<i>Objective</i>
Endogenous insulin clearance (EIC) is physiologically reduced at increasing
insulin secretion rate (ISR). Computing EIC at the prevailing ISR does not
distinguish the effects of hypersecretion from those of other mechanisms of
glucose homeostasis. We aimed to measure EIC in standardized ISR conditions
(i.e., at fixed ISR levels) and to analyze its associations with relevant
physiologic factors.
<p><i>Research
Design and Methods</i> We estimated standardized EIC (EIC<sub>ISR</sub>) by mathematical
modelling in 9 different studies with insulin and glucose infusions (N=2067).
EIC<sub>ISR</sub> 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).</p>
<p><i>Results</i>
Insulin sensitivity (as M/I from the euglycemic clamp) is the strongest
determinant of EIC<sub>ISR</sub>, ~4 times more influential than
insulin-resistance related hypersecretion. EIC<sub>ISR</sub> 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.</p>
<p><i>Conclusions</i>
Based on EIC<sub>ISR</sub>, we posit the existence of two adaptive processes
involving insulin clearance: the first reduces EIC<sub>ISR</sub> with insulin
resistance (not with higher BMI <i>per se</i>)
and is more relevant than the concomitant hypersecretion; the second reduces
EIC<sub>ISR</sub> with β-cell dysfunction. These processes are dysregulated in
type 2 diabetes. Finally, oral glucose ingestion <i>per se</i> reduces insulin clearance.<br>
</p>