Abstract A very fundamental paradox of insulin resistance is that in a wide variety of animal models impairment of insulin signaling increases life span. But in humans it increases the risk of a range of fatal disorders. The Klotho protein appears to resolve this paradox. Overexpression of the Klotho gene increases longevity in mammals by inducing insulin resistance. But the Klotho protein is simultaneously anti-inflammatory, antioxidant and pro-angiogenesis. A number of other studies have indicated that systemic inflammation, angiogenesis dysfunction and oxidative stress are the main causes of pathological complications of diabetes. The Klotho protein has demonstrated that insulin resistance can be decoupled from these pathogenic mechanisms and if decoupled it might contribute to longevity in humans as well. However, insulin resistance has always been treated as the therapeutic target for type 2 diabetes. Our hypothesis suggests that therapy for type 2 diabetes should deviate from insulin resistance and focus on normalizing angiogenic, inflammatory and oxidative mechanisms.