Glucagon receptor antagonist and GIP agonist combination for diet-induced obese mice.
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 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-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 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 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.
SAAD Centre for Pharmacy and DiabetesUniversity of Ulster, Coleraine, Northern Ireland, UK.
L M
LM
McShane
SAAD Centre for Pharmacy and DiabetesUniversity of Ulster, Coleraine, Northern Ireland, UK.
N
N
Irwin
Conway Institute of Biomolecular and Biomedical ResearchUCD, Belfield, Dublin 4, Ireland.
D
D
O'Flynn
SAAD Centre for Pharmacy and DiabetesUniversity of Ulster, Coleraine, Northern Ireland, UK.
Z J
ZJ
Franklin
Conway Institute of Biomolecular and Biomedical ResearchUCD, Belfield, Dublin 4, Ireland.
C M
CM
Hewage
SAAD Centre for Pharmacy and DiabetesUniversity of Ulster, Coleraine, Northern Ireland, UK fpm.oharte@ulster.ac.uk.
F P M
FP
O'Harte
D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000096:biosynthesis; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000503:physiopathology; D059305:Diet, High-Fat / Q000009:adverse effects; D004734:Energy Metabolism / Q000187:drug effects; D005749:Gastric Inhibitory Polypeptide / Q000008:administration & dosage / Q000819:agonists* / Q000031:analogs & derivatives; D005934:Glucagon / Q000008:administration & dosage / Q000031:analogs & derivatives; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D008297:Male; D051379:Mice; D008820:Mice, Obese; D009043:Motor Activity / Q000187:drug effects; D009765:Obesity / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D051381:Rats; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors*
D007328:Insulin; D018027:Receptors, Glucagon; D005749:Gastric Inhibitory Polypeptide; D005934:Glucagon; D000242:Cyclic AMP
GIP receptor agonist; diet-induced obese diabetic mice; glucagon; glucagon receptor antagonist; glucose homeostasis; glucose-dependent insulinotropic polypeptide (GIP); insulin secretion; insulin sensitivity