ABSTRACT/PROJECT SUMMARY Type 2 diabetes mellitus (T2DM) affects ~29.1 million individuals in the US and is associated with significant morbidity and mortality from both microvascular and macrovascular complications. The microvascular, and to a lesser extent macrovascular, complications primarily are related to hyperglycemia. Therefore, it is logical to initiate therapy early in the natural history of T2DM, at the “prediabetic” stage, with interventions that reverse specific pathophysiologic defects present in IGT and IFG. In both IGT and IFG, the progression to T2DM is characterized by progressive beta cell failure. Although both IGT and IFG represent high risk states for future T2DM, we have shown that they are characterized by distinct pathophysiologic defects. Individuals with IFG have impaired 1st phase insulin secretion and hepatic insulin resistance and both of these defects strongly are correlated with the increase in fasting plasma glucose concentration. In contrast, IGT subjects have decreased 2nd phase insulin secretion and severe muscle insulin resistance. Therefore, one would expect patients with IGT and IFG to respond differently to different pharmacologic interventions. Thus, dapagliflozin, an SGLT2 inhibitor that induces glucosuria, reduces the FPG, and reverses glucotoxicity might be expected to be effective in IFG, while pioglitazone, a thiazolidinedione that activates PPAR, reverses lipotoxicity, augments 2nd phase insulin secretion and improves muscle insulin sensitivity, would be expected to be most effective in IGT. Saxagliptin, a DPP4 inhibitor, that augments both 1st and 2nd phase insulin secretion, would be expected to work well in both IGT and IFG. We will test this hypothesis by treating individuals with isolated IGT and isolated IFG with the following interventions: (1) metformin; (2) dapagliflozin; (3) pioglitazone; (4) saxagliptin; (5) placebo for 30 months. After 30 months, all medications will be discontinued for 6 months to examine whether the beneficial effects on beta cell function (insulin secretion/insulin resistance [disposition] index) persist. At baseline, 30, and 36 months subjects will receive: (i) euglycemic insulin clamp, (ii) 2-step hyperglycemic clamp with GLP-1 infusion, (iii) OGTT with measurement of GLP-1 and GIP. This will provide state-of-the-art quantitation of beta cell function and insulin resistance and define the effect of the various pharmacologic interventions on these key pathophysiologic parameters.