Introduction & Objective: Insulin resistance is a central pathophysiologic feature of type 2 diabetes (T2D), and to varying degrees also present in type 1 diabetes (T1D) and prediabetes. This study aims to discern patterns of tissue-specific insulin resistance to understand its contribution to metabolic heterogeneity.
Methods: This study used k-means clustering in 759 participants (223 T1D, 346 T2D, 190 glucose-tolerant individuals as control, CON) of the German Diabetes Study (GDS). The clusters were defined based on glycemia (HbA1c), whole-body insulin sensitivity (M-value, Botnia clamps), and components of tissue-specific insulin sensitivity indices, comprising fasting endogenous glucose production and non-esterified fatty acids. We assessed diabetes-related outcomes utilizing data from prospective visits at recent-onset diabetes and 5 years, as well as annual interviews. All results were adjusted for age, sex, BMI and diabetes type.
Results: Three clusters were identified: one whole-body insulin sensitive (WISE, 73 T1D, 41 T2D, 265 CON), and two whole-body insulin resistant endotypes, one featuring higher adipose tissue insulin resistance (AIRE, 50 T1D, 210 T2D, 39 CON), and one exhibiting higher hepatic insulin resistance (HIRE, 100 T1D, 95 T2D, 0 CON) compared to both other endotypes. AIRE exhibited higher visceral adiposity and hepatocellular lipid content (HCL) than WISE and HIRE. This endotype also associated with increased incidence of nephropathy and peripheral neuropathy at the 5-year follow-up. HIRE had higher HCL than WISE, but lower HCL than AIRE. Compared to both other endotypes, HIRE was more likely to receive insulin treatment during 5-year follow-up period.
Conclusion: Tissue-specific insulin sensitivity allows to define phenotypic endotypes in a population covering a broad glucometabolic range with different risk profiles of diabetes-related comorbidities, independently of diabetes type.
K. Bódis: None. K. Prystupa: None. O.P. Zaharia: None. M. Schön: None. C. Möser: None. I. Yurchenko: None. D.M. Mendez Cardenas: None. P. Bobrov: None. G. Heilmann: None. V. Schrauwen-Hinderling: None. K. Strassburger: None. G.J. Bönhof: None. V. Burkart: None. R. Guthoff: Advisory Panel; Roche Pharma AG, BayerHealthCare. S. Meyhoefer: None. A.L. Birkenfeld: None. R. Jumpertz von Schwartzenberg: None. J. Seissler: None. A.F. Pfeiffer: Advisory Panel; Abbott. Speaker's Bureau; AstraZeneca, Novo Nordisk, Sanofi. Advisory Panel; Berlin-Chemie AG. M. Blüher: Speaker's Bureau; Amgen Inc., AstraZeneca, Bayer Inc., Daiichi Sankyo. Advisory Panel; Lilly Diabetes. Speaker's Bureau; Novartis AG. Advisory Panel; Novo Nordisk. Speaker's Bureau; Pfizer Inc., Sanofi. S.R. Bornstein: None. Z. Kender: None. A. Sulaj: None. M. Heni: Research Support; Boehringer-Ingelheim. Advisory Panel; Amryt Pharma Plc. Speaker's Bureau; Amryt Pharma Plc. Advisory Panel; Boehringer-Ingelheim, Boehringer-Ingelheim. Speaker's Bureau; Lilly Diabetes, Novartis AG, Novo Nordisk, Sanofi. J. Szendroedi: None. M. Roden: Advisory Panel; Eli Lilly and Company. Research Support; Boehringer-Ingelheim. Advisory Panel; Novo Nordisk. Research Support; Novo Nordisk. Advisory Panel; TARGET PharmaSolutions, Inc. Speaker's Bureau; AstraZeneca. R. Wagner: Speaker's Bureau; Sanofi. Advisory Panel; Lilly Diabetes. Speaker's Bureau; Boehringer-Ingelheim, Novo Nordisk.
German Federal Ministry Berlin Germany of Health (BMG); Ministry of Culture and Science of the state North Rhine-Westphalia (MKW, Düsseldorf, Germany); German Federal Ministry of Education and Research (BMBF, Berlin, Germany); German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) (236177352-SFB 1116) Schmutzler Stiftung; European Funds for Regional Development (EFRE-0400191)EUREKA Eurostars-2 (E! 113230 DIA-PEP)
