OBJECTIVE: Cardiovascular disease (CVD) remains the leading cause of death globally. Reducing high blood cholesterol, which is a dominant risk factor for CVD events, is an essential goal of medical treatment. Statins are known as first‐choice agents. However, clinical trials report that some statins increased the risk for type 2 diabetes (T2D). Our objective was to investigate the effect of different statins on insulin secretion and content from pancreatic β-cells after chronic and acute exposure and determine the underlying mechanisms.
METHODS: The effects of simvastatin, lovastatin and pitavastatin on GSIS and content were studied in clonal pancreatic β-cells (INS-1 832/13) cultured in high glucose (12 mM). Insulin content and secretion were measured after chronic and acute incubation of statins using homogenous time-resolved fluorescence (HTRF) insulin assay kit (Cisbio). Intracellular Ca2+ was measured using fura-2 AM (Invitrogen).
RESULTS: Simvastatin (25-200 nM) and lovastatin (50-200 nM) significantly inhibited GSIS and depleted insulin content in a dose-dependent manner after 72-hour exposure. When the secretion level was normalized for content, the inhibitory effect was not observed. Simvastatin (200 nM) also increased the amplitude of intracellular Ca2+ oscillations at low glucose, but this was not reflected in the amplitude of oscillatory insulin release. In contrast, pitavastatin (25-200 nM) did not affect GSIS and only decreased insulin content at the highest dose tested.
CONCLUSION: Inhibition of GSIS by simvastatin and lovastatin could be due to depletion of insulin content. Decreased Ca2+ sensitivity may also contribute to inhibition of GSIS by simvastatin. Pitavastatin had less inhibitory effect on GSIS and insulin content as compared to simvastatin and lovastatin indicating that not all lipophilic statins have a detrimental impact on GSIS. We suggest that statins may have differential mechanistic effects on β-cells some of which may contribute to the risk of T2D.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/36546 |
| Date | 12 June 2019 |
| Creators | Datu Tasik, Grace Marselina |
| Contributors | Deeney, Jude T., Hamilton, James A. |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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