Glucagon receptor antagonist and GIP agonist combination for diet-induced obese mice

• Published in: Journal of endocrinology Vol. 229; no. 3; pp. 319 - 330
• Main Authors: McShane, L M, Irwin, N, O’Flynn, D, Franklin, Z J, Hewage, C M, O’Harte, F P M
• Format: Journal Article
• Language: English
• Published: England Bioscientifica Ltd 01.06.2016
• Subjects: Animals; Cell Line; Cyclic AMP - biosynthesis; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - physiopathology; Diet, High-Fat - adverse effects; Energy Metabolism - drug effects; Gastric Inhibitory Polypeptide - administration & dosage; Gastric Inhibitory Polypeptide - agonists; Gastric Inhibitory Polypeptide - analogs & derivatives; Glucagon - administration & dosage; Glucagon - analogs & derivatives; Insulin - metabolism; Insulin Resistance; Insulin Secretion; Male; Mice; Mice, Obese; Motor Activity - drug effects; Obesity - drug therapy; Obesity - etiology; Obesity - physiopathology; Rats; Receptors, Glucagon - antagonists & inhibitors; glucose homeostasis; insulin sensitivity; GIP receptor agonist; diet-induced obese diabetic mice; glucagon; insulin secretion; glucagon receptor antagonist; glucose-dependent insulinotropic polypeptide (GIP)
• ISSN: 0022-0795; 1479-6805
• DOI: 10.1530/JOE-15-0463

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 desHis1Pro4Glu9(Lys12PAL)-glucagon (glucagon receptor antagonist) and d-Ala2GIP (GIP receptor agonist) in diet-induced obese mice. Glucagon receptor binding has been linked to alpha-helical structure and desHis1Pro4Glu9(Lys12PAL)-glucagon displayed enhanced alpha-helical content compared with native glucagon. In clonal pancreatic BRIN-BD11 beta-cells, desHis1Pro4Glu9(Lys12PAL)-glucagon was devoid of any insulinotropic or cAMP-generating actions, and did not impede d-Ala2GIP-mediated (P<0.01 to P<0.001) effects on insulin and cAMP production. Twice-daily injection of desHis1Pro4Glu9(Lys12PAL)-glucagon or d-Ala2GIP alone, and in combination, in high-fat-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-Ala2GIP. Interestingly, plasma glucagon concentrations were decreased (P<0.05) by sustained glucagon inhibition (day 28), but increased (P<0.05) by d-Ala2GIP 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-Ala2GIP-treated mice showed increased glucose-induced 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 desHis1Pro4Glu9(Lys12PAL)-glucagon-treated mice. These studies highlight the potential of glucagon receptor inhibition alone, and in combination with GIP receptor activation, for T2DM treatment.