Increase in hepatic and decrease in peripheral insulin clearance characterize abnormal temporal patterns of serum insulin in diabetic subjects

Kaoru Ohashi,Masashi Fujii,Hisako Komada,Shinya Kuroda,Wataru Ogawa,Hiroyuki Kubota,Kazuhiko Sakaguchi,Shinsuke Uda

doi:10.1038/s41540-018-0051-6

Abstract

Insulin plays a central role in glucose homeostasis, and impairment of insulin action causes glucose intolerance and leads to type 2 diabetes mellitus (T2DM). A decrease in the transient peak and sustained increase of circulating insulin following an infusion of glucose accompany T2DM pathogenesis. However, the mechanism underlying this abnormal temporal pattern of circulating insulin concentration remains unknown. Here we show that changes in opposite direction of hepatic and peripheral insulin clearance characterize this abnormal temporal pattern of circulating insulin concentration observed in T2DM. We developed a mathematical model using a hyperglycemic and hyperinsulinemic-euglycemic clamp in 111 subjects, including healthy normoglycemic and diabetic subjects. The hepatic and peripheral insulin clearance significantly increase and decrease, respectively, from healthy to borderline type and T2DM. The increased hepatic insulin clearance reduces the amplitude of circulating insulin concentration, whereas the decreased peripheral insulin clearance changes the temporal patterns of circulating insulin concentration from transient to sustained. These results provide further insight into the pathogenesis of T2DM, and thus may contribute to develop better treatment of this condition.

Highlights

Introduction2 h after a 75-g oral glucose load (2-h post-load glucose concentration; 2-h PG).[8] During this test, the circulating insulin concentration transiently increases and continuously increases or decreases, known as the early and late phases of insulin secretion, respectively.[9,10] The direct contribution of circulating glucose concentration to circulating insulin concentration is assessed by the use of an intravenous glucose tolerance test (IVGTT).[11] This test excludes the effects of intestinal absorption of glucose and incretins secretion that trigger insulin secretion, permitting quantitative estimates of the ability of circulating glucose to initiate insulin secretion
Insulin is the major anabolic hormone regulating the glucose homeostasis
Insulin and C-peptide should be secreted in an equimolar manner, the serum C-peptide concentration was higher than the serum insulin concentration because insulin—but not C-peptide—was removed by the liver and C-peptide clearance in the periphery was slower than insulin clearance

Summary

Introduction

2 h after a 75-g oral glucose load (2-h post-load glucose concentration; 2-h PG).[8] During this test, the circulating insulin concentration transiently increases and continuously increases or decreases, known as the early and late phases of insulin secretion, respectively.[9,10] The direct contribution of circulating glucose concentration to circulating insulin concentration is assessed by the use of an intravenous glucose tolerance test (IVGTT).[11] This test excludes the effects of intestinal absorption of glucose and incretins secretion that trigger insulin secretion, permitting quantitative estimates of the ability of circulating glucose to initiate insulin secretion. The circulating insulin concentration transiently increases during the first 10 min and continuously increases during the following 120 min, which are known as the first and second phase of insulin secretion, respectively.[12]

Methods

Results

Conclusion