TY - JOUR
T1 - Metabolomics insights into early type 2 diabetes pathogenesis and detection in individuals with normal fasting glucose
AU - Merino, Jordi
AU - Leong, Aaron
AU - Liu, Ching Ti
AU - Porneala, Bianca
AU - Walford, Geoffrey A.
AU - von Grotthuss, Marcin
AU - Wang, Thomas J.
AU - Flannick, Jason
AU - Dupuis, Josée
AU - Levy, Daniel
AU - Gerszten, Robert E.
AU - Florez, Jose C.
AU - Meigs, James B.
N1 - Publisher Copyright:
© 2018, Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2018/6/1
Y1 - 2018/6/1
N2 - Aims/hypothesis: Identifying the metabolite profile of individuals with normal fasting glucose (NFG [<5.55 mmol/l]) who progressed to type 2 diabetes may give novel insights into early type 2 diabetes disease interception and detection. Methods: We conducted a population-based prospective study among 1150 Framingham Heart Study Offspring cohort participants, age 40–65 years, with NFG. Plasma metabolites were profiled by LC-MS/MS. Penalised regression models were used to select measured metabolites for type 2 diabetes incidence classification (training dataset) and to internally validate the discriminatory capability of selected metabolites beyond conventional type 2 diabetes risk factors (testing dataset). Results: Over a follow-up period of 20 years, 95 individuals with NFG developed type 2 diabetes. Nineteen metabolites were selected repeatedly in the training dataset for type 2 diabetes incidence classification and were found to improve type 2 diabetes risk prediction beyond conventional type 2 diabetes risk factors (AUC was 0.81 for risk factors vs 0.90 for risk factors + metabolites, p = 1.1 × 10−4). Using pathway enrichment analysis, the nitrogen metabolism pathway, which includes three prioritised metabolites (glycine, taurine and phenylalanine), was significantly enriched for association with type 2 diabetes risk at the false discovery rate of 5% (p = 0.047). In adjusted Cox proportional hazard models, the type 2 diabetes risk per 1 SD increase in glycine, taurine and phenylalanine was 0.65 (95% CI 0.54, 0.78), 0.73 (95% CI 0.59, 0.9) and 1.35 (95% CI 1.11, 1.65), respectively. Mendelian randomisation demonstrated a similar relationship for type 2 diabetes risk per 1 SD genetically increased glycine (OR 0.89 [95% CI 0.8, 0.99]) and phenylalanine (OR 1.6 [95% CI 1.08, 2.4]). Conclusions/interpretation: In individuals with NFG, information from a discrete set of 19 metabolites improved prediction of type 2 diabetes beyond conventional risk factors. In addition, the nitrogen metabolism pathway and its components emerged as a potential effector of earliest stages of type 2 diabetes pathophysiology.
AB - Aims/hypothesis: Identifying the metabolite profile of individuals with normal fasting glucose (NFG [<5.55 mmol/l]) who progressed to type 2 diabetes may give novel insights into early type 2 diabetes disease interception and detection. Methods: We conducted a population-based prospective study among 1150 Framingham Heart Study Offspring cohort participants, age 40–65 years, with NFG. Plasma metabolites were profiled by LC-MS/MS. Penalised regression models were used to select measured metabolites for type 2 diabetes incidence classification (training dataset) and to internally validate the discriminatory capability of selected metabolites beyond conventional type 2 diabetes risk factors (testing dataset). Results: Over a follow-up period of 20 years, 95 individuals with NFG developed type 2 diabetes. Nineteen metabolites were selected repeatedly in the training dataset for type 2 diabetes incidence classification and were found to improve type 2 diabetes risk prediction beyond conventional type 2 diabetes risk factors (AUC was 0.81 for risk factors vs 0.90 for risk factors + metabolites, p = 1.1 × 10−4). Using pathway enrichment analysis, the nitrogen metabolism pathway, which includes three prioritised metabolites (glycine, taurine and phenylalanine), was significantly enriched for association with type 2 diabetes risk at the false discovery rate of 5% (p = 0.047). In adjusted Cox proportional hazard models, the type 2 diabetes risk per 1 SD increase in glycine, taurine and phenylalanine was 0.65 (95% CI 0.54, 0.78), 0.73 (95% CI 0.59, 0.9) and 1.35 (95% CI 1.11, 1.65), respectively. Mendelian randomisation demonstrated a similar relationship for type 2 diabetes risk per 1 SD genetically increased glycine (OR 0.89 [95% CI 0.8, 0.99]) and phenylalanine (OR 1.6 [95% CI 1.08, 2.4]). Conclusions/interpretation: In individuals with NFG, information from a discrete set of 19 metabolites improved prediction of type 2 diabetes beyond conventional risk factors. In addition, the nitrogen metabolism pathway and its components emerged as a potential effector of earliest stages of type 2 diabetes pathophysiology.
KW - Metabolomics
KW - Normoglycaemia
KW - Type 2 diabetes pathophysiology
KW - Type 2 diabetes prediction
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U2 - 10.1007/s00125-018-4599-x
DO - 10.1007/s00125-018-4599-x
M3 - Article
C2 - 29626220
AN - SCOPUS:85045033940
SN - 0012-186X
VL - 61
SP - 1315
EP - 1324
JO - Diabetologia
JF - Diabetologia
IS - 6
ER -