Diabetes is a growing epidemic, and it has become arguably one of the biggest health challenges of our time. Currently, more than 23 million Americans have diabetes, and the Centers for Disease Control and Prevention estimate that in the last 15 years, the number of people in the United States with diabetes has more than doubled. Diabetes is increasing at an alarming rate in Europe as well, and it is fast becoming a major health threat in developing countries such as India and China. Despite its high prevalence, however, diabetes remains somewhat of a mystery. Although type 1 diabetes mellitus could be attributed to insufficient insulin release by the ?-cells of the pancreas, the origins of type 2 diabetes mellitus (which accounts for >90% of the cases of diabetes) remain obscure. Insulin resistance is a cardinal feature of type 2 diabetes mellitus; however, it is not clear how whole-body insulin resistance develops, which specific tissues are affected first and which ones later, and how metabolic changes in individual tissues contribute to the overall development of the disease and its many secondary complications.