Early Metabolic Markers Of The Development Of Dysglycemia And Type 2 Diabetes And Their Physiological Significance

Metabolomic screening of fasting plasma from nondiabetic subjects identified alpha-hydroxybutyrate (AHB) and linoleoyl-glycerophosphocholine (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. 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. 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.kg_ffm^-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. 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.