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

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posted on 06.08.2021, 17:06 by Roberto Bizzotto, Domenico Tricò, Andrea Natali, Amalia Gastaldelli, Elza Muscelli, Ralph A. De Fronzo, Silva Arslanian, Ele Ferrannini, Andrea Mari
Objective 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.

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.

Conclusions 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.


This research has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n° 115156, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution. The DDMoRe project is also financially supported by contributions from Academic and SME partners.