Verapamil and beta cell function in adults with recent-onset type 1 diabetes

Abstract

Pancreatic beta cell loss is a key factor in the pathogenesis of type 1 diabetes (T1D), but therapies to halt this process are lacking. We previously reported that the approved antihypertensive calcium-channel blocker verapamil, by decreasing the expression of thioredoxin-interacting protein, promotes the survival of insulin-producing beta cells and reverses diabetes in mouse models1. To translate these findings into humans, we conducted a randomized double-blind placebo-controlled phase 2 clinical trial (NCT02372253) to assess the efficacy and safety of oral verapamil added for 12 months to a standard insulin regimen in adult subjects with recent-onset T1D. Verapamil treatment, compared with placebo was well tolerated and associated with an improved mixed-meal-stimulated C-peptide area under the curve, a measure of endogenous beta cell function, at 3 and 12 months (prespecified primary endpoint), as well as with a lower increase in insulin requirements, fewer hypoglycemic events and on-target glycemic control (secondary endpoints). Thus, addition of once-daily oral verapamil may be a safe and effective novel approach to promote endogenous beta cell function and reduce insulin requirements and hypoglycemic episodes in adult individuals with recent-onset T1D.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Screening, randomization and treatment.
Fig. 2: Effects of verapamil on endogenous beta cell function.
Fig. 3: Effects of verapamil on glycemic control and insulin requirements.
Fig. 4: Blood pressure and heart rate throughout the trial.

References

  1. 1.

    Xu, G., Chen, J., Jing, G. & Shalev, A. Preventing beta-cell loss and diabetes with calcium channel blockers. Diabetes 61, 848–856 (2012).

    CAS  Article  Google Scholar 

  2. 2.

    Davis, A. K. et al. Prevalence of detectable C-peptide according to age at diagnosis and duration of type 1 diabetes. Diabetes Care 38, 476–481 (2015).

    CAS  Article  Google Scholar 

  3. 3.

    Liu, E. H. et al. Pancreatic beta cell function persists in many patients with chronic type 1 diabetes, but is not dramatically improved by prolonged immunosuppression and euglycaemia from a beta cell allograft. Diabetologia 52, 1369–1380 (2009).

    CAS  Article  Google Scholar 

  4. 4.

    The Diabetes Control and Complications Trial Research Group. Effect of intensive therapy on residual beta-cell function in patients with type 1 diabetes in the diabetes control and complications trial: a randomized, controlled trial. Ann. Intern. Med. 128, 517–523 (1998).

  5. 5.

    Shalev, A. et al. Oligonucleotide microarray analysis of intact human pancreatic islets: identification of glucose-responsive genes and a highly regulated TGFbeta signaling pathway. Endocrinology 143, 3695–3698 (2002).

    CAS  Article  Google Scholar 

  6. 6.

    Chen, J. et al. Thioredoxin-interacting protein deficiency induces Akt/Bcl-xL signaling and pancreatic beta cell mass and protects against diabetes. FASEB J. 22, 3581–3594 (2008).

    CAS  Article  Google Scholar 

  7. 7.

    Chen, J., Saxena, G., Mungrue, I. N., Lusis, A. J. & Shalev, A. Thioredoxin-interacting protein: a critical link between glucose toxicity and beta cell apoptosis. Diabetes 57, 938–944 (2008).

    CAS  Article  Google Scholar 

  8. 8.

    Minn, A. H., Hafele, C. & Shalev, A. Thioredoxin-interacting protein is stimulated by glucose through a carbohydrate response element and induces beta-cell apoptosis. Endocrinology 146, 2397–2405 (2005).

    CAS  Article  Google Scholar 

  9. 9.

    Minn, A. H. et al. Gene expression profiling in INS-1 cells overexpressing thioredoxin-interacting protein. Biochem. Biophys. Res. Commun. 336, 770–778 (2005).

    CAS  Article  Google Scholar 

  10. 10.

    Chen, J., Cha-Molstad, H., Szabo, A. & Shalev, A. Diabetes induces and calcium channel blockers prevent cardiac expression of pro-apoptotic thioredoxin-interacting protein. Am. J. Physiol. Endocrinol. Metab. 296, 1133–1139 (2009).

    Article  Google Scholar 

  11. 11.

    Afzal, N. et al. Beneficial effects of verapamil in diabetic cardiomyopathy. Diabetes 37, 936–942 (1988).

    CAS  Article  Google Scholar 

  12. 12.

    Cohn, R. D. et al. Prevention of cardiomyopathy in mouse models lacking the smooth muscle sarcoglycan-sarcospan complex. J. Clin. Invest. 107, R1–R7 (2001).

    CAS  Article  Google Scholar 

  13. 13.

    Xu, G., Chen, J., Jing, G. & Shalev, A. Thioredoxin-interacting protein regulates insulin transcription through microRNA-204. Nat. Med. 19, 1141–1146 (2013).

  14. 14.

    Jo, S. et al. miR-204 controls glucagon-like peptide 1 receptor expression and agonist function. Diabetes 67, 256–264 (2018).

    CAS  Article  Google Scholar 

  15. 15.

    Zhou, R., Tardivel, A., Thorens, B., Choi, I. & Tschopp, J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat. Immunol. 11, 136–140 (2010).

    CAS  Article  Google Scholar 

  16. 16.

    Yin, T., Kuo, S. C., Chang, Y. Y., Chen, Y. T. & Wang, K. K. Verapamil use is associated with reduction of newly diagnosed diabetes mellitus. J. Clin. Endocrinol. Metab. 102, 2604–2610 (2017).

    Article  Google Scholar 

  17. 17.

    Cooper-Dehoff, R. et al. Predictors of development of diabetes mellitus in patients with coronary artery disease taking antihypertensive medications (findings from the INternational VErapamil SR-Trandolapril STudy [INVEST]). Am. J. Cardiol. 98, 890–894 (2006).

    CAS  Article  Google Scholar 

  18. 18.

    Cooper-DeHoff, R. M. et al. Blood pressure control and cardiovascular outcomes in high-risk Hispanic patients: findings from the International Verapamil SR/Trandolapril Study (INVEST). Am. Heart J. 151, 1072–1079 (2006).

    Article  Google Scholar 

  19. 19.

    Busch Sorensen, M. et al. Influence of short term verapamil treatment on glucose metabolism in patients with non-insulin dependent diabetes mellitus. Eur. J. Clin. Pharmacol. 41, 401–404 (1991).

    CAS  Article  Google Scholar 

  20. 20.

    Khodneva, Y., Shalev, A., Frank, S. J., Carson, A. P. & Safford, M. M. Calcium channel blocker use is associated with lower fasting serum glucose among adults with diabetes from the REGARDS study. Diabetes Res. Clin. Pract. 115, 115–121 (2016).

    CAS  Article  Google Scholar 

  21. 21.

    Nambam, B., Bratina, N. & Schatz, D. Immune interventions for type 1 diabetes mellitus. Diabetes Technol. & Ther. 19, S74–S81 (2017).

    Article  Google Scholar 

  22. 22.

    Alhadj Ali, M.et al. Metabolic and immune effects of immunotherapy with proinsulin peptide in human new-onset type 1 diabetes. Sci. Transl. Med. 9, eaaf7779 (2017).

  23. 23.

    Herold, K. C. et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. New Engl. J. Med. 346, 1692–1698 (2002).

    CAS  Article  Google Scholar 

  24. 24.

    Aronson, R. et al. Low-dose otelixizumab anti-CD3 monoclonal antibody DEFEND-1 study: results of the randomized phase III study in recent-onset human type 1 diabetes. Diabetes Care 37, 2746–2754 (2014).

    Article  Google Scholar 

  25. 25.

    Pescovitz, M. D. et al. Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. New Engl. J. Med. 361, 2143–2152 (2009).

    CAS  Article  Google Scholar 

  26. 26.

    Pozzilli, P., Maddaloni, E. & Buzzetti, R. Combination immunotherapies for type 1 diabetes mellitus. Nat. Rev. Endocrinol. 11, 289–297 (2015).

    CAS  Article  Google Scholar 

  27. 27.

    Greenbaum, C. J. et al. Fall in C-peptide during first 2 years from diagnosis: evidence of at least two distinct phases from composite Type 1 Diabetes TrialNet data. Diabetes 61, 2066–2073 (2012).

    CAS  Article  Google Scholar 

  28. 28.

    Hao, W. et al. Fall in C-peptide during first 4 years from diagnosis of type 1 diabetes: variable relation to age, HbA1c, and insulin dose. Diabetes Care 39, 1664–1670 (2016).

    CAS  Article  Google Scholar 

  29. 29.

    Greenbaum, C. J. et al. Mixed-meal tolerance test versus glucagon stimulation test for the assessment of beta-cell function in therapeutic trials in type 1 diabetes. Diabetes Care 31, 1966–1971 (2008).

    Article  Google Scholar 

  30. 30.

    Palmer, J. P. et al. C-peptide is the appropriate outcome measure for type 1 diabetes clinical trials to preserve beta-cell function: report of an ADA workshop, 21-22 October 2001. Diabetes 53, 250–264 (2004).

    CAS  Article  Google Scholar 

  31. 31.

    Lachin, J. M. et al. Sample size requirements for studies of treatment effects on beta-cell function in newly diagnosed type 1 diabetes. PLoS One 6, e26471 (2011).

    CAS  Article  Google Scholar 

  32. 32.

    Moore, C. G., Carter, R. E., Nietert, P. J. & Stewart, P. W. Recommendations for planning pilot studies in clinical and translational research. Clin. Transl. Sci. 4, 332–337 (2011).

    Article  Google Scholar 

  33. 33.

    Li, P., Stuart, E. A. & Allison, D. B. Multiple imputation: a flexible tool for handling missing data. JAMA 314, 1966–1967 (2015).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

The work was supported by JDRF grant 3-SRA-2014-302-M-R to A.S. The UAB Physiology Core was supported by DRC P30DK079626, and the UAB Center for Clinical and Translational Science was supported by UL1TR001417. We thank M. Preuss for excellent administrative support during the study.

Author information

Affiliations

Authors

Contributions

F.O., T.G. and A.J.P. were responsible for patient care, MMTTs, and sample and data collection. G.X., T.B.G. and L.A.T. helped with sample preparation. P.L. provided statistical advice. F.O. and A.S. designed the studies and analyzed the results. A.S. wrote the manuscript. All authors reviewed and approved the manuscript.

Corresponding author

Correspondence to Anath Shalev.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ovalle, F., Grimes, T., Xu, G. et al. Verapamil and beta cell function in adults with recent-onset type 1 diabetes. Nat Med 24, 1108–1112 (2018). https://doi.org/10.1038/s41591-018-0089-4

Download citation

Further reading

Search

Quick links

Sign up for the Nature Briefing newsletter for a daily update on COVID-19 science.
Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing