Novel Metabolic Markers for the Risk of Diabetes Development in American Indians

OBJECTIVE To identify novel metabolic markers for diabetes development in American Indians. RESEARCH DESIGN AND METHODS Using an untargeted high-resolution liquid chromatography-mass spectrometry, we conducted metabolomics analysis of study participants who developed incident diabetes (n = 133) and those who did not (n = 298) from 2,117 normoglycemic American Indians followed for an average of 5.5 years in the Strong Heart Family Study. Relative abundances of metabolites were quantified in baseline fasting plasma of all 431 participants. Prospective association of each metabolite with risk of developing type 2 diabetes (T2D) was examined using logistic regression adjusting for established diabetes risk factors. RESULTS Seven metabolites (five known and two unknown) significantly predict the risk of T2D. Notably, one metabolite matching 2-hydroxybiphenyl was significantly associated with an increased risk of diabetes, whereas four metabolites matching PC (22:6/20:4), (3S)-7-hydroxy-2',3',4',5',8-pentamethoxyisoflavan, or tetrapeptides were significantly associated with decreased risk of diabetes. A multimarker score comprising all seven metabolites significantly improved risk prediction beyond established diabetes risk factors including BMI, fasting glucose, and insulin resistance. CONCLUSIONS The findings suggest that these newly detected metabolites may represent novel prognostic markers of T2D in American Indians, a group suffering from a disproportionately high rate of T2D.