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Liraglutide improves pancreatic Beta cell mass and function in alloxan-induced diabetic mice.

Tamura K, Minami K, Kudo M, Iemoto K, Takahashi H, Seino S - PLoS ONE (2015)

Bottom Line: We found that chronic liraglutide treatment improved glucose tolerance and insulin response to oral glucose load.Thirty-day treatment with liraglutide resulted in a 2-fold higher mass of pancreatic beta cells than that in vehicle group.However, the relative abundance of YFP-labeled beta cells to total beta cells was no different before and after liraglutide treatment, suggesting no or little contribution of neogenesis to the increase in beta cell mass.

View Article: PubMed Central - PubMed

Affiliation: Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.

ABSTRACT
Glucagon-like peptide-1 (GLP-1) receptor agonists potentiate glucose-induced insulin secretion. In addition, they have been reported to increase pancreatic beta cell mass in diabetic rodents. However, the precise mode of action of GLP-1 receptor agonists still needs to be elucidated. Here we clarify the effects of the human GLP-1 analog liraglutide on beta cell fate and function by using an inducible Cre/loxP-based pancreatic beta cell tracing system and alloxan-induced diabetic mice. Liraglutide was subcutaneously administered once daily for 30 days. The changes in beta cell mass were examined as well as glucose tolerance and insulin secretion. We found that chronic liraglutide treatment improved glucose tolerance and insulin response to oral glucose load. Thirty-day treatment with liraglutide resulted in a 2-fold higher mass of pancreatic beta cells than that in vehicle group. Liraglutide increased proliferation rate of pancreatic beta cells and prevented beta cells from apoptotic cells death. However, the relative abundance of YFP-labeled beta cells to total beta cells was no different before and after liraglutide treatment, suggesting no or little contribution of neogenesis to the increase in beta cell mass. Liraglutide reduced oxidative stress in pancreatic islet cells of alloxan-induced diabetic mice. Furthermore, the beneficial effects of liraglutide in these mice were maintained two weeks after drug withdrawal. In conclusion, chronic liraglutide treatment improves hyperglycemia by ameliorating beta cell mass and function in alloxan-induced diabetic mice.

No MeSH data available.


Related in: MedlinePlus

Metabolic parameters in alloxan-diabetic mice treated with vehicle or liraglutide for 30 days.(a) Schematic representation of the study. (b) Body weight. There is no difference between two groups. (c) Food intake. Liraglutide slightly decreased food intake compared with vehicle. (d) Blood glucose. Blood glucose levels were significantly lower in liraglutide-treated group than in vehicle-treated group after day 13. (e) Serum insulin. Serum insulin levels were significantly higher in liraglutide-treated group than in vehicle-treated group on day 30. White circles and bars represent vehicle-treated group (Veh) (n = 9–13), and black circles and bars represent liraglutide-treated group (Lir) (n = 10–15). *p < 0.05, **p < 0.01
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pone.0126003.g001: Metabolic parameters in alloxan-diabetic mice treated with vehicle or liraglutide for 30 days.(a) Schematic representation of the study. (b) Body weight. There is no difference between two groups. (c) Food intake. Liraglutide slightly decreased food intake compared with vehicle. (d) Blood glucose. Blood glucose levels were significantly lower in liraglutide-treated group than in vehicle-treated group after day 13. (e) Serum insulin. Serum insulin levels were significantly higher in liraglutide-treated group than in vehicle-treated group on day 30. White circles and bars represent vehicle-treated group (Veh) (n = 9–13), and black circles and bars represent liraglutide-treated group (Lir) (n = 10–15). *p < 0.05, **p < 0.01

Mentions: Ins2-CreERT2/R26R-YFP double knock-in mice, in which the pancreatic beta cells can be labeled specifically and permanently upon injection of tamoxifen, were generated as described previously [16, 19]. All mice had free access to food and water and were kept on a 12 h light, 12 h dark cycle. For labeling and tracing of pancreatic beta cells, male Ins2-CreERT2/R26R-YFP mice at 6 weeks of age were injected intraperitoneally with tamoxifen (Sigma-Aldrich, St Louis, MO) five times (4 mg/head) within 2 weeks. Ten days after the last injection of tamoxifen, alloxan (Sigma-Aldrich) was administered intraperitoneally to the mice at 60 mg/kg body weight. On the next day (day 0), mice with blood glucose concentration above 300 mg/dl were used for the study (Fig 1A). Animal care and experimental procedures were approved by the Animal Ethics Committee of Kobe University Graduate School of Medicine (Permit Number: 23-06-09) and carried out according to the Kobe University Experimentation Regulations. All surgery was performed under sodium pentobarbital anesthesia, and all efforts were made to minimize suffering.


Liraglutide improves pancreatic Beta cell mass and function in alloxan-induced diabetic mice.

Tamura K, Minami K, Kudo M, Iemoto K, Takahashi H, Seino S - PLoS ONE (2015)

Metabolic parameters in alloxan-diabetic mice treated with vehicle or liraglutide for 30 days.(a) Schematic representation of the study. (b) Body weight. There is no difference between two groups. (c) Food intake. Liraglutide slightly decreased food intake compared with vehicle. (d) Blood glucose. Blood glucose levels were significantly lower in liraglutide-treated group than in vehicle-treated group after day 13. (e) Serum insulin. Serum insulin levels were significantly higher in liraglutide-treated group than in vehicle-treated group on day 30. White circles and bars represent vehicle-treated group (Veh) (n = 9–13), and black circles and bars represent liraglutide-treated group (Lir) (n = 10–15). *p < 0.05, **p < 0.01
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4418765&req=5

pone.0126003.g001: Metabolic parameters in alloxan-diabetic mice treated with vehicle or liraglutide for 30 days.(a) Schematic representation of the study. (b) Body weight. There is no difference between two groups. (c) Food intake. Liraglutide slightly decreased food intake compared with vehicle. (d) Blood glucose. Blood glucose levels were significantly lower in liraglutide-treated group than in vehicle-treated group after day 13. (e) Serum insulin. Serum insulin levels were significantly higher in liraglutide-treated group than in vehicle-treated group on day 30. White circles and bars represent vehicle-treated group (Veh) (n = 9–13), and black circles and bars represent liraglutide-treated group (Lir) (n = 10–15). *p < 0.05, **p < 0.01
Mentions: Ins2-CreERT2/R26R-YFP double knock-in mice, in which the pancreatic beta cells can be labeled specifically and permanently upon injection of tamoxifen, were generated as described previously [16, 19]. All mice had free access to food and water and were kept on a 12 h light, 12 h dark cycle. For labeling and tracing of pancreatic beta cells, male Ins2-CreERT2/R26R-YFP mice at 6 weeks of age were injected intraperitoneally with tamoxifen (Sigma-Aldrich, St Louis, MO) five times (4 mg/head) within 2 weeks. Ten days after the last injection of tamoxifen, alloxan (Sigma-Aldrich) was administered intraperitoneally to the mice at 60 mg/kg body weight. On the next day (day 0), mice with blood glucose concentration above 300 mg/dl were used for the study (Fig 1A). Animal care and experimental procedures were approved by the Animal Ethics Committee of Kobe University Graduate School of Medicine (Permit Number: 23-06-09) and carried out according to the Kobe University Experimentation Regulations. All surgery was performed under sodium pentobarbital anesthesia, and all efforts were made to minimize suffering.

Bottom Line: We found that chronic liraglutide treatment improved glucose tolerance and insulin response to oral glucose load.Thirty-day treatment with liraglutide resulted in a 2-fold higher mass of pancreatic beta cells than that in vehicle group.However, the relative abundance of YFP-labeled beta cells to total beta cells was no different before and after liraglutide treatment, suggesting no or little contribution of neogenesis to the increase in beta cell mass.

View Article: PubMed Central - PubMed

Affiliation: Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.

ABSTRACT
Glucagon-like peptide-1 (GLP-1) receptor agonists potentiate glucose-induced insulin secretion. In addition, they have been reported to increase pancreatic beta cell mass in diabetic rodents. However, the precise mode of action of GLP-1 receptor agonists still needs to be elucidated. Here we clarify the effects of the human GLP-1 analog liraglutide on beta cell fate and function by using an inducible Cre/loxP-based pancreatic beta cell tracing system and alloxan-induced diabetic mice. Liraglutide was subcutaneously administered once daily for 30 days. The changes in beta cell mass were examined as well as glucose tolerance and insulin secretion. We found that chronic liraglutide treatment improved glucose tolerance and insulin response to oral glucose load. Thirty-day treatment with liraglutide resulted in a 2-fold higher mass of pancreatic beta cells than that in vehicle group. Liraglutide increased proliferation rate of pancreatic beta cells and prevented beta cells from apoptotic cells death. However, the relative abundance of YFP-labeled beta cells to total beta cells was no different before and after liraglutide treatment, suggesting no or little contribution of neogenesis to the increase in beta cell mass. Liraglutide reduced oxidative stress in pancreatic islet cells of alloxan-induced diabetic mice. Furthermore, the beneficial effects of liraglutide in these mice were maintained two weeks after drug withdrawal. In conclusion, chronic liraglutide treatment improves hyperglycemia by ameliorating beta cell mass and function in alloxan-induced diabetic mice.

No MeSH data available.


Related in: MedlinePlus