Glycemic and Lipid Outcomes Associated with Bitter Melon Blood-Sugar-Modulating Protein and Metformin Use: A Translational Preclinical and Retrospective Study

Background/Objectives: Interactions between botanical supplements and standard antidiabetic therapies remain poorly understood. This study investigated the efficacy and mechanistic properties of a bitter melon blood-sugar-modulating protein (BMP) in relation to concurrent metformin use for improving glucose and lipid metabolism. Methods: A translational approach combined mechanistic evaluation in db/db mice with an exploratory, real-world observational cohort study of 119 individuals with prediabetes or diabetes. BMP was characterized by liquid chromatography-electrospray ionization-tandem mass spectrometry. In the retrospective self-controlled clinical arm, participants receiving daily BMP supplementation were stratified by metformin use and dosage to evaluate changes in glycated hemoglobin (HbA1c) and lipid profiles over 3 months. Results: In db/db mice, BMP significantly reduced fasting blood glucose and HbA1c, with greater glucose-lowering efficacy observed when combined with metformin compared to metformin alone (approximately 300 mg/dL vs. 200 mg/dL reduction; p < 0.05). Skeletal muscle transcriptomic analysis identified coordinated regulation of 27 shared pathways involved in glucose and lipid metabolism. In the clinical cohort, BMP supplementation was associated with reductions in HbA1c (−0.23%, p = 0.0028), total cholesterol (−7.5 mg/dL), and low-density lipoprotein cholesterol (−6.1 mg/dL) among metformin users, whereas no significant changes were observed in non-users. The greatest observed HbA1c reduction (−0.32%, p < 0.0001) occurred in participants receiving 1000 mg/day of metformin. Conclusions: Preclinical data demonstrate coordinated pathway remodeling in skeletal muscle and improved glycemic control when BMP is combined with metformin. In the clinical cohort, BMP supplementation was associated with modest reductions in HbA1c and lipid parameters, primarily among participants using concurrent metformin. Given the retrospective, self-controlled design and baseline clinical differences between treatment groups, these clinical findings reflect observational associations rather than causal effects. Overall, this study is the first to demonstrate that BMP, a major protein component of bitter melon, exhibits complementary metabolic effects when combined with first-line antidiabetic therapy in animal models. Furthermore, by revealing a corresponding observational association in human clinical settings, this work establishes an important foundation for nutritional protein research.