1513-P: The Severe Insulin-Resistant Diabetes Cluster Features Higher Liver Fat Content, but Also an Accelerated Risk of Liver Fibrosis over Five Years after Diagnosis

Cluster analysis using age, BMI, glycemia and homeostasis model estimates (HOMA-IR, -B) revealed distinct risk profiles for progression of diabetic nephropathy in large cohorts, but its relevance for other diabetes-related comorbidities remains unclear. We aimed to (i) examine whether intensified phenotyping would confirm the results of this cluster analysis and (ii) test the hypothesis that liver fat content (HCL), as marker of nonalcoholic fatty liver disease (NAFLD), differs among clusters at diabetes diagnosis and during follow-up. Thus, this cluster analysis was applied to recent-onset patients with non-autoimmune diabetes of the German Diabetes Study. This identified 286 mild age-related (MARD, 44%), 268 mild obesity-related (MOD, 42%), 66 severe insulin-resistant (SIRD, 10%) and 27 severe insulin-deficient (SIDD, 4%) diabetes patients. Furthermore, whole-body insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamps, HCL by magnetic resonance spectroscopy and hepatic fibrosis by a noninvasive score (NAFLD-FS). Congruently, whole-body insulin sensitivity was lowest in SIRD compared to MOD, SIDD and MARD (4.3±2.0 vs. 5.6±2.4, 6.5±2.6, 7.6±2.8 mg*kg-¹*min-¹, all p<0.05). In SIRD, HCL (14±4%) was higher than in SIDD (5±2%), MOD (9±1%) and MARD (7±1%) (all p<0.05). In SIRD, HCL negatively correlated with whole-body insulin sensitivity (r=-0.27, p<0.05). NAFLD-FS was highest in SIRD (0.4) compared to SIDD (-2.9), MOD (-0.8) and MARD (-0.8) (all p<0.05). At the 5-year follow-up (n=159), whole-body insulin sensitivity remained lowest in SIRD (p<0.05 vs. all clusters) with no difference in changes between clusters. Also, significant fibrosis (NAFLD-FS >0.6) was highest in SIRD (21%) compared to SIDD (0%), MOD (16%) and MARD (11%). In conclusion, patients of the SIRD cluster exhibit higher prevalence of steatosis at diagnosis and increased risk of NAFLD progression over 5 years. Disclosure O.P. Zaharia: None. K. Strassburger: None. Y. Kupriyanova: None. Y. Karusheva: None. S. Antoniou: None. K. Bodis: None. O. Asplund: Research Support; Self; Eli Lilly and Company. V. Burkart: None. K. Muessig: None. J. Hwang: None. O. Kuss: None. L. Groop: None. E. Ahlqvist: None. J. Szendroedi: None. M. Roden: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Poxel SA, Servier. Board Member; Self; Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. Speaker's Bureau; Self; Novo Nordisk Inc. Funding German Ministry of Culture and Science of the State of North Rhine-Westphalia; German Federal Ministry of Health; German Federal Ministry of Education and Research