PRESERVATION OF BETA CELL FUNCTION IN PREDIABETES: IGT AND IFG

Type 2 diabetes mellitus (T2DM) affects ~29.1 million individuals in the US and is associated withsignificant morbidity and mortality from both microvascular and macrovascular complications. Themicrovascular, and to a lesser extent macrovascular, complications primarily are related tohyperglycemia. 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 andIFG. 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 arecharacterized by distinct pathophysiologic defects. Individuals with IFG have impaired 1st phase insulinsecretion and hepatic insulin resistance and both of these defects strongly are correlated with theincrease in fasting plasma glucose concentration. In contrast, IGT subjects have decreased 2nd phaseinsulin secretion and severe muscle insulin resistance. Therefore, one would expect patients with IGTand IFG to respond differently to different pharmacologic interventions. Thus, dapagliflozin, an SGLT2inhibitor that induces glucosuria, reduces the FPG, and reverses glucotoxicity might be expected to beeffective 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 bemost effective in IGT. Saxagliptin, a DPP4 inhibitor, that augments both 1st and 2nd phase insulinsecretion, would be expected to work well in both IGT and IFG. We will test this hypothesis by treatingindividuals 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 medicationswill be discontinued for 6 months to examine whether the beneficial effects on beta cell function (insulinsecretion/insulin resistance [disposition] index) persist. At baseline, 30, and 36 months subjects willreceive: (i) euglycemic insulin clamp, (ii) 2-step hyperglycemic clamp with GLP-1 infusion, (iii) OGTTwith measurement of GLP-1 and GIP. This will provide state-of-the-art quantitation of beta cell functionand insulin resistance and define the effect of the various pharmacologic interventions on these keypathophysiologic parameters.