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

被引：13
作者：
McShane, L. M. [1 ,3 ]
Irwin, N. [1 ]
O'Flynn, D. [2 ]
Franklin, Z. J. [1 ,4 ]
Hewage, C. M. [2 ]
O'Harte, F. P. M. [1 ]
机构：
[1] Univ Ulster, SAAD Ctr Pharm & Diabet, Coleraine, Londonderry, North Ireland
[2] UCD, Conway Inst Biomol & Biomed Res, Dublin 4, Ireland
[3] Univ Liverpool, Sch Life Sci, Fac Hlth & Life Sci, Liverpool, Merseyside, England
[4] Kings Coll London, Div Diabet & Nutr Sci, Diabet Res Grp, London, England
来源：
JOURNAL OF ENDOCRINOLOGY | 2016年 / 229卷 / 03期
关键词：
glucagon; glucose-dependent insulinotropic polypeptide (GIP); glucose homeostasis; insulin secretion; insulin sensitivity; glucagon receptor antagonist; GIP receptor agonist; diet-induced obese diabetic mice; DEPENDENT INSULINOTROPIC POLYPEPTIDE; GASTRIC-INHIBITORY POLYPEPTIDE; IMPROVES GLUCOSE-TOLERANCE; BETA-CELL FUNCTION; BLOOD-GLUCOSE; REPLACEMENT ANALOGS; BODY-WEIGHT; PEPTIDE-1; GLP-1; HOMEOSTASIS;
D O I：
10.1530/JOE-15-0463
中图分类号：
R5 [内科学];
学科分类号：
1002 ; 100201 ;
摘要：
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.
引用
收藏
页码：319 / 330
页数：12
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