J Appl Biomed 20:130-140, 2022 | DOI: 10.32725/jab.2022.015

Exenatide prevents statin-related LDL receptor increase and improves insulin secretion in pancreatic beta cells (1.1E7) in a protein kinase A-dependent manner

Łukasz Bułdak1, *, Grzegorz Machnik1, Estera Skudrzyk1, Aleksandra Bołdys1, Mateusz Maligłówka1, Michał Kosowski1, Marcin Basiak1, Rafał Jakub Bułdak2, Bogusław Okopień1
1 Medical University of Silesia, School of Medicine in Katowice, Department of Internal Medicine and Clinical Pharmacology, Katowice, Poland
2 University of Opole, Institute of Medical Sciences, Opole, Poland

Statins are primary drugs in the treatment of hyperlipidemias. This group of drugs is known for its beneficial pleiotropic effects (e.g., reduction of inflammatory state). However, a growing body of evidence suggests its diabetogenic properties. The culpable mechanism is not completely understood and might be related to the damage to pancreatic beta cells. Therefore, we conceived an in vitro study to explore the impact of atorvastatin on pancreatic islet beta cells line (1.1.E7). We evaluated the influence on viability, insulin, low-density lipoprotein (LDL) receptor, and proprotein convertase subtilisin/kexin type 9 (PCSK9) expression. A significant drop in mRNA for proinsulin and insulin expression was noted. Concurrently, a rise in LDL receptor at the protein level in cells exposed to atorvastatin was noted. Further experiments have shown that exenatide - belonging to glucagon-like peptide 1 (GLP-1) analogs that are used in a treatment of diabetes and known for its weight reducing properties - can alleviate the observed alterations. In this case, the mechanism of action of exenatide was dependent on a protein kinase A pathway. In conclusion, our results support the hypothesis that statin may have diabetogenic properties, which according to our study is related to reduced insulin expression. The concomitant use of GLP-1 receptor agonist seemed to successfully revert insulin expression.

Keywords: Atorvastatin; Beta islet cells; Diabetes; GLP-1; In vitro; Insulin; LDL receptor; PCSK9; Pleiotropic effects
Grants and funding:

The study was supported by a research grant from the Medical University of Silesia. Grant No. PCN-1-055/N/1/1.

Conflicts of interest:

The authors have no conflict of interests to declare.

Received: May 31, 2022; Revised: October 19, 2022; Accepted: November 9, 2022; Prepublished online: November 22, 2022; Published: December 20, 2022  Show citation

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Bułdak Ł, Machnik G, Skudrzyk E, Bołdys A, Maligłówka M, Kosowski M, et al.. Exenatide prevents statin-related LDL receptor increase and improves insulin secretion in pancreatic beta cells (1.1E7) in a protein kinase A-dependent manner. J Appl Biomed. 2022;20(4):130-140. doi: 10.32725/jab.2022.015. PubMed PMID: 36708718.
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    References

    1. Abramoff MD, Magalhaes PJ, Ram SJ (2004). Image processing with ImageJ. Biophotonics Inter 11: 36-42.
    2. Anholm C, Kumarathurai P, Jürs A, Pedersen LR, Nielsen OW, Kristiansen OP, et al. (2019). Liraglutide improves the beta-cell function without increasing insulin secretion during a mixed meal in patients, who exhibit well-controlled type 2 diabetes and coronary artery disease. Diabetol Metab Syndr 11: 42. DOI: 10.1186/s13098-019-0438-6. Go to original source... Go to PubMed...
    3. Aoki K, Kamiyama H, Takihata M, Taguri M, Shibata E, Shinoda K, et al. (2020). Effect of liraglutide on lipids in patients with type 2 diabetes: a pilot study. Endocr J 67(9): 957-962. DOI: 10.1507/endocrj.EJ19-0464. Go to original source... Go to PubMed...
    4. Blanchet M, Le Q-T, Seidah NG, Labonté P (2016). Statins can exert dual, concentration dependent effects on HCV entry in vitro. Antiviral Res 128: 43-48. DOI: 10.1016/j.antiviral.2016.02.006. Go to original source... Go to PubMed...
    5. Buldak L, Dulawa-Buldak A, Labuzek K, Okopien B (2012). Effects of 90-day hypolipidemic treatment on insulin resistance, adipokines and proinflammatory cytokines in patients with mixed hyperlipidemia and impaired fasting glucose. Int J Clin Pharmacol Ther 50(11): 805-813. DOI: 10.5414/CP201735. Go to original source... Go to PubMed...
    6. Bułdak Ł, Skudrzyk E, Machnik G, Bołdys A, Bułdak R, Okopień B (2022). Exenatide improves antioxidant capacity and reduces the expression of LDL receptors and PCSK9 in human insulin-secreting 1.1E7 cell line subjected to hyperglycemia and oxidative stress. Postepy Hig Med Dosw 76(1): 16-23. DOI: 10.2478/ahem-2021-0037. Go to original source...
    7. Chamberlain LH (2001). Inhibition of isoprenoid biosynthesis causes insulin resistance in 3T3-L1 adipocytes. FEBS Lett 507(3): 357-361. DOI: 10.1016/s0014-5793(01)03007-1. Go to original source... Go to PubMed...
    8. Chen L-L, Zheng J-H (2021). Effects of atorvastatin on the insulin resistance in women of polycystic ovary syndrome: A systematic review and meta-analysis. Medicine (Baltimore) 100(24): e26289. DOI: 10.1097/MD.0000000000026289. Go to original source... Go to PubMed...
    9. Da Dalt L, Ruscica M, Bonacina F, Balzarotti G, Dhyani A, Di Cairano E, et al. (2019). PCSK9 deficiency reduces insulin secretion and promotes glucose intolerance: the role of the low-density lipoprotein receptor. Eur Heart J 40(4): 357-368. DOI: 10.1093/eurheartj/ehy357. Go to original source... Go to PubMed...
    10. Dong B, Wu M, Li H, Kraemer FB, Adeli K, Seidah NG, et al. (2010). Strong induction of PCSK9 gene expression through HNF1alpha and SREBP2: mechanism for the resistance to LDL-cholesterol lowering effect of statins in dyslipidemic hamsters. J Lipid Res 51(6): 1486-1495. DOI: 10.1194/jlr.M003566. Go to original source... Go to PubMed...
    11. FDA (2022). FDA approves weight management drug for patients aged 12 and older. [online] [cit. 2022-03-21]. Available from: https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-weight-management-drug-patients-aged-12-and-older
    12. Felder M, Maushart CI, Gashi G, Senn JR, Becker AS, Müller J, et al. (2021). Fluvastatin Reduces Glucose Tolerance in Healthy Young Individuals Independently of Cold Induced BAT Activity. Front Endocrinol (Lausanne) 12: 765807. DOI: 10.3389/fendo.2021.765807. Go to original source... Go to PubMed...
    13. Golan-Lavi R, Giacomelli C, Fuks G, Zeisel A, Sonntag J, Sinha S, et al. (2017). Coordinated Pulses of mRNA and of Protein Translation or Degradation Produce EGF-Induced Protein Bursts. Cell Rep 18(13): 3129-3142. DOI: 10.1016/j.celrep.2017.03.014. Go to original source... Go to PubMed...
    14. Grunwald SA, Haafke S, Grieben U, Kassner U, Steinhagen-Thiessen E, Spuler S (2022). Statins Aggravate the Risk of Insulin Resistance in Human Muscle. Int J Mol Sci 23(4): 2398. DOI: 10.3390/ijms23042398. Go to original source... Go to PubMed...
    15. Hafner M, Juvan P, Rezen T, Monostory K, Pascussi J-M, Rozman D (2011). The human primary hepatocyte transcriptome reveals novel insights into atorvastatin and rosuvastatin action. Pharmacogenet Genomics 21(11): 741-750. DOI: 10.1097/FPC.0b013e32834a5585. Go to original source... Go to PubMed...
    16. Halban PA, Polonsky KS, Bowden DW, Hawkins MA, Ling C, Mather KJ, et al. (2014). β-cell failure in type 2 diabetes: postulated mechanisms and prospects for prevention and treatment. Diabetes Care 37(6): 1751-1758. DOI: 10.2337/dc14-0396. Go to original source... Go to PubMed...
    17. Hausner H, Derving Karsbøl J, Holst AG, Jacobsen JB, Wagner FD, Golor G, Anderson TW (2017). Effect of Semaglutide on the Pharmacokinetics of Metformin, Warfarin, Atorvastatin and Digoxin in Healthy Subjects. Clin Pharmacokinet 56(11): 1391-1401. DOI: 10.1007/s40262-017-0532-6. Go to original source... Go to PubMed...
    18. Kothari S, Dhami-Shah H, Shah SR (2019). Antidiabetic Drugs and Statins in Nonalcoholic Fatty Liver Disease. J Clin Exp Hepatol 9(6): 723-730. DOI: 10.1016/j.jceh.2019.06.003. Go to original source... Go to PubMed...
    19. Khan SU, Rahman H, Okunrintemi V, Riaz H, Khan MS, Sattur S, et al. (2019). Association of Lowering Low-Density Lipoprotein Cholesterol With Contemporary Lipid-Lowering Therapies and Risk of Diabetes Mellitus: A Systematic Review and Meta-Analysis. J Am Heart Assoc 8(7): e011581. DOI: 10.1161/JAHA.118.011581. Go to original source... Go to PubMed...
    20. Livak KJ, Schmittgen TD (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2[-Delta Delta C(T)]. Method 25(4): 402-408. DOI: 10.1006/meth.2001.1262. Go to original source... Go to PubMed...
    21. Maligłówka M, Bułdak Ł, Okopień B, Bołdys A (2021). The consequences of PCSK9 inhibition in selected tissues. Postepy Hig Med Dosw 75(1): 385-397. DOI: 10.5604/01.3001.0014.9127. Go to original source...
    22. Panajatovic MV, Singh F, Krähenbühl S, Bouitbir J (2021). Effects of Simvastatin on Lipid Metabolism in Wild-Type Mice and Mice with Muscle PGC-1α Overexpression. Int J Mol Sci 22(9): 4950. DOI: 10.3390/ijms22094950. Go to original source... Go to PubMed...
    23. Sarsenbayeva A, Jui BN, Fanni G, Barbosa P, Ahmed F, Kristófi R, et al. (2021). Impaired HMG-CoA Reductase Activity Caused by Genetic Variants or Statin Exposure: Impact on Human Adipose Tissue, β-Cells and Metabolome. Metabolites 11(9): 574. DOI: 10.3390/metabo11090574. Go to original source... Go to PubMed...
    24. Sun H, Li Y, Sun B, Hou N, Yang J, Zheng M, et al. (2016). Atorvastatin inhibits insulin synthesis by inhibiting the Ras/Raf/ERK/CREB pathway in INS-1 cells. Medicine (Baltimore) 95(39): e4906. DOI: 10.1097/MD.0000000000004906. Go to original source... Go to PubMed...
    25. Tada H, Kawashiri MA, Yoshida T, Teramoto R, Nohara A, Konno T, et al. (2016). Lipoprotein(a) in Familial Hypercholesterolemia With Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Gain-of-Function Mutations. Circ J 80(2): 512-518. DOI: 10.1253/circj.CJ-15-0999. Go to original source... Go to PubMed...
    26. Takei S, Nagashima S, Takei A, Yamamuro D, Wakabayashi T, Murakami A, et al. (2020). β-Cell-Specific Deletion of HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) Reductase Causes Overt Diabetes due to Reduction of β-Cell Mass and Impaired Insulin Secretion. Diabetes 69(11): 2352-2363. DOI: 10.2337/db19-0996. Go to original source... Go to PubMed...
    27. Tricò D, Trifirò S, Mengozzi A, Morgantini C, Baldi S, Mari A, Natali A (2018). Reducing cholesterol and fat intake improves glucose tolerance by enhancing b cell function in nondiabetic subjects. J Clin Endocrinol Metab 103(2): 622-631. DOI: 10.1210/jc.2017-02089. Go to original source... Go to PubMed...
    28. Vergès B, Duvillard L, Pais de Barros JP, Bouillet B, Baillot-Rudoni S, Rouland A, et al. (2021). Liraglutide Increases the Catabolism of Apolipoprotein B100-Containing Lipoproteins in Patients With Type 2 Diabetes and Reduces Proprotein Convertase Subtilisin/Kexin Type 9 Expression. Diabetes Care 44(4): 1027-1037. DOI: 10.2337/dc20-1843. Go to original source... Go to PubMed...
    29. Vergès B, Hassid J, Rouland A, Bouillet B, Simoneau I, Petit J-M, Duvillard L (2022). Liraglutide reduces plasma PCSK9 in patients with type 2 diabetes not treated with statins. Diabetes Metab 48(2): 101284. DOI: 10.1016/j.diabet.2021.101284. Go to original source... Go to PubMed...
    30. Verma DR, Brinton EA (2014). Management of hypercholesterolemia for prevention of atherosclerotic cardiovascular disease: focus on the potential role of recombinant anti-PCSK9 monoclonal antibodies. Rev Cardiovasc Med 15(2): 86-101. DOI: 10.3909/ricm0741. Go to original source... Go to PubMed...
    31. Visseren FLJ, Mach F, Smulders YM, Carballo D, Koskinas KC, Bäck M, et al. (2021). ESC Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J 42(34): 3227-3337. DOI: 10.1093/eurheartj/ehab484. Go to original source... Go to PubMed...
    32. Yaluri N, Modi S, López Rodríguez M, Stančáková A, Kuusisto J, Kokkola T, Laakso M (2015). Simvastatin Impairs Insulin Secretion by Multiple Mechanisms in MIN6 Cells. PLoS One 10(11): e0142902. DOI: 10.1371/journal.pone.0142902. Go to original source... Go to PubMed...
    33. Yang X-Q, Mao Y-Q, Wang D-X (2020). More consideration of β-cell function and PCSK9/LDLR axis. Eur Heart J 41(1): 189. DOI: 10.1093/eurheartj/ehz654. Go to original source... Go to PubMed...
    34. Yebyo HG, Aschmann HE, Kaufmann M, Puhan MA (2019). Comparative effectiveness and safety of statins as a class and of specific statins for primary prevention of cardiovascular disease: A systematic review, meta-analysis, and network meta-analysis of randomized trials with 94,283 participants. Am Heart J 210: 18-28. DOI: 10.1016/j.ahj.2018.12.007. Go to original source... Go to PubMed...
    35. Yu Q, Chen Y, Xu C-B (2017). Statins and New-Onset Diabetes Mellitus: LDL Receptor May Provide a Key Link. Front Pharmacol 8: 372. DOI: 10.3389/fphar.2017.00372. Go to original source... Go to PubMed...
    36. Yu Q, Wang F, Meng X, Gong Y, Wang Y, Xu C, Wang S (2018). Short‑term use of atorvastatin affects glucose homeostasis and suppresses the expression of LDL receptors in the pancreas of mice. Mol Med Rep 18(3): 2780-2788. DOI: 10.3892/mmr.2018.9239. Go to original source... Go to PubMed...
    37. Zhang L, Gong D, Li S, Zhou X (2012). Meta-analysis of the effects of statin therapy on endothelial function in patients with diabetes mellitus. Atherosclerosis 223(1): 78-85. DOI: 10.1016/j.atherosclerosis.2012.01.031. Go to original source... Go to PubMed...

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