Team Players or Opponents: Coadministration of Selective Glucagon and GLP-1 Receptor Agonists in Obese Diabetic Monkeys

被引:18
作者
Elvert, Ralf [1 ]
Bossart, Martin [1 ]
Herling, Andreas W. [1 ]
Weiss, Tilo [1 ]
Zhang, Baohong [2 ]
Kannt, Aimo [1 ,3 ]
Wagner, Michael [1 ]
Haack, Torsten [1 ]
Evers, Andreas [1 ]
Dudda, Angela [1 ]
Keil, Stefanie [1 ]
Lorenz, Martin [1 ]
Lorenz, Katrin [1 ]
Riz, Michela [1 ]
Hennerici, Wolfgang [1 ]
Larsen, Philip J. [1 ]
机构
[1] Sanofi Aventis Deutschland GmbH, Ind Pk Hochst, D-65926 Frankfurt, Germany
[2] Sanofi Asia Pacific R&D, Shanghai 200040, Peoples R China
[3] Heidelberg Univ, Med Fac Mannheim, Inst Expt & Clin Pharmacol & Toxicol, D-68167 Mannheim, Germany
关键词
Y GASTRIC BYPASS; HEPATIC LIPID-METABOLISM; BETA-CELL FUNCTION; ENERGY-EXPENDITURE; BARIATRIC SURGERY; FOOD-INTAKE; GLUCOSE-PRODUCTION; CONTROLLED-TRIAL; CO-AGONISM; PPAR-ALPHA;
D O I
10.1210/en.2018-00399
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
We assessed the therapeutic contribution of the individual components of glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) agonists alone and in combination upon energy homeostasis and glycemic control in diet-induced obese, diabetic nonhuman primates. The pharmacological active dose ranges of selective agonists were established through a dose-finding study, followed by a 6-week chronic study. Repeated subcutaneous administration of a selective GCGR agonist (30 vg/kg once daily) did not affect food intake or body weight, whereas the selective GLP-1R agonist (3 vg/kg once daily) alone decreased energy intake by 18% and body weight by 3.8% +/- 0.9%. Combination of both agonists reduced significantly cumulative food intake by 27% and body weight by 6.6% +/- 0.9%. Fasting plasma glucose (FPG) was improved by GLP-1R agonist (baseline vs end of study, 176.7 +/- 34.0 vs 115.9 +/- 16.1 mg/dL). In contrast, groups exposed to GCGR agonist experienced nonsignificant elevations of FPG. More accurate assessment of therapeutic interventions on glucose homeostasis was tested by an IV glucose tolerance test. Glucose excursion was significantly elevated by chronic GCGR agonist administration, whereas it was significantly decreased in GLP-1R agonist treated monkeys. In the combination group, a nonsignificant increase of glucose excursion was seen, concomitantly with significantly increased insulin secretion. We conclude that chronic glucagon agonism does not affect energy homeostasis in nonhuman primates. In combination with GLP-1R agonism, glucagon agonism synergistically enhances negative energy balance with resulting larger body weight loss. However, adding GCGR to GLP-1R agonism diminishes glycemic control in diabetic monkeys. Therefore, long-term therapeutic implications of using GLP-1R/GCGR coagonists for weight management in diabetes warrants further scrutiny.
引用
收藏
页码:3105 / 3119
页数:15
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