7.1 Insulin and glucagon: structure, secretion, and action

Insulin and glucagon are crucial hormones that regulate blood sugar levels. Produced in the pancreas, insulin lowers glucose by promoting its uptake and storage, while glucagon raises it by stimulating glucose release. Their opposing actions maintain balance in the body's energy metabolism.

Understanding these hormones is key to grasping metabolic regulation. Insulin and glucagon respond to changes in blood glucose, coordinating the body's use and storage of energy. Their interplay affects not just sugar, but also fat and protein metabolism across various tissues.

Insulin and Glucagon Structure and Synthesis

Peptide Hormone Composition and Precursors

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• Insulin consists of two polypeptide chains (A and B) connected by disulfide bonds
• Glucagon forms a single-chain polypeptide hormone
• Both hormones originate from larger precursor molecules
  • Insulin derives from preproinsulin
  • Glucagon stems from preproglucagon
• Post-translational modifications transform precursors into active hormones

Pancreatic Islet Cell Production

• Beta cells in pancreatic islets of Langerhans produce insulin
• Alpha cells in the same islets generate glucagon
• Insulin synthesis involves multiple steps
  • Preproinsulin cleaves to form proinsulin
  • Proinsulin processing yields mature insulin and C-peptide
• Proglucagon cleavage produces glucagon and other bioactive peptides (GLP-1, GLP-2)

Structural Features and Storage

• Insulin's three-dimensional structure incorporates several alpha-helices
• Hydrophobic core in insulin proves crucial for its biological activity
• Both hormones reside in secretory granules within their respective cells
• Granules store hormones before release into the bloodstream

Regulation of Insulin and Glucagon Secretion

Glucose-Mediated Hormone Release

• Elevated blood glucose levels trigger insulin release from beta cells
• Glucose-stimulated insulin secretion (GSIS) pathway facilitates insulin release
  • Glucose uptake and metabolism generate ATP
  • ATP-sensitive potassium channels close
  • Membrane depolarization occurs
  • Voltage-gated calcium channels open
  • Calcium influx prompts insulin granule exocytosis
• Low blood glucose levels (hypoglycemia) stimulate glucagon secretion from alpha cells

Hormonal and Neural Influences

• Incretin hormones potentiate glucose-stimulated insulin secretion
  • Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) activate G-protein coupled receptors
• Autonomic nervous system regulates both insulin and glucagon secretion
  • Sympathetic activation generally inhibits insulin release
  • Sympathetic stimulation promotes glucagon secretion

Nutrient Effects on Hormone Secretion

• Amino acids stimulate both insulin and glucagon secretion
  • Arginine and leucine prove particularly effective (protein-rich meal)
• Free fatty acids exert complex effects on hormone release
  • Acute exposure may enhance insulin secretion
  • Chronic elevation can impair beta cell function (lipotoxicity)

Insulin vs Glucagon Actions on Tissues

Glucose Metabolism Regulation

• Insulin promotes glucose uptake in skeletal muscle and adipose tissue
  • Stimulates GLUT4 glucose transporter translocation to cell membrane
• Glucagon primarily acts on the liver to increase blood glucose levels
  • Promotes glycogenolysis (glycogen breakdown)
  • Enhances gluconeogenesis (glucose production from non-carbohydrate sources)
• Insulin suppresses hepatic glucose production
  • Inhibits glycogenolysis and gluconeogenesis
  • Promotes glycogen synthesis

Lipid Metabolism Effects

• Insulin stimulates lipogenesis in adipose tissue and liver
  • Enhances fatty acid and triglyceride synthesis
  • Promotes storage of excess energy as fat
• Insulin inhibits lipolysis in adipose tissue
  • Reduces breakdown of stored triglycerides
• Glucagon promotes lipolysis and fatty acid oxidation
  • Increases breakdown of stored fats for energy

Protein and Electrolyte Regulation

• Insulin promotes protein synthesis and inhibits protein breakdown
  • Enhances amino acid uptake by cells
  • Stimulates mRNA translation
• Glucagon stimulates protein catabolism
  • Increases amino acid release from muscle tissue
• Insulin enhances potassium uptake by cells
  • Helps regulate serum potassium levels
• Glucagon exerts minimal effects on electrolyte balance

Insulin and Glucagon in Glucose Homeostasis

Blood Glucose Level Maintenance

• Insulin and glucagon work antagonistically to maintain blood glucose levels
  • Normal fasting range typically 70-110 mg/dL
• Postprandial state triggers insulin secretion
  • Rising blood glucose stimulates insulin release
  • Insulin promotes glucose uptake and utilization by peripheral tissues
• Fasting or hypoglycemia activates glucagon secretion
  • Decreased insulin and increased glucagon raise blood glucose
  • Hepatic glucose production increases through glycogenolysis and gluconeogenesis

Hormonal Balance and Metabolic Disorders

• Insulin-to-glucagon ratio determines glucose flux direction
  • High ratio promotes glucose storage and utilization
  • Low ratio favors glucose production and release
• Insulin resistance impairs glucose homeostasis
  • Key feature of type 2 diabetes mellitus
  • Cells become less responsive to insulin's effects
• Counterregulatory response to hypoglycemia involves multiple hormones
  • Glucagon, epinephrine, cortisol, and growth hormone work together
  • Helps restore normal blood glucose levels

Pathological Conditions

• Dysfunction in insulin-glucagon axis leads to metabolic disorders
  • Diabetes mellitus results from insufficient insulin action
  • Insulinomas cause excessive insulin production (pancreatic tumor)
  • Glucagonomas lead to glucagon overproduction (rare endocrine tumor)
• Chronic imbalances in hormone levels can cause long-term complications
  • Microvascular damage (retinopathy, nephropathy)
  • Macrovascular issues (cardiovascular disease)