Hormonal Regulation of Metabolism

• Insulin, glucagon, somatostatin, epinephrine, growth hormone, and cortisol regulate metabolism.
• These hormones control glucose, protein, and fat metabolism.
• Gut hormones (GI hormones) and nutrients also play a role in controlling metabolism.

Definitions

• Glycogenesis: Glycogen formation.
• Glycogenolysis: Glycogen breakdown.
• Glycolysis: Glucose breakdown to pyruvate or lactate.
• Gluconeogenesis: Generation of glucose from non-carbohydrate substrates.
• Adipogenesis: Differentiation of pre-adipocytes into adipocytes.
• Lipogenesis: Conversion of acetyl-CoA to fatty acids.
• Lipolysis: Breakdown of fat and lipids to release fatty acids.

Hormones Regulating Carbohydrate and Lipid Metabolism

• Pancreas:
  • Insulin: Promotes glucose and lipid storage; acts on the liver, fat, and skeletal muscle.
  • Glucagon: Promotes glucose production; acts on the liver, fat, and skeletal muscle.
  • Somatostatin (SST): Regulates insulin and glucagon (inhibits them); acts on multiple sites.
  • Amylin: Inhibits glucagon; acts on multiple sites.
• Pituitary (Anterior):
  • Growth Hormone: Promotes glucose production; acts on the liver.
• Adrenal Gland:
  • Epinephrine, Cortisol: Increase glucose production; act on multiple sites.
• GI Tract:
  • GLP-1, GIP, Gastrin, Secretin, CCK: Alter insulin secretion; act on the pancreas.
• Adipose Tissue:
  • Leptin, Adiponectin, Resistin: Induce satiety, decrease glucose levels, and cause insulin resistance; act on the brain and other sites.
• Thyroid:
  • T3, T4: Regulate metabolism and metabolic rate; act on all cells.

Key Acronyms

• GH: Growth Hormone
• GLP-1: Glucagon-like peptide-1
• GIP: Gastric inhibitory polypeptide
• CCK: Cholecystokinin

Hormones and Glucose Levels

• Cortisol, Growth Hormone, Glucagon, and Epinephrine increase plasma glucose levels.

Anabolic vs. Catabolic Functions

• Anabolic Functions
  • Hormones: Insulin, Growth Hormone (protein synthesis only)
  • Builds storage forms such as protein, fat, and glycogen from smaller molecules.
• Catabolic Functions
  • Hormones: Glucagon, Epinephrine, Cortisol
  • Breaks down larger molecules into smaller ones to increase glucose level for metabolic needs (ex: glycogen to glucose)
• Insulin promotes the synthesis of protein, triglycerides, and glycogen.
• Growth hormone has an anabolic feature specifically in protein synthesis.
• Glucagon breaks down glycogen into glucose.
• Epinephrine and Cortisol also have catabolic functions.

Pancreatic Islets and Insulin Synthesis

• Alpha cells produce glucagon.
• Beta cells produce insulin.
• Delta cells produce somatostatin.
• PP cells produce pancreatic polypeptides.
• Insulin is synthesized as proinsulin in the rough ER, transported to the Golgi, and stored in granules.
• Upon receiving a signal for release, granules fuse with the cell membrane and release insulin.
• Insulin is a hydrophilic hormone.
• Proinsulin is cleaved by proteinase enzyme into insulin and C-peptide chain.
• C-peptide has no biological activity, but is measured to indirectly assess insulin levels (1:1 ratio with insulin).
• Real insulin has two chains connected by disulfide bonds.

Insulin Release

• Insulin is released from granules in response to increased plasma glucose levels.
• Glucose concentration increase serves as the stimulating signal for insulin secretion.
• Insulin is not a steroid hormone, it is a peptide hormone that requires processing (proteinase cleavage).
• The major function of insulin is anabolic.

Mechanism of Action of Insulin

• Insulin activates PI3 kinase when it binds to receptors.
• PI3 kinase helps insert GLUT4 into the cell membrane.
• Allows glucose to enter the cell.
• Glycogen storage and protein synthesis are promoted (anabolic).
• Transcriptional pathway: regulates synthesis of mRNA and proteins, controlling various cellular functions.
• Mitogenic pathway: regulated by MAP kinase to regulate mitogenic effects like proliferation.
• Vesicles with GLUT4 fuse with the cell membrane due to PI3 kinase activation allowing for the glucose to enter.

Speed of Insulin Action

• Rapid (seconds)
  • Transport of GLUT4 to the cell membrane
  • Potassium uptake into the cell
• Intermediate (minutes)
  • Stimulates protein synthesis
  • Activates glycolytic enzymes (glucose to pyruvate)
  • Activates glycogen synthase
• Slow (hours)
  • Inhibits phosphorylase and gluconeogenic enzymes
  • Increases mRNAs for lipogenic enzymes (fat metabolism)

Key Points

• Insulin decreases glucose concentration through various mechanisms.
• Insulin has a slow effect in synthesizing enzymes for fat synthesis and storage.
• Insulin receptors have binding sites on the cell surface and a kinase component in the cytoplasm.
• GLUT4 transporters are already synthesized inside the cell, needing only a signal for insertion.
• Insulin promotes protein synthesis, not degradation (anabolic).

Physiological Functions of Insulin in Different Organs

• Stimuli for Insulin Release: Glucose and amino acids.
• Liver:
  • Stimulates glucose uptake (metabolized or stored as glycogen).
  • Increases glycolysis, glycogen synthesis, lipid synthesis, protein synthesis
• Fat Tissue:
  • Synthesizes triglycerides (storage format).
• Skeletal Muscle:
  • Synthesizes protein from amino acids, increase glucose uptake, increase glycogen synthesis.
  • Decreases protein catabolism, gluconeogenesis from amino acids, and increases ketone and potassium uptake.
• Amylin, secreted from beta cells, inhibits glucagon and decreases glucose concentration by slowing gastric emptying and increasing satiety.

Insulin Actions in Fat Tissue (Adipose Tissue)

• Insulin binds to cell surface receptors.
• Increases glucose entry via GLUT4.
• Increases glycerol phosphate synthesis.
• Activates lipoprotein lipase (LPL).
  • LPL breaks down fat complexes in blood vessels, releasing fat for use by fat cells (adipocytes).
• Increases long-chain fatty acid entry via FATP transporter.
• Increases fatty acid synthesis and triglyceride deposition.
• Inhibits hormone-sensitive lipase (HSL).
  • HSL breaks down triglycerides into free fatty acids and glycerol.
• Increases potassium uptake into cells.

Insulin Actions in Skeletal Muscle

• Insulin binds to receptors.
• Increases amino acid uptake via SNAT-2 transporter for protein synthesis.
• Increases glucose uptake via GLUT-4.
• Increases glycogen synthesis.
• Decreases protein catabolism.
• Decreases release of gluconeogenic amino acids.
• Increases ketone uptake.
• Increases potassium uptake into the cells.

Insulin Actions in the Liver

• Glucose uptake is not insulin-dependent, it depends on the concentration gradient.
• Insulin increases glycolysis, decreasing intracellular glucose, creating a gradient for uptake.
• Increases glycogen synthesis.
• Decreases gluconeogenesis.
• Decreases ketogenesis (prevents ketoacidosis).
• Increases protein and lipid synthesis (anabolic features).

Glucose Stimulated Insulin Secretion in Beta Cells

• Beta cells in pancreatic islets secrete insulin.
• Glucose uptake via GLUT-2 in beta cells.
• Glucose is phosphorylated and metabolized to pyruvate.
• Pyruvate is oxidized in mitochondria, producing ATP.
• ATP inhibits potassium channels, leading to cell depolarization.
• Depolarization activates calcium channels, causing calcium influx.
• Calcium influx stimulates insulin granule fusion with cell membrane and insulin release.

Factors Affecting Insulin Secretion

• Stimulators:
  • Glucose, amino acids, beta-keto acids, glucagon, acetylcholine
  • Intestinal hormones (GIP, GLP, secretin, CCK)
  • Beta-adrenergic stimulators (theophylline)
  • Sulfonylurea drugs
• Inhibitors:
  • Low potassium concentration
  • Somatostatin, galanin
  • Adrenal stimulators (epinephrine, norepinephrine)
  • Propranolol, diazoxide, thiazide diuretics

GI Hormones that Stimulate Insulin

• GIP (Gastric Inhibitory Peptide/Glucose-dependent insulinotropic peptide):
  • Produced by intestinal K cells in the duodenum and jejunum.
  • Released in response to fat and glucose (fat more inhibitory).
  • Stimulates insulin secretion in the presence of glucose.
  • Enhances fatty acid incorporation into triglycerides, stimulates LPL.
  • Promotes beta cell proliferation and survival.
• GLP-1 (Glucagon-like peptide-1):
  • Secreted by intestinal L cells in the small bowel and colon.
  • Released in response to amino acids, fiber, sweeteners, sugars, glucose, and fatty acids.
  • Stimulates insulin secretion in the presence of glucose, reduces hypoglycemia.
  • Inhibits gastric emptying, decreases food intake.
  • Inhibits glucagon secretion, slows glucose production.
  • Protects beta cells from apoptosis and stimulates beta cell proliferation, maintaining beta cell mass.

Explore how insulin, glucagon, and other hormones regulate metabolic processes. Understand glycogenesis, lipolysis, and the roles of pancreatic hormones. Learn about carbohydrate and lipid metabolism.