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Cardiovascular Drugs and Therapy

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01-10-2014 | ORIGINAL ARTICLE

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

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

Published in: Cardiovascular Drugs and Therapy | Issue 5/2014

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.

Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto Jr AM, Kastelein JJ, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195–207.PubMedCrossRef

Sattar N, Taskinen MR. Statins are diabetogenic–myth or reality? Atheroscler Suppl. 2012;13(1):1–10.PubMedCrossRef

Rajpathak SN, Kumbhani DJ, Crandall J, Barzilai N, Alderman M, Ridker PM. Statin therapy and risk of developing type 2 diabetes: a meta-analysis. Diabetes Care. 2009;32(10):1924–9.PubMedCrossRefPubMedCentral

Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010;375(9716):735–42.PubMedCrossRef

Waters DD, Ho JE, DeMicco DA, Breazna A, Arsenault BJ, Wun CC, et al. Predictors of new-onset diabetes in patients treated with atorvastatin: results from 3 large randomized clinical trials. J Am Coll Cardiol. 2011;57(14):1535–45.PubMedCrossRef

Newman CB, Szarek M, Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, et al. The safety and tolerability of atorvastatin 10 mg in the Collaborative Atorvastatin Diabetes Study (CARDS). Diab Vasc Dis Res. 2008;5(3):177–83.PubMedCrossRef

Moutzouri E, Liberopoulos E, Mikhailidis DP, Kostapanos MS, Kei AA, Milionis H, et al. Comparison of the effects of simvastatin vs. rosuvastatin vs. simvastatin/ezetimibe on parameters of insulin resistance. Int J Clin Pract. 2011;65(11):1141–8.PubMedCrossRef

Mensah K, Mocanu MM, Yellon DM. Failure to protect the myocardium against ischemia/reperfusion injury after chronic atorvastatin treatment is recaptured by acute atorvastatin treatment: a potential role for phosphatase and tensin homolog deleted on chromosome ten? J Am Coll Cardiol. 2005;45(8):1287–91.PubMedCrossRef

Ye Y, Lin Y, Atar S, Huang MH, Perez-Polo JR, Uretsky BF, et al. Myocardial protection by pioglitazone, atorvastatin, and their combination: mechanisms and possible interactions. Am J Physiol Heart Circ Physiol. 2006;291(3):H1158–69.PubMedCrossRef

10.

Teresi RE, Shaiu CW, Chen CS, Chatterjee VK, Waite KA, Eng C. Increased PTEN expression due to transcriptional activation of PPARgamma by Lovastatin and Rosiglitazone. Int J Cancer. 2006;118(10):2390–8.PubMedCrossRef

11.

Teresi RE, Planchon SM, Waite KA, Eng C. Regulation of the PTEN promoter by statins and SREBP. Hum Mol Genet. 2008;17(7):919–28.PubMedCrossRef

12.

Ye Y, Nishi SP, Manickavasagam S, Lin Y, Huang MH, Perez-Polo JR, et al. Activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) by atorvastatin is mediated by 15-deoxy-delta-12,14-PGJ2. Prostaglandins Other Lipid Mediat. 2007;84(1–2):43–53.PubMedCrossRef

13.

Qian J, Ling S, Castillo AC, Long B, Birnbaum Y, Ye Y. Regulation of phosphatase and tensin homolog on chromosome 10 in response to hypoxia. Am J Physiol Heart Circ Physiol. 2012;302(9):H1806–17.PubMedCrossRef

14.

Wong JT, Kim PT, Peacock JW, Yau TY, Mui AL, Chung SW, et al. Pten (phosphatase and tensin homologue gene) haploinsufficiency promotes insulin hypersensitivity. Diabetologia. 2007;50(2):395–403.PubMedCrossRefPubMedCentral

15.

Birnbaum Y, Castillo AC, Qian J, Ling S, Ye H, Perez-Polo JR, et al. Phosphodiesterase III inhibition increases cAMP levels and augments the infarct size limiting effect of a DPP-4 inhibitor in mice with type-2 diabetes mellitus. Cardiovasc Drugs Ther. 2012;26(6):445–56.PubMedCrossRef

16.

Mocanu MM, Field DC, Yellon DM. A potential role for PTEN in the diabetic heart. Cardiovasc Drugs Ther. 2006;20(4):319–21.PubMedCrossRef

17.

Wang B, Raedschelders K, Shravah J, Hui Y, Safaei HG, Chen DD, et al. Differences in myocardial PTEN expression and Akt signalling in type 2 diabetic and nondiabetic patients undergoing coronary bypass surgery. Clin Endocrinol (Oxf). 2011;74(6):705–13.CrossRef

18.

Song P, Wu Y, Xu J, Xie Z, Dong Y, Zhang M, et al. Reactive nitrogen species induced by hyperglycemia suppresses Akt signaling and triggers apoptosis by upregulating phosphatase PTEN (phosphatase and tensin homologue deleted on chromosome 10) in an LKB1-dependent manner. Circulation. 2007;116(14):1585–95.PubMedCrossRef

19.

Hu Z, Lee IH, Wang X, Sheng H, Zhang L, Du J, et al. PTEN expression contributes to the regulation of muscle protein degradation in diabetes. Diabetes. 2007;56(10):2449–56.PubMedCrossRef

20.

Hu Z, Wang H, Lee IH, Modi S, Wang X, Du J, et al. PTEN inhibition improves muscle regeneration in mice fed a high-fat diet. Diabetes. 2010;59(6):1312–20.PubMedCrossRefPubMedCentral

21.

Planavila A, Rodriguez-Calvo R, Palomer X, Coll T, Sanchez RM, Merlos M, et al. Atorvastatin inhibits GSK-3beta phosphorylation by cardiac hypertrophic stimuli. Biochim Biophys Acta. 2008;1781(1–2):26–35.PubMedCrossRef

22.

Wijesekara N, Konrad D, Eweida M, Jefferies C, Liadis N, Giacca A, et al. Muscle-specific Pten deletion protects against insulin resistance and diabetes. Mol Cell Biol. 2005;25(3):1135–45.PubMedCrossRefPubMedCentral

23.

Ye Y, Qian J, Castillo AC, Ling S, Ye H, Perez-Polo JR, et al. Phosphodiesterase-3 inhibition augments the myocardial infarct size-limiting effects of exenatide in mice with type 2 diabetes. Am J Physiol Heart Circ Physiol. 2013;304(1):H131–41.PubMedCrossRef

24.

Samson SL, Sathyanarayana P, Jogi M, Gonzalez EV, Gutierrez A, Krishnamurthy R, et al. Exenatide decreases hepatic fibroblast growth factor 21 resistance in non-alcoholic fatty liver disease in a mouse model of obesity and in a randomised controlled trial. Diabetologia. 2011;54(12):3093–100.PubMedCrossRefPubMedCentral

25.

Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28(7):412–9.PubMedCrossRef

26.

Ryu D, Seo WY, Yoon YS, Kim YN, Kim SS, Kim HJ, et al. Endoplasmic reticulum stress promotes LIPIN2-dependent hepatic insulin resistance. Diabetes. 2011;60(4):1072–81.PubMedCrossRefPubMedCentral

27.

Nunemaker CS, Chen M, Pei H, Kimble SD, Keller SR, Carter JD, et al. 12-Lipoxygenase-knockout mice are resistant to inflammatory effects of obesity induced by Western diet. Am J Physiol Endocrinol Metab. 2008;295(5):E1065–75.PubMedCrossRefPubMedCentral

28.

Neto-Ferreira R, Rocha VN, Souza-Mello V, Mandarim-de-Lacerda CA, de Carvalho JJ. Pleiotropic effects of rosuvastatin on the glucose metabolism and the subcutaneous and visceral adipose tissue behavior in C57Bl/6 mice. Diabetol Metab Syndr. 2013;5(1):32.PubMedCrossRefPubMedCentral

29.

Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care. 1999;22(9):1462–70.PubMedCrossRef

30.

Miller AW, Tulbert CD, Busija DW. Rosuvastatin treatment reverses impaired coronary artery vasodilation in fructose-fed, insulin-resistant rats. Am J Physiol Regul Integr Comp Physiol. 2004;287(1):R157–60.PubMedCrossRef

31.

Kim S, Kim CH, Vaziri ND. Upregulation of hepatic LDL receptor-related protein in nephrotic syndrome: response to statin therapy. Am J Physiol Endocrinol Metab. 2005;288(4):E813–7.PubMedCrossRef

32.

Alisi A, Da Sacco L, Bruscalupi G, Piemonte F, Panera N, De Vito R, et al. Mirnome analysis reveals novel molecular determinants in the pathogenesis of diet-induced nonalcoholic fatty liver disease. Lab Invest. 2011;91(2):283–93.PubMedCrossRef

33.

Butler M, McKay RA, Popoff IJ, Gaarde WA, Witchell D, Murray SF, et al. Specific inhibition of PTEN expression reverses hyperglycemia in diabetic mice. Diabetes. 2002;51(4):1028–34.PubMedCrossRef

34.

Kurlawalla-Martinez C, Stiles B, Wang Y, Devaskar SU, Kahn BB, Wu H. Insulin hypersensitivity and resistance to streptozotocin-induced diabetes in mice lacking PTEN in adipose tissue. Mol Cell Biol. 2005;25(6):2498–510.PubMedCrossRefPubMedCentral

35.

Stiles B, Wang Y, Stahl A, Bassilian S, Lee WP, Kim YJ, et al. Liver-specific deletion of negative regulator Pten results in fatty liver and insulin hypersensitivity [corrected]. Proc Natl Acad Sci U S A. 2004;101(7):2082–7.PubMedCrossRefPubMedCentral

36.

Iida S, Ono A, Sayama K, Hamaguchi T, Fujii H, Nakajima H, et al. Accelerated decline of blood glucose after intravenous glucose injection in a patient with Cowden disease having a heterozygous germline mutation of the PTEN/MMAC1 gene. Anticancer Res. 2000;20(3B):1901–4.PubMed

37.

Ishihara H, Sasaoka T, Kagawa S, Murakami S, Fukui K, Kawagishi Y, et al. Association of the polymorphisms in the 5′-untranslated region of PTEN gene with type 2 diabetes in a Japanese population. FEBS Lett. 2003;554(3):450–4.PubMedCrossRef

38.

Pal A, Barber TM, Van de Bunt M, Rudge SA, Zhang Q, Lachlan KL, et al. PTEN mutations as a cause of constitutive insulin sensitivity and obesity. N Engl J Med. 2012;367(11):1002–11.PubMedCrossRefPubMedCentral

39.

Paintlia AS, Paintlia MK, Singh AK, Orak JK, Singh I. Activation of PPAR-gamma and PTEN cascade participates in lovastatin-mediated accelerated differentiation of oligodendrocyte progenitor cells. Glia. 2010;58(14):1669–85.PubMedCrossRefPubMedCentral

40.

Miraglia E, Hogberg J, Stenius U. Statins exhibit anticancer effects through modifications of the pAkt signaling pathway. Int J Oncol. 2012;40(3):867–75.PubMed

41.

Lee JH, Kim KY, Lee YK, Park SY, Kim CD, Lee WS, et al. Cilostazol prevents focal cerebral ischemic injury by enhancing casein kinase 2 phosphorylation and suppression of phosphatase and tensin homolog deleted from chromosome 10 phosphorylation in rats. J Pharmacol Exp Ther. 2004;308(3):896–903.PubMedCrossRef

42.

Kim KY, Shin HK, Lee JH, Kim CD, Lee WS, Rhim BY, et al. Cilostazol enhances casein kinase 2 phosphorylation and suppresses tumor necrosis factor-alpha-induced increased phosphatase and tensin homolog deleted from chromosome 10 phosphorylation and apoptotic cell death in SK-N-SH cells. J Pharmacol Exp Ther. 2004;308(1):97–104.PubMedCrossRef

43.

Nakaya Y, Minami A, Sakamoto S, Niwa Y, Ohnaka M, Harada N, et al. Cilostazol, a phosphodiesterase inhibitor, improves insulin sensitivity in the Otsuka Long-Evans Tokushima Fatty Rat, a model of spontaneous NIDDM. Diabetes Obes Metab. 1999;1(1):37–41.PubMedCrossRef

44.

Park SY, Lee JH, Kim KY, Kim EK, Yun SJ, Kim CD, et al. Cilostazol increases 3 T3-L1 preadipocyte differentiation with improved glucose uptake associated with activation of peroxisome proliferator-activated receptor-gamma transcription. Atherosclerosis. 2008;201(2):258–65.PubMedCrossRef

45.

Park SY, Shin HK, Lee JH, Kim CD, Lee WS, Rhim BY, et al. Cilostazol ameliorates metabolic abnormalities with suppression of proinflammatory markers in a db/db mouse model of type 2 diabetes via activation of peroxisome proliferator-activated receptor gamma transcription. J Pharmacol Exp Ther. 2009;329(2):571–9.PubMedCrossRef

46.

Fraulob JC, Souza-Mello V, Aguila MB, Mandarim-de-Lacerda CA. Beneficial effects of rosuvastatin on insulin resistance, adiposity, inflammatory markers and non-alcoholic fatty liver disease in mice fed on a high-fat diet. Clin Sci (Lond). 2012;123(4):259–70.CrossRef

47.

Naples M, Federico LM, Xu E, Nelken J, Adeli K. Effect of rosuvastatin on insulin sensitivity in an animal model of insulin resistance: evidence for statin-induced hepatic insulin sensitization. Atherosclerosis. 2008;198(1):94–103.PubMedCrossRef

48.

Hermida N, Markl A, Hamelet J, Van Assche T, Vanderper A, Herijgers P, et al. HMGCoA reductase inhibition reverses myocardial fibrosis and diastolic dysfunction through AMP-activated protein kinase activation in a mouse model of metabolic syndrome. Cardiovasc Res. 2013;99(1):44–54.PubMedCrossRef

49.

Tian XY, Wong WT, Xu A, Chen ZY, Lu Y, Liu LM, et al. Rosuvastatin improves endothelial function in db/db mice: role of angiotensin II type 1 receptors and oxidative stress. Br J Pharmacol. 2011;164(2b):598–606.PubMedCrossRefPubMedCentral

50.

Hausenloy DJ, Baxter G, Bell R, Botker HE, Davidson SM, Downey J, et al. Translating novel strategies for cardioprotection: the Hatter Workshop Recommendations. Basic Res Cardiol. 2010;105(6):677–86.PubMedCrossRefPubMedCentral

Title: PTEN Upregulation May Explain the Development of Insulin Resistance and Type 2 Diabetes with High Dose Statins
Authors: Yochai Birnbaum
Manjyot K. Nanhwan
Shukuan Ling
Jose R. Perez-Polo
Yumei Ye
Mandeep Bajaj
Publication date: 01-10-2014
Publisher: Springer US
Published in: Cardiovascular Drugs and Therapy / Issue 5/2014
Print ISSN: 0920-3206
Electronic ISSN: 1573-7241
DOI: https://doi.org/10.1007/s10557-014-6546-5

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

Abstract

Purpose

Methods

Results

Conclusions

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