Abstract
Diabetes mellitus is a metabolic disorder projected to afflict 700 million people globally by 2045. Fundamental to the progression of diabetes is an insufficient supply of insulin to meet metabolic demand. The MIN6-K8 cell line is a mouse insulinoma model of pancreatic β-cells frequently used to study the mechanisms of insulin secretion. Here, we evaluated the effects of short-term exposure to dimethyl sulfoxide (DMSO), a polar aprotic solvent commonly used in drug screening, on physiological characteristics of MIN6-K8 cells. Short-term exposure of MIN6-K8 cells to DMSO enhanced glucose-induced and tolbutamide-stimulated insulin secretion without significant effects on basal secretion or potassium responsiveness. Calcium influx was enhanced during glucose and tolbutamide treatments, suggesting that DMSO’s mechanism of action is upstream of calcium-dependent insulin granule exocytosis. Based on these studies, investigators should use caution when conducting experiments with DMSO in the MIN6-K8 cell line and should report all DMSO concentrations when used as a solvent.
Availability of data
The datasets generated during the current study are available from the corresponding author on reasonable request.
Change history
09 May 2021
A Correction to this paper has been published: https://doi.org/10.1007/s00418-021-01988-9
References
Brayton CF (1986) Dimethyl sulfoxide (DMSO): a review. Cornell Vet 76(1):61–90
Briscoe CP, Peat AJ, McKeown SC, Corbett DF, Goetz AS, Littleton TR, McCoy DC, Kenakin TP, Andrews JL, Ammala C, Fornwald JA, Ignar DM, Jenkinson S (2006) Pharmacological regulation of insulin secretion in MIN6 cells through the fatty acid receptor GPR40: identification of agonist and antagonist small molecules. Br J Pharmacol 148(5):619–628. https://doi.org/10.1038/sj.bjp.0706770
Burns SM, Vetere A, Walpita D, Dančík V, Khodier C, Perez J, Clemons PA, Wagner BK, Altshuler D (2015) High-throughput luminescent reporter of insulin secretion for discovering regulators of pancreatic Beta-cell function. Cell Metab 21(1):126–137. https://doi.org/10.1016/j.cmet.2014.12.010
Carmean CM, Yokoi N, Takahashi H, Oduori OS, Kang C, Kanagawa A, Kirkley AG, Han G, Landeche M, Hidaka S, Katoh M, Sargis RM, Seino S (2018) Arsenic modifies serotonin metabolism through glucuronidation in pancreatic β-cells. Am J Physiol Endocrinol Metab. https://doi.org/10.1152/ajpendo.00302.2018
Ferdaoussi M, Dai X, Jensen MV, Wang R, Peterson BS, Huang C, Ilkayeva O, Smith N, Miller N, Hajmrle C, Spigelman AF, Wright RC, Plummer G, Suzuki K, Mackay JP, van de Bunt M, Gloyn AL, Ryan TE, Norquay LD, Brosnan MJ, Trimmer JK, Rolph TP, Kibbey RG, Manning Fox JE, Colmers WF, Shirihai OS, Neufer PD, Yeh ET, Newgard CB, MacDonald PE (2015) Isocitrate-to-SENP1 signaling amplifies insulin secretion and rescues dysfunctional β cells. J Clin Invest 125(10):3847–3860. https://doi.org/10.1172/JCI82498
Gheni G, Ogura M, Iwasaki M, Yokoi N, Minami K, Nakayama Y, Harada K, Hastoy B, Wu X, Takahashi H, Kimura K, Matsubara T, Hoshikawa R, Hatano N, Sugawara K, Shibasaki T, Inagaki N, Bamba T, Mizoguchi A, Fukusaki E, Rorsman P, Seino S (2014) Glutamate acts as a key signal linking glucose metabolism to incretin/cAMP action to amplify insulin secretion. Cell Rep 9(2):661–673. https://doi.org/10.1016/j.celrep.2014.09.030
Gurtovenko AA, Anwar J (2007) Modulating the structure and properties of cell membranes: the molecular mechanism of action of dimethyl sulfoxide. J Phys Chem B 111(35):10453–10460. https://doi.org/10.1021/jp073113e
Hashim M, Yokoi N, Takahashi H, Gheni G, Okechi OS, Hayami T, Murao N, Hidaka S, Minami K, Mizoguchi A, Seino S (2018) Inhibition of SNAT5 induces incretin-responsive state from incretin-unresponsive state in pancreatic β-cells: study of β-cell spheroid clusters as a model. Diabetes 67(9):1795–1806. https://doi.org/10.2337/db17-1486
He F, Liu W, Zheng S, Zhou L, Ye B, Qi Z (2012) Ion transport through dimethyl sulfoxide (DMSO) induced transient water pores in cell membranes. Mol Membr Biol 29(3–4):107–113. https://doi.org/10.3109/09687688.2012.687460
Henquin JC (2009) Regulation of insulin secretion: a matter of phase control and amplitude modulation. Diabetologia 52(5):739–751. https://doi.org/10.1007/s00125-009-1314-y
Iwasaki M, Minami K, Shibasaki T, Miki T, Miyazaki J, Seino S (2010) Establishment of new clonal pancreatic β-cell lines (MIN6-K) useful for study of incretin/cyclic adenosine monophosphate signaling. J Diabetes Investig 1(4):137–142. https://doi.org/10.1111/j.2040-1124.2010.00026.x
Kalwat MA, Cobb MH (2017) Mechanisms of the amplifying pathway of insulin secretion in the β cell. Pharmacol Ther 179:17–30. https://doi.org/10.1016/j.pharmthera.2017.05.003
Kibbey RG, Pongratz RL, Romanelli AJ, Wollheim CB, Cline GW, Shulman GI (2007) Mitochondrial GTP regulates glucose-stimulated insulin secretion. Cell Metab 5(4):253–264. https://doi.org/10.1016/j.cmet.2007.02.008
Morley P, Whitfield JF (1993) The differentiation inducer, dimethyl sulfoxide, transiently increases the intracellular calcium ion concentration in various cell types. J Cell Physiol 156(2):219–225. https://doi.org/10.1002/jcp.1041560202
Notman R, Anwar J (2013) Breaching the skin barrier–insights from molecular simulation of model membranes. Adv Drug Deliv Rev 65(2):237–250. https://doi.org/10.1016/j.addr.2012.02.011
Raphemot R, Weaver CD, Denton JS (2013) High-throughput screening for small-molecule modulators of inward rectifier potassium channels. J Vis Exp. https://doi.org/10.3791/4209
Rawls WF, Cox L, Rovner ES (2017) Dimethyl sulfoxide (DMSO) as intravesical therapy for interstitial cystitis/bladder pain syndrome: a review. Neurourol Urodyn 36(7):1677–1684. https://doi.org/10.1002/nau.23204
Saeedi P, Petersohn I, Salpea P, Malanda B, Karuranga S, Unwin N, Colagiuri S, Guariguata L, Motala AA, Ogurtsova K, Shaw JE, Bright D, Williams R (2019) Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9(th) edition. Diabetes Res Clin Pract 157:107843. https://doi.org/10.1016/j.diabres.2019.107843
Sandler S, Andersson A (1982) Short- and long-term effects of dimethyl sulfoxide on mouse pancreatic islet B-cell function in vitro. Cryobiology 19(3):299–305. https://doi.org/10.1016/0011-2240(82)90158-4
Seino S, Sugawara K, Yokoi N, Takahashi H (2017) beta-Cell signalling and insulin secretagogues: a path for improved diabetes therapy. Diabetes Obes Metab 19(Suppl 1):22–29. https://doi.org/10.1111/dom.12995
Spollett G, Edelman SV, Mehner P, Walter C, Penfornis A (2016) Improvement of Insulin Injection Technique: Examination of Current Issues and Recommendations. Diabetes Educ 42(4):379–394. https://doi.org/10.1177/0145721716648017
Szabat M, Modi H, Ramracheya R, Girbinger V, Chan F, Lee JT, Piske M, Kamal S, Carol Yang YH, Welling A, Rorsman P, Johnson JD (2015) High-content screening identifies a role for Na(+) channels in insulin production. R Soc Open Sci 2(12):150306. https://doi.org/10.1098/rsos.150306
Acknowledgements
Many thanks to Rui Tang and Eben Alsberg for their technical assistance during the described study. The authors would also like to thank Graeme Bell and Susumu Seino for their constructive feedback and guidance.
Funding
This work was supported by the National Institutes of Health (R01-ES-028879; P30-ES-027792; and P30-DK-020595).
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All authors contributed to study design, coordination, and drafting of the manuscript. The study was conceived by CMC. Data was analyzed by CMC and LZ. The study was overseen by RMS. All authors read and approved the final manuscript.
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RMS has received honoraria from CVS/Health and the American Medical Forum. The authors have no conflicts of interest or competing interests to disclose related to this work.
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Carmean, C.M., Zhao, L., Landeche, M. et al. Dimethyl sulfoxide acutely enhances regulated insulin secretion in the MIN6-K8 mouse insulinoma cell line. Histochem Cell Biol 156, 69–73 (2021). https://doi.org/10.1007/s00418-021-01984-z
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DOI: https://doi.org/10.1007/s00418-021-01984-z