@article{4fc64d3ef89a40ee8d6f3087f4fd1506,
title = "New insights on the interactions between insulin clearance and the main glucose homeostasis mechanisms",
abstract = "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 modeling in nine different studies with insulin and glucose infusions (N 5 2,067). EICISR association with various traits was analyzed by stepwise multivariable regression in studies with both euglycemic clamp and oral glucose tolerance test (OGTT) (N 5 1,410). We also tested whether oral glucose ingestion, as opposed to intravenous infusion, has an independent effect on EIC (N 5 1,555). RESULTS Insulin sensitivity (as M/I from the euglycemic clamp) is the strongest determinant of EICISR, approximately four 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.",
author = "Roberto Bizzotto and Domenico Tric{\`o} and Andrea Natali and Amalia Gastaldelli and Elza Muscelli and {De Fronzo}, {Ralph A.} and Silva Arslanian and Ele Ferrannini and Andrea Mari",
note = "Funding Information: Acknowledgments. The authors thank Toni Giorgino, PhD, for the technical support in using the software adopted for the analysis and acknowledge the CINECA award under the Italian SuperComputing Resource Allocation initiative for the availability of high-performance computing resources and support. Funding. This research has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement 115156, the resources of which are composed of financial contributions from the European Union's Seventh Framework Programme (FP7/ 2007–2013) and European Federation of Pharmaceutical Industries and Associations companies{\textquoteright} in-kind contribution. The Drug Disease Model Resources (DDMoRe) project is also financially supported by contributions from academic and small and medium-sized enterprise partners. Duality of Interest. A.N. has received financial support for clinical research from Boehringer Ingelheim and Eli Lilly and Company. S.A. has participated in advisory boards for Eli Lilly and Company, Novo Nordisk, and Boehringer Ingelheim; has received research funding from Eli Lilly and Company and Novo Nordisk; and is on the Data and Safety Monitoring Board for AstraZeneca. E.F. has participated in advisory boards for Boehringer Ingelheim, Eli Lilly and Company, and Sanofi; has received research funding from Boehringer Ingelheim and AstraZeneca; and has received honoraria for speaking engagements from AstraZeneca, Sanofi, Boehringer Ingelheim, Eli Lilly and Company, and Merck Sharp & Dohme. A.M. has received financial support from Eli Lilly and Company and is a consultant for Eli Lilly and Company. No other potential conflicts of interest relevant to this article were reported. Author Contributions. R.B. and A.M. designed the analysis, analyzed the data, and wrote the manuscript. A.N., A.G., E.M., R.A.D.F., S.A., and E.F. provided useful data for the analysis. A.M. supervised the analysis. D.T., A.N., A.G., S.A., and E.F. reviewed the manuscript. R.B. is the guarantor of this work and, as such, had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Publisher Copyright: {\textcopyright} 2021 by the American Diabetes Association.",
year = "2021",
month = sep,
doi = "10.2337/dc21-0545",
language = "English (US)",
volume = "44",
pages = "2115--2123",
journal = "Diabetes Care",
issn = "1935-5548",
publisher = "American Diabetes Association Inc.",
number = "9",
}