Glucagon in type 2 diabetes: Friend or foe?

Hyperglucagonemia is one of the "ominous" eight factors underlying the pathogenesis of type 2 diabetes (T2D). Glucagon is a peptide hormone involved in maintaining glucose homeostasis by increasing hepatic glucose output to counterbalance insulin action. Long neglected, the introduction of dual and triple agonists exploiting glucagon signaling pathways has rekindled the interest in this hormone beyond its classic effect on glycemia. Glucagon can promote weight loss by regulating food intake, energy expenditure and brown and white adipose tissue functions through mechanisms still to be fully elucidated, thus its role in T2D pathogenesis should be further investigated. Moreover, the role of glucagon in the development of T2D micro- and macro-vascular complications is elusive. Mounting evidence suggests its beneficial effect in non-alcoholic fatty liver disease (NAFLD), while few studies postulated its favorable role in peripheral neu-ropathy and retinopathy. Contrarily, glucagon receptor agonism might induce renal changes resembling those in to diabetic nephropathy, and data concerning glucagon actions on the cardiovascular system are conflicting. This review aims to summarize the available findings on the role of glucagon in the pathogenesis of T2D and its complications. Further experimental and clinical data are warranted to better understand the implications of glucagon signaling modulation with the new antidiabetic drugs.