Type 2 Diabetes Mellitus: a Disease of the Governance of the Glucose-Insulin System. An Experimental Metabolic Control Analysis Study.

Abstract: Background and Aims. The relatives role of each component of the glucose-insulin system in determining hyperglycemia in type 2 diabetes is still under debate. Metabolic Control Analysis (MCA) quantifies the control exerted by each component of a system on a variable of interest, by computing the relevant coefficients of control (CCs), which are systemic properties. We applied MCA to the intravenous glucose tolerance test (IVGTT) to quantify the CCs of the main components of the glucoseinsulin system on intravenous glucose tolerance. Methods and Results. We combined in vivo phenotyping (IVGTT/euglycaemic insulin clamp) and in silico modeling (GLUKINSLOOP.1) to compute the CCs of intravenous glucose tolerance in healthy insulin-sensitive (n=9, NGR-IS), healthy insulin-resistant (n=7, NGR-IR) and subdiabetic hyperglycemic (n=8, PreT2DM) individuals and in patients with newly diagnosed type 2 diabetes (n=7, T2DM). Altered insulin secretion and action were documented in NGR-IR and PreT2DM groups, but only 1st phase insulin secretion was significantly lower in T2DM than in PreT2DM (p<0.05). The CCs changed little in the nondiabetic groups. However, several CCs were significantly altered in the patients (e.g. CCs of beta cell: -0.75±0.10, -0.64±0.15, -0.56±0.09 and -0.19±0.04 in NGR-IS, NGR-IR, PreT2DM and T2DM, respectively; p<0.01 by MANOVA), and they could not be corrected by matching in silico nondiabetic and T2DM groups for 1st phase secretion. Conclusions. Type 2 diabetes is characterized not only by loss of function of the elements of the glucose-insulin system but also by changes in systemic properties (CCs). As such, it could be considered a disease of the governance of the glucose-insulin system.