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Ablation of glucagon receptor signaling represents a potential treatment option for type 2 diabetes (T2DM). Additionally, activation of glucose-dependent insulinotropic polypeptide (GIP) receptor signaling also holds therapeutic promise for T2DM. Therefore, this study examined both independent and combined metabolic actions of desHis 1 Pro 4 Glu 9 (Lys 12 PAL)-glucagon (glucagon receptor antagonist) and d-Ala 2 GIP (GIP receptor agonist) in diet-induced obese mice. Glucagon receptor binding has been linked to alpha-helical structure and desHis 1 Pro 4 Glu 9 (Lys 12 PAL)-glucagon displayed enhanced alpha-helical content compared with native glucagon. In clonal pancreatic BRIN-BD11 beta-cells, desHis 1 Pro 4 Glu 9 (Lys 12 PAL)-glucagon was devoid of any insulinotropic or cAMP-generating actions, and did not impede d-Ala 2 GIP-mediated (P < 0.01 to P < 0.001) effects on insulin and cAMP production. Twice-daily injection of desHis 1 Pro 4 Glu 9 (Lys 12 PAL)-glucagon or d-Ala 2 GIP alone, and in combination, in highfat-fed mice failed to affect body weight or energy intake. Circulating blood glucose levels were significantly (P < 0.05 to P < 0.01) decreased by all treatments regimens, with plasma and pancreatic insulin elevated (P < 0.05 to P < 0.001) in all mice receiving d-Ala 2 GIP. Interestingly, plasma glucagon concentrations were decreased (P < 0.05) by sustained glucagon inhibition (day 28), but increased (P < 0.05) by d-Ala 2 GIP therapy, with a combined treatment resulting in glucagon concentration similar to saline controls. All treatments improved (P < 0.01) intraperitoneal and oral glucose tolerance, and peripheral insulin sensitivity. d-Ala 2 GIP-treated mice showed increased glucoseinduced insulin secretion in response to intraperitoneal and oral glucose. Metabolic rate and ambulatory locomotor activity were increased (P < 0.05 to P < 0.001) in all desHis 1 Pro 4 Glu 9 (Lys 12 PAL)-glucagon-treated mice. These studies highlight the potential of glucagon receptor inhibition alone, and in combination with GIP receptor activation, for T2DM treatment.

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Discerning modification to the amino acid sequence of native glucagon can generate specific glucagon receptor (GCGR) antagonists, that include desHis1Pro4Glu9-glucagon and the acylated form desHis1Pro4Glu9(Lys12PAL)-glucagon. In the current study, we have evaluated the metabolic benefits of once daily injection of these peptide-based GCGR antagonists for 18 days in insulin-resistant high fat fed (HFF) mice with streptozotocin (STZ)-induced insulin deficiency, namely HFF-STZ mice. Administration of desHis1Pro4Glu9-glucagon moderately (P<0.05) decreased STZ-induced elevations of food intake. Body weight was not different between groups of HFF-STZ mice and both treatment interventions delayed (P<0.05) the onset of hyperglycaemia. The treatments reduced (P<0.05 - P<0.001) circulating and pancreatic glucagon, whilst desHis1Pro4Glu9(Lys12PAL)-glucagon also substantially increased (P<0.001) pancreatic insulin stores. Oral glucose tolerance was appreciably improved (P<0.05) by both antagonists, despite lack of augmentation of glucose-stimulated insulin release. Interestingly, positive effects on intraperitoneal glucose tolerance were less obvious suggesting important beneficial effects on gut function. Metabolic benefits were accompanied by decreased (P<0.05 - P<0.01) locomotor activity and increases (P<0.001) in energy expenditure and respiratory exchange ratio in both treatment groups. In addition, desHis1Pro4Glu9-glucagon increased (P<0.01 - P<0.001) O2 consumption and CO2 production. Together, these data provide further evidence that peptidic GCGR antagonists are effective treatment options for obesity-driven forms of diabetes, even when accompanied by insulin deficiency.

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