Glucose Homeostasis and Insulin

Glucose Homeostasis

• Brain function relies on a consistent glucose supply
• Brain functions might be impaired when glucose concentrations dip below 5 mM
• Elevated glucose levels above 5 mM can disrupt blood osmotic pressure and cause protein glycosylation
• For glucose to nourish the brain, it must traverse the blood-brain barrier

Insulin Production and Secretion

• Pancreas synthesizes and releases insulin and glucagon, key hormones in glucose regulation
• Insulin includes two peptide chains joined by disulfide bonds: An alpha chain containing 21 amino acids and a beta chain with 30 amino acids
• Preproinsulin, a single-chain precursor, is used in insulin production
• Prohormone convertases (PC1/3 and PC2) along with carboxypeptidase E (CPE) convert proinsulin into insulin and C-peptide
• Insulin secretion occurs in response to glucose

Insulin's Role

• Insulin triggers anabolic processes, promoting carbohydrate and lipid storage and protein synthesis
• Three primary target tissues for insulin are the liver, muscles, and adipose tissue
• GLUT4 serves as a key determinant of glucose homeostasis
• Synthesis of proteins, storage of lipids and carbohydrates, and release of glucose maintains an anabolic state
• Insulin is released from beta cells granules in response to glucose

Membrane Polarization Mechanics

• The ATP-dependent sodium-potassium pump establishes membrane polarization
• Cell membranes are more permeable to K+ than Na+ in a resting state
• There is a continuous loss of K+
• Na+/K+-pump requireis ATP to maintain proper ionic gradients
• For every 3 Na+ ions expelled, 2 K+ ions enter the cell
• Losing a net positive charge causes hyperpolarization
• The Na+/K+-pump is electrogenic

ATP and Potassium Channels

• Beta cells feature an ATP-sensitive potassium channel complex made of KIR6.2 and SUR1 peptides
• KIR6.2 is responsible for forming the K+-transporting pore, whereas SUR1 (sulfonylurea-binding peptides) serves regulatory functions
• Resting potential for beta cells is around -60 mV
• Voltage-dependent Ca2+ channels open when the membrane depolarizes to -40 mV or less, facilitating calcium entry into the cell

Insulin Secretion Activation

• Insulin is secreted from granules bound to the cell membrane
• Calcium influx into the beta cell activates insulin release
• Reducing cell membrane K+ conductance depolarizes the cell
• Depolarization starts voltage-gated Ca2+ channels, increasing Ca2+ influx
• Increased Ca2+ influx triggers insulin exocytosis

Factors Affecting Potassium Channels

• Potassium channels, which are ATP-sensitive in beta cells and other tissues, control membrane polarization
• When the K+ channel is open, the cell membrane is polarized, which prevents voltage-gated Ca2+ channels from allowing insulin exocytosis from the beta-cell
• Tolbutamide (a sulfonylurea drug) blocks the potassium channel from opening, increasing insulin secretion
• Diazoxide activates potassium channels, which inhibits insulin secretion

The Role of Glucokinase

• The beta-cell glucose sensor is glucokinase
• There is minimal insulin release below a certain rate of G6P formation, the basal level
• Above a certain rate (the set point), insulin is released
• High-Km glucose transporter GLUT2 aids glucose uptake and sensing in beta cells

Mutations Affecting Glucokinase

• A glucokinase mutant (elevated Km) inhibits insulin secretion until blood glucose hits 10 mM, as opposed to 5 mM
• A mutation impacting Glucokinase's Vmax prevents glucose from surpassing the set point, thereby preventing insulin release beyond basal levels
• Gastrointestinal hormones, like glucose-dependent insulinotropic peptide (GIP), secreted in food ingestion, boosts insulin secretion
• Cholinergic signals activate phospholipase C, resulting in intracellular calcium mobilization and insulin release
• Cephalic phase insulin release anticipates glucose sensing in the pancreatic beta-cells

Insulin Binding

• Insulin binds extracellularly, changing the cytoplasmic domain conformation and initiating autophosphorylation
• Phosphorylated domain interacts with intracellular signaling proteins known as insulin receptor substrate (IRS) proteins

Metabolic Effects of Insulin

• Triggering fuel uptake and storage is the goal
• Glycolysis and glycogen synthesis are stimulated by insulin in the liver
• Adipose tissue triacylglycerol synthesis is stimulated by insulin by utilizing glycerol-3-phosphate and fatty acids
• The stimulation of glucose transport, glycogen synthesis, glucose metabolism, and the uptake of protein and amino acids are stimulated by insulin in MUSCLE

Counter-Regulatory Signaling

• The hypothalamus synthesizes and secretes a hormone that triggers glucagon release from pancreatic alpha-cells in response to signals
• Counter-regulatory hormones restore blood glucose levels by inhibiting glucose storage pathways and activating glucose release pathways

Glucagon and Glucose

• Glucagon secretion in pancreatic alpha-cells is boosted by low glucose levels and suppressed by high glucose levels
• Glucagon activates a G protein-coupled receptor, which in turn generates second messenger molecules like cAMP, cGMP, -IP3, DAG, and Ca+2
• Kinase A exists as an inactive heterotetramer where regulatory subunits hinder the enzyme's active site

Cortisol Function

• The adrenal cortex produces cortisol in response to ACTH (corticotropin) signals
• Cortisol triggers muscle protein breakdown, releasing amino acids for liver-based glucose synthesis
• Cortisol stimulates PEPCK, a key enzyme in gluconeogenesis, in the liver

The Extremes of Glucose Levels

• Hyperglycemia happens when fasting blood glucose surpasses 8 mM
• Values as high as 50 mM are common
• This results in dehydration and thirst from the excretion of large volumes of urine
• When glucose cannot be reabsorbed in the kidney, the excess is excreted out in the urine
• Hypoglycemia: the blood glucose level drops to dangerously low levels
• Hypoglycemia is and acute threat to brain survival
• The rate of ATP synthesis can not keep up with hydrolysis during hypoglycemia
• Chronic hypoglycemia impairs brain development

Pathologies Due to Signaling Dysfunction

• Congenital Hyperinsulinism (HI) or CHOP is when a child has constantly low plasma glucose levels (2.2 to 3.2 mM)
• Plasma insulin levels are elevated in HI. Feeding every four hours prevented the symptoms of hypoglycemia, although plasma glucose levels remained largely between 2.8 to 3.3 mM

Genetic Mutations

• Mutations in genes that encode subunits of the ATP-sensitive potassium (K_ATP) channels in pancreatic β-cells, they remain closed, causing the β-cells to release insulin regardless of blood glucose levels

Take Home Points

• Glucose homeostasis relies on liver, adipose tissue, skeletal muscle, and pancreas interactions
• Conditions like hypoglycemia and diabetes mellitus result from disrupted glucose homeostasis
• Antiinsulin hormones increase plasma glucose through glycogenolysis and gluconeogenesis
• Routine assessment of plasma glucose involves glucose, ketone, HbA1c testing, and renal function tests in diabetic patients