Longitudinal Associations of Branched-chain and Aromatic Amino Acids with Decreased Insulin Secretion and Insulin Sensitivity among Japanese Americans

Thesis (Master's)--University of Washington, 2021Background: Type 2 diabetes (T2D) is characterized by diminished insulin sensitivity and insulin secretion. Identification of metabolic biomarkers such as branched-chain (BCAA) and aromatic amino acids (AAA) that could be used for early identification of increased risk for decreased insulin sensitivity and secretion among Japanese Americans could improve health outcomes and reduce health disparities for this minority population. We characterized cross-sectional and longitudinal associations of plasma BCAA and AAA levels with insulin sensitivity and secretion in Japanese Americans. Methods: We used mass spectrometry to measure plasma BCAA and AAA levels obtained from Japanese American participants without diabetes who were in a study of diabetes risk factors (Japanese American Community Diabetes Study Biomarker Discovery Project, n=347, 51% men, 49% women). We calculated Gutt, Matsuda, and oral disposition indices (DIO) using weight and oral glucose tolerance test results from baseline and five years later. Linear regression was used to evaluate cross-sectional and longitudinal associations between BCAA and AAA levels and insulin sensitivity and secretion indices overall and in sex-stratified models. Results: On average, participants were 55 years old. At baseline, the mean and standard deviations were 60.9(16.5) for Gutt, 3.3(1.6) for Matsuda, and 1.1(1.2) for oral disposition indices (DIO). In cross-sectional analyses, isoleucine was associated with Matsuda index (β -0.03 [95%CI -0.05,-0.003]). In men, tryptophan was associated with Matsuda index (β 0.05 [95%CI 0.01,0.09]) and isoleucine with DIO (β -0.001 [95%CI -0.002,-0.00003]). In longitudinal analyses, tyrosine was associated with Gutt index (β -0.27 [95%CI -0.51,-0.02]) and phenylalanine with Matsuda index (β -0.04 [95%CI -0.08,-0.01]). In men, tyrosine was associated with Gutt index (β -0.48 [95%CI -0.86,-0.10]), and phenylalanine and tyrosine with Matsuda index (β -0.05 [95%CI -0.10,-0.01], β -0.03 [95% CI -0.06,-0.003], respectively). In women, no BCAA or AAA was associated with any index in cross-sectional or longitudinal analyses. There was no statistical evidence for effect modification by sex. Conclusions: BCAA and AAA including tryptophan, isoleucine, tyrosine, and phenylalanine were associated with insulin sensitivity and insulin secretion; however, magnitudes of associations were small in comparison to means and standard deviations of respective indices. BCAA and AAA were inversely associated with insulin sensitivity and secretion, except tyrosine which was positively associated with Matsuda index at baseline in men. Our study highlights the need for continued metabolomics research pertaining to chronic diseases of global significance, such as T2D