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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 Leprdb/db mice exhibited comparable weight gain and normal glucose tolerance despite being insulin resistant with normal β-cell function. A: Weight of wild-type (WT), RIPcre+ Pten+/+ Leprdb/db (db/db), and RIPcre+ Ptenfl/fl Leprdb/db (−/−; db/db) mice at 2 and 7 months of age (n >7). B: Fed blood glucose of wild-type, RIPcre+ Pten+/+ Leprdb/db, and RIPcre+ Ptenfl/fl Leprdb/db mice from 2 to 7 months of age (n >7). C: Glucose tolerance test of wild-type, RIPcre+ Pten+/+ Leprdb/db, and RIPcre+ Ptenfl/fl Leprdb/db mice at 7 months of age (n >7). D: Insulin tolerance test of wild-type, RIPcre+ Pten+/+ Leprdb/db, and RIPcre+ Ptenfl/fl Leprdb/db mice at 7 months of age (n >7). E: In vivo glucose-stimulated insulin secretion of wild-type, RIPcre+ Pten+/+ Leprdb/db, and RIPcre+ Ptenfl/fl Leprdb/db mice at 7 months of age (n = 3). F and G: Insulin secretion per 60 islets during perifusion analysis (F) and quantification of area under the curve (G) of wild-type, RIPcre+ Pten+/+ Leprdb/db, and RIPcre+ Ptenfl/fl Leprdb/db mice (n = 3). *P < 0.05 for RIPcre+ Ptenfl/fl Leprdb/db mice compared with RIPcre+ Pten+/+ Leprdb/db mice or as indicated; φP < 0.05 for both RIPcre+ Pten+/+ Leprdb/db and RIPcre+ Ptenfl/fl Leprdb/db mice compared with wild-type mice. Results are presented as mean ± SE.
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Figure 6: RIPcre+ Ptenfl/fl Leprdb/db mice exhibited comparable weight gain and normal glucose tolerance despite being insulin resistant with normal β-cell function. A: Weight of wild-type (WT), RIPcre+ Pten+/+ Leprdb/db (db/db), and RIPcre+ Ptenfl/fl Leprdb/db (−/−; db/db) mice at 2 and 7 months of age (n >7). B: Fed blood glucose of wild-type, RIPcre+ Pten+/+ Leprdb/db, and RIPcre+ Ptenfl/fl Leprdb/db mice from 2 to 7 months of age (n >7). C: Glucose tolerance test of wild-type, RIPcre+ Pten+/+ Leprdb/db, and RIPcre+ Ptenfl/fl Leprdb/db mice at 7 months of age (n >7). D: Insulin tolerance test of wild-type, RIPcre+ Pten+/+ Leprdb/db, and RIPcre+ Ptenfl/fl Leprdb/db mice at 7 months of age (n >7). E: In vivo glucose-stimulated insulin secretion of wild-type, RIPcre+ Pten+/+ Leprdb/db, and RIPcre+ Ptenfl/fl Leprdb/db mice at 7 months of age (n = 3). F and G: Insulin secretion per 60 islets during perifusion analysis (F) and quantification of area under the curve (G) of wild-type, RIPcre+ Pten+/+ Leprdb/db, and RIPcre+ Ptenfl/fl Leprdb/db mice (n = 3). *P < 0.05 for RIPcre+ Ptenfl/fl Leprdb/db mice compared with RIPcre+ Pten+/+ Leprdb/db mice or as indicated; φP < 0.05 for both RIPcre+ Pten+/+ Leprdb/db and RIPcre+ Ptenfl/fl Leprdb/db mice compared with wild-type mice. Results are presented as mean ± SE.

Mentions: Both RIPcre+ Ptenfl/fl Leprdb/db mice and RIPcre+ Pten+/+ Leprdb/db littermates exhibited similar degrees of weight gain and insulin resistance (Fig. 6A and D). However, despite severe insulin resistance in RIPcre+ Ptenfl/fl Leprdb/db mice, they continued to remain remarkably euglycemic and showed normal glucose tolerance (Fig. 6B and C). Furthermore, in vivo GSIS experiments showed robust insulin secretion in response to glucose stimulation in RIPcre+ Ptenfl/fl Leprdb/db mice (Fig. 6E). Interestingly, islets of RIPcre+ Ptenfl/fl Leprdb/db mice demonstrated similar degrees of hypertrophy and proliferation as those of RIPcre+ Pten+/+ Leprdb/db islets and did not show a further increase in β-cell mass compared with db/db controls (Fig. 7B and C). Islets of RIPcre+ Ptenfl/fl Leprdb/db mice showed no signs of disorganized architecture (Fig. 7A).


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 Leprdb/db mice exhibited comparable weight gain and normal glucose tolerance despite being insulin resistant with normal β-cell function. A: Weight of wild-type (WT), RIPcre+ Pten+/+ Leprdb/db (db/db), and RIPcre+ Ptenfl/fl Leprdb/db (−/−; db/db) mice at 2 and 7 months of age (n >7). B: Fed blood glucose of wild-type, RIPcre+ Pten+/+ Leprdb/db, and RIPcre+ Ptenfl/fl Leprdb/db mice from 2 to 7 months of age (n >7). C: Glucose tolerance test of wild-type, RIPcre+ Pten+/+ Leprdb/db, and RIPcre+ Ptenfl/fl Leprdb/db mice at 7 months of age (n >7). D: Insulin tolerance test of wild-type, RIPcre+ Pten+/+ Leprdb/db, and RIPcre+ Ptenfl/fl Leprdb/db mice at 7 months of age (n >7). E: In vivo glucose-stimulated insulin secretion of wild-type, RIPcre+ Pten+/+ Leprdb/db, and RIPcre+ Ptenfl/fl Leprdb/db mice at 7 months of age (n = 3). F and G: Insulin secretion per 60 islets during perifusion analysis (F) and quantification of area under the curve (G) of wild-type, RIPcre+ Pten+/+ Leprdb/db, and RIPcre+ Ptenfl/fl Leprdb/db mice (n = 3). *P < 0.05 for RIPcre+ Ptenfl/fl Leprdb/db mice compared with RIPcre+ Pten+/+ Leprdb/db mice or as indicated; φP < 0.05 for both RIPcre+ Pten+/+ Leprdb/db and RIPcre+ Ptenfl/fl Leprdb/db mice compared with wild-type mice. Results are presented as mean ± SE.
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Figure 6: RIPcre+ Ptenfl/fl Leprdb/db mice exhibited comparable weight gain and normal glucose tolerance despite being insulin resistant with normal β-cell function. A: Weight of wild-type (WT), RIPcre+ Pten+/+ Leprdb/db (db/db), and RIPcre+ Ptenfl/fl Leprdb/db (−/−; db/db) mice at 2 and 7 months of age (n >7). B: Fed blood glucose of wild-type, RIPcre+ Pten+/+ Leprdb/db, and RIPcre+ Ptenfl/fl Leprdb/db mice from 2 to 7 months of age (n >7). C: Glucose tolerance test of wild-type, RIPcre+ Pten+/+ Leprdb/db, and RIPcre+ Ptenfl/fl Leprdb/db mice at 7 months of age (n >7). D: Insulin tolerance test of wild-type, RIPcre+ Pten+/+ Leprdb/db, and RIPcre+ Ptenfl/fl Leprdb/db mice at 7 months of age (n >7). E: In vivo glucose-stimulated insulin secretion of wild-type, RIPcre+ Pten+/+ Leprdb/db, and RIPcre+ Ptenfl/fl Leprdb/db mice at 7 months of age (n = 3). F and G: Insulin secretion per 60 islets during perifusion analysis (F) and quantification of area under the curve (G) of wild-type, RIPcre+ Pten+/+ Leprdb/db, and RIPcre+ Ptenfl/fl Leprdb/db mice (n = 3). *P < 0.05 for RIPcre+ Ptenfl/fl Leprdb/db mice compared with RIPcre+ Pten+/+ Leprdb/db mice or as indicated; φP < 0.05 for both RIPcre+ Pten+/+ Leprdb/db and RIPcre+ Ptenfl/fl Leprdb/db mice compared with wild-type mice. Results are presented as mean ± SE.
Mentions: Both RIPcre+ Ptenfl/fl Leprdb/db mice and RIPcre+ Pten+/+ Leprdb/db littermates exhibited similar degrees of weight gain and insulin resistance (Fig. 6A and D). However, despite severe insulin resistance in RIPcre+ Ptenfl/fl Leprdb/db mice, they continued to remain remarkably euglycemic and showed normal glucose tolerance (Fig. 6B and C). Furthermore, in vivo GSIS experiments showed robust insulin secretion in response to glucose stimulation in RIPcre+ Ptenfl/fl Leprdb/db mice (Fig. 6E). Interestingly, islets of RIPcre+ Ptenfl/fl Leprdb/db mice demonstrated similar degrees of hypertrophy and proliferation as those of RIPcre+ Pten+/+ Leprdb/db islets and did not show a further increase in β-cell mass compared with db/db controls (Fig. 7B and C). Islets of RIPcre+ Ptenfl/fl Leprdb/db mice showed no signs of disorganized architecture (Fig. 7A).

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