Anath Shalev, M.D.UAB Comprehensive Diabetes Center (UCDC) Director Anath Shalev, M.D., was invited to write a mini-review for Endocrinology, the flagship journal of the Endocrine Society, as part of the 75th anniversary celebration of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).
Diabetes is the most expensive chronic disease in the United States, with more than $400 billion in annual costs, and it affects more than 38 million Americans. While major advances in drug treatment have been made for Type 2 diabetes (T2D) and the often-associated obesity, Shalev points out in her review that there are still no approved and effective medications targeting a major underlying cause of both Type 1 (T1D) and T2D—beta cell loss or islet dysfunction. In addition, there are no oral medications for T1D approved in the U.S. more than 100 years after the discovery of insulin. However, attractive therapeutic targets are starting to emerge.
“As we celebrate the 75th anniversary of the NIDDK, progress is finally being made in this area with NIDDK support,” Shalev writes in her review, “Target Discovery to Diabetes Therapy – TXNIP from Bench to Bedside with NIDDK,” published in Endocrinology’s May 2025 issue.
As a world-renowned diabetes researcher, Shalev outlines the history of diabetes treatment and how our understanding of the underlying mechanisms and the pathogenesis of diabetes has evolved dramatically since NIDDK was founded in 1950. As an example, she relays her own discovery of thioredoxin-interacting protein (TXNIP) in pancreatic islet biology and diabetes more than two decades ago when her work found TXNIP to be the top glucose-induced gene in a human islet microarray study in work initially conducted intramurally at the NIDDK.
Further work supported by an NIDDK R01 research grant was able to demonstrate that TXNIP deficiency and beta-cell–specific genetic TXNIP deletion protected mice against diabetes in models of T1D and T2D, which suggested TXNIP might represent a promising therapeutic target. This groundbreaking discovery eventually paved the way for the development of pharmacological approaches to inhibit TXNIP and normalize its expression back to nondiabetic levels, representing great opportunities for clinical translation.
Now, human trials are underway with the Investigational New Drug, TIX100, a TXNIP inhibitor developed by Shalev and UAB startup, TIXiMED, Inc. as an orally available antidiabetic for T1D.
TIXiMED recently reported the successful dosing of the first cohort of healthy human volunteers, and TIX100 was well tolerated, and no clinically significant adverse findings or safety concerns were noted.
TIX100 has also recently been shown in preclinical studies to protect against diet-induced glucose intolerance, hyperglucagonemia, hyperlipidemia, and liver enzyme abnormalities and to dramatically improve glucose control in genetic mouse models of obesity and T2D.
Shalev writes that it is essential to continue to study the many aspects of TXNIP signaling and its inhibition in islet biology, diabetes, and metabolic disease. In fact, several such projects are in the pipeline.
“Thus, the work supported by the NIDDK in the past, in the present, and hopefully in the future, promises to enable the next major breakthroughs in diabetes, including T1D, and this may change the landscape of these chronic metabolic diseases forever,” Shalev concludes.
Read the full Mini-review in Endocrinology here.