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.

Obesity is a critical global epidemic, a leading cause of preventable death, and a source of skyrocketing healthcare costs. Currently more than two thirds of US adults are overweight and at least one third are consideredobese.

Frailty is a geriatric syndrome which leads to poor health outcomes in older adults, such as falls, disability,hospitalization, institutionalization, and death. Due to the dramatic growth in the U.S. aging population and thehealth care costs associated with frailty (estimated at more than $18 billion per year), frailty is a major healthcare problem. There has been little research into potential pharmacologic interventions that would delay orreduce the incidence of frailty. Thus, the major goal of this study is to test metformin as a novel intervention forthe prevention of frailty.

Inhibition of the renal SGLT2 transporter has proven to be an effective therapeutic interventionto reduce plasma glucose levels and HbA1c in type 2 diabetic patients. The glycemic-loweringefficacy of the SGLT2 inhibitors results from two distinct mechanisms: (i) induction ofglucosuria, which amounts to ~70-90 grams per day and (ii) amelioration of glucotoxicity leadingto increased insulin sensitivity in muscle and improved beta cell function (JCI 124:509-514,2014).