Diabetes is an enormous and growing public health problem. In the United States, the disease afflicts 20.8 million people, or 7% of the population, the overwhelming majority of whom have Type-2 diabetes. The US spends approximately $132 billion annually on diabetes in direct and indirect costs, and that number rises each year. Major research efforts seek ways to better understand and treat this prevalent disease. A landmark clinical trial, the Diabetes Prevention Program, showed that either a physically active lifestyle OR treatment with the drug metformin, the most commonly prescribed diabetes drug, causes impressive reductions in the transition from [unreadable]high-risk[unreadable] status to diagnosed Type-2 diabetes. In 2008, the American Diabetes Association recommended for people with pre-diabetes 150 minutes per week of moderate activity and metformin for prevention/delay of Type-2 diabetes. As a result, this approach very likely will soon become the standard of care for this enormous patient population. However, based on the scientific literature, it is unclear whether combining these two treatments will result in greater benefits. The combination of these therapies may elicit additive, synergistic, or even subtractive effects on several key components of metabolic health, given that metformin and exercise have different mechanisms of action. The experiments described in this proposal aim at understanding the efficacy of combined exercise training and metformin treatment in order to allow an evidence-based medicine approach to clinical recommendations for this patient population. Seventy-two overweight men and women with [unreadable]prediabetes[unreadable] (metabolic abnormalities that put them at high-risk of developing Type-2 diabetes) will complete a 10-week program in which they receive exercise training, metformin, training-plus-metformin, or a placebo. Results at various time-points in the four conditions will be compared on measures of: Aim 1. whole-body metabolic health (whole-body and hepatic insulin sensitivity; metabolic flexibility; and changes in a series of hormones and substrates related to one[unreadable]s metabolic profile); and Aim 2. cellular processes that contribute to those benefits (myocellular proteins related to energy, carbohydrate, and lipid metabolism.) The collective experience and expertise of our research team in wholebody metabolism, intracellular signaling, clinical management, and statistical analyses create an integrative environment to address the aims of this proposal from cellular mechanisms through clinically-relevant outcomes. Results from this translational research may benefit public health approaches to obesity, prediabetes, and Type-2 diabetes. Millions of Americans are, or will be, taking metformin and encouraged to increase physical activity. In light of this massive public health effort, we must understand the efficacy of combined therapy and its mechanisms of action in order to formulate the most effective public health response.