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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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Related in: MedlinePlus

RIPcre+ Ptenfl/fl mice showed maintained glucose metabolism and in vivo glucose stimulated insulin secretion after prolonged HFD while demonstrating drastic weight gain. A: Weight of RIPcre+ Pten+/+ (+/+) and RIPcre+ Ptenfl/fl (−/−) mice at the start of HFD (2 months of age) and after HFD (9 months of age) with chow-fed RIPcre+ Pten+/+ and RIPcre+ Ptenfl/fl mice at the same time points. B: Fasting blood glucose of RIPcre+ Pten+/+ and RIPcre+ Ptenfl/fl mice fed either chow or HFD for 7 months (n >7). C: Glucose tolerance tests of RIPcre+ Pten+/+ and RIPcre+ Ptenfl/fl mice after 7 months of either chow or HFD feeding (n >7). D: in vivo glucose stimulated insulin secretions of RIPcre+ Pten+/+ and RIPcre+ Ptenfl/fl mice after 7 months of either chow or HFD feeding (n >3). *P < 0.05. The results are presented as mean ± SE.
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Figure 3: RIPcre+ Ptenfl/fl mice showed maintained glucose metabolism and in vivo glucose stimulated insulin secretion after prolonged HFD while demonstrating drastic weight gain. A: Weight of RIPcre+ Pten+/+ (+/+) and RIPcre+ Ptenfl/fl (−/−) mice at the start of HFD (2 months of age) and after HFD (9 months of age) with chow-fed RIPcre+ Pten+/+ and RIPcre+ Ptenfl/fl mice at the same time points. B: Fasting blood glucose of RIPcre+ Pten+/+ and RIPcre+ Ptenfl/fl mice fed either chow or HFD for 7 months (n >7). C: Glucose tolerance tests of RIPcre+ Pten+/+ and RIPcre+ Ptenfl/fl mice after 7 months of either chow or HFD feeding (n >7). D: in vivo glucose stimulated insulin secretions of RIPcre+ Pten+/+ and RIPcre+ Ptenfl/fl mice after 7 months of either chow or HFD feeding (n >3). *P < 0.05. The results are presented as mean ± SE.

Mentions: We have previously shown that RIPcre+ Ptenfl/fl mice exhibit an increase in β-cell mass and function under basal conditions (23). To investigate whether these positive attributes of PTEN deletion in pancreatic β-cells conferred protection against type 2 diabetes, we fed these mice a prolonged HFD for 7 months. Efficient PTEN deletion in β-cells, along with partial deletion in the hypothalamus, persisted in the RIPcre+ Ptenfl/fl mice on prolonged HFD (Fig. 2A and B). Despite their increased weight gain upon HFD feeding, RIPcre+ Ptenfl/fl mice remained remarkably euglycemic throughout the duration of prolonged HFD, in contrast to the gradual increase in blood glucose levels in control littermates (Fig. 3A and B). They also exhibited improved glucose tolerance (Fig. 3C). The attenuation of insulin secretion in response to glucose is a characteristic β-cell defect in type 2 diabetes (1–3). Indeed, this attenuation was observed in both the first and second phases of insulin secretion after in vivo glucose challenge in wild-type mice after a prolonged HFD. In contrast, insulin secretion in response to glucose was preserved in RIPcre+ Ptenfl/fl mice (Fig. 3D).


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 showed maintained glucose metabolism and in vivo glucose stimulated insulin secretion after prolonged HFD while demonstrating drastic weight gain. A: Weight of RIPcre+ Pten+/+ (+/+) and RIPcre+ Ptenfl/fl (−/−) mice at the start of HFD (2 months of age) and after HFD (9 months of age) with chow-fed RIPcre+ Pten+/+ and RIPcre+ Ptenfl/fl mice at the same time points. B: Fasting blood glucose of RIPcre+ Pten+/+ and RIPcre+ Ptenfl/fl mice fed either chow or HFD for 7 months (n >7). C: Glucose tolerance tests of RIPcre+ Pten+/+ and RIPcre+ Ptenfl/fl mice after 7 months of either chow or HFD feeding (n >7). D: in vivo glucose stimulated insulin secretions of RIPcre+ Pten+/+ and RIPcre+ Ptenfl/fl mice after 7 months of either chow or HFD feeding (n >3). *P < 0.05. The results are presented as mean ± SE.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2992773&req=5

Figure 3: RIPcre+ Ptenfl/fl mice showed maintained glucose metabolism and in vivo glucose stimulated insulin secretion after prolonged HFD while demonstrating drastic weight gain. A: Weight of RIPcre+ Pten+/+ (+/+) and RIPcre+ Ptenfl/fl (−/−) mice at the start of HFD (2 months of age) and after HFD (9 months of age) with chow-fed RIPcre+ Pten+/+ and RIPcre+ Ptenfl/fl mice at the same time points. B: Fasting blood glucose of RIPcre+ Pten+/+ and RIPcre+ Ptenfl/fl mice fed either chow or HFD for 7 months (n >7). C: Glucose tolerance tests of RIPcre+ Pten+/+ and RIPcre+ Ptenfl/fl mice after 7 months of either chow or HFD feeding (n >7). D: in vivo glucose stimulated insulin secretions of RIPcre+ Pten+/+ and RIPcre+ Ptenfl/fl mice after 7 months of either chow or HFD feeding (n >3). *P < 0.05. The results are presented as mean ± SE.
Mentions: We have previously shown that RIPcre+ Ptenfl/fl mice exhibit an increase in β-cell mass and function under basal conditions (23). To investigate whether these positive attributes of PTEN deletion in pancreatic β-cells conferred protection against type 2 diabetes, we fed these mice a prolonged HFD for 7 months. Efficient PTEN deletion in β-cells, along with partial deletion in the hypothalamus, persisted in the RIPcre+ Ptenfl/fl mice on prolonged HFD (Fig. 2A and B). Despite their increased weight gain upon HFD feeding, RIPcre+ Ptenfl/fl mice remained remarkably euglycemic throughout the duration of prolonged HFD, in contrast to the gradual increase in blood glucose levels in control littermates (Fig. 3A and B). They also exhibited improved glucose tolerance (Fig. 3C). The attenuation of insulin secretion in response to glucose is a characteristic β-cell defect in type 2 diabetes (1–3). Indeed, this attenuation was observed in both the first and second phases of insulin secretion after in vivo glucose challenge in wild-type mice after a prolonged HFD. In contrast, insulin secretion in response to glucose was preserved in RIPcre+ Ptenfl/fl mice (Fig. 3D).

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