The response to weight loss intervention is heterogeneous both in weight loss amount and improvement in metabolism. We seek to identify biomarkers predictive of long-term weight loss and type 2 diabetes (T2D) remission in the Longitudinal Assessment of Bariatric Surgery (LABS) and the Look AHEAD (Action for Health in Diabetes) studies.

Methods: LABS is a longitudinal observational study of 2458 consecutive cases (2006-2009) of bariatric surgery. Look AHEAD is an RCT comparing an intensive lifestyle intervention to T2D support and education in 5,145 U.S. adults with obesity and T2D enrolled between 2001-2004. Targeted mass spectrometry-based profiling of 135 metabolites was performed in pre-intervention blood samples from individuals selected based on sustained T2D remission (N=93 LABS, N=80 Look AHEAD) and extremes (top and bottom 13th percentile) of weight loss (N=151 LABS, 23 with T2D) at 4 or 5 years. We used PCA for dimensionality reduction of metabolites and logistic regression models to determine association between metabolic factors and phenotype. Improvement in model fit and net reclassification index analyses were performed to determine if metabolites improved a clinical model for predicting remission.

Results: One factor composed of branched chain amino acids (BCAA) and tyrosine (p=0.045), and one composed of betaine and choline (p=0.02) were associated with T2D remission. Inclusion of these factors in a clinical prediction model improved the fit (p=0.04). Only one factor, composed of C31:1-C37:1 sphingomyelins, associated with weight loss at 5 years (p=0.036).

Conclusions. Our findings define novel associations between metabolites in the BCAA and trimethylamine-N-oxide-microbiome-related pathways that are independently and incrementally associated with sustained T2D remission after weight loss. Future studies of these analytes could help in the discovery of metabolic regulatory mechanisms, and guide more personalized weight loss interventions in individuals with T2D.


L.C. Kwee: None. O. Ilkayeva: None. M. Muehlbauer: None. B.M. Wolfe: None. J.Q. Purnell: Advisory Panel; Self; Novo Nordisk A/S. H. Chen: None. C.B. Newgard: None. S.H. Shah: Research Support; Self; AstraZeneca, Verily Life Sciences LLC.


National Institute of Diabetes and Digestive and Kidney Diseases (R01DK108580)

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