Biochemistry - lecture 17 - Glucose Homeostasis

Learning Outcomes

After this lecture, you should be able to:

  • Explain the importance of glucose as a metabolic fuel.

  • Describe the sources of glucose available to the body.

  • Outline how blood glucose homeostasis evolves after a meal.

  • Explain the role of liver and skeletal muscle glycogen in maintaining blood glucose levels.

  • Outline the enzyme reactions involved in glycogen synthesis and degradation.

  • Discuss control mechanisms in glycogen metabolism regulation.

  • Outline gluconeogenesis in the liver.

  • Summarize the roles of insulin and glucagon in glucose homeostasis.

Importance of Glucose

  • Continuous Requirement:

    • Glucose is the preferred fuel source for all tissues, especially those with constant dependence on it.

  • Blood Glucose Levels:

    • Physiological concentration: 3.9-6.7 mM

    • Average fasting level: 4.4-5 mM in adults

    • Critical levels: < 2.5 mM can cause coma/death; prolonged high levels lead to dehydration and tissue wasting.

Roles of Glucose

  • Energy Source: Serves as a primary energy source and is needed for synthetic reactions (e.g., fatty acids, steroids).

  • Pentose Phosphate Pathway: Converts glucose to pentose sugars for nucleotide synthesis and reduces NADP to NADPH for further synthetic reactions.

  • Carbon Source: Acts as a carbon source for other sugars and glycoconjugates.

Advantages and Disadvantages of Glucose

  • Advantages:

    • Water-soluble; no carrier needed for circulation.

    • Can cross blood-brain barrier.

    • Possible anaerobic oxidation.

  • Disadvantages:

    • Lower ATP yield per mole compared to fatty acids.

    • Osmotically active leading to potential cellular damage or toxic by-product accumulation in high concentrations.

Sources of Blood Glucose

  • Diet: 0-4 hours after eating

  • Liver Glycogen: 2-24 hours (max range)

  • Gluconeogenesis: Starts around 4 hours post-ingestion or until death.

Glucose and Glycogen Structure

  • Glucose:

    • Monosaccharide, approx. 10 g in plasma, acts as an immediate energy source.

  • Glycogen:

    • Polysaccharide, approx. 400 g in stored tissues, serves as a medium-term energy source, low osmolarity.

Glycogen Structure

  • Composed of branched structures with:

    • a-1,4 glycosidic bonds

    • a-1,6 bonds for branching.

Role of Glycogen

  • In Liver: Maintains blood glucose levels, sensitive to insulin and glucagon.

  • In Muscle: Serves as a fuel during exercise, sensitive to energy requirements (e.g., adrenaline, AMP).

    • energy for contraction

Glycogen Metabolism

  • Glycogen Synthesis:

    • Catalyzed by glycogen synthase, requires ATP and activated intermediates (e.g., UDP glucose).

    • hexokinase/glucokinase: glucose + ATP → glucose 6-phosphate

    • phosphoglucomutase: glucose 6-phosphate ↔ glucose 1-phosphate

    • UDP glucose pyrophosphorylase: glucose 1-phosphate + UTP → UDP glucose + PPi


  • Glycogen Breakdown (glycogenolysis):

    • Catalyzed by glycogen phosphorylase via phosphorolysis using inorganic phosphate.

    • glycogen phosphorylase: glycogen chain + Pi → glucose-1-phosphate + glycogen chain

    • phosphoglucomutase: glucose-1-phosphate + glycogen chain → glucoe-6-phosphatase

    • glucose-6-phosphatase (liver/kidney): glucose-6-phosphate + H2O → glucose + Pi

    • Final products: glucose in the liver and glucose-6-phosphate in muscle (enters glycolysis).

      • muscles don’t have glucose-6-phosphatase

Regulation of Glycogen Metabolism

  • Regulated by:

    • Allosteric control

    • Hormonal control (e.g., glucagon/adrenaline)

    • Example: Hormones activate signaling pathways that modulate enzyme activities (glycogen phosphorylase and glycogen synthase).

      • hormone binds to cell surface receptor and activates internal signaling pathway which activates a protein kinase

Gluconeogenesis

  • Synthesizes glucose from non-carbohydrate sources like lactate, glucogenic amino acids, and glycerol (not fatty acids since pyruvate dehydrogenase is irreversible).

  • Irreversible Reactions: Have to be bypassed in gluconeogenesis, catalyzed by specific enzymes.

    • hexokinase/glucokinase - glucose-6-phosphotase

    • phosphofructokinase - fructose-1,6-biphosphatase

    • pyruvate kinase - pyruvate → (pyruvate carboxylase) oxaloacetate + GTP → (PEP carboxykinase) PEP

    • all in cytosol

The Cori Cycle

  • Converts lactate from muscle back to glucose in the liver then returns to the muscle and used for glycolysis, facilitated by lactate dehydrogenase.


Blood Glucose Maintenance

  • Coordinated by hormones (insulin, glucagon, adrenaline) across liver, adipose, and muscle tissues to maintain physiological blood glucose levels for glucose-dependent tissues (i.e brain).

  • pancreas - islets of langerhans: alpha cells secrete glucagon and beta cells secrete insulin

Insulin vs. Glucagon

  • Insulin:

    • An anabolic hormone that promotes synthesis and storage of glucose, amino acids, and fatty acids.

  • Glucagon:

    • A catabolic hormone that stimulates glycogenolysis and gluconeogenesis to increase blood glucose levels.

    • promotes degradation of stored fuel

Metabolic Effects of Insulin

  • Liver: Activates glycogen synthesis, increases amino acid uptake/protein synthesis, increases fatty acid synthesis/lipid assembly, and inhibits gluconeogenesis.

  • Muscle: activates glycogen synthesis, increases amino acid uptake and protein synthesis, and increases glucose uptake via translocation of glucose transporters (GLUT4) to the membrane.

Metabolic Effects of Glucagon

  • Increases blood glucose through glycogenolysis and gluconeogenesis in the liver; promotes lipolysis in adipose tissue.

  • Increases circulating fatty acids and ketone bodies

  • Decreases plasma amino acids