The worldwide epidemic of obesity is closely linked to insulin resistance and type 2 diabetes (T2D), which have led to a critical need for new drug development. Insulin resistance and T2D contribute to the pathogenesis of many diseases including fatty liver disease, cardiovascular disease, kidney failure and retinal disease. Moreover, the incidence of T2D increases with age, and several epidemiological studies have shown that it is directly related to vascular dementia and Alzheimer disease in the elderly population (Samaras et al. Ther. Adv. Endocrinol. Metab., 2012, 3:189-96). A growing body of work indicates that increased hepatic glucose production is central to the pathophysiology of these alterations. Excessive glucagon signaling, due to elevated glucagon levels and lack of glucagon suppression, in the setting of insufficient hepatic insulin action contribute to disproportionate hepatic glucose production (Lin and Accili Cell Metab., 2011, 14:9-19).