(442j) Effects of Flavonoids from Recombinant Microorganisms on Pancreatic Β-Cell Insulin Regulation

Flavonoids are known for their beneficial effects as antioxidants and anticancer agents but in a number of studies, flavonoids have also been shown to alter insulin regulation. Although the exact mechanism(s) for such alteration is not clear, flavonoids affect the activity of enzymes linked to insulin regulation and blood glucose homeostasis. In patients with Type 2 diabetes, insulin release from the pancreas is altered and no longer compensates for insulin resistance due to increasing obesity, aging, or illness. Evidently, pharmacological agents with insulinotropic properties are used to treat patients with Type 2 diabetes. Therefore, flavonoids with such properties may have a great potential as diabetes therapeutics. Flavonoid biosynthesis can be achieved through metabolic engineering of industrially important microorganisms Escherichia coli and Saccharomyces cerevisiae using inexpensive phenylpropanoic precursors and glucose. Artificial flavonoid biosynthetic pathways were inserted and optimized in these microorganisms through simultaneous episomal expression of plant-derived genes resulting in the biosynthesis of a library of flavonoid molecules such as flavanones, flavones, flavonols, flavanols, and anthocyanins. By applying a mutasynthesis approach, various flavonoid analogues were produced from the recombinant strains. In this study, we examined the insulinotropic properties for various flavonoids focusing primarily on unnatural flavonoids produced in recombinant microorganisms. Afzelechin, for example, was shown to modulate the secretory characteristics of pancreatic β-cell lines used as models of native β-cells. Upon glucose stimulation, insulin secretion was enhanced in afzelechin-treated cells compared to non-treated control cultures. In addition, transcription of the preproinsulin gene was modulated when β-cells were exposed to afzelechin. At the concentration levels that afzelechin was employed, no adverse effects were observed on cell viability even after prolonged incubation. Also, studies will be presented aiming at understanding the mechanism(s) by which flavonoids effect changes on the signaling of insulin and its secretion.