PTEN upregulation may explain the development of insulin resistance and type 2 diabetes with high dose statins

Yochai Birnbaum, Manjyot K. Nanhwan, Shukuan Ling, Jose R. Perez-Polo, Yumei Ye, Mandeep Bajaj

Research output: Contribution to journalArticle

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Abstract

PURPOSE: Statins increase the incidence of new onset diabetes. Prolonged statin therapy upregulates PTEN expression. PTEN levels are also elevated in diabetic animals. Activation of protein kinase A by cAMP decreases PTEN expression. We assessed whether prolonged treatment with rosuvastatin (ROS) induces glucose intolerance by upregulating Phosphatase and Tensin Homologue on Chromosome 10 (PTEN) in mice receiving normal (ND) or Western Diet (WD) and whether concomitant treatment with cilostazol (CIL, a phosphodiesterase-3 inhibitor) attenuates the effects.

METHODS: PTEN(loxp/cre) or PTEN(+/-) mice received ND or WD without or with ROS (10 mg/kg/day). Wild-type mice received ND or WD without or with ROS, CIL (10 mg/kg/day), or ROS+CIL for 30 days. Fasting insulin and glucose tolerance test were measured as well as PTEN and P-AKT levels in skeletal muscle.

RESULTS: Serum glucose after intraperitoneal injection of glucose was higher in PTEN(loxp/cre) mice receiving WD or ROS and especially WD+ROS. Levels were lower in PTEN(+/-) mice compared to PTEN(loxp/cre) in each treatment group. CIL decreased glucose levels in mice receiving WD, ROS and their combination. Insulin levels were higher in the WD+ROS group. CIL decreased insulin in mice receiving WD+ROS. WD, ROS and especially their combination increased PTEN and decreased P-AKT levels. CIL attenuated the effect of WD, ROS and their combination.

CONCLUSIONS: Long-term ROS can induce diabetes by upregulating PTEN. CIL attenuates these changes. Partial knockdown of PTEN also ameliorates ROS-induced insulin resistance. Further studies are needed to assess the effects of increasing cAMP levels to prevent the induction of diabetes by statins.

Original languageEnglish (US)
Pages (from-to)447-457
Number of pages11
JournalCardiovascular Drugs and Therapy
Volume28
Issue number5
DOIs
StatePublished - Oct 1 2014

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Hydroxymethylglutaryl-CoA Reductase Inhibitors
Type 2 Diabetes Mellitus
Insulin Resistance
Up-Regulation
Insulin
Glucose
Rosuvastatin Calcium
Phosphodiesterase 3 Inhibitors
Western Diet
Chromosomes, Human, Pair 10
Glucose Intolerance
Therapeutics
Glucose Tolerance Test
Cyclic AMP-Dependent Protein Kinases
Intraperitoneal Injections
Phosphoric Monoester Hydrolases

ASJC Scopus subject areas

  • Medicine(all)

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PTEN upregulation may explain the development of insulin resistance and type 2 diabetes with high dose statins. / Birnbaum, Yochai; Nanhwan, Manjyot K.; Ling, Shukuan; Perez-Polo, Jose R.; Ye, Yumei; Bajaj, Mandeep.

In: Cardiovascular Drugs and Therapy, Vol. 28, No. 5, 01.10.2014, p. 447-457.

Research output: Contribution to journalArticle

Birnbaum, Yochai ; Nanhwan, Manjyot K. ; Ling, Shukuan ; Perez-Polo, Jose R. ; Ye, Yumei ; Bajaj, Mandeep. / PTEN upregulation may explain the development of insulin resistance and type 2 diabetes with high dose statins. In: Cardiovascular Drugs and Therapy. 2014 ; Vol. 28, No. 5. pp. 447-457.
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abstract = "PURPOSE: Statins increase the incidence of new onset diabetes. Prolonged statin therapy upregulates PTEN expression. PTEN levels are also elevated in diabetic animals. Activation of protein kinase A by cAMP decreases PTEN expression. We assessed whether prolonged treatment with rosuvastatin (ROS) induces glucose intolerance by upregulating Phosphatase and Tensin Homologue on Chromosome 10 (PTEN) in mice receiving normal (ND) or Western Diet (WD) and whether concomitant treatment with cilostazol (CIL, a phosphodiesterase-3 inhibitor) attenuates the effects.METHODS: PTEN(loxp/cre) or PTEN(+/-) mice received ND or WD without or with ROS (10 mg/kg/day). Wild-type mice received ND or WD without or with ROS, CIL (10 mg/kg/day), or ROS+CIL for 30 days. Fasting insulin and glucose tolerance test were measured as well as PTEN and P-AKT levels in skeletal muscle.RESULTS: Serum glucose after intraperitoneal injection of glucose was higher in PTEN(loxp/cre) mice receiving WD or ROS and especially WD+ROS. Levels were lower in PTEN(+/-) mice compared to PTEN(loxp/cre) in each treatment group. CIL decreased glucose levels in mice receiving WD, ROS and their combination. Insulin levels were higher in the WD+ROS group. CIL decreased insulin in mice receiving WD+ROS. WD, ROS and especially their combination increased PTEN and decreased P-AKT levels. CIL attenuated the effect of WD, ROS and their combination.CONCLUSIONS: Long-term ROS can induce diabetes by upregulating PTEN. CIL attenuates these changes. Partial knockdown of PTEN also ameliorates ROS-induced insulin resistance. Further studies are needed to assess the effects of increasing cAMP levels to prevent the induction of diabetes by statins.",
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T1 - PTEN upregulation may explain the development of insulin resistance and type 2 diabetes with high dose statins

AU - Birnbaum, Yochai

AU - Nanhwan, Manjyot K.

AU - Ling, Shukuan

AU - Perez-Polo, Jose R.

AU - Ye, Yumei

AU - Bajaj, Mandeep

PY - 2014/10/1

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N2 - PURPOSE: Statins increase the incidence of new onset diabetes. Prolonged statin therapy upregulates PTEN expression. PTEN levels are also elevated in diabetic animals. Activation of protein kinase A by cAMP decreases PTEN expression. We assessed whether prolonged treatment with rosuvastatin (ROS) induces glucose intolerance by upregulating Phosphatase and Tensin Homologue on Chromosome 10 (PTEN) in mice receiving normal (ND) or Western Diet (WD) and whether concomitant treatment with cilostazol (CIL, a phosphodiesterase-3 inhibitor) attenuates the effects.METHODS: PTEN(loxp/cre) or PTEN(+/-) mice received ND or WD without or with ROS (10 mg/kg/day). Wild-type mice received ND or WD without or with ROS, CIL (10 mg/kg/day), or ROS+CIL for 30 days. Fasting insulin and glucose tolerance test were measured as well as PTEN and P-AKT levels in skeletal muscle.RESULTS: Serum glucose after intraperitoneal injection of glucose was higher in PTEN(loxp/cre) mice receiving WD or ROS and especially WD+ROS. Levels were lower in PTEN(+/-) mice compared to PTEN(loxp/cre) in each treatment group. CIL decreased glucose levels in mice receiving WD, ROS and their combination. Insulin levels were higher in the WD+ROS group. CIL decreased insulin in mice receiving WD+ROS. WD, ROS and especially their combination increased PTEN and decreased P-AKT levels. CIL attenuated the effect of WD, ROS and their combination.CONCLUSIONS: Long-term ROS can induce diabetes by upregulating PTEN. CIL attenuates these changes. Partial knockdown of PTEN also ameliorates ROS-induced insulin resistance. Further studies are needed to assess the effects of increasing cAMP levels to prevent the induction of diabetes by statins.

AB - PURPOSE: Statins increase the incidence of new onset diabetes. Prolonged statin therapy upregulates PTEN expression. PTEN levels are also elevated in diabetic animals. Activation of protein kinase A by cAMP decreases PTEN expression. We assessed whether prolonged treatment with rosuvastatin (ROS) induces glucose intolerance by upregulating Phosphatase and Tensin Homologue on Chromosome 10 (PTEN) in mice receiving normal (ND) or Western Diet (WD) and whether concomitant treatment with cilostazol (CIL, a phosphodiesterase-3 inhibitor) attenuates the effects.METHODS: PTEN(loxp/cre) or PTEN(+/-) mice received ND or WD without or with ROS (10 mg/kg/day). Wild-type mice received ND or WD without or with ROS, CIL (10 mg/kg/day), or ROS+CIL for 30 days. Fasting insulin and glucose tolerance test were measured as well as PTEN and P-AKT levels in skeletal muscle.RESULTS: Serum glucose after intraperitoneal injection of glucose was higher in PTEN(loxp/cre) mice receiving WD or ROS and especially WD+ROS. Levels were lower in PTEN(+/-) mice compared to PTEN(loxp/cre) in each treatment group. CIL decreased glucose levels in mice receiving WD, ROS and their combination. Insulin levels were higher in the WD+ROS group. CIL decreased insulin in mice receiving WD+ROS. WD, ROS and especially their combination increased PTEN and decreased P-AKT levels. CIL attenuated the effect of WD, ROS and their combination.CONCLUSIONS: Long-term ROS can induce diabetes by upregulating PTEN. CIL attenuates these changes. Partial knockdown of PTEN also ameliorates ROS-induced insulin resistance. Further studies are needed to assess the effects of increasing cAMP levels to prevent the induction of diabetes by statins.

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