New Insights on the Interactions Between Insulin Clearance and the Main Glucose Homeostasis Mechanisms
Research Design and Methods We estimated standardized EIC (EICISR) by mathematical modelling in 9 different studies with insulin and glucose infusions (N=2067). EICISR association with various traits was analyzed by stepwise multivariable regression, in studies with euglycemic clamp and OGTT (N=1410). We also tested whether oral glucose ingestion, as opposed to intravenous infusion, has an independent effect on EIC (N=1555).
Results Insulin sensitivity (as M/I from the euglycemic clamp) is the strongest determinant of EICISR, ~4 times more influential than insulin-resistance related hypersecretion. EICISR independently associates positively with M/I, fasting and mean OGTT glucose or type 2 diabetes, and β-cell glucose sensitivity, and negatively with African American or Hispanic race, female sex, and female age. With oral glucose ingestion, an ISR-independent ~10% EIC reduction is necessary to explain the observed insulin concentration profiles.
Based on EICISR, we posit the existence of two adaptive processes
involving insulin clearance: the first reduces EICISR with insulin
resistance (not with higher BMI per se)
and is more relevant than the concomitant hypersecretion; the second reduces
EICISR with β-cell dysfunction. These processes are dysregulated in
type 2 diabetes. Finally, oral glucose ingestion per se reduces insulin clearance.