Natural Flavonoid Isobavachalcone Outperforms Sitagliptin at Blocking the Enzyme That Destroys GLP-1

What the researchers found

Out of 241 flavonoid compounds screened computationally, isobavachalcone (IBC) showed the highest binding energy to DPP-4 and the lowest IC50 value, making it the most potent inhibitor identified. In Caco-2 intestinal cells, IBC reduced DPP4 mRNA and protein expression.

In mice on a high-fat diet, IBC reduced hyperglycemia more effectively than sitagliptin by increasing circulating GLP-1 and insulin levels. IBC also decreased DPP-4 activity and expression while increasing GLUT2 expression in the liver and GLUT4 expression in muscles — both critical glucose transporters. Additionally, IBC promoted human skeletal muscle cell proliferation and differentiation, indicating potential benefits for diabetes-related muscle atrophy.

Why it matters

Millions of people take DPP-4 inhibitors for type 2 diabetes, but these synthetic drugs can cause side effects. Finding a natural compound that works even better could eventually lead to safer, plant-derived diabetes treatments. The added muscle-building benefit is particularly notable since muscle loss is a common and underappreciated complication of type 2 diabetes.

How the study worked

The study used a three-tier approach: (1) computational screening of 241 flavonoid compounds using molecular docking to identify potential DPP-4 inhibitors, (2) in vitro testing in Caco-2 intestinal cells to confirm DPP-4 inhibition and measure IC50 values, and (3) in vivo testing in mice fed a high-fat diet to assess blood sugar control, GLP-1 levels, insulin levels, and glucose transporter expression. Muscle cell effects were tested separately using human skeletal muscle cells.

What this study cannot tell us

The in vivo results are from mice on a high-fat diet, which is a model for type 2 diabetes but not identical to human disease. The study did not test long-term safety or toxicity of IBC. Bioavailability of IBC in humans is unknown — compounds that work in mice may not absorb well or reach effective concentrations in people. No human clinical trials have been conducted. The muscle growth effects were observed in cell cultures, not in animals or humans.

How to read the evidence

This study combines computational screening, in vitro cell studies, and in vivo animal experiments, providing a solid preclinical evidence package. However, no human data exists, so clinical relevance remains to be confirmed.

When this study was published

Published in 2026, this is a very recent study contributing to the active search for natural DPP-4 inhibitors and GLP-1-preserving compounds.

The bigger picture

This study is part of a growing effort to find natural alternatives to synthetic diabetes medications. DPP-4 inhibitors are a $10+ billion drug class, and identifying natural compounds with similar or superior activity could expand treatment options. The dual benefit of blood sugar control and muscle support is particularly significant as researchers increasingly recognize sarcopenia (muscle loss) as a serious diabetes complication.

Questions still open

• Is isobavachalcone bioavailable enough in humans to achieve the same DPP-4 inhibition seen in mice?
• Could IBC be developed into a supplement or pharmaceutical for type 2 diabetes management?
• Does the muscle-building effect of IBC persist long-term, and could it prevent diabetes-related sarcopenia in older adults?

Common questions

Read the original research

Isobavachalcone reduces blood glucose and promotes muscle development via dipeptidyl peptidase-4 inhibition.

International journal of biological macromolecules, 339(Pt 1), 149858

Citation

Lee, Eun Ju; Shaikh, Sibhghatulla; Ahmad, Khurshid; Lee, Si Han; Choi, Jae-Moon; Lee, Yong Ho; Choi, Inho. (2026). Isobavachalcone reduces blood glucose and promotes muscle development via dipeptidyl peptidase-4 inhibition.. International journal of biological macromolecules, 339(Pt 1), 149858. https://doi.org/10.1016/j.ijbiomac.2025.149858