Glucagon-like peptide-1 (GLP-1) receptor agonists and dual agonists have changed the treatment landscape of obesity and Type 2 diabetes (T2D), but significant limitations have emerged due to their gastrointestinal side effects, loss of lean mass, and necessity for ongoing subcutaneous injections.

UAB Comprehensive Diabetes Center (UCDC) Director Anath Shalev, M.D., and her lab, therefore, aimed to test an investigational new drug developed for Type 1 diabetes (T1D) as a different and potentially better tolerated oral medication for the treatment of T2D.

By inhibiting thioredoxin-interacting protein (TXNIP), the drug TIX100 protects against beta cell loss in the pancreas, an underlying cause of both T1D and TD2.

Researchers now studied for the first time TIX100’s effect on high-fat diet (HFD)-induced glucose intolerance and weight control in mouse models. Their findings were recently published in the paper, “Oral TIX100 protects against obesity-associated glucose intolerance and diet-induced adiposity,” in the peer-reviewed journal Diabetes, Obesity and Metabolism.

Results showed that TIX100 protects against HFD-induced glucose intolerance as typically seen in T2D.

TIX100 also reduced fat mass resulting in 15% lower weight in treated mice as compared with control mice fed the high-fat diet, while preserving lean mass.

Importantly though, researchers found that the improvement in glucose homeostasis was independent of any weight loss.

Shalev said she was surprised by the treatment’s effect on fat mass and the striking preservation of lean mass.

“Even though this is milder weight loss than what you see with GLP-1 agonists, it was based entirely on reduction in fat mass, not in lean mass,” she said. “I was positively surprised that it had such beneficial effects on weight in the context of high-fat diet induced obesity, a model that is very much akin to what you would see in human obesity.”

Shalev noted the weight loss was not as extreme or associated with any impairment in gastric emptying, therefore, it would unlikely cause the gastrointestinal side effects commonly seen with GLP-1 agonists.

The study also showed TIX100 was very effective in lowering hyperglucagonemia (elevated glucagon, the counter regulatory hormone to insulin). This is a common problem in both types of diabetes, but particularly prominent in T2D and leads to excessive glucose production in the face of already high blood glucose levels.

In contrast to some glucagon receptor antagonists that have been reported to cause liver enzyme abnormalities and elevation in plasma cholesterol and glucagon, the study showed TIX100 improved plasma cholesterol, triglycerides, and alanine aminotransferase (ALT) levels in the context of HFD.

Researchers concluded that TIX100 may represent a new oral medication not only for T1D, but also for T2D by targeting several common underlying disease processes like beta cell loss, islet cell stress and dysfunction, and hyperglucagonemia.

TIX100 also should protect against obesity-associated glucose intolerance, but without aggressive reduction in food intake and body weight, and, importantly, without loss of lean mass.

“Even though we started TIX100 off with the goal to target beta cell health in the context of T1D, these preclinical studies indicate that it would be equally beneficial in T2D,” Shalev said.

With further investigation, Shalev suggested TIX100 could potentially also be used for more sustained weight control by those who need to stop taking GLP-1s due to gastrointestinal side effects, cost, and other factors.

Shalev is the Nancy R. and Eugene C. Gwaltney Family Endowed Chair in Juvenile Diabetes Research in the Division of Endocrinology, Diabetes and Metabolism in the UAB Department of Medicine.

Other study authors from the Shalev Lab include SeongHo Jo, Ph.D., Gu Jing, Ph.D., Junqin Chen Ph.D., and Guanlan Xu Ph.D.

TIX100 was developed through TIXiMED, Inc., a UAB startup company that began in the Bill L. Harbert Institute for Innovation and Entrepreneurship. Shalev founded TIXiMED and serves as its chief scientific officer. Phase 1 clinical trials studying TIX100 as an investigational new drug for T1D began in January 2025.