Abstract
BackgroundThe glucagon-like peptide-1 receptor (GLP1R) agonist liraglutide improves glycemic control and reduces body weight of adult type 2 diabetic patients. However, efficacy and safety of liraglutide in adolescents has not been systematically investigated. Furthermore, possible pro-proliferative effects of GLP1R agonists on the endocrine and exocrine pancreas need to be further evaluated. We studied effects of liraglutide in adolescent pigs expressing a dominant-negative glucose-dependent insulinotropic polypeptide receptor (GIPRdn) in the beta-cells, leading to a pre-diabetic condition including disturbed glucose tolerance, reduced insulin secretion and progressive reduction of functional beta-cell mass.MethodsTwo-month-old GIPRdn transgenic pigs were treated daily with liraglutide (0.6-1.2 mg per day) or placebo for 90 days. Glucose homeostasis was evaluated prior to and at the end of the treatment period by performing mixed meal and intravenous glucose tolerance tests (MMGTT and IVGTT). Finally animals were subjected to necropsy and quantitative-stereological analyses were performed for evaluation of alpha- and beta-cell mass, beta-cell proliferation as well as acinus-cell proliferation.ResultsMMGTT at the end of the study revealed 23% smaller area under the curve (AUC) for glucose, a 36% smaller AUC insulin, and improved insulin sensitivity, while IVGTT showed a 15% smaller AUC glucose but unchanged AUC insulin in liraglutide- vs. placebo-treated animals. Liraglutide led to marked reductions in body weight gain (-31%) and food intake (-30%) compared to placebo treatment, associated with reduced phosphorylation of insulin receptor beta (INSRB)/insulin-like growth factor-1 receptor beta (IGF1RB) and protein kinase B (AKT) in skeletal muscle. Absolute alpha- and beta-cell mass was reduced in liraglutide-treated animals, but alpha- and beta-cell mass-to-body weight ratios were unchanged. Liraglutide neither stimulated beta-cell proliferation in the endocrine pancreas nor acinus-cell proliferation in the exocrine pancreas, excluding both beneficial and detrimental effects on the pig pancreas.ConclusionsAlthough plasma liraglutide levels of adolescent transgenic pigs treated in our study were higher compared to human trials, pro-proliferative effects on the endocrine or exocrine pancreas or other liraglutide-related side-effects were not observed.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0431-2) contains supplementary material, which is available to authorized users.
Highlights
The glucagon-like peptide-1 receptor (GLP1R) agonist liraglutide improves glycemic control and reduces body weight of adult type 2 diabetic patients
Since the function of the GLP1R is not disturbed in this pig model [7], we performed a treatment trial with the GLP1R agonist liraglutide in order to address the following questions: 1.) How does liraglutide physiologically affect adolescent organisms? 2.) Can liraglutide maintain or expand physiological beta-cell mass? 3.) Does liraglutide induce cell proliferation in the endocrine or exocrine pancreas?
Reduced body weight gain Liraglutide-treated Dominant-negative GIPR (GIPRdn) transgenic pigs gained distinctly less body weight compared to their placebotreated counterparts, resulting in a 31% reduced body weight (63.7 ± 2.4 kg vs. 91.6 ± 3.7 kg; p < 0.001) at the end of the 90-day treatment period (Figure 2A)
Summary
The glucagon-like peptide-1 receptor (GLP1R) agonist liraglutide improves glycemic control and reduces body weight of adult type 2 diabetic patients. We studied effects of liraglutide in adolescent pigs expressing a dominant-negative glucose-dependent insulinotropic polypeptide receptor (GIPRdn) in the beta-cells, leading to a pre-diabetic condition including disturbed glucose tolerance, reduced insulin secretion and progressive reduction of functional beta-cell mass. The use of an adolescent animal model is important to gain insight into efficacy and safety of liraglutide in adolescent patients and to evaluate possible pro-proliferative effects of incretin-based therapies in the endocrine and exocrine pancreas at a young age with presumably high cell proliferation capacity [7,8]. Studies in numerous different rodent models that evaluated the effect of the GLP1R agonist liraglutide on beta-cell mass, proliferation and apoptosis showed variable results.
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