Increase in hepatic and decrease in peripheral insulin clearance characterize abnormal temporal patterns of serum insulin in diabetic subjects. (December 2018)

• Record Type: Journal Article
• Authors: Ohashi, Kaoru; Fujii, Masashi; Uda, Shinsuke; Kubota, Hiroyuki; Komada, Hisako; Sakaguchi, Kazuhiko; Ogawa, Wataru; Kuroda, Shinya
• Is Part Of: Npj systems biology and applications. Volume 4(2018)
• Page Start: 1
• Page End: 12
• Publication Date: 2018-12
• Subjects: Systems biology -- Periodicals; 570.113
• DOI: 10.1038/s41540-018-0051-6
• Languages: English
• ISSNs: 2056-7189

Abstract

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. Glucose homeostasis: roles of insulin clearance Type 2 diabetes mellitus (T2DM) is one of the fastest growing public health problems, characterized by chronic hyperglycemia with the failure of glucose homeostasis. Evaluating alteration in biological functions regulating circulating glucose concentration is complicated due to the mutual relation between circulating glucose and insulin. A team led by Wataru Ogawa at Kobe University designed clinical experiments for breaking such feedback relations, and a team led by Shinya Kuroda at University of Tokyo developed mathematical models for specifically quantifying the functions from the clinical data. The estimated model parameters revealed the significant increase in hepatic and decrease in peripheral insulin clearance, which occur before and after insulin delivery into systemic circulation, respectively, from healthy to T2DM subjects. Model analysis suggested these insulin clearances centrally regulate the dynamics of circulating insulin concentration in the glucose-insulin regulatory system.