Early Metabolic Markers of Dysglycemia and Type 2 Diabetes
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.
There is increasing interest in identifying markers of chronic diseases. A useful biomarker is a molecule that 1) is easily and specifically measurable in accessible body fluids, 2) improves prediction algorithms, 3) tracks an underlying pathophysiological mechanism, 4) changes consensually with the mechanism, and possibly, 5) maps onto a new disease pathway. This search hopes not only to provide a more accurate prediction of disease but also follow its evolution and response to intervention and expose new potential therapeutic targets.
Recent studies have used different extents of metabolomic profiling to uncover metabolic signatures of obesity, fatty liver disease, and type 2 diabetes (T2D). In previous work, we screened several hundred metabolites to identify novel circulating biomarkers of insulin resistance (IR)—as measured by the euglycemic clamp technique—in selected subjects in the Relationship between Insulin Sensitivity and Cardiovascular Disease (RISC) study, a cohort of well-phenotyped nondiabetic individuals. The top biomarker of IR emerging from this analysis was a previously unrecognized metabolite identified as α-hydroxybutyrate (α-HB), an organic acid positioned at an interesting crossroad of intermediary metabolism—amino acid catabolism and glutathione synthesis—and upstream to the tricarboxylic acid (TCA) cycle. The next top-ranking biomarker was linoleoyl-glycerophosphocholine (L-GPC), an independent correlate of insulin sensitivity and a putative lipid-signaling molecule.
Because these biomarkers of insulin sensitivity were independently associated with glucose intolerance and IR is a risk factor for T2D, we carried out a clinically validated assay of these metabolites in the entire RISC cohort at baseline and follow-up to evaluate their predictivity of incident dysglycemia. Furthermore, because these biomarkers have not been previously evaluated in clinical outcome studies, we tested their ability to predict T2D in a long-term observational cohort of at-risk subjects in the Botnia Prospective Study. Finally, we initiated additional in vivo and in vitro studies to gain understanding of the physiological basis for these associations.
Abstract and Introduction
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.
Introduction
There is increasing interest in identifying markers of chronic diseases. A useful biomarker is a molecule that 1) is easily and specifically measurable in accessible body fluids, 2) improves prediction algorithms, 3) tracks an underlying pathophysiological mechanism, 4) changes consensually with the mechanism, and possibly, 5) maps onto a new disease pathway. This search hopes not only to provide a more accurate prediction of disease but also follow its evolution and response to intervention and expose new potential therapeutic targets.
Recent studies have used different extents of metabolomic profiling to uncover metabolic signatures of obesity, fatty liver disease, and type 2 diabetes (T2D). In previous work, we screened several hundred metabolites to identify novel circulating biomarkers of insulin resistance (IR)—as measured by the euglycemic clamp technique—in selected subjects in the Relationship between Insulin Sensitivity and Cardiovascular Disease (RISC) study, a cohort of well-phenotyped nondiabetic individuals. The top biomarker of IR emerging from this analysis was a previously unrecognized metabolite identified as α-hydroxybutyrate (α-HB), an organic acid positioned at an interesting crossroad of intermediary metabolism—amino acid catabolism and glutathione synthesis—and upstream to the tricarboxylic acid (TCA) cycle. The next top-ranking biomarker was linoleoyl-glycerophosphocholine (L-GPC), an independent correlate of insulin sensitivity and a putative lipid-signaling molecule.
Because these biomarkers of insulin sensitivity were independently associated with glucose intolerance and IR is a risk factor for T2D, we carried out a clinically validated assay of these metabolites in the entire RISC cohort at baseline and follow-up to evaluate their predictivity of incident dysglycemia. Furthermore, because these biomarkers have not been previously evaluated in clinical outcome studies, we tested their ability to predict T2D in a long-term observational cohort of at-risk subjects in the Botnia Prospective Study. Finally, we initiated additional in vivo and in vitro studies to gain understanding of the physiological basis for these associations.
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