Signaling Pathways Behind the Effect of Atorvastatin in Glucose Homeostasis

Section: Research Paper
Issue
Vol. 47 No. 2 (2025): Volume 47 Issue 2
Published
Dec 29, 2025
Pages
185-193

Abstract

Background: cardiovascular diseases (CVD) are significantly increased by dyslipidemia, while statins, especially atorvastatin, efficiently lower low-density lipoprotein (LDL) cholesterol levels, and decrease the risk of cardiovascular diseases. However, there are raising concern about the potential role of statins in inducing diabetes.


Aim: to highlight the impact of atorvastatin on glucose homeostasis, focusing on the mechanisms through which atorvastatin influences glucose metabolism.


Method: An extensive literature search has been conducted on various electronic databases such as PubMed, Scopus, Web of Science, and Science Direct. The review reported the effect of atorvastatin on main organs that are related to glucose homeostasis such as liver, adipose tissue and skeletal muscle. The mechanisms that underlie the atorvastatin-induced glucose intolerance effects include decreased insulin signaling in both muscle and adipose tissues, increased hepatic gluconeogenesis, and suppression of the mevalonate pathway.


Conclusions: The present knowledge regarding the impact of atorvastatin on glucose metabolism has been improved but several molecular/cellular signaling pathways are yet to be determined.


 

References

  1. Waters DD, Ho JE, Boekholdt SM, DeMicco DA, Kastelein JJP, Messig M, Breazna A, Pedersen TR. Cardiovascular Event Reduction Versus New-Onset Diabetes During Atorvastatin Therapy. J Am Coll Cardiol [Internet]. 2013 Jan;61(2):148–52. Available from: 10.1016/j.jacc.2012.09.042
  2. Angelidi AM, Stambolliu E, Adamopoulou KI, Kousoulis AA. Is Atorvastatin Associated with New Onset Diabetes or Deterioration of Glycemic Control? Systematic Review Using Data from 1.9 Million Patients. Int J Endocrinol [Internet]. 2018 Oct 22;2018:1–17. Available from: 10.1155/2018/8380192
  3. Abdullah MI, Abed MN, Khanim F, Richardson A. Screening a library of approved drugs reveals that prednisolone synergizes with pitavastatin to induce ovarian cancer cell death. Sci Rep. 2019;9(1).
  4. Qasim Z. The Antimycotic Activity of Rosuvastatin. Iraqi J Pharm [Internet]. 2022 Dec 31;19(2):84–92. Available from: 10.33899/iphr.2022.176654
  5. Abdullah MI, Abed MN, Richardson A. Inhibition of the mevalonate pathway augments the activity of pitavastatin against ovarian cancer cells. Sci Rep [Internet]. 2017 Aug 14;7(1):8090. Available from: 10.1038/s41598-017-08649-9
  6. Sattar N, Preiss D, Murray HM. Statins and risk of incident diabetes: A collaborative meta-analysis of randomised statin trials. Vol. 29, Revista Portuguesa de Cardiologia. 2010. p. 1077–8.
  7. Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet [Internet]. 2012 Aug;380(9841):565–71. Available from: 10.1016/S0140-6736(12)61190-8
  8. Almukhtar HM, Faisal IM, Merkhan MM. Acute effect of atorvastatin in comparison with rosuvastatin on glucose homeostasis in hypercholesteremic patients. Curr Top Pharmacol. 2021;25:25–34.
  9. Galicia-Garcia U, Jebari S, Larrea-Sebal A, Uribe KB, Siddiqi H, Ostolaza H, Benito-Vicente A, Martín C. Statin Treatment-Induced Development of Type 2 Diabetes: From Clinical Evidence to Mechanistic Insights. Int J Mol Sci [Internet]. 2020 Jul 2;21(13):4725. Available from: 10.3390/ijms21134725
  10. Yu Q, Wang F, Meng X, Gong Y, Wang Y, Xu C, Wang S. Short-term use of atorvastatin affects glucose homeostasis and suppresses the expression of LDL receptors in the pancreas of mice. Mol Med Rep. 2018;18(3):2780–8.
  11. Cheng D, Wang Y, Gao S, Wang X, Sun W, Bai L, Cheng G, Chu Y, Zhao S, Liu E. Atorvastatin delays the glucose clearance rate in hypercholesterolemic rabbits. Biomed Pharmacother. 2015;72:24–9.
  12. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. Int J Surg. 2010;
  13. Packard CJ, Boren J, Taskinen MR. Causes and Consequences of Hypertriglyceridemia. Vol. 11, Frontiers in Endocrinology. 2020.
  14. Seshadri S, Rapaka N, Prajapati B, Mandaliya D, Patel S, Muggalla CS, Kapadia B, Babu PP, Misra P, Saxena U. Statins exacerbate glucose intolerance and hyperglycemia in a high sucrose fed rodent model. Sci Rep. 2019;9(1).
  15. Cederberg H, Stančáková A, Yaluri N, Modi S, Kuusisto J, Laakso M. Increased risk of diabetes with statin treatment is associated with impaired insulin sensitivity and insulin secretion: a 6 year follow-up study of the METSIM cohort. Diabetologia. 2015;58(5):1109–17.
  16. Bellia A, Rizza S, Lombardo MF, Donadel G, Fabiano R, Andreadi K, Quon MJ, Sbraccia P, Federici M, Tesauro M, Cardillo C, Lauro D. Deterioration of glucose homeostasis in type 2 diabetic patients one year after beginning of statins therapy. Atherosclerosis. 2012;223(1):197–203.
  17. Yokote K, Saito Y, Bujo H, Hanaoka H, Shinomiya M, Mikami K, Shirai K, Nishikawa T, Kodama T, Tada N, Ban T, Endo K, Hashimoto N, Hayashi R, Hirai A, Honjo S, Itaya T, Ito K, et al. Influence of statins on glucose tolerance in patients with type 2 diabetes mellitus: Subanalysis of the collaborative study onhypercholesterolemia drug intervention and their benefits for atherosclerosis prevention (CHIBA Study). J Atheroscler Thromb. 2009;16(3):297–8.
  18. Gibson CM, Pride YB, Hochberg CP, Sloan S, Sabatine MS, Cannon CP. Effect of Intensive Statin Therapy on Clinical Outcomes Among Patients Undergoing Percutaneous Coronary Intervention for Acute Coronary Syndrome. PCI-PROVE IT: A PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis I. J Am Coll Cardiol. 2009;54(24):2290–5.
  19. Alvarez‐Jimenez L, Moreno‐Cabañas A, Ramirez‐Jimenez M, Morales‐Palomo F, Ortega JF, Mora‐Rodriguez R. Effects of statins and exercise on postprandial lipoproteins in metabolic syndrome vs metabolically healthy individuals. Br J Clin Pharmacol [Internet]. 2021 Mar 12;87(3):955–64. Available from: 10.1111/bcp.14447
  20. Alvarez-Jimenez L, Morales-Palomo F, Moreno-Cabañas A, Ortega JF, Mora-Rodríguez R. Effects of statin therapy on glycemic control and insulin resistance: A systematic review and meta-analysis. Vol. 947, European Journal of Pharmacology. 2023.
  21. Tabaei BS, Mousavi SN, Rahimian A, Rostamkhani H, Mellati AA, Jameshorani M. Co-administration of vitamin e and atorvastatin improves insulin sensitivity and peroxisome proliferator-activated receptor-γ expression in type 2 diabetic patients: A randomized double-blind clinical trial. Iran J Med Sci. 2021;
  22. Thakker D, Nair S, Pagada A, Jamdade V, Malik A. Statin use and the risk of developing diabetes: a network meta-analysis. Pharmacoepidemiol Drug Saf. 2016;25(10):1131–49.
  23. Abbasi F, Lamendola C, Harris CS, Harris V, Tsai MS, Tripathi P, Abbas F, Reaven GM, Reaven PD, Snyder MP, Kim SH, Knowles JW. Statins Are Associated With Increased Insulin Resistance and Secretion. Arterioscler Thromb Vasc Biol [Internet]. 2021 Nov;41(11):2786–97. Available from: 10.1161/ATVBAHA.121.316159
  24. Svec A, Adameova A. Facts and ideas on statins with respect to their lipophilicity: a focus on skeletal muscle cells and bone besides known cardioprotection. Mol Cell Biochem [Internet]. 2023 Aug 5;478(8):1661–7. Available from: 10.1007/s11010-022-04621-y
  25. Climent E, Benaiges D, Pedro-Botet J. Hydrophilic or Lipophilic Statins? Front Cardiovasc Med [Internet]. 2021 May 20;8. Available from: 10.3389/fcvm.2021.687585
  26. Wei L, Yamamoto M, Harada M, Otsuki M. Treatment with atorvastatin attenuates progression of insulin resistance and pancreatic fibrosis in the Otsuka Long-Evans Tokushima fatty rats. Metabolism. 2016;
  27. Fong CW. Statins in therapy: Understanding their hydrophilicity, lipophilicity, binding to 3-hydroxy-3-methylglutaryl-CoA reductase, ability to cross the blood brain barrier and metabolic stability based on electrostatic molecular orbital studies. Eur J Med Chem [Internet]. 2014 Oct;85:661–74. Available from: 10.1016/j.ejmech.2014.08.037
  28. Lai SW, Lin CL, Liao KF. Rosuvastatin and risk of acute pancreatitis in a population-based case–control study. Int J Cardiol [Internet]. 2015 May;187(1):417–20. Available from: 10.1016/j.ijcard.2015.03.373
  29. Brault M, Ray J, Gomez YH, Mantzoros CS, Daskalopoulou SS. Statin treatment and new-onset diabetes: A review of proposed mechanisms. Metabolism [Internet]. 2014 Jun;63(6):735–45. Available from: 10.1016/j.metabol.2014.02.014
  30. Ward NC, Watts GF, Eckel RH. Statin Toxicity. Circ Res [Internet]. 2019 Jan 18;124(2):328–50. Available from: 10.1161/CIRCRESAHA.118.312782
  31. Harrison KD, Park EJ, Gao N, Kuo A, Rush JS, Waechter CJ, Lehrman MA, Sessa WC. Nogo-B receptor is necessary for cellular dolichol biosynthesis and protein N-glycosylation. EMBO J. 2011;
  32. Li JJ, Liu HH, Wu NQ, Yeo KK, Tan K, Ako J, Krittayaphong R, Tan RS, Aylward PE, Baek SH, Dalal J, Fong AYY, Li YH, O’Brien RC, Lim TSE, Koh SYN, Scherer DJ, Tada H, et al. Statin intolerance: an updated, narrative review mainly focusing on muscle adverse effects. Expert Opinion on Drug Metabolism and Toxicology. 2020.
  33. Elam MB, Majumdar G, Mozhui K, Gerling IC, Vera SR, Fish-Trotter H, Williams RW, Childress RD, Raghow R. Patients experiencing statin-induced myalgia exhibit a unique program of skeletal muscle gene expression following statin re-challenge. PLoS One. 2017;
  34. Bell G, Thoma A, Hargreaves IP, Lightfoot AP. The Role of Mitochondria in Statin-Induced Myopathy. Drug Safety. 2024.
  35. Muntean DM, Thompson PD, Catapano AL, Stasiolek M, Fabis J, Muntner P, Serban MC, Banach M. Statin-associated myopathy and the quest for biomarkers: can we effectively predict statin-associated muscle symptoms? Drug Discovery Today. 2017.
  36. P TP, J D V. A review of muscle-related adverse effects of statins. Int J Pharm Res Dev. 2021;
  37. Wang HJ, Park JY, Kwon O, Choe EY, Kim CH, Hur KY, Lee MS, Yun M, Cha BS, Kim YB, Lee H, Kang ES. Chronic HMGCR/HMG-CoA reductase inhibitor treatment contributes to dysglycemia by upregulating hepatic gluconeogenesis through autophagy induction. Autophagy. 2015;11(11):2089–101.
  38. Song S, Niu M, Liang Q, Wang L, Min H, Peng Y, Wang H, Gao Q. Statin Treatment Induced a Lipogenic Expression Hierarchical Network Centered by SREBF2 in the Liver. Front Endocrinol (Lausanne). 2021;
  39. Nakata M, Nagasaka S, Kusaka I, Matsuoka H, Ishibashi S, Yada T. Effects of statins on the adipocyte maturation and expression of glucose transporter 4 (SLC2A4): Implications in glycaemic control. Diabetologia. 2006;49(8):1881–92.
  40. Mancini GBJ, Baker S, Bergeron J, Fitchett D, Frohlich J, Genest J, Gupta M, Hegele RA, Ng D, Pearson GJ, Pope J, Tashakkor AY. Diagnosis, Prevention, and Management of Statin Adverse Effects and Intolerance: Canadian Consensus Working Group Update (2016). Can J Cardiol [Internet]. 2016 Jul;32(7):S35–65. Available from: 10.1016/j.cjca.2016.01.003
  41. Chadt A, Al-Hasani H. Glucose transporters in adipose tissue, liver, and skeletal muscle in metabolic health and disease. Pflügers Arch - Eur J Physiol [Internet]. 2020 Sep 26;472(9):1273–98. Available from: 10.1007/s00424-020-02417-x
  42. Koh KK, Lim S, Sakuma I, Quon MJ. Caveats to aggressive lowering of lipids by specific statins. Vol. 154, International Journal of Cardiology. 2012. p. 97–101.
  43. Hussain A, Kaler J, Ray SD. The Benefits Outweigh the Risks of Treating Hypercholesterolemia: The Statin Dilemma. Cureus [Internet]. 2023 Jan 11; Available from: 10.7759/cureus.33648
  44. Zhu ML, Gao ZT, Lu JX, Wang Y, Wang G, Zhu TT, Li P, Liu C, Wang SX, Yang L. Amorphous nano-selenium quantum dots prevent pulmonary arterial hypertension through recoupling endothelial nitric oxide synthase. Aging (Albany NY) [Internet]. 2021 Feb 15;13(3):3368–85. Available from: 10.18632/aging.202215
  45. Takaguri A, Satoh K, Itagaki M, Tokumitsu Y, Ichihara K. Effects of atorvastatin and pravastatin on signal transduction related to glucose uptake in 3T3L1 adipocytes. J Pharmacol Sci. 2008;107(1):80–9.
  46. Mahmood AAJ, Zainal AA, Khalaf MM. Cholinesterase activity in non-alcoholic-fatty liver disease in diabetic patients taking oral antidiabetic drugs. Curr Top Pharmacol. 2021;25:43–51.
  47. Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, Cooney MT, Corrà U, Cosyns B, Deaton C, Graham I, Hall MS, Hobbs FDR, Løchen ML, Löllgen H, Marques-Vidal P, Perk J, Prescott E, et al. 2016 European guidelines on cardiovascular disease prevention in clinical practice. The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representati. G Ital Cardiol (Rome). 2017;18(7):547–612.
  48. Ahrén B, Simonsson E, Scheurink AJW, Mulder H, Myrsén U, Sundler F. Dissociated insulinotropic sensitivity to glucose and carbachol in high- fat diet-induced insulin resistance in C57BL/6J mice. Metabolism. 1997;46(1):97–106.
  49. Brookheart RT, Michel CI, Schaffer JE. As a Matter of Fat. Vol. 10, Cell Metabolism. 2009. p. 9–12.
  50. Liu P, Jiang L, Kong W, Xie Q, Li P, Liu X, Zhang J, Liu M, Wang Z, Zhu L, Yang H, Zhou Y, Zou J, Liu X, Liu L. PXR activation impairs hepatic glucose metabolism partly via inhibiting the HNF4α–GLUT2 pathway. Acta Pharm Sin B. 2022;12(5):2391–405.
  51. Colbert CL, Kim CW, Moon YA, Henry L, Palnitkar M, McKean WB, Fitzgerald K, Deisenhofer J, Horton JD, Kwon HJ. Crystal structure of Spot 14, a modulator of fatty acid synthesis. Proc Natl Acad Sci U S A. 2010;107(44):18820–5.
  52. Carnagarin R, Dharmarajan AM, Dass CR. Molecular aspects of glucose homeostasis in skeletal muscle - A focus on the molecular mechanisms of insulin resistance. Vol. 417, Molecular and Cellular Endocrinology. 2015. p. 52–62.
  53. van Gerwen J, Shun-Shion AS, Fazakerley DJ. Insulin signalling and GLUT4 trafficking in insulin resistance. Vol. 51, Biochemical Society Transactions. 2023. p. 1057–69.
  54. Haghani K, Pashaei S, Vakili S, Taheripak G, Bakhtiyari S. TNF-α knockdown alleviates palmitate-induced insulin resistance in C2C12 skeletal muscle cells. Biochem Biophys Res Commun. 2015;460(4):977–82.
  55. LaFave LT, Augustin LB, Mariash CN. S14: Insights from knockout mice. Vol. 147, Endocrinology. 2006. p. 4044–7.
  56. Zhu Q, Anderson GW, Mucha GT, Parks EJ, Metkowski JK, Mariash CN. The spot 14 protein is required for de Novo lipid synthesis in the lactating mammary gland. Endocrinology. 2005;146(8):3343–50.
  57. Sanvee GM, Panajatovic M V., Bouitbir J, Krähenbühl S. Mechanisms of insulin resistance by simvastatin in C2C12 myotubes and in mouse skeletal muscle. Biochem Pharmacol. 2019;164:23–33.
  58. Sadler JBA, Bryant NJ, Gould GW, Welburn CR. Posttranslational modifications of GLUT4 affect its subcellular localization and translocation. Vol. 14, International Journal of Molecular Sciences. 2013. p. 9963–78.
  59. Takagi T, Matsuda M, Abe M, Kobayashi H, Fukuhara A, Komuro R, Kihara S, Caslake MJ, McMahon A, Shepherd J, Funahashi T, Shimomura I. Effect of pravastatin on the development of diabetes and adiponectin production. Atherosclerosis. 2008;196(1):114–21.

Authors

Dalya Mohammed

College of Pharmacy, University of Mosul

Hani Almukhtar

Department of Pharmacology and Toxicology, College of Pharmacy, University of Mosul

Abdulla Ahmad

Department of clinical and laboratory sciences, College of Pharmacy, University of Mosul, Mosul, Iraq

Identifiers

https://doi.org/10.33899/acmm.v47i2.60191
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Mohammed D, Almukhtar H, Ahmad A. Signaling Pathways Behind the Effect of Atorvastatin in Glucose Homeostasis. Ann. coll. Med. Mosul [Internet]. 2025 Dec. 29 [cited 2026 Jan. 2];47(2):185-93. Available from: https://mmed.uomosul.edu.iq/index.php/mmed/article/view/60191