucagon: catabolic hormone promoting degradation of stored fuel, with effects on liver, muscle, and adipose tissue metabolism.

Glucose Tolerance Curves

• Normal glucose tolerance curves show a rapid increase in blood glucose after a meal, followed by a rapid decrease to basal levels.
• Diabetes type 1 and type 2 show impaired glucose tolerance, with a slower and more prolonged increase in blood glucose after a meal.