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Effects of the glucagon-like peptide-1 receptor agonist liraglutide in juvenile transgenic pigs modeling a pre-diabetic condition.

Streckel E, Braun-Reichhart C, Herbach N, Dahlhoff M, Kessler B, Blutke A, Bähr A, Übel N, Eddicks M, Ritzmann M, Krebs S, Göke B, Blum H, Wanke R, Wolf E, Renner S - J Transl Med (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Chair for Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, Munich, Germany. e.streckel@gen.vetmed.uni-muenchen.de.

ABSTRACT

Background: The 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 (GIPR(dn)) 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.

Methods: Two-month-old GIPR(dn) 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.

Results: MMGTT 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.

Conclusions: Although 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.

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Body weight gain and food intake in liraglutide- and placebo-treated GIPRdntransgenic pigs. (A) Body weight gain of GIPRdn transgenic pigs during pre-treatment and treatment period, black arrows indicate beginning/end of liraglutide/placebo administration. (B) Representative physical appearance of two female littermates (L = liraglutide-treated pig, P = placebo-treated pig) during the last third of the treatment period. (C) Food intake and (D) feeding efficiency of liraglutide- vs. placebo-treated GIPRdn transgenic pigs during the treatment period, n = number of animals investigated. Data are means ± SEM. For statistical analysis (ANOVA; Linear Mixed Models; SAS 8.2), data were square-root transformed. *: p < 0.05, **: p < 0.01, ***: p < 0.001.
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Fig2: Body weight gain and food intake in liraglutide- and placebo-treated GIPRdntransgenic pigs. (A) Body weight gain of GIPRdn transgenic pigs during pre-treatment and treatment period, black arrows indicate beginning/end of liraglutide/placebo administration. (B) Representative physical appearance of two female littermates (L = liraglutide-treated pig, P = placebo-treated pig) during the last third of the treatment period. (C) Food intake and (D) feeding efficiency of liraglutide- vs. placebo-treated GIPRdn transgenic pigs during the treatment period, n = number of animals investigated. Data are means ± SEM. For statistical analysis (ANOVA; Linear Mixed Models; SAS 8.2), data were square-root transformed. *: p < 0.05, **: p < 0.01, ***: p < 0.001.

Mentions: Liraglutide-treated GIPRdn transgenic pigs gained distinctly less body weight compared to their placebo-treated 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). In addition to the reduced body weight, liraglutide-treated pigs appeared slightly smaller in size and shape than the corresponding placebo-treated pigs (for representative examples, see Figure 2B).Figure 2


Effects of the glucagon-like peptide-1 receptor agonist liraglutide in juvenile transgenic pigs modeling a pre-diabetic condition.

Streckel E, Braun-Reichhart C, Herbach N, Dahlhoff M, Kessler B, Blutke A, Bähr A, Übel N, Eddicks M, Ritzmann M, Krebs S, Göke B, Blum H, Wanke R, Wolf E, Renner S - J Transl Med (2015)

Body weight gain and food intake in liraglutide- and placebo-treated GIPRdntransgenic pigs. (A) Body weight gain of GIPRdn transgenic pigs during pre-treatment and treatment period, black arrows indicate beginning/end of liraglutide/placebo administration. (B) Representative physical appearance of two female littermates (L = liraglutide-treated pig, P = placebo-treated pig) during the last third of the treatment period. (C) Food intake and (D) feeding efficiency of liraglutide- vs. placebo-treated GIPRdn transgenic pigs during the treatment period, n = number of animals investigated. Data are means ± SEM. For statistical analysis (ANOVA; Linear Mixed Models; SAS 8.2), data were square-root transformed. *: p < 0.05, **: p < 0.01, ***: p < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4362632&req=5

Fig2: Body weight gain and food intake in liraglutide- and placebo-treated GIPRdntransgenic pigs. (A) Body weight gain of GIPRdn transgenic pigs during pre-treatment and treatment period, black arrows indicate beginning/end of liraglutide/placebo administration. (B) Representative physical appearance of two female littermates (L = liraglutide-treated pig, P = placebo-treated pig) during the last third of the treatment period. (C) Food intake and (D) feeding efficiency of liraglutide- vs. placebo-treated GIPRdn transgenic pigs during the treatment period, n = number of animals investigated. Data are means ± SEM. For statistical analysis (ANOVA; Linear Mixed Models; SAS 8.2), data were square-root transformed. *: p < 0.05, **: p < 0.01, ***: p < 0.001.
Mentions: Liraglutide-treated GIPRdn transgenic pigs gained distinctly less body weight compared to their placebo-treated 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). In addition to the reduced body weight, liraglutide-treated pigs appeared slightly smaller in size and shape than the corresponding placebo-treated pigs (for representative examples, see Figure 2B).Figure 2

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Chair for Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, Munich, Germany. e.streckel@gen.vetmed.uni-muenchen.de.

ABSTRACT

Background: The 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 (GIPR(dn)) 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.

Methods: Two-month-old GIPR(dn) 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.

Results: MMGTT 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.

Conclusions: Although 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.

Show MeSH
Related in: MedlinePlus