New Insights on the Interactions Between Insulin Clearance and the Main Glucose Homeostasis Mechanisms.

ObjectiveEndogenous insulin clearance (EIC) is physiologically reduced at increasinginsulin secretion rate (ISR). Computing EIC at the prevailing ISR does notdistinguish the effects of hypersecretion from those of other mechanisms ofglucose homeostasis. We aimed to measure EIC in standardized ISR conditions(i.e., at fixed ISR levels) and to analyze its associations with relevantphysiologic factors. ResearchDesign and Methods We estimated standardized EIC (EICISR) by mathematicalmodelling in 9 different studies with insulin and glucose infusions (N=2067).EICISR association with various traits was analyzed by stepwisemultivariable regression, in studies with euglycemic clamp and OGTT (N=1410).We also tested whether oral glucose ingestion, as opposed to intravenousinfusion, has an independent effect on EIC (N=1555).ResultsInsulin sensitivity (as M/I from the euglycemic clamp) is the strongestdeterminant of EICISR, ~4 times more influential thaninsulin-resistance related hypersecretion. EICISR independentlyassociates positively with M/I, fasting and mean OGTT glucose or type 2diabetes, and β-cell glucose sensitivity, and negatively with African Americanor Hispanic race, female sex, and female age. With oral glucose ingestion, anISR-independent ~10% EIC reduction is necessary to explain the observed insulinconcentration profiles.ConclusionsBased on EICISR, we posit the existence of two adaptive processesinvolving insulin clearance: the first reduces EICISR with insulinresistance (not with higher BMI per se)and is more relevant than the concomitant hypersecretion; the second reducesEICISR with β-cell dysfunction. These processes are dysregulated intype 2 diabetes. Finally, oral glucose ingestion per se reduces insulin clearance.