TXNIP inhibitors: A New Class of Agents for Diabetes Treatment

Diabetes mellitus (DM) is a chronic metabolic disorder that presents with consistently elevated blood glucose levels due to either a lack of insulin (T1D) or resistance to insulin (T2D). The prevalence of DM in the United States has risen over the past several decades and poses a significant disease burden if not properly treated. Failure to properly manage this disease through strict blood glucose control and medication adherence can result in microvascular and macrovascular damage with organ complications and high mortality risk.¹

Current treatments for T2Dinclude insulin, metformin, sulfonylureas,thiazolidinediones, glucagon-like peptide-1 (GLP-1) receptor agonists, sodium glucose co-transporter-2 (SGLT2) inhibitors, and dipeptidyl peptidase-4 (DPP-4)-inhibitors. Encouragingly, some of these medications, namely SGLT2 inhibitors and GLP-1 agonists, have exhibited additional benefits in cardiovascular and renal outcomes. Such therapies have allowed providers to address multiple disease states with one agent. While established treatments continue to show diverse benefits, there have been several novel pharmaceutical agents with different mechanisms of action that show the potential to further combat this chronic disease.

Thioredoxin-interacting protein (TXNIP) has recently been identified as a glucose-regulated protein involved in the apoptosis of pancreatic beta-cells which could indicate beta cell toxicity.² TXNIP promotes oxidative stresswithin beta cells, inducing antiproliferative effects by causing cell cycle arrest at the G0/G1 phase. This ultimatelyincreases the risk of apoptosis in fibroblast and cardiomyocytes.

High levels of glucose stimulate TXNIP transcription and results in elevated TXNIP mRNA expression. Together, these deleterious effects of TXNIP on the body could indicate a causal relationship in glucotoxic beta-cell death associated with diabetes.² Many studies have been conducted in mice to investigate the benefit of mutation or removal of the TXNIP gene. In one report written by Thielen and Shalev, removal of the gene in mice increased beta cell mass, decreased beta cell apoptosis, elevated insulin levels, and was shown to prevent type 1 and type 2 diabetes.³ Another report written by Chen et al noted that TXNIP-deficient mice did not have glucose-toxic beta-cell apoptosis.²

Because this novel mechanism could be crucial in understanding the pathogenesis of beta cell loss in diabetes, other pharmaceutical agents with anti-TXNIP activity are being studied for the treatment of diabetes.For example, verapamil, a non-dihydropyridine calcium channel blocker traditionally used for the treatment of hypertension, has been found to have an inhibitory effect on TXNIP expression by blocking the L-type and T-type calcium channels and decreasing intracellular calcium.^1,4 One small study (n=44) evaluated the safety and efficacy of verapamil on fasting blood glucose (FBG), hemoglobin A1c (HbA1c) and lipid profiles in patients with T2D who are taking metformin and sitagliptin. The results concluded that there was a significant decrease of 0.5% in A1c after 3 months, although changes in FBG and lipid profiles were not statistically significant.⁵ Although these results demonstrate that TXNIP may be a suitable therapeutic target for the management diabetes and cardiometabolic disease overall, larger trials are warranted to further substantiate this therapeutic benefit.

Another TXNIP inhibitor molecule being investigated for the treatment of diabetes is SRI-37330. In vivo studies have revealed that SRI-37330 inhibited the expression and signaling of TXNIPin mice, rat, and human islet cells.⁶ By preventing the induction of TXNIP, SRI-37330 reduced hepatic glucose production and reversed hepatic steatosis.^1,6This agent is still undergoing in vivo studies and has yet to reach clinical trials to studyitssafety and efficacy in human subjects,but has shown to be highly effective in human islet cells with minimal side effects in mice.⁶

TXNIP expression may also contribute to the comorbidities of diabetes, such as nonalcoholic fatty liver disease (NAFLD). One pathway that is targeted involves TXNIP-protein arginine methyltransferase-1 (PRMT1) and peroxisome proliferator activated receptor gamma co activator α (PGC-1α), which ultimately leads to fat accumulation in hepatocytes.⁷ In this cascade, elevated levels of fatty acids lead to TXNIP overexpression, which induces the TXNIP-PRMT1 interaction. This interaction induces the expression of PGC-1α, a metabolic regulator found in the liver. Increases in PGC-1α are reflected in metabolic syndrome and fatty livers.⁷

One therapeutic combination—allopurinol and quercetin—is being studied in rats with T1D and to assess its potential in NAFLD. Both medications have significant activity in TXNIP inhibition. The results of the study demonstrated that this combination reduced blood glucose levels, hepatic stress, inflammation, and steatosis.⁸

Such studies have brought light to this novel approach of TXNIP inhibition, which could prevent beta cell loss and protect beta cell function to potentially contribute to diabetes management and its complications. Inhibition of this protein can hopefully increase beta cell mass and even possibly reverse the detrimental effects of both T1D and T2D. Although extensive research is still necessary, these recent discoveries may pave an innovative pathway for drug targeting.

Penel

REFERENCES

1. Wondafrash DZ, Nire’a AT, Tafere GG, Desta DM, Berhe DA, Zewdie KA. Thioredoxin-Interacting Protein as a Novel Potential Therapeutic Target in Diabetes Mellitus and Its Underlying Complications. Diabetes Metab Syndr Obes. 2020;13:43-51. doi:10.2147/DMSO.S232221

2. Chen, J., Saxena, G., Mungrue, I., Lusis, A. and Shalev, A., 2008. Thioredoxin-Interacting Protein: A Critical Link Between Glucose Toxicity and beta-Cell Apoptosis. Diabetes, [online] 57(4), pp.938-944. Available at: <https://diabetes.diabetesjournals.org/content/57/4/938> [Accessed 16 October 2021].

3. Thielen L, Shalev A. Diabetes pathogenic mechanisms and potential new therapies based upon a novel target called TXNIP. Curr Opin Endocrinol Diabetes Obes. 2018;25(2):75-80. doi:10.1097/MED.0000000000000391

4. Shalev A. Minireview: Thioredoxin-interacting protein: regulation and function in the pancreatic β-cell. Mol Endocrinol. 2014;28(8):1211-1220. doi:10.1210/me.2014-1095

5. Malayeri A, Zakerkish M, Ramesh F, Galehdari H, Hemmati AA, Angali KA. The Effect of Verapamil on TXNIP Gene Expression, GLP1R mRNA, FBS, HbA1c, and Lipid Profile in T2DM Patients Receiving Metformin and Sitagliptin. Diabetes Ther. 2021;12(10):2701-2713. doi:10.1007/s13300-021-01145-4

6. Thielen LA, Chen J, Jing G, et al. Identification of an Anti-diabetic, Orally Available Small Molecule that Regulates TXNIP Expression and Glucagon Action. Cell Metabolism. 2020;32(3):353-365.e8. doi:10.1016/j.cmet.2020.07.002

7. Park M-J, Kim D-I, Lim S-K, et al. Thioredoxin-interacting protein mediates hepatic lipogenesis and inflammation via PRMT1 and PGC-1α regulation in vitro and in vivo. Journal of Hepatology. 2014;61(5):1151-1157. doi:10.1016/j.jhep.2014.06.032

8. Wang W, Wang C, Ding X-Q, et al. Quercetin and allopurinol reduce liver thioredoxin-interacting protein to alleviate inflammation and lipid accumulation in diabetic rats. Br J Pharmacol. 2013;169(6):1352-1371. doi:10.1111/bph.12226