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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

Proliferation and apoptosis of pancreatic beta cells.(a) Quantification of proliferating beta cells. Photographs are representative images of islets stained for insulin (green) and Ki67 (red). White arrows indicate Ki67- and insulin double-positive cells. Scale bars, 100 μm. The number of Ki67-positive beta cells was significantly increased in liraglutide-group compared to vehicle-group on day 30. (b) Quantification of apoptotic beta cells. Photographs are representative images of islets with insulin and TUNEL staining. White arrows indicate TUNEL- and insulin double-positive cells. Scale bars, 100 μm. The number of TUNEL-positive beta cells was significantly decreased in liraglutide-group compared to vehicle-group. White bars represent vehicle-treated group (Veh) (n = 4–6), and black bars represent liraglutide-treated group (Lir) (n = 4–6). NS, difference not significant. *p < 0.05
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pone.0126003.g004: Proliferation and apoptosis of pancreatic beta cells.(a) Quantification of proliferating beta cells. Photographs are representative images of islets stained for insulin (green) and Ki67 (red). White arrows indicate Ki67- and insulin double-positive cells. Scale bars, 100 μm. The number of Ki67-positive beta cells was significantly increased in liraglutide-group compared to vehicle-group on day 30. (b) Quantification of apoptotic beta cells. Photographs are representative images of islets with insulin and TUNEL staining. White arrows indicate TUNEL- and insulin double-positive cells. Scale bars, 100 μm. The number of TUNEL-positive beta cells was significantly decreased in liraglutide-group compared to vehicle-group. White bars represent vehicle-treated group (Veh) (n = 4–6), and black bars represent liraglutide-treated group (Lir) (n = 4–6). NS, difference not significant. *p < 0.05

Mentions: Proliferation of beta cells was evaluated by Ki67 staining. Ki67/insulin double-positive cells were approximately 1% of total insulin-positive cells in normal mice. Alloxan treatment significantly decreased the percentage to about 0.3%. Pancreatic beta cells of liraglutide-treated mice showed a significantly higher proliferating rate than that in vehicle-treated mice on day 30: the rate was comparable to that found in normal mice (Fig 4A). Apoptotic cell death of beta cells determined by the TUNEL method was significantly increased by alloxan treatment (~0.3% in normal to ~2.6% in alloxan-treated mice). Chronic liraglutide treatment decreased TUNEL-positive beta cells to a level similar to that in normal mice (Fig 4B). These data suggest that liraglutide prevents further loss of beta cells by both increasing the proliferation rate and decreasing apoptosis.


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)

Proliferation and apoptosis of pancreatic beta cells.(a) Quantification of proliferating beta cells. Photographs are representative images of islets stained for insulin (green) and Ki67 (red). White arrows indicate Ki67- and insulin double-positive cells. Scale bars, 100 μm. The number of Ki67-positive beta cells was significantly increased in liraglutide-group compared to vehicle-group on day 30. (b) Quantification of apoptotic beta cells. Photographs are representative images of islets with insulin and TUNEL staining. White arrows indicate TUNEL- and insulin double-positive cells. Scale bars, 100 μm. The number of TUNEL-positive beta cells was significantly decreased in liraglutide-group compared to vehicle-group. White bars represent vehicle-treated group (Veh) (n = 4–6), and black bars represent liraglutide-treated group (Lir) (n = 4–6). NS, difference not significant. *p < 0.05
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4418765&req=5

pone.0126003.g004: Proliferation and apoptosis of pancreatic beta cells.(a) Quantification of proliferating beta cells. Photographs are representative images of islets stained for insulin (green) and Ki67 (red). White arrows indicate Ki67- and insulin double-positive cells. Scale bars, 100 μm. The number of Ki67-positive beta cells was significantly increased in liraglutide-group compared to vehicle-group on day 30. (b) Quantification of apoptotic beta cells. Photographs are representative images of islets with insulin and TUNEL staining. White arrows indicate TUNEL- and insulin double-positive cells. Scale bars, 100 μm. The number of TUNEL-positive beta cells was significantly decreased in liraglutide-group compared to vehicle-group. White bars represent vehicle-treated group (Veh) (n = 4–6), and black bars represent liraglutide-treated group (Lir) (n = 4–6). NS, difference not significant. *p < 0.05
Mentions: Proliferation of beta cells was evaluated by Ki67 staining. Ki67/insulin double-positive cells were approximately 1% of total insulin-positive cells in normal mice. Alloxan treatment significantly decreased the percentage to about 0.3%. Pancreatic beta cells of liraglutide-treated mice showed a significantly higher proliferating rate than that in vehicle-treated mice on day 30: the rate was comparable to that found in normal mice (Fig 4A). Apoptotic cell death of beta cells determined by the TUNEL method was significantly increased by alloxan treatment (~0.3% in normal to ~2.6% in alloxan-treated mice). Chronic liraglutide treatment decreased TUNEL-positive beta cells to a level similar to that in normal mice (Fig 4B). These data suggest that liraglutide prevents further loss of beta cells by both increasing the proliferation rate and decreasing apoptosis.

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