TXNIP inhibition in the treatment of diabetes. Verapamil as a novel therapeutic modality in diabetic patients

Abstract

Loss of pancreatic β–cell is a critical factor in the pathogenesis of type 1 diabetes and it also occurs in type 2. TXNIP (thioredoxin – interacting protein), also known as vitamin D3-upregulated protein 1, or thioredoxin-binding-protein-2, regulates this process and modulates cellular redox balance. TXNIP is localized primarily in the nucleus, but under oxidative stress it moves to mitochondria, where it interacts with mitochondrial thioredoxin 2. Overexpression of TXNIP induced by hyperglycaemia is typical for diabetes and insulin resistance and leads to apoptosis of pancreatic β– cell, cardiomyopathy, metabolic disorders and multiple harmful effects. It activates NLRP3 inflamasomme and IL–1β, a cytokine involved in type 2 diabetes and insulin resistance. TXNIP influences peroxisome proliferator-activated receptor alpha transcriptional activity, expression of glucose transporter–1, nitric oxide production in endothelium and insulin production in β–cells. TXNIP overexpression leads to diabetic retinopathy, nephropathy, atherosclerosis, it occurs in cancers and autoimmune diseases, while its deficiency protects β cells. Reduction of TXNIP is an important target in diabetes treatment. In this mechanism insulin, metformin and inhibitors of dipeptydylopeptydase IV are involved. It has been observed that calcium channel blockers (CCB) used in hypertension also inhibit TXNIP expression in cardiomyocytes. L–type channels identification in pancreatic β-cells revealed that CCB inhibit TXNIP expression also in β–cells. For the first time, verapamil was distinguished as an agent that not only inhibits TXNIP expression in pancreatic β-cells, but also enhances β cell survival and function, and possibly prevents diabetes.

Effect of Verapamil on Pancreatic Beta Cell Function in Newly Diagnosed Pediatric Type 1 Diabetes

“…Thioredoxin-interacting protein overexpression has been shown to induce pancreatic beta cell apoptosis and be involved in glucotoxicity-induced beta cell death in culture and mouse models . Calcium channel blockers, such as verapamil, reduce thioredoxin-interacting protein expression and beta cell apoptosis and may be beneficial in beta cell preservation after a type 1 diabetes diagnosis. In 2018, a placebo-controlled, pilot and feasibility randomized clinical trial was published that found a 35% relative increase in stimulated C-peptide levels after 12 months in 11 adults with newly diagnosed type 1 diabetes treated with oral verapamil compared with 13 adults taking placebo.…”

Molecular glues of the regulatory ChREBP/14-3-3 complex protect beta cells from glucolipotoxicity

“…ChREBP has long been identified as a potential mediator of this decline, in part by activating the pro-oxidative protuberant, TXNIP (70,(84)(85)(86). Indeed, clinical trials have been launched with compounds that inhibit the induction of TXNIP in T1D (87)(88)(89). We recently described the destructive feedforward production of ChREBPβ in β-cells in the context of prolonged hyperglycemia and diabetes (42,(87)(88)(89).…”

DRG Explant Model: Elucidating Mechanisms of Oxaliplatin-Induced Peripheral Neuropathy and Identifying Potential Therapeutic Targets

“…Given the potential connection between neuropathic pain and oxidative stress/inflammation on another, we used our DRG explant assay to investigate whether inhibiting the TXNIP’s activity with a known TXNIP inhibitor verapamil (78) suppresses the negative role of oxaliplatin on DRG regrowth and oxidative stress. Our results showed moderate but statistically significant improvement of the neurite outgrowth ( Figure 4A ) and suppression of the ROS in the DRG ( Figure 4B ) with even a small level of verapamil (ratio verapamil to oxaliplatin 1:100).…”