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Deletion of Pten in pancreatic ß-cells protects against deficient ß-cell mass and function in mouse models of type 2 diabetes.

Wang L, Liu Y, Yan Lu S, Nguyen KT, Schroer SA, Suzuki A, Mak TW, Gaisano H, Woo M - Diabetes (2010)

Bottom Line: Their β-cell function and islet PI3K signaling remained intact, in contrast to HFD-fed wild-type and db/db islets that exhibited diminished β-cell function and attenuated PI3K signaling.These protective effects in β-cells occurred in the absence of compromised response to DNA-damaging stimuli.PTEN exerts a critical negative effect on both β-cell mass and function.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.

ABSTRACT

Objective: Type 2 diabetes is characterized by diminished pancreatic β-cell mass and function. Insulin signaling within the β-cells has been shown to play a critical role in maintaining the essential function of the β-cells. Under basal conditions, enhanced insulin-PI3K signaling via deletion of phosphatase with tensin homology (PTEN), a negative regulator of this pathway, leads to increased β-cell mass and function. In this study, we investigated the effects of prolonged β-cell-specific PTEN deletion in models of type 2 diabetes.

Research design and methods: Two models of type 2 diabetes were employed: a high-fat diet (HFD) model and a db/db model that harbors a global leptin-signaling defect. A Cre-loxP system driven by the rat insulin promoter (RIP) was employed to obtain mice with β-cell-specific PTEN deletion (RIPcre(+) Pten(fl/fl)).

Results: PTEN expression in islets was upregulated in both models of type 2 diabetes. RIPcre(+) Pten(fl/fl) mice were completely protected against diabetes in both models of type 2 diabetes. The islets of RIPcre(+) Pten(fl/fl) mice already exhibited increased β-cell mass under basal conditions, and there was no further increase under diabetic conditions. Their β-cell function and islet PI3K signaling remained intact, in contrast to HFD-fed wild-type and db/db islets that exhibited diminished β-cell function and attenuated PI3K signaling. These protective effects in β-cells occurred in the absence of compromised response to DNA-damaging stimuli.

Conclusions: PTEN exerts a critical negative effect on both β-cell mass and function. Thus PTEN inhibition in β-cells can be a novel therapeutic intervention to prevent the decline of β-cell mass and function in type 2 diabetes.

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RIPcre+ Ptenfl/fl mice maintained high islet mass and β-cell size with protection against HFD-induced β-cell dysfunction. A and B: Insulin staining (A) and quantification (B) of pancreas sections of RIPcre+ Pten+/+ (+/+) and RIPcre+ Ptenfl/fl (−/−) mice fed either chow or HFD (n = 3), Scale bar, 500 μm. C: Percentage of Ki67 positive cells in islets from RIPcre+ Pten+/+ and RIPcre+ Ptenfl/fl mice fed either chow or HFD (n = 3). D: proportion of small (<10 cells), medium (10–200 cells) and large (>200 cells) islet in pancreas from RIPcre+ Pten+/+ and RIPcre+ Ptenfl/fl mice fed either chow or HFD (n = 3). E and F: Immunofluorescent staining of insulin/DAPI (E) and quantification of β-cell size (F) of pancreas from RIPcre+ Pten+/+ and RIPcre+ Ptenfl/fl mice fed either chow or HFD (n = 3), Scale bar, 50 μm. G and H: Insulin secretion per 60 islets during perifusion analysis (G) and quantification of area under the curve (AUC) (H) of chow-fed RIPcre+ Pten+/+ and RIPcre+ Ptenfl/fl islets (n = 3). I and J: Insulin secretion per 60 islets during perifusion analysis (I) and quantification of area under the curve (J) of HFD-fed RIPcre+ Pten+/+ and RIPcre+ Ptenfl/fl islets (n = 3). *P < 0.05. Results are presented as mean ± SE. (A high-quality digital representation of this figure is available in the online issue.)
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Figure 4: RIPcre+ Ptenfl/fl mice maintained high islet mass and β-cell size with protection against HFD-induced β-cell dysfunction. A and B: Insulin staining (A) and quantification (B) of pancreas sections of RIPcre+ Pten+/+ (+/+) and RIPcre+ Ptenfl/fl (−/−) mice fed either chow or HFD (n = 3), Scale bar, 500 μm. C: Percentage of Ki67 positive cells in islets from RIPcre+ Pten+/+ and RIPcre+ Ptenfl/fl mice fed either chow or HFD (n = 3). D: proportion of small (<10 cells), medium (10–200 cells) and large (>200 cells) islet in pancreas from RIPcre+ Pten+/+ and RIPcre+ Ptenfl/fl mice fed either chow or HFD (n = 3). E and F: Immunofluorescent staining of insulin/DAPI (E) and quantification of β-cell size (F) of pancreas from RIPcre+ Pten+/+ and RIPcre+ Ptenfl/fl mice fed either chow or HFD (n = 3), Scale bar, 50 μm. G and H: Insulin secretion per 60 islets during perifusion analysis (G) and quantification of area under the curve (AUC) (H) of chow-fed RIPcre+ Pten+/+ and RIPcre+ Ptenfl/fl islets (n = 3). I and J: Insulin secretion per 60 islets during perifusion analysis (I) and quantification of area under the curve (J) of HFD-fed RIPcre+ Pten+/+ and RIPcre+ Ptenfl/fl islets (n = 3). *P < 0.05. Results are presented as mean ± SE. (A high-quality digital representation of this figure is available in the online issue.)

Mentions: During HFD-induced diabetes, development of peripheral insulin resistance leads to a compensatory increase in β-cell mass to meet the increasing demands for insulin. This compensatory proliferation was observed in RIPcre+ Pten+/+ islets on HFD (Fig. 4A and B). RIPcre+ Ptenfl/fl islets showed an already increased β-cell mass under chow-fed conditions, and we observed no further increase in β-cell mass in the mice on HFD. The increased β-cell mass was due to both an increase in proliferation and β-cell size in RIPcre+ Ptenfl/fl mice under both chow and HFD conditions, which likely reflects the direct effects of PTEN deletion in their β-cells (Fig. 4C, E, and F). Furthermore, age-matched chow- and HFD-fed RIPcre+ Ptenfl/fl mice showed similarly increased proportion of large islets (Fig. 4D). Despite the increased proliferation and cellular growth in RIPcre+ Ptenfl/fl islets, their architectures were maintained (Fig. 5A).


Deletion of Pten in pancreatic ß-cells protects against deficient ß-cell mass and function in mouse models of type 2 diabetes.

Wang L, Liu Y, Yan Lu S, Nguyen KT, Schroer SA, Suzuki A, Mak TW, Gaisano H, Woo M - Diabetes (2010)

RIPcre+ Ptenfl/fl mice maintained high islet mass and β-cell size with protection against HFD-induced β-cell dysfunction. A and B: Insulin staining (A) and quantification (B) of pancreas sections of RIPcre+ Pten+/+ (+/+) and RIPcre+ Ptenfl/fl (−/−) mice fed either chow or HFD (n = 3), Scale bar, 500 μm. C: Percentage of Ki67 positive cells in islets from RIPcre+ Pten+/+ and RIPcre+ Ptenfl/fl mice fed either chow or HFD (n = 3). D: proportion of small (<10 cells), medium (10–200 cells) and large (>200 cells) islet in pancreas from RIPcre+ Pten+/+ and RIPcre+ Ptenfl/fl mice fed either chow or HFD (n = 3). E and F: Immunofluorescent staining of insulin/DAPI (E) and quantification of β-cell size (F) of pancreas from RIPcre+ Pten+/+ and RIPcre+ Ptenfl/fl mice fed either chow or HFD (n = 3), Scale bar, 50 μm. G and H: Insulin secretion per 60 islets during perifusion analysis (G) and quantification of area under the curve (AUC) (H) of chow-fed RIPcre+ Pten+/+ and RIPcre+ Ptenfl/fl islets (n = 3). I and J: Insulin secretion per 60 islets during perifusion analysis (I) and quantification of area under the curve (J) of HFD-fed RIPcre+ Pten+/+ and RIPcre+ Ptenfl/fl islets (n = 3). *P < 0.05. Results are presented as mean ± SE. (A high-quality digital representation of this figure is available in the online issue.)
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
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Figure 4: RIPcre+ Ptenfl/fl mice maintained high islet mass and β-cell size with protection against HFD-induced β-cell dysfunction. A and B: Insulin staining (A) and quantification (B) of pancreas sections of RIPcre+ Pten+/+ (+/+) and RIPcre+ Ptenfl/fl (−/−) mice fed either chow or HFD (n = 3), Scale bar, 500 μm. C: Percentage of Ki67 positive cells in islets from RIPcre+ Pten+/+ and RIPcre+ Ptenfl/fl mice fed either chow or HFD (n = 3). D: proportion of small (<10 cells), medium (10–200 cells) and large (>200 cells) islet in pancreas from RIPcre+ Pten+/+ and RIPcre+ Ptenfl/fl mice fed either chow or HFD (n = 3). E and F: Immunofluorescent staining of insulin/DAPI (E) and quantification of β-cell size (F) of pancreas from RIPcre+ Pten+/+ and RIPcre+ Ptenfl/fl mice fed either chow or HFD (n = 3), Scale bar, 50 μm. G and H: Insulin secretion per 60 islets during perifusion analysis (G) and quantification of area under the curve (AUC) (H) of chow-fed RIPcre+ Pten+/+ and RIPcre+ Ptenfl/fl islets (n = 3). I and J: Insulin secretion per 60 islets during perifusion analysis (I) and quantification of area under the curve (J) of HFD-fed RIPcre+ Pten+/+ and RIPcre+ Ptenfl/fl islets (n = 3). *P < 0.05. Results are presented as mean ± SE. (A high-quality digital representation of this figure is available in the online issue.)
Mentions: During HFD-induced diabetes, development of peripheral insulin resistance leads to a compensatory increase in β-cell mass to meet the increasing demands for insulin. This compensatory proliferation was observed in RIPcre+ Pten+/+ islets on HFD (Fig. 4A and B). RIPcre+ Ptenfl/fl islets showed an already increased β-cell mass under chow-fed conditions, and we observed no further increase in β-cell mass in the mice on HFD. The increased β-cell mass was due to both an increase in proliferation and β-cell size in RIPcre+ Ptenfl/fl mice under both chow and HFD conditions, which likely reflects the direct effects of PTEN deletion in their β-cells (Fig. 4C, E, and F). Furthermore, age-matched chow- and HFD-fed RIPcre+ Ptenfl/fl mice showed similarly increased proportion of large islets (Fig. 4D). Despite the increased proliferation and cellular growth in RIPcre+ Ptenfl/fl islets, their architectures were maintained (Fig. 5A).

Bottom Line: Their β-cell function and islet PI3K signaling remained intact, in contrast to HFD-fed wild-type and db/db islets that exhibited diminished β-cell function and attenuated PI3K signaling.These protective effects in β-cells occurred in the absence of compromised response to DNA-damaging stimuli.PTEN exerts a critical negative effect on both β-cell mass and function.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.

ABSTRACT

Objective: Type 2 diabetes is characterized by diminished pancreatic β-cell mass and function. Insulin signaling within the β-cells has been shown to play a critical role in maintaining the essential function of the β-cells. Under basal conditions, enhanced insulin-PI3K signaling via deletion of phosphatase with tensin homology (PTEN), a negative regulator of this pathway, leads to increased β-cell mass and function. In this study, we investigated the effects of prolonged β-cell-specific PTEN deletion in models of type 2 diabetes.

Research design and methods: Two models of type 2 diabetes were employed: a high-fat diet (HFD) model and a db/db model that harbors a global leptin-signaling defect. A Cre-loxP system driven by the rat insulin promoter (RIP) was employed to obtain mice with β-cell-specific PTEN deletion (RIPcre(+) Pten(fl/fl)).

Results: PTEN expression in islets was upregulated in both models of type 2 diabetes. RIPcre(+) Pten(fl/fl) mice were completely protected against diabetes in both models of type 2 diabetes. The islets of RIPcre(+) Pten(fl/fl) mice already exhibited increased β-cell mass under basal conditions, and there was no further increase under diabetic conditions. Their β-cell function and islet PI3K signaling remained intact, in contrast to HFD-fed wild-type and db/db islets that exhibited diminished β-cell function and attenuated PI3K signaling. These protective effects in β-cells occurred in the absence of compromised response to DNA-damaging stimuli.

Conclusions: PTEN exerts a critical negative effect on both β-cell mass and function. Thus PTEN inhibition in β-cells can be a novel therapeutic intervention to prevent the decline of β-cell mass and function in type 2 diabetes.

Show MeSH
Related in: MedlinePlus