Type 2 diabetes mellitus: A disease of the governance of the glucose-insulin system An experimental metabolic control analysis study M. Trombetta a , L. Boselli a , A. Cretti a , A. Calı ` a , M. Vettore d , B. Caruso c , R. Dorizzi c , A. Avogaro d , M. Muggeo a,b , E. Bonora a,b , R.C. Bonadonna a,b, * a Department of Medicine, Section of Endocrinology, University of Verona School of Medicine, Verona, Italy b Division of Endocrinology and Metabolic Diseases, Azienda Ospedaliera Universitaria Integrata, Verona, Italy c Division of Laboratory Medicine, Azienda Ospedaliera Universitaria Integrata, Verona, Italy d Department of Clinical and Experimental Medicine, Section of Metabolic Diseases, University of Padova School of Medicine, Padova, Italy Received 18 August 2010; received in revised form 28 April 2011; accepted 6 May 2011 Available online 19 September 2011 KEYWORDS Metabolic control analysis; Type 2 diabetes mellitus; Insulin secretion; Insulin action 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 proper- ties. We applied MCA to the intravenous glucose tolerance test (IVGTT) to quantify the CCs of the main components of the glucose-insulin 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 Z 9, NGR-IS), healthy insulin-resistant (n Z 7, NGR-IR) and sub- diabetic hyperglycemic (n Z 8, PreT2DM) individuals and in patients with newly diagnosed type 2 diabetes (n Z 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. * Corresponding author. Division of Endocrinology, Ospedale Civile Maggiore, Piazzale Stefani 1, 37126 Verona, Italy. Tel.: þ39 0458123115; fax: þ39 045917374. E-mail address: riccardo.bonadonna@tiscali.it (R.C. Bonadonna). available at www.sciencedirect.com journal homepage: www.elsevier.com/locate/nmcd Nutrition, Metabolism & Cardiovascular Diseases (2013) 23, 23e30 0939-4753/$ - see front matter ª 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.numecd.2011.05.006