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AIM: Berberine (BBR) is a well-established natural product lowing glucose and promoting insulin secretion in mice and diabetic patients. However, the bioavailability of BBR is low and the target remains unclear. Here, a BBR analog dihydroberberine (DHB) showed higher bioavailability in promoting insulin secretion by targeting glucokinase (GCK) that has been reported as a powerful regulator of diabetes by promoting insulin secretion. MATERIALS AND METHODS: To evaluate the effects and mechanisms of drugs in MIN6 and INS-1 cells, cell viability, glucose-stimulated insulin secretion (GSIS) and the expression of genes associated with insulin secretion and cell function were assessed. Glucose tolerance, insulin secretion and insulin tolerance experiment were conducted to confirm the effects of DHB in vivo. Molecular docking, CETSAs, and knockdown experiments were used to predict and validate the target. RESULTS: DHB promoted glucose-stimulated insulin secretion (GSIS) in INS-1 and MIN6 cells. DHB might be one of the most effective BBR analog, as validated by the improved oral glucose tolerance test (GTT) and insulin released test (IRT) assays in mice. In addition, molecular docking and cellular thermal shift assay (CETSA) revealed that DHB formed compact complexes with GCK. Importantly, the effects of DHB were significantly diminished in INS-1 cells upon deprivation of GCK in siRNA knockdown assay, supporting that GCK is required for DHB promoting glucose-stimulated insulin secretion (GSIS) and preventing cell apoptosis in pancreatic β-cells. CONCLUSIONS: Our findings suggest DHB might be one of the most effective compound via regulating GCK.
Zhang et al. (Mon,) studied this question.