L 13-14 Nutrient Metabolism: Insulin & Glucagon
Nutrient Metabolism: Insulin & Glucagon
Overview of Concepts and Definitions
Excess Carbohydrate Storage:
Stored as Glycogen or converted to Triglycerides (Fatty Acids)
Breakdown of Substrates (Catabolism)
Primary Catabolic Pathways:
Glycolysis:
Process: Glucose → CO₂ + H₂O + ATP
Fatty Acid Oxidation:
Process: Fatty Acids → CO₂ + H₂O + ATP
Other Catabolic Processes:
Glycogenolysis: Breakdown of stored glycogen to glucose
Lipolysis: Breakdown of stored triglycerides to fatty acids & glycerol
Synthesis of Substrates (Anabolism)
Anabolic Pathways:
Gluconeogenesis: Generation of new glucose from amino acids, lactic acid, or glycerol
Ketogenesis: Generation of ketones from fatty acids
Cellular Energy Source:
Cells primarily use glucose or fatty acids in normal metabolism.
Types of Tissues & Glucose Transport
Glucose-Dependent Tissues
Characteristics:
Can only use Glucose.
Examples:
Brain, neurons, red blood cells, intestinal mucosa, renal medulla.
Transporter: GLUT (glucose transporter) present on plasma membrane.
Concentration Gradient: Must maintain at least 60 mg/dl blood glucose to drive glucose entry into cells.
Insulin-Independent Transport:
Glucose-dependent cells transport glucose into the cell without insulin assistance.
Glucose-Independent Tissues
Characteristics:
Can use glucose or fatty acids for energy.
Examples:
Skeletal Muscle, Adipose Tissue, Liver.
Insulin-Dependent Transport:
Insulin activates a second messenger system to increase GLUT4 transporter on the cell surface.
Cells can utilize fatty acids when glucose levels are low.
Metabolic Phases
Absorptive Phase
Definition: Active eating and digesting a meal while absorbing nutrients.
Plasma Concentrations After Meal:
Elevated levels of glucose, amino acids, and fatty acids.
Goals of Absorptive Phase:
Lower plasma concentrations of glucose, fatty acids, and amino acids.
Maximize glucose uptake by glucose-independent tissues via insulin release.
Mobilize GLUT4 to plasma membrane.
Metabolize glucose for energy (ATP production).
Synthesize structural and functional proteins.
Store excess nutrients as glycogen or triglycerides.
Inhibit endogenous substrate degradation.
Memorization Point:
Normal glucose ≤ 180 mg/dl after meals (indication for insulin function).
Fasting Phase
Definition: Period with at least 8 hours without nutrient intake.
Goals of Fasting Phase:
Maintain plasma glucose between 70-100 mg/dl.
Breakdown stored glycogen and triglycerides to supply glucose-independent cells.
Preserve glucose for brain function.
Perform gluconeogenesis in the liver, utilizing glycerol and amino acids.
Deliver fatty acids to glucose-independent tissues via lipolysis.
Maintain stored glucose for brain utilization only.
Memorization Point:
During fasting phases, plasma glucose levels maintained at 70-100 mg/dl.
Hormonal Regulation of Nutrient Metabolism
Endocrine Regulation
Source: Hormones are secreted by endocrine cells in pancreatic islets.
Cell Types:
Alpha cells: Produce Glucagon.
Beta cells: Produce Insulin.
Delta cells: Produce Somatostatin.
F cells: Produce Pancreatic Polypeptide.
Absorptive Phase: Dominated by insulin, decreases plasma glucose.
Fasting Phase: Dominated by glucagon, increases plasma glucose.
Insulin Secretion Mechanism
Process of Insulin Secretion from Pancreatic Cells
Glucose enters the pancreatic cell through an insulin-independent transporter.
Glucose is metabolized to form ATP.
Increased ATP levels inhibit ATP-sensitive K+ channels causing cell membrane depolarization.
Depolarization activates voltage-gated Ca2+ channels prompting Ca2+ influx.
Elevation in intracellular calcium initiates Ca2+-induced calcium release from the endoplasmic reticulum (ER).
Increased intracellular calcium concentrations trigger the exocytosis of insulin stored in secretory granules.
Regulation:
Insulin lowers plasma glucose by promoting its entry into cells, forming a negative feedback loop.
Memorization Point:
Insulin threshold for secretion is detected at plasma glucose of 80 mg/dl.
Factors Decreasing Insulin Secretion
Low plasma glucose levels.
Low concentrations of plasma amino acids.
Sympathetic stimulation (norepinephrine and epinephrine) maintains glucose levels in the blood.
Gastrointestinal Incretin Hormones
Role in Insulin Secretion
Released in response to elevated glucose levels in the distal small intestine, augmenting insulin secretion (GLP-1 and GIP).
GLP-1 (Glucagon-Like Peptide-1):
Half-life: 2 minutes; degraded into inactive fragments by dipeptidyl peptidase IV (DPP-IV).
Diabetes Treatment:
Antagonists of DPP-IV to prolong GLP-1 action.
DPP-IV-resistant GLP-1 analogs.
Albumin-based GLP-1 forms.
GLP-1 analogs that activate the receptor and inhibit internalization.
Insulin Receptor Structure
Composed of:
2 Subunits
Extracellular Alpha Subunit: Binds insulin.
Transmembrane Beta Subunit: Autophosphorylation of intracellular tyrosine kinase.
Tyrosine kinase phosphorylates important metabolic enzymes leading to effects such as GLUT transporters being mobilized to the membrane allowing glucose entry into the cells.
Metabolism of Insulin:
Half-life: 5-8 minutes; primarily eliminated by liver and kidney (40-50% removed before systemic circulation).
C-peptide serves as a marker for pancreatic function and insulin secretion.
Glucagon
Secretion and Effects
As plasma glucose levels decrease, glucagon levels increase with the physiological effect of raising plasma glucose levels.
Memorization Point:
Glucagon secretion threshold is at plasma glucose of 65-70 mg/dl.
Metabolism of Glucagon
Half-life: 5 minutes; cleared from the plasma by the kidney and liver (up to 80% removed before systemic circulation).
Continuous Glucose Monitoring
Used to assess fasting and feeding states in patients with diabetes.
Helps establish timing and regulation of insulin and glucagon secretion, catering to metabolic needs.
Insulin:Glucagon Ratio
Context of Ratios
Low concentrations of glucose result in high glucagon and low insulin secretion indicating a fasting phase.
Physiological Effects of Low Insulin:Glucagon Ratio:
Stimulated breakdown of endogenous storage depots.
Maintains adequate plasma glucose and fatty acid levels.
Effects on Nutrient Metabolism: During fasting when insulin is low, glucose, amino acids, fatty acids, and ketones increase in concentration.
Changes During Fasting
Effects on Different Tissues
Skeletal Muscle:
Reduced glucose uptake and utilization.
Net glycogen and protein catabolism — releases amino acids.
Adipose Tissue:
Low glucose uptake.
Net triglyceride catabolism with releases of glycerol and fatty acids.
Liver:
Increased glucose release due to glycogenolysis and gluconeogenesis.
Enhanced ketone synthesis and release.
Insulin Effects During Absorptive Phase
Physiological Effects of High Insulin Level
Skeletal Muscle:
Increased glucose uptake and utilization, net glycogen synthesis, amino acid uptake, and protein synthesis.
Adipose Tissue:
Enhanced glucose uptake and triglyceride synthesis.
Liver:
Encourages glucose uptake, net glycogen synthesis, triglyceride synthesis, and prevents ketone synthesis.
Mechanisms of Fatty Acid Delivery to Adipocytes
Insulin enhances fatty acid delivery and triglyceride synthesis by:
Stimulating lipoprotein lipase (LPL) in adipose tissue to break down chylomicrons.
Enhancing glucose uptake by adipocytes through transporters.
Stimulating triglyceride synthesis within adipocytes.
Energy Source for the Brain
Brain's Energy Preferences
Short-term: Primarily uses glucose available during the absorptive phase.
Long-term Fasting: Upon depletion of glycogen stores, the brain will utilitize ketones to minimize protein breakdown.
Physiological Effects During Extended Fasting
Metabolic Changes Over Days of Fasting
Glycogen stores become depleted.
Increased gluconeogenesis.
Enhanced lipolysis in adipose tissues.
High plasma glucagon results in physiological actions on specific tissues — influencing metabolic substrates distinctly.
Hormonal Control of Glucose Levels
Counter-Regulatory Hormones
Insulin (lowers glucose) vs. Glucagon, Epinephrine, Cortisol, and Growth Hormone (all raise glucose).
Protects against hypoglycemia. Symptoms of hypoglycemia include early cognitive dysfunction, lethargy, coma, and death at levels <20.
Pathophysiology of Hormones in Metabolism
Adipose Tissue Hormone Dynamics
Hormones Secreted from Adipose Tissue:
Leptin: Decreases food intake, increases energy expenditure.
Adipokines (TNFα, IL-6, IL-1β): Affect insulin sensitivity and metabolic processes.
Adiponectin: Promotes beta cell proliferation.
Pathophysiology of Obesity
Abdominal obesity alters secretion of adipose tissue hormones, leading to increased leptin and insulin resistance, increased secretion of adipokines, and decreased adiponectin.
Insulin Resistance
Characteristics and Effects
A normal insulin concentration results in inadequate glucose uptake by target cells due to signal transduction impairment.
Leads to lipid accumulation in glucose-independent tissues.
Contributes to obesity and metabolic dysfunction.
Results include ineffective insulin response on hepatocyte glucose production and glucagon secretion.
Impaired Insulin Secretion
Effects of Insulin Secreting Tumors
Decrease blood glucose levels, leading to increased hunger.
Reduction of beta cell mass contributes to decreased insulin secretion over time leading to Type 2 Diabetes Mellitus (T2DM) complications.
Diabetes Mellitus Overview
Type 1 Diabetes Mellitus (~10%):
Characterized by destruction of pancreatic beta cells; results in hyperglycemia and very low or absent insulin secretion.
Type 2 Diabetes Mellitus (~90%):
Associations with obesity; target cells exhibit insulin resistance; evolving pancreatic islet dysfunction leads to impaired glucose regulation.
Summary of Low Effective Insulin and High Glucagon Effects
Skeletal Muscle: Low glucose uptake, net glycogen catabolism, low amino acid uptake.
Adipocytes: Low glucose uptake and triglyceride catabolism.
Liver: High glucose release due to glycogen breakdown and gluconeogenesis, high ketone synthesis and release.