Reply to Petersen et al.: An alternative hypothesis for why exposure to static magnetic and electric fields treats type 2 diabetes

Point:CounterpointReply to Petersen et al.: An alternative hypothesis for why exposure to static magnetic and electric fields treats type 2 diabetesCalvin S. Carter, Sunny C. Huang, Charles C. Searby, Benjamin Cassaidy, Michael J. Miller, Wojciech J. Grzesik, Ted B. Piorczynski, Thomas K. Pak, Susan A. Walsh, Michael Acevedo, Qihong Zhang, Kranti A. Mapuskar, Ginger L. Milne, Antentor O. Hinton Jr., Deng-Fu Guo, Robert Weiss, Kyle Bradberry, Eric B. Taylor, Adam J. Rauckhorst, David W. Dick, Vamsidhar Akurathi, Kelly C. Falls-Hubert, Brett A. Wagner, Walter A. Carter, Kai Wang, Andrew W. Norris, Kamal Rahmouni, Garry R. Buettner, Jason M. Hansen, Douglas R. Spitz, E. Dale Abel, and Val C. SheffieldCalvin S. CarterDivision of Medical Genetics and Genomics, Department of Pediatrics, University of Iowa Hospitals & Clinics, Iowa City, Iowa, Sunny C. HuangDivision of Medical Genetics and Genomics, Department of Pediatrics, University of Iowa Hospitals & Clinics, Iowa City, IowaMedical Scientist Training Program, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, Charles C. SearbyDivision of Medical Genetics and Genomics, Department of Pediatrics, University of Iowa Hospitals & Clinics, Iowa City, Iowa, Benjamin CassaidyDivision of Medical Genetics and Genomics, Department of Pediatrics, University of Iowa Hospitals & Clinics, Iowa City, Iowa, Michael J. MillerDepartment of Physics and Astronomy, University of Iowa, Iowa City, Iowa, Wojciech J. GrzesikFraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, Ted B. PiorczynskiDepartment of Physiology and Developmental Biology, Brigham Young University, Provo, Utah, Thomas K. PakDivision of Medical Genetics and Genomics, Department of Pediatrics, University of Iowa Hospitals & Clinics, Iowa City, IowaMedical Scientist Training Program, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, Susan A. WalshDivision of Nuclear Medicine, Department of Radiology, University of Iowa Hospitals & Clinics, Iowa City, Iowa, Michael AcevedoDivision of Nuclear Medicine, Department of Radiology, University of Iowa Hospitals & Clinics, Iowa City, Iowa, Qihong ZhangDivision of Medical Genetics and Genomics, Department of Pediatrics, University of Iowa Hospitals & Clinics, Iowa City, Iowa, Kranti A. MapuskarFree Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa Hospitals & Clinics, Iowa City, Iowa, Ginger L. MilneDepartment of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, Antentor O. Hinton Jr.Fraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, Deng-Fu GuoDepartment of Neuroscience and Pharmacology, University of Iowa Hospitals & Clinics, Iowa City, Iowa, Robert WeissDivision of Cardiology, Department of Internal Medicine, University of Iowa Hospitals & Clinics, Iowa City, Iowa, Kyle BradberryFraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, Eric B. TaylorFraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IowaDepartment of Molecular Physiology and Biophysics, University of Iowa Hospitals & Clinics, Iowa City, Iowa, Adam J. RauckhorstFraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IowaDepartment of Molecular Physiology and Biophysics, University of Iowa Hospitals & Clinics, Iowa City, Iowa, David W. DickDivision of Nuclear Medicine, Department of Radiology, University of Iowa Hospitals & Clinics, Iowa City, Iowa, Vamsidhar AkurathiDivision of Nuclear Medicine, Department of Radiology, University of Iowa Hospitals & Clinics, Iowa City, Iowa, Kelly C. Falls-HubertMedical Scientist Training Program, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IowaFree Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa Hospitals & Clinics, Iowa City, Iowa, Brett A. WagnerFree Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa Hospitals & Clinics, Iowa City, Iowa, Walter A. CarterDivision of Medical Genetics and Genomics, Department of Pediatrics, University of Iowa Hospitals & Clinics, Iowa City, Iowa, Kai WangDivision of Medical Genetics and Genomics, Department of Pediatrics, University of Iowa Hospitals & Clinics, Iowa City, Iowa, Andrew W. NorrisDivision of Medical Genetics and Genomics, Department of Pediatrics, University of Iowa Hospitals & Clinics, Iowa City, IowaFraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, Kamal RahmouniDepartment of Neuroscience and Pharmacology, University of Iowa Hospitals & Clinics, Iowa City, Iowa, Garry R. BuettnerFree Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa Hospitals & Clinics, Iowa City, Iowa, Jason M. HansenDivision of Nuclear Medicine, Department of Radiology, University of Iowa Hospitals & Clinics, Iowa City, Iowa, Douglas R. SpitzFree Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa Hospitals & Clinics, Iowa City, Iowa, E. Dale AbelFraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IowaDivision of Endocrinology and Metabolism, Department of Internal Medicine, University of Iowa Hospitals & Clinics, Iowa City, Iowa, and Val C. SheffieldDivision of Medical Genetics and Genomics, Department of Pediatrics, University of Iowa Hospitals & Clinics, Iowa City, IowaPublished Online:02 Jun 2021https://doi.org/10.1152/ajpendo.00119.2021This is the final version - click for previous versionMoreSectionsPDF (362 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat We appreciate this forum to discuss our findings. We thank Petersen et al. (1) for sharing their perspectives. These discussions will help the research community to clarify thinking on possible mechanisms by which static magnetic and electric (sBE) fields can improve glycemia and enhance insulin sensitivity.Petersen et al. (1) comment on our article in which we demonstrate that orthogonally oriented static magnetic (sB) and static electric (sE) fields, the combination of which are referred to as sBE fields, can be used to improve glycemia and enhance insulin sensitivity in mouse models of type 2 diabetes (2). Furthermore, we report that sBE fields modulate the systemic glutathione-to-glutathione disulfide (2GSH/GSSG) redox couple. Notably, interfering with sBE-induced changes to redox homeostasis via scavenging of mitochondrial superoxide in the liver or by generating a more oxidized extracellular redox environment attenuates the insulin-sensitizing effects of sBE (2). These findings support our hypothesis that sBE fields ameliorate insulin resistance by inducing a systemic reducing redox environment that promotes insulin sensitivity (1).Petersen et al. (1) propose an alternative mechanistic hypothesis, in which the insulin sensitization from sBE is the result of vestibular stress, inducing a system wide stress response. The premise of this alternative hypothesis is based on a phenomenon whereby strong electromagnetic fields, commonly generated by MRIs, can induce vestibular stress as a result of a Lorentz force within inner ear endolymph fluid (2).There are a number of reasons why we think that this alternative hypothesis is unlikely to explain the insulin sensitizing effects of sBE. To start, the fields used in our studies (3 mT) are ∼1/2300th the strength of the strong fields cited (7000 mT) as being “sufficient to induce these effects” (3–6). Prior literature reporting on possible vestibular stress as a result of weak fields (<25 mT) is scant. In our study, all euglycemic-hyperinsulinemic clamp measurements were made in the presence of ongoing sBE exposure. Thus, the alternative hypothesis of an acclimation-withdrawal response is not supported. Importantly, we find no evidence consistent with this alternative hypothesis, including no evidence of a vestibular phenotype (unpublished data), no increase in AMPK activation in high-fat-diet mice (unpublished data) and no increases in stress hormones, including corticosterone and catecholamines in sBE exposed animals (Fig. 1).Figure 1.sBE exposure does not increase stress hormones in nondiabetic or diabetic mice. (Left): plasma corticosterone levels measured from wild-type mice on a normal chow diet (WT, 4-h fasted), high-fat diet-fed mice (HFD, 16-h fasted), and leptin receptor deficient mice on a normal chow diet (db/db, 16-h fasted). (Right): urine catecholamine levels measured from WT (4-h fasted) and HFD mice (nonfasted). Mice were continuously exposed to sBE for the following durations: 5.5 mo (WT), 3 days (HFD), and 30 days (db/db). *P < 0.05. sBE, static magnetic and electric fields.Download figureDownload PowerPointIn contrast to the predictions made by this alternative hypothesis, neither decreases in liver glycogen nor increases in glucose uptake into muscle were observed with sBE exposure (2). Moreover, in direct contrast to the predictions of this alternative hypothesis, sBE exposure substantially increases liver glycogen both in vivo and in primary hepatocytes in vitro (2). Because cells lack a vestibular system, the observation of increased glycogen in primary human hepatocytes with sBE exposure cannot be explained by this alternative hypothesis.Although the complete mechanisms underlying the insulin-sensitizing effects of sBE require further investigation, our findings to date support a redox-dependent mechanism that involves sBE-induced changes to hepatic superoxide homeostasis and the induction of an adaptive redox response (i.e., reducing redox environment) that is insulin sensitizing (2).GRANTSThis work was supported by the National Institutes of Health (NIH) Grant 5T32GM007337 (to S.C.H.), the National Cancer Institute (NCI) Grant P01CA217797 (to G.R.B. and D.R.S), the NCI Grant P42ES013661 (to G.R.B.), the NIH Grant R01CA169046 (to G.R.B.), the NCI Grant R01CA182804 (to D.R.S), the NIH Grant 1S10OD026835 (to S.A.W.), the NCI Grant F30CA213817 (to K.F-H.), the NIH Grant R01 DK104998 (to E.B.T), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Grant DK-20593 (to G.L.M.), the NIDDK Grant R01DK115791 (to A.W.N.), the NIH Grant P01 HL084207 (to K.R.), the NIH Grants R01 HL127764 and HL112413 (to E.D.A.), the American Diabetes Association Research Foundation Grant 119PMF030 (C.S.C.), the American Diabetes Association Research Foundation Grant 1-18-PDF-060 (A.J.R.), the Office of Extramural Research, National Institutes of Health (OER) Grant P30CA086862 (to D.R.S and D.W.D.), and the NIH Grants R01EY11298, R01EY017168, and P30EY025580 (to V.C.S.).DISCLOSURESC.S.C., S.C.H., C.C.S., M.J.M., and V.C.S. have patents pending related to this work. C.S.C., S.C.H., and W.A.C. are founders of Geminii, Inc.AUTHOR CONTRIBUTIONSC.S.C., S.C.H., and V.C.S. conceived and designed research; C.C.S., S.C.H., and V.C.S. edited and revised manuscript; C.C.S., B.C., M.J.M., W.J.G., T.B.P., T.K.P., S.A.W., M.A., Q.Z., K.A.M., G.L.M., A.O.H., D-F.G., R.W., K.B., E.B.T., A.J.R., D.W.D., V.A., K.C.F-H., B.A.W., W.A.C., K.W., A.W.N., K.R., G.R.B., J.M.H., D.R.S., and E.D.A. approved final version of manuscript.REFERENCES1. Petersen KF, Rothman D, Shulman GI. Point: An alternative hypothesis for why exposure to static magnetic and electric fields treats type 2 diabetes. Am J Physiol Endocrinol Metab. doi:10.1152/ajpendo.00657.2020.Link | Google Scholar2. Carter CS, Huang SC, Searby CC, Cassaidy B, Miller MJ, Grzesik WJ, Piorczynski TB, Pak TK, et al.. Exposure to static magnetic and electric fields treats type 2 diabetes. Cell Metab 32: 561–574.e7, 2020. doi:10.1016/j.cmet.2020.09.012. Crossref | PubMed | ISI | Google Scholar3. Roberts DC, Marcelli V, Gillen JS, Carey JP, Della Santina CC, Zee DS. MRI magnetic field stimulates rotational sensors of the brain. Curr Biol 21: 1635–1640, 2011. doi:10.1016/j.cub.2011.08.029. Crossref | PubMed | ISI | Google Scholar4. Ward BK, Roberts DC, Della Santina CC, Carey JP, Zee DS. Vestibular stimulation by magnetic fields. Ann N Y Acad Sci 1343: 69–79, 2015. doi:10.1111/nyas.12702. Crossref | PubMed | ISI | Google Scholar5. Ward BK, Tan GX-J, Roberts DC, Della Santina CC, Zee DS, Carey JP. Strong static magnetic fields elicit swimming behaviors consistent with direct vestibular stimulation in adult zebrafish. PLoS One 9: e92109, 2014. doi:10.1371/journal.pone.0092109. Crossref | PubMed | ISI | Google Scholar6. Ward BK, Roberts DC, Otero-Millan J, Zee DS. A decade of magnetic vestibular stimulation: from serendipity to physics to the clinic. J Neurophysiol 121: 2013–2019, 2019. doi:10.1152/jn.00873.2018. Link | ISI | Google ScholarAUTHOR NOTESCorrespondence: V. C. Sheffield ([email protected]edu). Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation Related ArticlesPoint: An alternative hypothesis for why exposure to static magnetic and electric fields treats type 2 diabetes 02 Jun 2021American Journal of Physiology-Endocrinology and MetabolismReply to Carter et al.: An alternative hypothesis for why exposure to static magnetic and electric fields treats type 2 diabetes 02 Jun 2021American Journal of Physiology-Endocrinology and MetabolismCounterpoint: An alternative hypothesis for why exposure to static magnetic and electric fields treats type 2 diabetes 02 Jun 2021American Journal of Physiology-Endocrinology and Metabolism More from this issue > Volume 320Issue 5May 2021Pages E1004-E1005 Crossmark Copyright & PermissionsCopyright © 2021 the American Physiological Societyhttps://doi.org/10.1152/ajpendo.00119.2021PubMed33843283History Received 29 March 2021 Accepted 31 March 2021 Published online 2 June 2021 Published in print 1 May 2021 Metrics