Thioredoxin-Interacting Protein as a Novel Potential Therapeutic Target in Diabetes Mellitus and Its Underlying Complications

Abstract

Diabetes mellitus (DM) is a common metabolic disorder which is characterized by a persistent increment of blood glucose. Globally, DM affects millions of people and the prevalence is increasing alarmingly. The critical step in the pathophysiology of DM is the loss of β-cells of the pancreas, which are responsible for the secretion of insulin. Thioredoxin-interacting protein (TXNIP) is among the factors that control the production and loss of the pancreatic β-cells. TXNIP is an α-arrestin that can bind and inhibit thioredoxin (the antioxidant protein) which is produced in the pancreatic islet after glucose intake. Numerous studies illustrated that elevated TXNIP levels were found to induce β-cell apoptosis; whereas TXNIP deficiency protects against type I and type II diabetes by promoting β-cell survival. Nowadays, TXNIP depletion is becoming a key factor in pancreatic β-cell survival enhancement. In the present review, targeting TXNIP is found to be relevant as a unique therapeutic opportunity, not only to improve insulin secretion and sensitivity, but also ameliorating the long term microvascular and macrovascular complications of the disease. Thus, TXNIP inhibitors that could reduce the expression and/or activity of TXNIP to non-diabetic levels are promising agents to halt the alarming rate of diabetes and its related complications.

Keywords: TXNIP; TXNIP modulators; diabetes mellitus; thioredoxin; verapamil.

Figure 1

Thioredoxin mediated redox reaction. Abbreviations: H+, Hydrogen; NADPH, Nicotinamide adenine dinucleotide phosphate; S2, Disulphide; SH, Disulphide hydride; TXN, Thioredoxin; TXNR, Thioredoxin reductase.