↑ blood glucose (post-meal) → β-cell glucose sensing — GLUT2 + glucokinase → ↑ ATP/ADP — via glucokinase is the rate-setting glucose sensor of the pancreatic β-cell. Glucose entering the pancreatic β-cell is phosphorylated by glucokinase — the low-affinity “glucose sensor” whose rate sets the threshold for insulin release. Rising glucose lifts the ATP/ADP ratio; inactivating glucokinase mutations cause MODY2 and activating ones cause hyperinsulinism, proving its gatekeeper role.
β-cell glucose sensing — GLUT2 + glucokinase → ↑ ATP/ADP → KATP closure → depolarization → Ca²⁺ influx → insulin exocytosis — via ATP closes the KATP channel (Kir6.2/SUR1); sulfonylureas & glinides close it pharmacologically. The ATP/ADP rise closes the KATP channel (Kir6.2 pore + SUR1 subunit), depolarizing the β-cell to open voltage-gated Ca²⁺ channels and trigger insulin-granule exocytosis. Sulfonylureas and meglitinides bind SUR1 to force this closure — raising insulin regardless of glucose, hence their hypoglycemia risk.
KATP closure → depolarization → Ca²⁺ influx → insulin exocytosis → secreted insulin → insulin receptor (IR) activation (muscle/fat/liver) — via insulin and its analogs bind the IR, a receptor tyrosine kinase; autophosphorylation recruits IRS-1. Secreted insulin binds the insulin receptor (IR), a receptor tyrosine kinase that autophosphorylates and recruits IRS adaptors on target tissues. Injected insulin and engineered analogs (glargine, lispro) act here, differing mainly in absorption kinetics — the basis of basal versus prandial insulin dosing.
secreted insulin → insulin receptor (IR) activation (muscle/fat/liver) → IRS-1 → PI3K → AKT (metabolic arm) — via the PI3K/AKT branch carries insulin’s metabolic actions; PPAR-γ tunes peripheral sensitivity. The IR signals through IRS-1/PI3K/AKT — the metabolic arm that drives glucose uptake and suppresses hepatic output. Insulin resistance is a blunting of this arm; thiazolidinediones (pioglitazone, rosiglitazone) activate adipocyte PPAR-γ to improve peripheral insulin sensitivity, indirectly restoring AKT signaling.
IRS-1 → PI3K → AKT (metabolic arm) → GLUT4 translocation → peripheral glucose uptake (muscle, fat) — via AKT drives GLUT4 vesicles to the membrane; exercise does this insulin-independently. AKT triggers translocation of GLUT4 transporters to the cell membrane, letting muscle and fat take up glucose — the main route of postprandial glucose disposal. Exercise recruits GLUT4 by an insulin-independent (AMPK) route, which is why physical activity lowers glucose even in insulin resistance.
IRS-1 → PI3K → AKT (metabolic arm) → liver: ↓ gluconeogenesis + ↑ glycogen synthesis (↓ hepatic glucose output) — via insulin restrains hepatic glucose output; metformin & berberine lower it via AMPK. In the liver, insulin signaling suppresses gluconeogenesis and promotes glycogen synthesis, cutting hepatic glucose output — the main driver of fasting hyperglycemia in type 2 diabetes. Metformin (mild complex-I inhibition → AMPK) and berberine lower output here, which is why metformin is first-line and rarely causes hypoglycemia.
gut L/K-cells (incretin response to a meal) → GLP-1/GIP → β-cell GLP-1R/GIP-R → glucose-dependent insulin release — via incretins amplify glucose-stimulated secretion only when glucose is high. Nutrients trigger gut L- and K-cells to release the incretins GLP-1 and GIP, which act on β-cell Gs-coupled receptors (raising cAMP) to potentiate insulin secretion — but only when glucose is high, keeping hypoglycemia risk low. GLP-1 agonists (semaglutide, liraglutide) and the dual GIP/GLP-1 agonist tirzepatide exploit this, adding weight loss via central appetite effects.
gut L/K-cells (incretin response to a meal) → DPP-4 rapid degradation of GLP-1/GIP (incretin termination) — via DPP-4 inactivates incretins within minutes; gliptins block it. The incretin signal is short-lived because the enzyme DPP-4 cleaves and inactivates GLP-1/GIP within minutes. DPP-4 inhibitors (“gliptins”: sitagliptin, linagliptin) block this degradation to raise endogenous incretin levels — a weight-neutral, oral, glucose-dependent way to enhance insulin secretion.
renal proximal tubule — filtered glucose → SGLT2 reabsorption (insulin-independent glucose handling) — via SGLT2 reclaims ~90% of filtered glucose; inhibitors dump it in urine. Independently of insulin, the kidney reclaims filtered glucose via SGLT2 in the proximal tubule. SGLT2 inhibitors (empagliflozin, dapagliflozin, canagliflozin) block reabsorption to excrete glucose in urine, lowering glycemia without insulin — and they deliver cardiovascular and renal protection that made them guideline-preferred beyond glucose control.
Known Modulators
insulin (activator) — InsR (RTK). regular human insulin; covers prandial glucose; CV use also via potassium shift treatment for hyperkalemia