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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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Glucose control and insulin sensitivity during MMGTT in liraglutide- and placebo-treated GIPRdntransgenic pigs. (A) Plasma glucose levels and AUC glucose as well as (B) plasma insulin levels and AUC insulin and (C) plasma glucagon levels and AUC glucagon during MMGTT in 18-hour fasted GIPRdn transgenic pigs after the 90-day treatment period, 0 min. = point of glucose administration. (D) Insulin sensitivity indices prior to (2-month-old pigs) and after the treatment period (5-month-old pigs), mo = months of age, 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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Fig3: Glucose control and insulin sensitivity during MMGTT in liraglutide- and placebo-treated GIPRdntransgenic pigs. (A) Plasma glucose levels and AUC glucose as well as (B) plasma insulin levels and AUC insulin and (C) plasma glucagon levels and AUC glucagon during MMGTT in 18-hour fasted GIPRdn transgenic pigs after the 90-day treatment period, 0 min. = point of glucose administration. (D) Insulin sensitivity indices prior to (2-month-old pigs) and after the treatment period (5-month-old pigs), mo = months of age, 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: GIPRdn transgenic pigs allocated to the liraglutide and placebo treatment groups did not show significant differences in glucose tolerance and insulin secretion during MMGTT and IVGTT performed prior to treatment (Table 1). However, during the second MMGTT at the end of the 90-day treatment period, plasma glucose increased much less in liraglutide- than in placebo-treated pigs, resulting in a 23% smaller AUC glucose (p < 0.001, Figure 3A). Accordingly, AUC insulin of liraglutide-treated pigs was 36% reduced (p < 0.05; Figure 3B) as compared to their placebo-treated counterparts. Glucagon levels during the MMGTT were not significantly different between liraglutide- and placebo-treated animals (Figure 3C). Moreover, liraglutide markedly improved insulin sensitivity, as shown by significantly reduced HOMA-IR and increased ISI(Matsuda) after the treatment period (Figure 3D). The IVGTT at the end of the treatment period revealed a 15% decreased AUC glucose in liraglutide- vs. placebo-treated animals (p < 0.01; Figure 4A). The slopes of the net glucose elimination rate for the placebo (P: -0.0274 ± 0.0014) and liraglutide (L: -0.0355 ± 0.0011) groups were significantly different (p <0.001; Figure 4A). AUC insulin did not differ between the treatment groups (p = 0.73), although insulin levels were a tendency higher at the first time points after glucose administration and significantly lower at time points 40 and 50 minutes after glucose administration in liraglutide- vs. placebo-treated animals (Figure 4B).Figure 3


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)

Glucose control and insulin sensitivity during MMGTT in liraglutide- and placebo-treated GIPRdntransgenic pigs. (A) Plasma glucose levels and AUC glucose as well as (B) plasma insulin levels and AUC insulin and (C) plasma glucagon levels and AUC glucagon during MMGTT in 18-hour fasted GIPRdn transgenic pigs after the 90-day treatment period, 0 min. = point of glucose administration. (D) Insulin sensitivity indices prior to (2-month-old pigs) and after the treatment period (5-month-old pigs), mo = months of age, 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
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getmorefigures.php?uid=PMC4362632&req=5

Fig3: Glucose control and insulin sensitivity during MMGTT in liraglutide- and placebo-treated GIPRdntransgenic pigs. (A) Plasma glucose levels and AUC glucose as well as (B) plasma insulin levels and AUC insulin and (C) plasma glucagon levels and AUC glucagon during MMGTT in 18-hour fasted GIPRdn transgenic pigs after the 90-day treatment period, 0 min. = point of glucose administration. (D) Insulin sensitivity indices prior to (2-month-old pigs) and after the treatment period (5-month-old pigs), mo = months of age, 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: GIPRdn transgenic pigs allocated to the liraglutide and placebo treatment groups did not show significant differences in glucose tolerance and insulin secretion during MMGTT and IVGTT performed prior to treatment (Table 1). However, during the second MMGTT at the end of the 90-day treatment period, plasma glucose increased much less in liraglutide- than in placebo-treated pigs, resulting in a 23% smaller AUC glucose (p < 0.001, Figure 3A). Accordingly, AUC insulin of liraglutide-treated pigs was 36% reduced (p < 0.05; Figure 3B) as compared to their placebo-treated counterparts. Glucagon levels during the MMGTT were not significantly different between liraglutide- and placebo-treated animals (Figure 3C). Moreover, liraglutide markedly improved insulin sensitivity, as shown by significantly reduced HOMA-IR and increased ISI(Matsuda) after the treatment period (Figure 3D). The IVGTT at the end of the treatment period revealed a 15% decreased AUC glucose in liraglutide- vs. placebo-treated animals (p < 0.01; Figure 4A). The slopes of the net glucose elimination rate for the placebo (P: -0.0274 ± 0.0014) and liraglutide (L: -0.0355 ± 0.0011) groups were significantly different (p <0.001; Figure 4A). AUC insulin did not differ between the treatment groups (p = 0.73), although insulin levels were a tendency higher at the first time points after glucose administration and significantly lower at time points 40 and 50 minutes after glucose administration in liraglutide- vs. placebo-treated animals (Figure 4B).Figure 3

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