The Effect of Verapamil on TXNIP Gene Expression, GLP1R mRNA, FBS, HbA1c, and Lipid Profile in T2DM Patients Receiving Metformin and Sitagliptin

Abstract

Introduction Type 2 diabetes mellitus (T2DM) is the most common type of diabetes. A decrease in the number of pancreatic beta cells is a pathological sign of diabetes, and to date there is no drug treatment that targets damage to these cells. Pancreatic beta cells have a weak antioxidant system and are highly sensitive to oxidative stress reactions that occur within cells. Thioredoxin interacting protein (TXNIP) inhibits thioredoxin, which is part of the intracellular antioxidant system, thereby accelerating oxidative stress and apoptosis of pancreatic beta cells. Verapamil is a non-dihydropyridine calcium channel blocker. The efficacy of this drug to improve beta cell survival and glucose homeostasis by inhibiting TXNIP expression has been demonstrated in in vitro studies. Although several retrospective studies have shown a lower incidence of T2DM with verapamil treatment, no prospective intervention studies have determined the efficacy of this drug in patients with T2DM. Methods The aim of this randomized, double-blind, placebo-controlled study was to evaluate the efficacy and safety of oral verapamil administration in T2DM patients. In this 90-day study, the effects of verapamil on fasting blood sugar (FBS), hemoglobin A1C (HbA1c), and the lipid profile were evaluated and compared with those of the placebo. Results There was a significant decrease in HbA1c (about 0.5%) in the verapamil group at the end of the intervention period. The effects of verapamil on TXNIP gene expression and glucagon-like peptide-1 receptor (GLP1R) mRNA were compared with those of the placebo (at baseline, after 15 and 30 days, and at the end of the study). During the first month of the study, decreased TXNIP gene expression and increased GLP1R mRNA were associated with the administration of verapamil when compared with the placebo, although the differences were not significant. Conclusion Verapamil can lead to better control of T2DM by reducing TXNIP gene expression and increasing beta cell survival and, possibly, by other mechanisms. Clinical Trial Registration IRCT registration no.: IRCT20180417039339N1 ( https://www.IRCT.ir ).

Verapamil and Its Role in Diabetes

“…In this regard, insulin represents the main player for promotion and maintenance of metabolism [32]. In the scientific community it is an accepted fact that diabetes is associated with a reduction in β-cell mass and to date there is no approved drug treatment that targets damage to these cells [33,34]. Pancreatic β-cells have, as reported in several studies, a weak antioxidant capacity and are very sensitive to oxidative stress interactions occurring within the cells [31,33].…”

“…In the scientific community it is an accepted fact that diabetes is associated with a reduction in β-cell mass and to date there is no approved drug treatment that targets damage to these cells [33,34]. Pancreatic β-cells have, as reported in several studies, a weak antioxidant capacity and are very sensitive to oxidative stress interactions occurring within the cells [31,33]. Although several trials have studied the mechanisms of β-cell loss in the different types of diabetes, there is less information referring to the residual β-cells in autoimmune T1D [35].…”

“…These previously described positive effects of orally administrated verapamil, based on retrospective population-based and observational data analyses [6,[25][26][27] as well as the presented data of a randomized, double-blind, placebo-controlled trial [33], could elucidate the positive effects of TXNIP regulation on glucose metabolism. Additionally, positive findings were revealed by Hong et al in mouse models of T2D, who demonstrated for the first time new mechanistic insights and novel links between TXNIP and proinflammatory cytokines and microRNA signaling [50].…”

“…Next to the reported studies, which have shown a lower incidence of T2D in verapamiltreated subjects, Malayeri et al could reveal positive effects in T2D subjects in a randomized, double-blind, placebo-controlled trial [33]. In this study, verapamil administration showed a better glycemic control by means of decrease of HbA1c, decrease of TXNIP expression and increased glucagon-like peptide-1 receptor (GLP1R) mRNA providing increasing β-cell survival [33]. Additional findings by Carbovale et al revealed significantly lowered plasma glucose levels in verapamil-treated subjects with T2D [63].…”

Verapamil chronicles: advances from cardiovascular to pancreatic β-cell protection

“…To investigate this annotation, an elegant study was conducted by Malayeri et al, who evaluated the efficacy and safety of oral verapamil in patients with T2D. This randomized, double-blind, placebo-controlled clinical trial showed a significant reduction in Hb1Ac levels in patients with T2D, following treatment with verapamil ( Malayeri et al, 2021 ). It is noteworthy that co-treatment with verapamil and metformin significantly improved the glycemic control in patients with T2D by reducing HbA1c and fasting plasma glucose levels ( Wang et al, 2022 ).…”