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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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Study design and plasma liraglutide levels. (A) Study outline/liraglutide dosage regimen, mo = months of age, GTT = glucose tolerance testing including mixed meal glucose tolerance test (MMGTT) and intravenous glucose tolerance test (IVGTT). (B) Plasma liraglutide levels at the end of the treatment period in non-fasted GIPRdn transgenic pigs after 1.2 mg liraglutide injection; 0 hours = point of liraglutide administration.
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Fig1: Study design and plasma liraglutide levels. (A) Study outline/liraglutide dosage regimen, mo = months of age, GTT = glucose tolerance testing including mixed meal glucose tolerance test (MMGTT) and intravenous glucose tolerance test (IVGTT). (B) Plasma liraglutide levels at the end of the treatment period in non-fasted GIPRdn transgenic pigs after 1.2 mg liraglutide injection; 0 hours = point of liraglutide administration.

Mentions: Eighteen hemizygous GIPRdn transgenic pigs [7] were randomly assigned to liraglutide treatment using prefilled pens (Victoza®, 6 mg/ml, Novo Nordisk A/S) or placebo treatment (0.9% NaCl, B. Braun), injected subcutaneously once daily for 90 days. Liraglutide doses (0.6-1.2 mg per day, Figure 1A) were based on human dosages adjusted for pig body weight. Pigs were housed in planar single pens with straw litter and had ad libitum access to water and a standard pig diet (see Additional file 1: Table S1 for diet composition). All animal experiments were performed in accordance with the German Animal Welfare Act and approved by the responsible animal welfare authority. Pigs were treated with liraglutide (n = 9; 5 females, 4 males) or placebo (n = 9; 5 females, 4 males) from 2 to 5 months of age. At the age of 2 months untreated GIPRdn transgenic pigs show disturbed oral glucose tolerance and delayed insulin secretion, but unaltered total beta-cell volume [7]. The physiological characteristics of the pigs prior to liraglutide/placebo treatment are summarized in Table 1.Figure 1


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)

Study design and plasma liraglutide levels. (A) Study outline/liraglutide dosage regimen, mo = months of age, GTT = glucose tolerance testing including mixed meal glucose tolerance test (MMGTT) and intravenous glucose tolerance test (IVGTT). (B) Plasma liraglutide levels at the end of the treatment period in non-fasted GIPRdn transgenic pigs after 1.2 mg liraglutide injection; 0 hours = point of liraglutide administration.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig1: Study design and plasma liraglutide levels. (A) Study outline/liraglutide dosage regimen, mo = months of age, GTT = glucose tolerance testing including mixed meal glucose tolerance test (MMGTT) and intravenous glucose tolerance test (IVGTT). (B) Plasma liraglutide levels at the end of the treatment period in non-fasted GIPRdn transgenic pigs after 1.2 mg liraglutide injection; 0 hours = point of liraglutide administration.
Mentions: Eighteen hemizygous GIPRdn transgenic pigs [7] were randomly assigned to liraglutide treatment using prefilled pens (Victoza®, 6 mg/ml, Novo Nordisk A/S) or placebo treatment (0.9% NaCl, B. Braun), injected subcutaneously once daily for 90 days. Liraglutide doses (0.6-1.2 mg per day, Figure 1A) were based on human dosages adjusted for pig body weight. Pigs were housed in planar single pens with straw litter and had ad libitum access to water and a standard pig diet (see Additional file 1: Table S1 for diet composition). All animal experiments were performed in accordance with the German Animal Welfare Act and approved by the responsible animal welfare authority. Pigs were treated with liraglutide (n = 9; 5 females, 4 males) or placebo (n = 9; 5 females, 4 males) from 2 to 5 months of age. At the age of 2 months untreated GIPRdn transgenic pigs show disturbed oral glucose tolerance and delayed insulin secretion, but unaltered total beta-cell volume [7]. The physiological characteristics of the pigs prior to liraglutide/placebo treatment are summarized in Table 1.Figure 1

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