Background and aims: Metabolomic screening of fasting plasma from nondiabetic subjects identified alpha-hydroxybutyrate (AHB) and linoleoylglycerophosphocholine (L-GPC) as joint markers of insulin resistance (IR) and glucose intolerance. We tested their predictivity for incident dysglycemia and investigated their potential physiological role. Materials and methods: Metabolite profiling was carried out in 1,261 nondiabetic participants of the RISC study and 2,580 subjects of the Botnia cohort. Three-year (RISC) and 9.5-year (Botnia) follow-up data were analyzed. Results: In both RISC and Botnia baseline data, AHB was a positive correlate, and L-GPC a negative correlate, of insulin sensitivity; AHB was also reciprocally related to indices of beta cell function. In a subgroup of Botnia subjects, higher AHB was associated with higher branched-chain amino acid and free fatty acid levels, and decreased glycine (constituent of glutathione). In follow-up, AHB was a positive predictor (adjusted odds ratios 1.25 [95%CI:1.00-1.60] and 1.26 [95%CI:1.07-1.48], respectively) and L-GPC a negative predictor (adj. odds ratios 0.64 [95%CI:0.48-0.85] and 0.67 [95%CI: 0.54-0.84]) of dysglycemia (RISC) or type 2 diabetes (Botnia), independent of familial diabetes, sex, age, BMI, and fasting plasma glucose, with ROC area-under-curves of 0.791 and 0.783. In morbidly obese subjects undergoing bariatric surgery, AHB halved (6.14[3.64] to 3.47[1.43] microg/ml, p<0.0001) as insulin sensitivity doubled (19.9[17.4] to 41.4[10.5] micromol.min-1.kgffm -1, p<0.0001). Consistent with their association with insulin sensitivity and secretion, in INS-1e cell cultures, AHB inhibited and L-GPC stimulated glucose/arginine-induced insulin release at physiological concentrations. Conclusion: AHB and L-GPC are early independent predictors of worsening glucose tolerance in diverse populations. Physiologically, AHB and L-GPC appear to be signatures of IR, beta cell dysfunction, and metabolic overload.
Early metabolic markers of the development of dysglycaemia and type 2 diabetes and their physiological significance
NATALI, ANDREA;CAMASTRA, STEFANIA;NANNIPIERI, MONICA;
2012-01-01
Abstract
Background and aims: Metabolomic screening of fasting plasma from nondiabetic subjects identified alpha-hydroxybutyrate (AHB) and linoleoylglycerophosphocholine (L-GPC) as joint markers of insulin resistance (IR) and glucose intolerance. We tested their predictivity for incident dysglycemia and investigated their potential physiological role. Materials and methods: Metabolite profiling was carried out in 1,261 nondiabetic participants of the RISC study and 2,580 subjects of the Botnia cohort. Three-year (RISC) and 9.5-year (Botnia) follow-up data were analyzed. Results: In both RISC and Botnia baseline data, AHB was a positive correlate, and L-GPC a negative correlate, of insulin sensitivity; AHB was also reciprocally related to indices of beta cell function. In a subgroup of Botnia subjects, higher AHB was associated with higher branched-chain amino acid and free fatty acid levels, and decreased glycine (constituent of glutathione). In follow-up, AHB was a positive predictor (adjusted odds ratios 1.25 [95%CI:1.00-1.60] and 1.26 [95%CI:1.07-1.48], respectively) and L-GPC a negative predictor (adj. odds ratios 0.64 [95%CI:0.48-0.85] and 0.67 [95%CI: 0.54-0.84]) of dysglycemia (RISC) or type 2 diabetes (Botnia), independent of familial diabetes, sex, age, BMI, and fasting plasma glucose, with ROC area-under-curves of 0.791 and 0.783. In morbidly obese subjects undergoing bariatric surgery, AHB halved (6.14[3.64] to 3.47[1.43] microg/ml, p<0.0001) as insulin sensitivity doubled (19.9[17.4] to 41.4[10.5] micromol.min-1.kgffm -1, p<0.0001). Consistent with their association with insulin sensitivity and secretion, in INS-1e cell cultures, AHB inhibited and L-GPC stimulated glucose/arginine-induced insulin release at physiological concentrations. Conclusion: AHB and L-GPC are early independent predictors of worsening glucose tolerance in diverse populations. Physiologically, AHB and L-GPC appear to be signatures of IR, beta cell dysfunction, and metabolic overload.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
