Rosiglitazone Increases Visceral and Subcutaneous Fat in Youth with Type 2 Diabetes (T2D) in the TODAY Study

Abstract

Objective: In TODAY, metformin + rosiglitazone (M+R) was better in maintaining glycemic control than metformin alone (M) or metformin + lifestyle (M+L), but longitudinal differences in whole body adiposity were small and unrelated to treatment group. As excess visceral adipose tissue (VAT) and nonalcoholic fatty liver disease (NAFLD) are common in T2D, we hypothesized that changes in VAT, subcutaneous adipose tissue (SAT), and liver enzymes, as a marker of NAFLD, would be related to treatment effect. Methods: TODAY enrolled 699 youth 11-17 y/o with T2D <2 year. In 626 subjects, VAT and SAT (by DXA) and AST and ALT were measured at baseline (BL) and 24 mo. Changes from BL to 24 mo were analyzed in baseline-adjusted repeated measures models. Results: At BL, mean age was 13.9 year, 66.4% were female, 41.1% hispanic, 31.1% non-hispanic black, 20.3% non-hispanic white (NHW). Mean BMI was 33.7 kg/m2 and BMI z-score +2.2. 3.3% had ALT ≥1.5 upper limit of normal (ULN), suggestive of NAFLD, and 0.3% had AST ≥1.5 ULN. At 24 mo, BMI, BMI z-score, VAT, and SAT all increased. VAT increased most in M+R and least in M+L (14.2% vs. 3.1%, p<0.001). SAT increased more in M+R (15.7%) than M+L (6.9%, p<0.0001) or M (8.7%, p<0.001). At 24 mo, between-group differences in VAT:SAT ratio and AST were not significant, but ALT increased more in M+L than M+R (23.1% vs. 2.7%, p=0.015). Sex did not moderate treatment effects on VAT and SAT. Greater increases in VAT occurred in NHW in M+R than M (p<0.001) or M+L (p<0.001). VAT and SAT increases correlated with higher HbA1c (p<0.001), and lower insulin sensitivity (p<0.033), and c-peptide oral disposition index (p<0.038), but did not differ by treatment group. Conclusion: Unlike in adults, in youth in TODAY, VAT rise was greater in M+R than M+L. VAT and SAT changes were not related to treatment group differences in glycemic control. Increased VAT and SAT correlated with lower insulin sensitivity and secretion. In T2D youth, R may blunt the rise in ALT, but does not lower the VAT:SAT ratio. Disclosure R. Dhaliwal: None. J.A. Shepherd: None. L. El Ghormli: None. K.C. Copeland: Other Relationship; Self; Novo Nordisk Inc. M. Geffner: Other Relationship; Self; Daiichi Sankyo Company, Limited. J. Higgins: None. L.L. Levitsky: Consultant; Self; Eli Lilly and Company. K.J. Nadeau: None. R.S. Weinstock: Research Support; Self; Medtronic MiniMed, Inc., Mylan, Kowa Pharmaceuticals America, Inc., Diasome Pharmaceuticals, Inc., Calibra Medical, Dexcom, Inc., Ultradian Diagnostics LLC., JAEB Center For Health Research, JDRF, National Institute of Diabetes and Digestive and Kidney Diseases. N.H. White: None.