Defining the Relative Role of Insulin Clearance in Early Dysglycemia in Relation to Insulin Sensitivity and Insulin Secretion: The Microbiome and Insulin Longitudinal Evaluation Study (MILES).

Alexis C Wood,Stephen S Rich,Elizabeth T Jensen,Jerome I Rotter,Alain G Bertoni,Gautam Ramesh,Yii-Der I Chen,Mark O Goodarzi

doi:10.3390/metabo11070420

Abstract

Insulin resistance and insufficient insulin secretion are well-recognized contributors to type 2 diabetes. A potential role of reduced insulin clearance has been suggested, but few studies have investigated the contribution of insulin clearance while simultaneously examining decreased insulin sensitivity and secretion. The goal of this study was to conduct such an investigation in a cohort of 353 non-Hispanic White and African American individuals recruited in the Microbiome and Insulin Longitudinal Evaluation Study (MILES). Participants underwent oral glucose tolerance tests from which insulin sensitivity, insulin secretion, insulin clearance, and disposition index were calculated. Regression models examined the individual and joint contributions of these traits to early dysglycemia (prediabetes or newly diagnosed diabetes). In separate models, reduced insulin sensitivity, reduced disposition index, and reduced insulin clearance were associated with dysglycemia. In a joint model, only insulin resistance and reduced insulin secretion were associated with dysglycemia. Models with insulin sensitivity, disposition index, or three insulin traits had the highest discriminative value for dysglycemia (area under the receiver operating characteristics curve of 0.82 to 0.89). These results suggest that in the race groups studied, insulin resistance and compromised insulin secretion are the main independent underlying defects leading to early dysglycemia.

Highlights

In this study featuring all three aspects of insulin homeostasis, we found that while decreased insulin clearance was associated with an increased prevalence of early dysglycemia, the correlation between clearance and dysglycemia was no longer significant when jointly analyzed with insulin sensitivity and insulin secretion
Insulin sensitivity and insulin secretion remained as significant independent predictors of dysglycemia, consistent with the prevailing notion that insulin resistance and deficient insulin secretion are key to the pathogenesis of diabetes
It has been well-documented that insulin clearance is lower in states of obesity, prediabetes, and diabetes [21]; most studies reporting this did not attempt to adjust for effects of insulin sensitivity or insulin secretion

Summary

Introduction

Type 2 diabetes is a leading cause of blindness, kidney failure, and amputation worldwide, and is associated with a high risk of coronary heart disease and stroke. In order to increase circulating insulin levels, the insulin homeostatic system responds to insulin resistance by increasing insulin secretion and reducing insulin clearance. Failure of insulin secretion to overcome insulin resistance is regarded by many as the key event leading to type 2 diabetes [4]. This concept is supported by the observation that the majority of genetic loci implicated in type 2 diabetes appear to act via compromising beta cell development or function [5]. In contrast to the substantial body of work focused on insulin secretion, relatively fewer studies have examined the role of insulin clearance in the development of diabetes

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