CoChat
Sign Up
Cited by 249Diabetes and associated disordersPancreatic function and diabetesDiabetes Management and Research

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

Open access
Ovalle, Fernando, Grimes, Tiffany, Xu, Guanlan, Patel, Anish J., Grayson, Truman B., Thielen, Lance A., Li, Peng, Shalev, Anath·2018·Nature Medicine
DOI 10.1038/s41591-018-0089-4PMC PMC6092963
Open this paper in CoChat — free account

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 models 1. 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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41591-018-0089-4

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In two trials-one in adults and the other in children, both with stage 3 type 1 diabetes-verapamil slowed the decline in C-peptide responses to a mixed meal, more than placebo.

    “In two trials-one in adults and the other in children, both with stage 3 type 1 diabetes-verapamil slowed the decline in Cpeptide responses to a mixed meal, more than placebo.36,37”

    From The future of type 1 diabetes therapy (2025) · cites this paper as [36]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

No citation lists for this paper

No citation lists for this paper yet — checked again daily.

References 33 · Cited by 249

Research works printed but not linked: 31

  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). 22442301 PMC3314354
  2. [2]Davis AK, Prevalence of detectable C-Peptide according to age at diagnosis and duration of type 1 diabetes. Diabetes Care 38, 476– 481 (2015). 25519448
  3. [3]Liu EH, 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). 19418039 PMC2756111
  4. [4]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. The Diabetes Control and Complications Trial Research Group. Ann Intern Med 128, 517– 523 (1998). 9518395
  5. [5]Shalev A, 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). 12193586
  6. [6]Chen J, Thioredoxin-Interacting Protein Deficiency Induces Akt/Bcl-xL Signaling and Pancreatic Beta Cell Mass and Protects Against Diabetes. FASEB J 22, 3581– 3594 (2008). 18552236 PMC2537437
  7. [7]Chen J, Saxena G, Mungrue IN, Lusis AJ & Shalev A Thioredoxin-Interacting Protein: A Critical Link between Glucose Toxicity and Beta Cell Apoptosis. Diabetes 57, 938– 944 (2008). 18171713 PMC3618659
  8. [8]Minn AH, 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). 15705778
  9. [9]Minn AH, Gene expression profiling in INS-1 cells overexpressing thioredoxin-interacting protein. Biochem Biophys Res Commun 336, 770– 778 (2005). 16143294
  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). PMC2681312 19258488
  11. [11]Afzal N, Beneficial effects of verapamil in diabetic cardiomyopathy. Diabetes 37, 936– 942 (1988). 3384188
  12. [12]Cohn RD, Prevention of cardiomyopathy in mouse models lacking the smooth muscle sarcoglycan-sarcospan complex. J Clin Invest 107, R1– 7 (2001). 11160141 PMC199179
  13. [13]Xu G, Chen J, Jing G & Shalev A Thioredoxin-interacting protein regulates insulin transcription through microRNA-204. Nat Med (2013). PMC3835787 23975026
  14. [14]Jo S, miR-204 Controls Glucagon-Like Peptide 1 Receptor Expression and Agonist Function. Diabetes 67, 256– 264 (2018). 29101219 PMC5780066
  15. [16]Yin T, Kuo SC, Chang YY, Chen YT & Wang KK Verapamil Use Is Associated With Reduction of Newly Diagnosed Diabetes Mellitus. J Clin Endocrinol Metab 102, 2604– 2610 (2017). 28368479
  16. [17]Cooper-Dehoff R, 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). 16996868
  17. [18]Cooper-DeHoff RM, 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). 16644338
  18. [19]Busch Sorensen M, Influence of short term verapamil treatment on glucose metabolism in patients with non-insulin dependent diabetes mellitus. European journal of clinical pharmacology 41, 401– 404 (1991). 1761065
  19. [20]Khodneva Y, Shalev A, Frank SJ, Carson AP & Safford MM 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). 26818894 PMC4887408
  20. [21]Nambam B, Bratina N & Schatz D Immune Interventions for Type 1 Diabetes Mellitus. Diabetes technology & therapeutics 19, S74– S81 (2017). 28192018
  21. [22]Alhadj Ali M, Metabolic and immune effects of immunotherapy with proinsulin peptide in human new-onset type 1 diabetes. Science translational medicine 9(2017). 28794283
  22. [23]Herold KC, Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. The New England journal of medicine 346, 1692– 1698 (2002). 12037148
  23. [24]Aronson R, 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). 25011949 PMC4392937
  24. [26]Pozzilli P, Maddaloni E & Buzzetti R Combination immunotherapies for type 1 diabetes mellitus. Nature reviews. Endocrinology 11, 289– 297 (2015). 25688000
  25. [27]Greenbaum CJ, 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). 22688329 PMC3402330
  26. [28]Hao W, 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). 27422577 PMC5033079
  27. [29]Greenbaum CJ, 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). 18628574 PMC2551636
  28. [30]Palmer JP, 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). 14693724
  29. [31]Lachin JM, Sample size requirements for studies of treatment effects on beta-cell function in newly diagnosed type 1 diabetes. PLoS One 6, e26471 (2011). 22102862 PMC3213096
  30. [32]Moore CG, Carter RE, Nietert PJ & Stewart PW Recommendations for planning pilot studies in clinical and translational research. Clinical and translational science 4, 332– 337 (2011). 22029804 PMC3203750
  31. [33]Li P, Stuart EA & Allison DB Multiple Imputation: A Flexible Tool for Handling Missing Data. JAMA 314, 1966– 1967 (2015). 26547468 PMC4638176

Authors
Ovalle, F., Grimes, T., Xu, G., Patel, A. J., Grayson, T. B., Thielen, L. A., Li, P., & Shalev, A.
Affiliations
University of Alabama at Birmingham (US)
Corresponding author
Shalev, Anath
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2018-07-09
Volume
24
Issue
8
Pages
1108-1112
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/s41591-018-0089-4
PMC
PMC6092963
OpenAlex
W2851535791
Cited by
249
References
33
Citations by year
2026: 19 · 2025: 38 · 2024: 47 · 2023: 47 · 2022: 33 · 2021: 34 · 2020: 20 · 2019: 6 · 2018: 4 · 2017: 1
FWCI
9.79
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (UL1TR001417)
  • Center for Clinical and Translational Sciences, University of Texas Health Science Center at Houston
  • Center for Clinical and Translational Science, University of Alabama at Birmingham
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK078752, P30DK079626)
  • National Center for Research Resources (M01RR000032)
  • National Center for Advancing Translational Sciences
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
Keywords
verapamil, type 1 diabetes, recent-onset type 1 diabetes, beta-cell function, calcium channel blockers, TXNIP, C-peptide, insulin requirement, hypoglycemia, beta-cell survival
MeSH terms
Adult, Blood Pressure, Diabetes Mellitus, Type 1, Heart Rate, Humans, Insulin, Verapamil, Insulin-Secreting Cells

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review