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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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Western blot analysis of the mTOR mediated insulin-stimulated pathway. (A) Overview of the growth-regulating mTOR signaling pathway. (B) Western blot analyses of protein extracted from skeletal muscle showing blots of phosphorylated (upper panel) and not phosphorylated (lower panel) up- and down-stream regulators of the mTOR pathway in liraglutide- (left side of the blot) and placebo-treated (right side of the blot) GIPRdn transgenic pigs. For elF4E not phosphorylated molecule (upper panel) is referred to tubulin (lower panel). (C) Quantitative analysis of Western blot signals, results are expressed as ratio of phosphorylated to not phosphorylated regulator and for eIF4E as absolute fold expression, related to the mean value of the placebo group, respectively, and presented as box plots with median, n = number of animals investigated, black plots = liraglutide-treated animals, white plots = placebo-treated animals, * = p < 0.05.
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Fig6: Western blot analysis of the mTOR mediated insulin-stimulated pathway. (A) Overview of the growth-regulating mTOR signaling pathway. (B) Western blot analyses of protein extracted from skeletal muscle showing blots of phosphorylated (upper panel) and not phosphorylated (lower panel) up- and down-stream regulators of the mTOR pathway in liraglutide- (left side of the blot) and placebo-treated (right side of the blot) GIPRdn transgenic pigs. For elF4E not phosphorylated molecule (upper panel) is referred to tubulin (lower panel). (C) Quantitative analysis of Western blot signals, results are expressed as ratio of phosphorylated to not phosphorylated regulator and for eIF4E as absolute fold expression, related to the mean value of the placebo group, respectively, and presented as box plots with median, n = number of animals investigated, black plots = liraglutide-treated animals, white plots = placebo-treated animals, * = p < 0.05.

Mentions: Western blot analyses investigating the growth regulating mammalian target of rapamycin (mTOR) complex including up- and downstream pathways revealed decreased phosphorylation of the INSRB/IGF1RB and AKT and increased phosphorylation of eukaryotic initiation factor 4E binding protein (4EBP1) in liraglutide- vs. placebo-treated pigs (p < 0.05, Figure 6). The phosphorylation status of mTOR, AMP-activated protein kinase (AMPK), S6 kinase 1 (S6K1) and glycogen synthase kinase 3 beta (GSK3β) was not affected by liraglutide treatment. The amount of the eukaryotic translation initiation factor 4E (elF4E) was significantly reduced in liraglutide- vs. placebo-treated animals (p < 0.05, Figure 6).Figure 6


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)

Western blot analysis of the mTOR mediated insulin-stimulated pathway. (A) Overview of the growth-regulating mTOR signaling pathway. (B) Western blot analyses of protein extracted from skeletal muscle showing blots of phosphorylated (upper panel) and not phosphorylated (lower panel) up- and down-stream regulators of the mTOR pathway in liraglutide- (left side of the blot) and placebo-treated (right side of the blot) GIPRdn transgenic pigs. For elF4E not phosphorylated molecule (upper panel) is referred to tubulin (lower panel). (C) Quantitative analysis of Western blot signals, results are expressed as ratio of phosphorylated to not phosphorylated regulator and for eIF4E as absolute fold expression, related to the mean value of the placebo group, respectively, and presented as box plots with median, n = number of animals investigated, black plots = liraglutide-treated animals, white plots = placebo-treated animals, * = p < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig6: Western blot analysis of the mTOR mediated insulin-stimulated pathway. (A) Overview of the growth-regulating mTOR signaling pathway. (B) Western blot analyses of protein extracted from skeletal muscle showing blots of phosphorylated (upper panel) and not phosphorylated (lower panel) up- and down-stream regulators of the mTOR pathway in liraglutide- (left side of the blot) and placebo-treated (right side of the blot) GIPRdn transgenic pigs. For elF4E not phosphorylated molecule (upper panel) is referred to tubulin (lower panel). (C) Quantitative analysis of Western blot signals, results are expressed as ratio of phosphorylated to not phosphorylated regulator and for eIF4E as absolute fold expression, related to the mean value of the placebo group, respectively, and presented as box plots with median, n = number of animals investigated, black plots = liraglutide-treated animals, white plots = placebo-treated animals, * = p < 0.05.
Mentions: Western blot analyses investigating the growth regulating mammalian target of rapamycin (mTOR) complex including up- and downstream pathways revealed decreased phosphorylation of the INSRB/IGF1RB and AKT and increased phosphorylation of eukaryotic initiation factor 4E binding protein (4EBP1) in liraglutide- vs. placebo-treated pigs (p < 0.05, Figure 6). The phosphorylation status of mTOR, AMP-activated protein kinase (AMPK), S6 kinase 1 (S6K1) and glycogen synthase kinase 3 beta (GSK3β) was not affected by liraglutide treatment. The amount of the eukaryotic translation initiation factor 4E (elF4E) was significantly reduced in liraglutide- vs. placebo-treated animals (p < 0.05, Figure 6).Figure 6

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