Early metabolic markers of the development of dysglycemia and type 2 diabetes and their physiological significance

Abstract

Metabolomic screening of fasting plasma from nondiabetic subjects identified α-hydroxybutyrate (α-HB) and linoleoyl-glycerophosphocholine (L-GPC) as joint markers of insulin resistance (IR) and glucose intolerance. To test the predictivity of α-HB and L-GPC for incident dysglycemia, α-HB and L-GPC measurements were obtained in two observational cohorts, comprising 1,261 nondiabetic participants from the Relationship between Insulin Sensitivity and Cardiovascular Disease (RISC) study and 2,580 from the Botnia Prospective Study, with 3-year and 9.5-year follow-up data, respectively. In both cohorts, α-HB was a positive correlate and L-GPC a negative correlate of insulin sensitivity, with α-HB reciprocally related to indices of β-cell function derived from the oral glucose tolerance test (OGTT). In follow-up, α-HB was a positive predictor (adjusted odds ratios 1.25 [95% CI 1.00-1.60] and 1.26 [1.07-1.48], respectively, for each standard deviation of predictor), and L-GPC was a negative predictor (0.64 [0.48-0.85] and 0.67 [0.54-0.84]) of dysglycemia (RISC) or type 2 diabetes (Botnia), independent of familial diabetes, sex, age, BMI, and fasting glucose. Corresponding areas under the receiver operating characteristic curve were 0.791 (RISC) and 0.783 (Botnia), similar in accuracy when substituting α-HB and L-GPC with 2-h OGTT glucose concentrations. When their activity was examined, α-HB inhibited and L-GPC stimulated glucose-induced insulin release in INS-1e cells. α-HB and L-GPC are independent predictors of worsening glucose tolerance, physiologically consistent with a joint signature of IR and β-cell dysfunction.

FIG. 1.

Multivariate logistic regression for incident dysglycemia (RISC) or T2D (Botnia). Odds ratios (95% CI) for α-HB are 1.25 (1.00–1.60) and 1.26 (1.07–1.48), respectively, for RISC and Botnia cohorts. The corresponding odds ratios (95% CI) for L-GPC are 0.64 (0.48–0.85) and 0.67 (0.54–0.84). Odds ratios are calculated for 1 SD of the explanatory variables. (A high-quality color representation of this figure is available in the online issue.)

FIG. 2.

Relationship between L-GPC, α-HB, BCAA, and oleate levels and insulin sensitivity. Fasting plasma concentrations of the BCAAs (sum of leucine, isoleucine, and valine) by quartile of α-HB concentrations in 542 subjects from the Botnia study are shown. Also plotted are plasma L-GPC and oleate concentrations, and eM values by quartile of α-HB. Plots are mean ± SEM. Note that the horizontal scale for oleate and L-GPC has been shifted to avoid overlapping symbols.

FIG. 3.

Reconstruction of the metabolic pathway featuring α-HB and L-GPC. Unmeasured metabolites are in italic, and statistically significant changes between progressors and nonprogressors are indicated in red. α-KB, α-ketobutyrate; GSH, glutathione; oc-FFA, odd-chain FFA. See text for further explanation.