Genipin

Uncoupling protein 2 (UCP2) is a mitochondrial carrier protein that is expressed in pancreatic islets and has been shown to negatively regulate glucose-stimulated insulin secretion.^1,2 High levels of UCP2 expression can disrupt pancreatic β cell function and downregulate insulin secretion thereby contributing to the development of type 2 diabetes.³ Genipin, a compound isolated from Gardenis jasminoides Ellis fruits, was originally identified as a protein cross-linking agent. Genipin is a cell-permeable inhibitor of UCP2 activity.⁴ Genipin, at 5 µM, increases glucose-stimulated insulin secretion in isolated pancreatic islets chronically exposed to high levels of glucose.⁵ Genipin also exhibits anti-inflammatory and anti-angiogenic properties by inducing apoptosis in FaO rat hepatoma cells and human hepatocarcinoma Hep3B cells.⁶

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1. Chan, C.B., De Leo, D., Joseph, J.W., et al. Increased uncoupling protein-2 levels in ß-cells are associated with impaired glucose-stimulated insulin secretion mechanism of action. Diabetes 50(6), 1302-1310 (2001).

2. Zhang, C.Y., Baffy, G., Perret, P., et al. Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, ß cell dysfunction, and type 2 diabetes. Cell 105(6), 745-755 (2001).

3. Sesti, G., Cardellini, M., Marini, M.A., et al. A common polymorphism in the promoter of UCP2 contributes to the variation in insulin secretion in glucose-tolerant subjects. Diabetes 52(5), 1280-1283 (2003).

4. Parton, L.E., Ye, C.P., Coppari, R., et al. Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity. Nature 449(7159), 228-232 (2007).

5. Zhang, C.Y., Parton, L.E., Ye, C.P., et al. Genipin inhibits UCP2-mediated proton leak and acutely reverses obesity-and high glucose-induced ß cell dysfunction in isolated pancreatic islets. Cell Metab. 3(6), 417-427 (2006).

6. Kim, B.C., Kim, H.G., Lee, S.A., et al. Genipin-induced apoptosis in hepatoma cells is mediated by reactive oxygen species/c-Jun NH2-terminal kinase-dependent activation of mitochondrial pathway. Biochem. Pharmacol. 70(9), 1398-1407 (2005).