ESPE Yearbook of Paediatric Endocrinology

Brief Summary: This study examined the potential benefits of Verapamil, a calcium channel blocker traditionally used to treat hypertension, in Type 1 Diabetes (T1D). It shows that Verapamil can prevent the decline of Insulin-like Growth Factor I (IGF-I) levels, which are crucial for β-cell survival and insulin production. Moreover, Verapamil reduced the expression of IGF-binding protein 3 (IGFBP3), enhancing IGF-I signaling and protecting β-cells from apoptosis. Hence, Verapamil may be effective in preserving β-cells and improving glucose control in T1D patients.

Verapamil, an approved antihypertensive drug, has recently been proposed to have antidiabetic effects. Verapamil protects against β-cell death and diabetes in different mouse models of diabetes (1). Furthermore, a randomized controlled clinical trial with Verapamil showed an improvement of endogenous β-cell function with decreased insulin requirements in adults with recent-onset T1D (2). This preservation of β-cell function has also been further confirmed in a recent, independent Verapamil trial in children with T1D (3). IGF-1 and IGF-binding proteins are involved in insulin secretion and β-cell survival (4-6) and IGF-I levels are lower in subjects with T1D, correlating with β-cell function (7).

This study tested the hypothesis that the effects of Verapamil on β-cell function may be mediated by a modulation of the IGF system. Using serum samples of individuals with T1D before and after 1 year of treatment with Verapamil or placebo, and primary human and mouse islets as well as INS-1 cells, the authors found that Verapamil is able to preserve circulating IGF-I levels, downregulate islet IGFBPs, and promote IGF-I signaling.

To further explore the effects of verapamil on β-cell function and survival, experiments in human and mouse β-cells were conducted. Exposure to Verapamil reduced the expression of four of the six members of the IGFBP family. By reducing IGFBP-3 levels, Verapamil may thus enhance IGF-I bioavailability and signaling and contribute to the preservation of β-cell function. Finally, Verapamil decreased the expression of the proapoptotic thioredoxin-interacting protein (TXNIP) in human islets exposed to T1D-associated inflammatory cytokines. TXNIP promotes IGFBP-3 expression and inhibits the phosphorylation/activation of IGF1R.

In conclusion, the protective effect of Verapamil on β-cells may be partly mediated by the regulation of IGF-I signaling, which is crucial for β-cell survival and function.

References: 1. Xu G, Chen J, Jing G, Shalev A. Preventing β-cell loss and diabetes with calcium channel blockers. Diabetes. 2012 Apr;61(4):848-56. doi: 10.2337/db11-0955. PMID: 22442301; PMCID: PMC3314354.2. van Haeften TW, Twickler TB. Insulin-like growth factors and pancreas beta cells. Eur J Clin Invest. 2004 Apr;34(4):249-55. doi: 10.1111/j.1365-2362.2004.01337.x. PMID: 15086355.3. Ovalle F, Grimes T, Xu G, Patel AJ, Grayson TB, Thielen LA, Li P, Shalev A. Verapamil and beta cell function in adults with recent-onset type 1 diabetes. Nat Med. 2018 Aug;24(8):1108-1112. doi: 10.1038/s41591-018-0089-4. Epub 2018 Jul 9. PMID: 29988125; PMCID: PMC6092963.4. Forlenza GP, McVean J, Beck RW, Bauza C, Bailey R, Buckingham B, DiMeglio LA, Sherr JL, Clements M, Neyman A, Evans-Molina C, Sims EK, Messer LH, Ekhlaspour L, McDonough R, Van Name M, Rojas D, Beasley S, DuBose S, Kollman C, Moran A; CLVer Study Group. Effect of Verapamil on Pancreatic Beta Cell Function in Newly Diagnosed Pediatric Type 1 Diabetes: A Randomized Clinical Trial. JAMA. 2023 Mar 28;329(12):990-999. doi: 10.1001/jama.2023.2064. PMID: 36826844; PMCID: PMC9960020.5. Xuan S, Kitamura T, Nakae J, Politi K, Kido Y, Fisher PE, Morroni M, Cinti S, White MF, Herrera PL, Accili D, Efstratiadis A. Defective insulin secretion in pancreatic beta cells lacking type 1 IGF receptor. J Clin Invest. 2002 Oct;110(7):1011-9. doi: 10.1172/JCI15276. PMID: 12370279; PMCID: PMC151144.6. Silha JV, Gui Y, Murphy LJ. Impaired glucose homeostasis in insulin-like growth factor-binding protein-3-transgenic mice. Am J Physiol Endocrinol Metab. 2002 Nov;283(5):E937-45. doi: 10.1152/ajpendo.00014.2002. PMID: 12376320.7. Ekman B, Nyström F, Arnqvist HJ. Circulating IGF-I concentrations are low and not correlated to glycaemic control in adults with type 1 diabetes. Eur J Endocrinol. 2000 Oct;143(4):505-10. doi: 10.1530/eje.0.1430505. PMID: 11022197.8. Palta M, LeCaire TJ, Sadek-Badawi M, Herrera VM, Danielson KK. The trajectory of IGF-1 across age and duration of type 1 diabetes. Diabetes Metab Res Rev. 2014 Nov;30(8):777-83. doi: 10.1002/dmrr.2554. PMID: 24845759; PMCID: PMC4236234.