Glucose Homeostasis

glucose homeostasis

Identify major metabolic fuels, explain insulin and glucagon actions, describe fed/fasted/stress metabolism, understand type II diabetes mechanisms and treatments

Major metabolic fuels

Glucose and fatty acids are the primary fuels stored as glycogen and triglycerides for later use

Fatty acid energy density

Fatty acids provide 9 kcal/g, more than carbohydrates or proteins, supporting long‑term energy needs

Organ fuel specialization

Brain uses glucose but can switch to ketones, liver maintains blood glucose

Fatty acid metabolism overview

Fatty acids synthesized from acetyl‑CoA, stored as triglycerides, and broken down by lipolysis

Ketone body production

Acetyl‑CoA from fatty acid oxidation forms acetoacetate and β‑hydroxybutyrate

Glycogen storage roles

Liver stores glycogen to maintain blood glucose, muscle stores glycogen for its own contraction energy

Glycogen synthesis pathway

Glucose → G6P → G1P → UDP‑glucose → glycogen via glycogen synthase

Muscle glucose export limitation

Muscle lacks glucose‑6‑phosphatase and cannot release free glucose into blood

Gluconeogenesis definition

Formation of glucose from lactate, alanine, and glycerol using liver‑specific enzymes

Key gluconeogenesis enzymes

PEPCK, fructose‑1,6‑bisphosphatase, and glucose‑6‑phosphatase bypass irreversible glycolysis steps

Fatty acids cannot form glucose

Acetyl‑CoA carbons enter TCA cycle and are lost as CO₂, preventing net glucose synthesis

Glucogenic vs ketogenic amino acids

Glucogenic amino acids feed into glucose production, ketogenic feed into acetyl‑CoA or ketone bodies

Cori cycle

Muscle releases lactate and alanine to liver for gluconeogenesis, recycling carbons

Daily glucose maintenance

Blood glucose is maintained by glycogenolysis, dietary intake, and gluconeogenesis

Hormonal glucose regulation

Insulin lowers blood glucose, glucagon raises it, metabolic state depends on insulin/glucagon ratio

Pancreatic hormone secretion

β‑cells produce insulin, α‑cells produce glucagon within islets of Langerhans

Islet cell staining differences

β‑cells stain light purple, α‑cells stain red due to glucagon granules

Insulin structure

Two peptide chains (A and B) linked by disulfide bonds, processed from preproinsulin

C‑peptide significance

Released with insulin, used clinically to measure β‑cell function

Insulin receptor

Tyrosine kinase receptor requiring dimerization and autophosphorylation for signaling

Insulin functions

Promotes fuel storage, GLUT4 translocation, enzyme phosphorylation, and gene expression changes

Insulin secretion mechanism

Glucose metabolism increases ATP → closes K⁺ channel → Ca²⁺ influx → insulin release

GLUT4 translocation

Insulin moves GLUT4 to membrane, increasing glucose uptake 10–40 fold

Insulin effects on glycogen metabolism

Activates glycogen synthase and inhibits glycogen phosphorylase to promote storage

Insulin inhibition of gluconeogenesis

Blocks PEPCK expression and other gluconeogenic enzymes to prevent futile cycling

IRS–PI3K pathway

IRS binds PI3K via SH2 domains, activating metabolic signaling cascades

Insulin actions summary

Muscle: glucose uptake and protein synthesis

liver: inhibit glucose production

adipose: store triglycerides

Glucagon function

Opposes insulin, stimulates glucose release and gluconeogenesis in liver

Glucagon structure

Single α‑helix peptide, 29 amino acids long

Glucagon processing

Tissue‑specific cleavage produces glucagon or extended peptides with distinct functions

Glucagon receptor

GPCR with large extracellular domain enabling glucagon binding

Glucagon signaling

Activates G‑protein → adenylate cyclase → ↑ cAMP → ↑ glycogen breakdown and gluconeogenesis

Insulin vs glucagon enzyme effects

Insulin inhibits G6Pase, FBPase, and PEPCK glucagon activates them

Fed state metabolism

Insulin promotes glycogen formation, triglyceride storage, protein synthesis, and suppresses gluconeogenesis

Overnight fast metabolism

Glucagon drives gluconeogenesis, glycogen breakdown, lipolysis, and alanine/lactate transport to liver

Starvation metabolism

High glucagon, depleted glycogen, ketone body production, protein sparing, reduced Cori cycle

Stress metabolism

Epinephrine inhibits insulin, increases gluconeogenesis, mobilizes glucose, and increases protein breakdown

Diabetes types

Type 1: autoimmune β‑cell destruction

Type 2: insulin resistance due to genetic and environmental factors

OGTT diagnosis

Diabetes diagnosed if 2‑hr glucose ≥ 11.1 mM or fasting ≥ 7.0 mM

A1C test

Measures hemoglobin glycation to assess long‑term glucose control

Metabolic changes in diabetes

Hyperglycemia from impaired uptake and increased gluconeogenesis

excess fatty acids cause ketone buildup

Type 2 diabetes causes

Insulin resistance arises from genetic predisposition and environmental factors