Given that low testosterone levels predict type 2 diabetes mellitus (T2DM) in men, we sought to dissect the relationship between testosterone and insulin sensitivity in men. We showed a positive correlation between serum testosterone levels and insulin sensitivity in men across the full spectrum of glucose tolerance. Men with hypogonadal testosterone levels were twice as insulin resistant as eugonadal controls. By dissecting the hypothalamic-pituitary-gonadal axis, we demonstrated that the cause of low testosterone was a decrease in testicular responsiveness to luteinizing hormone (LH). Using functional and genetic studies, we provided evidence that hypogonadism may induce insulin resistance by causing mitochondrial dysfunction. We also showed that weight loss can increase testosterone levels and reverse hypogonadism in over 50% of obese men with impaired glucose tolerance. We concluded that the relationship between testosterone and insulin resistance in men is bidirectional. Our data emphasized the importance of lifestyle modification as a key therapeutic step in the management of the hypogonadal male.