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PTEN Upregulation May Explain the Development of Insulin Resistance and Type 2 Diabetes with High Dose Statins

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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

PTENloxp/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 PTENloxp/cre mice receiving WD or ROS and especially WD+ROS. Levels were lower in PTEN+/− mice compared to PTENloxp/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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Support

This work was supported by a Translational Science Research Grant from the American Diabetes Association to MB.

Relations with Industry

Yochai Birnbaum: Research grants: Merck, Astra Zeneca

Yumei Ye: Research grants: Merck, Roche, Astra Zeneca; Amylin, BMS

Shukuan Ling: None. Manjyot Nanhwan: None. Jose R. Perez-Polo: None

Mandeep Bajaj: Research grants from Amylin, Eli Lilly, Boehringer-Ingelheim, Novo Nordisk, Bristol-Myers Squibb, and Astra Zenica; lecture fees from Takeda and Sanofi-Aventis; and has served as a consultant to Genentech.

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Authors and Affiliations

  1. The Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA

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

  2. The Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA

    Yochai Birnbaum

  3. State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China

    Shukuan Ling

  4. The Section of Endocrinology, Department of Medicine, Baylor College of Medicine, 6620 Main Street, Suite 11C05, Houston, TX, 77030, USA

    Mandeep Bajaj

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  1. Yochai Birnbaum
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  2. Manjyot K. Nanhwan
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  3. Shukuan Ling
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  4. Jose R. Perez-Polo
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Correspondence to Mandeep Bajaj.

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Birnbaum, Y., Nanhwan, M.K., Ling, S. et al. PTEN Upregulation May Explain the Development of Insulin Resistance and Type 2 Diabetes with High Dose Statins. Cardiovasc Drugs Ther 28, 447–457 (2014). https://doi.org/10.1007/s10557-014-6546-5

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