1335-P: Insulin-Sensitive and Resistant Endotypes in Persons With and Without Recent-Onset Diabetes and Their Association with Diabetes-Related Outcomes

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.