Lecture 12

BM210 Hormonal Control of Metabolic Pathways

Learning Outcomes

  • Understand how metabolism changes in absorptive (fed) and post-absorptive (fasted) states.

  • Explain how insulin is released in response to increased blood glucose.

  • Describe how insulin and glucagon regulate metabolic pathways to control blood glucose levels.

  • Demonstrate that loss of insulin and/or insulin resistance can cause diabetes.

Importance of Glucose

  • Key Energy Source: Brain, nerve cells, erythrocytes, testes, and kidney medulla have an absolute requirement for glucose for energy.

Whole Body Glucose Homeostasis

  • Mechanisms to Maintain Blood Sugar Levels: Blood sugar levels are maintained constant by various homeostatic mechanisms.

    • Excess Glucose: Stored as glycogen (in liver and muscle) or triglycerides (in adipose tissue).

    • Low Glucose Levels: These tissues act as exporters of glucose or fatty acids.

  • Terminology:

    • Hyperglycaemia: High blood glucose levels.

    • Hypoglycaemia: Low blood glucose levels.

Organization of Glucose Metabolic Pathways

  • Levels of Organization: Metabolic pathways are organized at multiple levels:

    • System Level: E.g., human, migrating bird, hibernating brown bear.

    • Tissue/Organ Level: E.g., brain, liver, gut.

    • Cellular Level: E.g., liver vs. muscle response to glucose levels.

    • Subcellular Level: E.g., mitochondria, lipid droplets, cytosol.

Regulatory Challenges

  • Key Questions:

    • How is food intake regulated and sensed?

    • How does the body communicate between tissues?

    • How is the response integrated by specific organs/tissues?

    • How are changes transduced into cellular metabolism?

    • What happens in disease?

    • How does genetics influence susceptibility to diseases?

Blood Glucose Regulation

  • Hormonal Regulation:

    • Insulin: Released from pancreatic beta cells in response to increased blood glucose.

    • Glucagon: Released from pancreatic alpha cells when blood glucose levels fall. Both hormones have opposing actions.

The Actions of Insulin and Glucagon

  • Insulin:

    • Increases glucose uptake into fat and muscle.

    • Increases glycogen synthesis in liver.

    • Inhibits gluconeogenesis in the liver.

    • Signals the fed state and promotes removal of glucose from blood.

  • Glucagon:

    • Stimulates gluconeogenesis.

    • Inhibits glycogen synthesis in the liver.

    • Triggers lipid breakdown.

    • Signals the release of glucose into the blood.

Absorptive vs. Post-Absorptive States

  • Absorptive State:

    • Nutrients enter bloodstream from the GI tract.

    • These nutrients support the body’s energy requirements, and excess is stored.

  • Post-Absorptive State:

    • No nutrients enter the bloodstream.

    • Body switches to net catabolism of stores (glycogen, fat, protein) to maintain blood glucose levels, primarily for brain energy.

Key Events

  • Absorptive State:

    • Cells utilize glucose to produce ATP.

    • Excess glucose is stored as glycogen in the liver and muscle or as triglycerides in adipose tissue.

  • Post-Absorptive State:

    • Fatty acids are the main energy source.

    • Glucose is produced by the liver via gluconeogenesis and glycogen breakdown; released into the blood, essential for brain function. Glycogen breakdown also occurs in skeletal muscle without glucose export.

Hormonal Function of Insulin

  • Definition of Hormones:

    • Chemical messengers released from specific cells in response to stimuli, influencing target organs through the circulatory system with long-range effects. Target cells express specific receptors for hormone response.

Pancreatic Hormones and Metabolism

  • Role of Insulin:

    • Crucial for blood glucose homeostasis, with levels of insulin rising in response to increasing glucose. Its secretion regulates metabolic events during the absorptive state.

Insulin Secretion Mechanism

  • Increased blood glucose levels signal pancreatic beta cells to release insulin. The nutrient levels in the bloodstream influence this mechanism.

Metabolism During Absorptive State

  • Liver Functions:

    • Glucose uptake, glycogen synthesis, and gluconeogenesis regulation.

  • Skeletal Muscle Functions:

    • Glucose uptake, glycogen synthesis, and breakdown regulation.

  • Adipose Tissue Functions:

    • Glucose uptake, triglyceride/fatty acid synthesis, and breakdown regulation.

Insulin Receptor Signaling Pathway

  1. Insulin binds to insulin receptor (IR), leading to receptor autophosphorylation.

  2. Phosphorylated IR residues serve as binding sites for insulin receptor substrates (IRS).

  3. IRS proteins are phosphorylated (4 tyrosine residues) leading to activation of downstream signaling pathways.

  4. Phosphoinositide 3-kinase (PI3K): Binds to IRS proteins converting PIP2 to PIP3.

  5. PDK1 Activation: PIP3 activates PDK1 which phosphorylates and activates kinases like PKB (also known as Akt).

Akt/PKB Signaling Pathway and Effects

  • Key Events of Akt Activation:

    • Regulation of glucose uptake into adipocytes and muscle.

    • Control of glycogen synthesis in liver and muscle.

    • Modulation of gluconeogenesis in the liver.

Mechanism of Glucose Uptake

  • GLUT4 Transporter Action:

    • GLUT4 stored in vesicles; AS160 protein retains these vesicles within the cell.

    • Akt/PKB inactivates AS160 via phosphorylation, allowing GLUT4 vesicles to fuse with the plasma membrane, increasing glucose uptake in cells.

Metabolic Pathway Drives

  • Glycogen Metabolism:

    • Key regulatory enzymes govern metabolic pathways, allowing integration of metabolic processes (e.g., glycogen phosphorylase for breakdown and glycogen synthase for synthesis).

Key Regulatory Enzymes

  • Glycogen synthase activity regulated through phosphorylation from glycogen synthase kinase (GSK).

  • Insulin activates pathways that lead to increased glycogen synthesis, while glucagon opposes this action.

Gluconeogenesis Regulation

  • FoxO1 Transcription Factor:

    • Regulates genes involved in gluconeogenesis (e.g., PEPCK, G6Pase).

    • Insulin signaling leads to phosphorylation and subsequent inhibition of FoxO1, reducing gluconeogenic gene expression.

Consequences of Low Blood Glucose

  • Less insulin is released, affecting glucose uptake, glycogen synthesis, and gluconeogenesis processes, leading to glucagon release from the pancreas.

Defects in Insulin Regulation and Diabetes Types

  • Type 1 Diabetes: Caused by autoimmune destruction of pancreatic beta cells, leading to loss of insulin secretion.

  • Type 2 Diabetes: Associated with insulin resistance and decreased secretion; often linked to obesity. Onset generally occurs in adulthood but is becoming earlier.

Summary of Key Learning Points

  • Differences in metabolism for absorptive vs. post-absorptive states.

  • Function and regulation of pancreatic hormones (insulin and glucagon).

  • Mechanism of insulin signaling and its effects on metabolic pathways.

  • Role of leptin and ghrelin in hunger regulation.

  • Understanding diabetes mechanisms related to insulin dysfunction.

Further Reading

  • Stryer Biochemistry (8th Ed):

    • p. 407-411, 632-635, 808-812