In patients with type diabetes

In patients with type 2 diabetes glucagon receptor antagonism led lowered fasting glucose however not postprandial glucose levels [9], which may reflect that glucagon may not be of particular importance for the diabetic hyperglycemia upon a meal. Current glucagon receptor antagonists have however been associated with liver-related side effects including altered lipid metabolism (resulting in increased lipid deposition in the hepatocytes) and increases of aminotransferases: aspartate transaminase (AST) and alanine aminotransferase (ALAT) [49] thereby diminishing their clinical potentiality. The latter seems to be of minor magnitude however, it is being discussed if the increases in liver enzymes (the aminotransferease) actually reflect the physiological actions of glucagon (increasing the enzymes of ureagenesis and gluconeogenesis), rather than side effects of the drug, that upon results in increased plasma levels of L-Mimosine due to a defective hepatic glucagon receptor signaling. In addition, glucagon receptor antagonists have also been associated with alpha cell hyperplasia in some but not all animals studies [50] and this may be related to duration of treatment. Importantly, these findings do not necessarily eliminate glucagon receptor antagonists as targets for treatment of diabetes but merely suggest that further studies and perhaps new way of inhibiting the glucagon receptor, such as biased signaling or targeted delivery [51], may be needed to include glucagon receptor antagonism in clinical standard care of diabetes.
Combining glucagon receptor activation with incretins Combining glucagon and GLP-1 receptor analogues (thereby in theory mimicking the effects of oxyntomodulin, which activates both the GCGr and the GLP-1r) has shown effective body weight lowering effects in rodents [52], [53], [54]. In line with these observations, administration of oxyntomodulin in obese humans markedly inhibits food intake [4], [55]. Although, and somewhat surprisingly, is the observations that in rats oxyntomodulin analogue(s) increase food intake, which has been suggested to be due to glucagon receptor activation, and the development of oxyntomodulin analogues may therefore need to include such inter-species considerations [56]. Several studies in mice [4], [51], [57], [58], [59] has demonstrated the therapeutic benefits of combining GLP-1, GIP and glucagon (triple agonism). Recently, this has been replicated in a in a 12 week randomized placebo-controlled double-blinded clinical study [60] but only for the combination of GLP-1 and GIP and in this author’s opinion without major clinical differences (such as lipid metabolism which may be clinical important) compared to the low-dose (1.8mg) GLP-1 analogue liraglutide. On the other hand, a recent study by the Bloom group demonstrated that by matching ‘post-gastric bypass levels’ of GLP-1, oxyntomodulin and peptide YY (PYY) via subcutaneous infusion in obese individuals, one may reach similar effects on appetite and food intake pharmacologically [61]. This highlights the potential applicability of triple agonism in humans in order to lower body weight. Recently, allosteric activation through the receptor activity modifying protein (RAMP)2 of the GCGr has suggested to be of importance for the hepatic effects of glucagon [62] and future studies investigating the hepatic signaling cascade may be crucial for understanding glucagon biological actions and how to design glucagon analogues that selectively targets glucogenolytic signaling pathways to increase blood glucose in patients with type 1 diabetes or lower blood glucose by turning off these mechanisms in patients with type 2 diabetes.
Amino acids and glucagon − a ‘Revised glucagonocentric era’? Removal of the hepatic glucagon receptor has been linked to a) hyperglucagonemia and b) alpha cell hyperplasia [12]. These data obtained by Longuet et al. highlights that an endocrine feedback might exist between the liver and the pancreatic alpha cells. However, the key questions ‘what and how?’ have until recently remained unknown.