This was elegantly done by measuring the glucose response to a pharmacological dose of GLP-1, and comparing this measure to situations with either elevated insulin (without glucagon suppression) or glucagon suppression (without elevated insulin) using somatostatin clamps on separate days. or antagonize the glucagon receptor. In this review, the physiological actions of glucagon and the role of glucagon in type 2 diabetic pathophysiology are outlined. Furthermore, potential advantages and limitations of antagonizing the glucagon receptor or suppressing glucagon secretion in the treatment of GB110 type 2 diabetes are discussed with a focus on already marketed drugs and drugs in clinical development. It is concluded that the development of novel glucagon receptor antagonists are confronted with several safety issues. At present, available pharmacological agents based on the glucose-dependent glucagonostatic effects of GLP-1 represent the most favorable way to apply constraints to the alpha-cell in type 2 diabetes. studies . Nevertheless, in supraphysiological doses, the extrahepatic effects of glucagon become clearer (Figure ?(Figure1).1). Thus, glucagon has been used as a drug in emergency medicine to counteract hypoglycemia and for its inotropic and chronotropic cardiac effects as a part of the treatment against cardiodepressive drug overdoses [9, 10]. Furthermore, at supraphysiological levels, glucagon has been shown to decrease appetite and food intake in humans, possibly via centrally mediated Gcgr activation combined GB110 with inhibitory effects on gastrointestinal motility including gastric emptying [11-13] (Figure ?(Figure1).1). Finally, indirect calorimetry studies in humans have demonstrated that glucagon may increase the rate of energy expenditure . Open in a separate window Figure 1 Organ-specific pharmacological effects of glucagonIn the central nervous system, glucagon mediates satiety. Other possible central effects of glucagon are increased energy expenditure and, on the longer term, body weight reduction. In the gastrointestinal (GI) tract, glucagon reduces motility and GB110 may slow gastric emptying. In the pancreas, glucagon induces insulin release and exerts feedback inhibition of glucagon release. In the liver, glucagon increases hepatic glucose production and affects amino acid metabolism and lipid metabolism. In the heart, glucagon increases contractility and heart rate. Diabetic hyperglucagonemia The finely tuned balance of the two major pancreatic hormones, insulin and glucagon, is perturbed in type 2 diabetic subjects. These patients feature a bihormonal disorder where absolute insulin insufficiency or relative lack of insulin (in relation to prevailing insulin resistance) are present alongside fasting and postprandial hyperglucagonemia. It is important to note that the level of glucagon is undesirably high in the specific context of hyperglycemia and hyperinsulinemia, whereas in untreated type 2 diabetes the level is sometimes not elevated in absolute terms . Interestingly, it has recently been reported that the well-known disturbed pulsatility GB110 of insulin secretion in type 2 diabetes  is present alongside a disturbed glucagon pulsatility (higher pulse mass in patients with type 2 diabetes), possibly contributing to the hyperglucagonemia in these patients . The “bihormonal hypothesis”, i.e. the notion that the combination of elevated glucagon and relative lack of insulin is a major determinant in diabetic hyperglycemia, was first proposed by Unger and Orci in 1975 , and has since then been a matter of controversy [15, 18]. Key arguments against the concept of glucagon as a major contributor to diabetic hyperglycemia are that hyperglycemia and ketoacidosis occurs despite pancreatectomy in man , and that most of the scientific evidence demonstrating hyperglycemic effects of glucagon have used the somatostatin clamp method. The somatostatin clamp technique consists of a somatostatin infusion to suppress endogenous glucagon and insulin secretion. This technique allows plasma concentrations of glucagon and insulin to be clamped at pre-specified levels by exogenous administration. However, beside suppression of glucagon, the clamp technique affects several non-glucagon-mediated mechanisms involved in glucose homeostasis . Pancreatectomy as a model for diabetes without glucagon is still a matter of controversy, because of the unclear physiological role of extrapancreatic glucagon , and the limitations in determining the origin and exact size of the glucagon measured with the current glucagon assays. However, in past decades, increasing evidence, including various interventions GB110 targeting glucagon secretion, has emerged to unequivocally support the role of fasting and postprandial hyperglucagonemia as major contributing factors for the elevated levels of blood glucose that characterize diabetes . It is well established now that elevated levels of glucagon lead to increased rates of hepatic glucose output, and thereby to the elevation of postabsorptive and postprandial blood glucose levels in type 2 diabetes. In fact, studies indicate that postabsorptive hyperglucagonemia can be regarded as responsible for 50% of the pathological increment in plasma glucose excursions following oral glucose ingestion in diabetics [22-24]. Interestingly, in the postprandial state, the prevailing hyperglucagonemia is aggravated by the oral intake of glucose (compared to intravenous administration producing the same plasma glucose excursions). This implies Gipc1 that gut-derived factors contribute to the derangement of postprandial glucagon responses [25, 26],.