AIMS: Glucagon-like peptide 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. Our objective was, therefore, to test a novel small molecule as a different and potentially better tolerated oral medications to improve obesity-associated impairment in glucose homeostasis. MATERIALS AND METHODS: High-fat diet (HFD)-fed mice or severely obese, leptin-deficient ob/ob mice were randomly assigned to serve as controls or receive oral TIX100, a novel thioredoxin-interacting protein (TXNIP) inhibitor just approved by the FDA as an investigational new drug for type 1 diabetes (T1D). The TIX100 effects on glucose intolerance and weight control were then assessed. RESULTS: TIX100 protected against HFD-induced glucose intolerance, hyperinsulinemia, and hyperglucagonemia. TIX100 also reduced diet-induced adiposity resulting in 15% lower weight in treated mice as compared with controls on HFD (p <
0.05), while preserving lean mass. Even though the TIX100 weight effects were lost in ob/ob mice, TIX100 improved glucose control leading to a dramatic 2.3% reduction in HbA1C (p <
0.05), independent of any weight loss. This is consistent with the beneficial effects of TIX100 in non-obese diabetes models and its protection against elevated TXNIP and islet cell stress common to all diabetes types. CONCLUSIONS: Thus, TIX100 may provide a novel, oral therapy for T2D that targets underlying disease pathology including islet cell dysfunction and hyperglucagonemia and promotes metabolic health and weight control without aggressive weight loss.