The data point to a time-line in the molecular pathologies ultimately leading to type 2 diabetes; the changes found in the control/UQ comparison likely precede those in the UQ/GDM comparison. A second early Batimastat alteration was the relative fall in plasma LCFA and LCFA-carnitines, along with minor increases in fasting plasma glucose and HbA1c levels. Those are consistent with a glucose-sparing mitochondrial fuel economy, related to the increased abdominal circumference in the UQ and GDM groups. Many changes occurred in clusters of metabolite classes, for example phospholipids, lysophospholipids, LCFA, LCFA-carnitines, and SCFA/SCFA-metabolites, pointing to mechanisms that affect large subsets of these metabolite classes, long before the emergence of overt disease. Differences in relative timings of activation in different potential pathways to the onset/progression of T2DM pathogenesis were also observed. Ebastine Modified lysophospholipid metabolism possibly implies elevated pro-inflammatory stress; lowered LCFA/LCFA-carnitine levels are consistent with early metabolic fuel substitution leading to preferential mitochondrial oxidation of LCFA as opposed to glucose, providing an early hyperglycemic stimulus; a widespread increase in SCFA/SCFA-metabolites suggest potential early defects in their generation and/or defective mitochondrial utilisation. Finally, we found early adiponectin deficiency which may initiate or contribute to several of the metabolic disturbances, The results point to a probable defect in adipose tissue regulation contributing to the initiation of T2DM pathogenesis; further characterisation of the early changes in adiponectin synthesis and post-translational modifications and its causes will be useful. Our current conclusions are reminiscent in several respects of those from a recent study of the antecedents of type 1 diabetes wherein dysregulation of lipid and amino acid metabolism preceded islet autoimmunity in children who later progressed to overt disease.Our study paves the way for targeted investigation of the pathogenic biochemical pathways that lead to or cause type 2 diabetes and more effective prevention and therapy, notably of blood vessel damage.