Nontargeted and Targeted Metabolomic Profiling Reveals Novel Metabolite Biomarkers of Incident Diabetes in African Americans

Abstract

Nontargeted metabolomics methods have increased potential to identify new disease biomarkers, but assessments of the additive information provided in large human cohorts by these less biased techniques are limited. To diversify our knowledge of diabetes associated metabolites, we leveraged a method that measures 305 targeted or “known” and 2,342 nontargeted or “unknown” compounds in fasting plasma samples from 2,750 participants (315 incident cases) in the Jackson Heart Study (JHS)—a community cohort of self-identified African Americans (AAs), who are underrepresented in omics studies. We found 307 unique compounds (82 known) associated with diabetes after adjusting for age and sex at a false discovery rate (FDR) <0.05 and 124 compounds (35 known, including 11 not previously associated) after further adjustments for BMI and fasting plasma glucose (FPG). Of these, 144 and 68 associations, respectively, replicated in a multi-ethnic cohort. Among these is an apparently novel isomer of the 1-deoxyceramide Cer(m18:1/24:0) with functional geonomics and high-resolution mass spectrometry. Overall, known and unknown metabolites provided complementary information (median correlation ρ=0.29) and their inclusion with clinical risk factors improved diabetes prediction modeling. Our findings highlight the importance of including nontargeted metabolomics methods to provide new insights into diabetes development in ethnically diverse cohorts.

Metabolomic profiling of glucose homeostasis in African Americans: the Insulin Resistance Atherosclerosis Family Study (IRAS-FS)

“…Decades of epidemiology studies have established that elevated levels of circulating BCAAs and their metabolites are associated with insulin resistance and type 2 diabetes risk in populations of European ancestry (Felig et al, 1969 ; Gall et al, 2010 ; Guasch-Ferre et al, 2016 ; Huffman et al, 2009 ; Menni et al, 2013 ; Newgard et al, 2009 ; Shah et al, 2012 ; Stancakova et al, 2012 ; Tillin et al, 2015 ; Wang et al, 2011 ; Wurtz et al, 2012a , 2012b , 2013 ). These associations were recently confirmed in populations of Asian (Arany & Neinast, 2018 ; Chen et al, 2016 , 2019 ; Tai et al, 2010 ; Takashina et al, 2016 ; Tillin et al, 2015 ), African (Chen et al, 2022 ) and Mexican (Lee et al, 2016 ; Palmer et al, 2015 , 2018 ) ancestries. In this study, we observed in African Americans that increased levels of BCAA-related metabolites (isoleucine, 3-methyl-2-oxovalerate and 3-hydroxy-2-ethylpropionate in isoleucine metabolism; leucine, 4-methyl-2-oxopentanoate and isovalerylcarnitine in leucine metabolism; valine, 3-methyl-2-oxobutyrate and 3-hydroxyisobutyrate in valine metabolism; Supplementary Table 4a-f) were positively associated with basal measures of HOMA-IR but negatively associated with dynamic measures of S I , DI and S G .…”

“…Circulating levels of glycine were lower in obese (Felig et al, 1969 ; Okekunle et al, 2017 ; Takashina et al, 2016 ; Yan et al, 2012 ) and insulin-resistant individuals (Ejaz et al, 2016 ; Gall et al, 2010 ; Newgard et al, 2009 ; Takashina et al, 2016 ) as compared to healthy individuals in populations of European and East Asian ancestries. Plasma glycine levels were also negatively associated with fasting glucose levels and type 2 diabetes risk (Chen et al, 2022 ; Ferrannini et al, 2013 ; Floegel et al, 2013 ; Guasch-Ferre et al, 2016 ; Newgard et al, 2009 ; Palmer et al, 2015 ; Svingen et al, 2016 ; Vangipurapu et al, 2019 ; Walford et al, 2016 ; Wang-Sattler et al, 2012 ). In concordance with the previous findings, we observed that the metabolites (glycine, N-acetylglycine or serine; Supplementary Table 4a-f) in the glycine, serine and threonine metabolism sub-pathway were positively associated with dynamic measures of S I and DI but negatively associated with basal measures of HOMA-IR and HOMA-B in IRAS-FS African Americans.…”

“…Oral glutamate supplementation was previously shown to impair insulin sensitivity in a short-term dietary intervention (Chevassus et al, 2002 ). Increased circulating levels of glutamate were previously associated with insulin resistance (Chen et al, 2022 ; Cheng et al, 2012 ; Newgard et al, 2009 ; Vangipurapu et al, 2019 ) and type 2 diabetes risk in populations of European (Chen et al, 2019 ; Cheng et al, 2012 ; Ferrannini et al, 2013 ; Liu et al, 2019 ; Stancakova et al, 2012 ; Vangipurapu et al, 2019 ), Asian (Chen et al, 2019 ; Takashina et al, 2016 ) and African (Chen et al, 2022 ). ancestries.…”

“…Similarly, the metabolite arginine in this pathway was negatively associated with S I but positively associated with HOMA-IR and HOMA-B levels (Supplementary Table 4a-f). Increased plasma levels of 2-oxoarginine and arginine were positively associated with HOMA-B measures in IRAS-FS Mexican Americans (Palmer et al, 2018 ), and increased circulating arginine levels were associated with increased type 2 diabetes risk in populations of European (Guasch-Ferre et al, 2016 ) and African (Chen et al, 2022 ) ancestries. The metabolite 2-oxoarginine is a guanidino compound metabolite of arginine catabolism.…”

“…Many of the amino acids are replicated for association with insulin resistance and type 2 diabetes risk in Asians (Chen et al, 2016 , 2019 ; Tai et al, 2010 ). Similarly, several amino acids, lipids and carbohydrate metabolites are associated with insulin resistance, incident and prevalent type 2 diabetes in African Americans, Mexican Americans and multi-ethnic populations(Chen et al, 2022 ; Lee et al, 2016 ; Palmer et al, 2015 , 2018 ; Rebholz et al, 2018 ). Large-scale multi-ethnic studies such as The Consortium of Metabolomics Studies (COMETS) are ongoing with available fasting glucose and insulin levels (Yu et al, 2019 ).…”