Verapamil Restores β-Cell Mass and Function in Diabetogenic Stress Models via Proliferation and Mitochondrial Respiration

TL;DR

Verapamil, a drug for high blood pressure, helps protect and restore pancreatic β-cells in diabetes models by boosting cell growth and energy production.

Contribution

Verapamil's novel role in promoting β-cell proliferation and mitochondrial respiration under diabetogenic stress is demonstrated across multiple models.

Findings

Verapamil elevated cholecystokinin levels and preserved mitochondrial function in MIN6 β-cells under stress.

In zebrafish, verapamil promoted β-cell recovery and regeneration after ablation.

Verapamil showed protective effects before, during, and after stressors in a model-dependent manner.

Abstract

Diabetes remains a global health challenge, characterized by persistent hyperglycemia and gradual depletion or impairment of pancreatic β-cells. Current treatments focus on managing glycemic control, but do not mitigate β-cell mass. Verapamil, an FDA-approved calcium channel blocker for hypertension, has shown potential therapeutic action towards β-cells in the context of diabetes. In this study, we investigated the cytoprotective and metabolic efficacy of verapamil on mouse-derived MIN6 β-cells under metabolic and diabetogenic stressors like high glucose, toxins, and an inflammatory cytokine cocktail, as well as investigated a zebrafish model. At safe, non-toxic doses, verapamil elevated the levels of cholecystokinin (CCK), an incretin associated with β-cell preservation and enhanced mitochondrial respiration. Notably, pretreatment and co-treatment of verapamil in the presence of stressors offered substantial protection and preserved mitochondrial function, whereas post-treatment effects were moderate and model dependent. In the zebrafish model, verapamil promoted β-cell recovery and regeneration before, during, and after targeted ablation. The drug seemed to work in several ways: inducing proliferation, reducing stress on β cells, boosting their energy production, and activating survival signals. Together, our data aligned with earlier human clinical trials showing that verapamil administration preserved β-cell mass and function in patients with recent-onset type 1 diabetes. The high efficacy, affordability, and broad mechanisms of action make verapamil a desirable therapeutic candidate for diabetes. Nevertheless, further mechanistic studies and long-term clinical trials are warranted to establish its utility in diabetes management.

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