The long-range goal of this research is to identify and characterize natural agents that can effectively prevent type 2 diabetes (T2D). T2D is a result of chronic insulin resistance and loss of ?-cell mass and function. Therefore, a method to simultaneously prevent insulin resistance and protect functional ?-cell mass could be a more effective strategy to prevent T2D. We discovered for the first time that genistein, an isoflavone present in soybean and some Chinese herbs, directly protect pancreatic ?-cells from apoptosis and ameliorates hyperglycemia without affecting insulin sensitivity in diabetic mice, while kaempferol, a flavonol present in gingko biloba, improves insulin sensitivity and glucose homeostasis in obese mice. Notably, genistein in combination with kaempferol produces a potent additive effect on blood glycemic control in middle-aged obese diabetic mice. We used mice at this age because T2D usually occurs at middle and older age in humans. These exciting findings demonstrate a great potential for using these natural compounds to effectively prevent T2D. The goal of this application is to determine molecular mechanisms by which genistein and kaempferol exert an anti-diabetic effect. The central hypothesis of this grant is that dietary intae of both genistein and kaempferol simultaneously preserves functional ?-cell mass and improves insulin sensitivity, thereby exerting the additive effect in preventing T2D.
Aim #1 will determine whether genistein protects against ?-cell apoptosis through the G-protein coupled receptor GPR30-mediated activation of G?s, and subsequent stimulation of the cAMP/PKA/CREB and PI3K/Akt pathways. Isolated mouse and human islets will be used to identify the signaling molecules targeted by genistein. Specifically, GPR30-deficient mice and genetic and pharmacological probes will be utilized to explore whether these pathways mediate the anti-apoptotic action of genistein in ?-cells.
Aim #2 will explore the effects of genistein, kaempferol, or a combination of both on pancreatic beta-cell function, energy metabolism, and insulin sensitivity as well as the underlying molecular mechanisms for these actions in vivo. We will first use GPR30-deificent diabetic mice to determine whether genistein improves glucose homeostasis and ?-cell survival and mass via this receptor. We will then test whether kaempferol promotes energy metabolism and insulin sensitivity and whether these effects are mediated via activation of AMPK??, a master regulator of cellular energy homeostasis and potential therapeutic target for T2D. Completion of this grant is expected to define novel mechanisms by which genistein and kaempferol exert the anti-diabetic effects, which may potentially lead to the development of complementary or alternative (CAM) strategies using these low-cost natural compounds for the prevention of diabetes, a major and growing public health problem in the U.S. and worldwide.

Public Health Relevance

Diabetes mellitus is a growing health problem, which presently affects 23.6 million or 7.8% of the American population, and this number is projected to double by 2025. Loss of insulin secreting ?-cell mass through apoptosis is central to the development of both type 1 and type 2 diabetes. The results of this research, which is aimed at identifying and characterizing natural agents that are capable of protecting ?-cells from death, may allow us to develop low-cost alternative treatment for this disease.

National Institute of Health (NIH)
National Center for Complementary & Alternative Medicine (NCCAM)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAT1-SM (24))
Program Officer
Hopp, Craig
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Virginia Polytechnic Institute and State University
Schools of Earth Sciences/Natur
United States
Zip Code
Cheng, Zhiyong; Schmelz, Eva M; Liu, Dongmin et al. (2014) Targeting mitochondrial alterations to prevent type 2 diabetes--evidence from studies of dietary redox-active compounds. Mol Nutr Food Res 58:1739-49
Nallasamy, Palanisamy; Si, Hongwei; Babu, Pon Velayutham Anandh et al. (2014) Sulforaphane reduces vascular inflammation in mice and prevents TNF-?-induced monocyte adhesion to primary endothelial cells through interfering with the NF-?B pathway. J Nutr Biochem 25:824-33
Si, Hongwei; Liu, Dongmin (2014) Dietary antiaging phytochemicals and mechanisms associated with prolonged survival. J Nutr Biochem 25:581-91
Babu, Pon Velayutham Anandh; Liu, Dongmin; Gilbert, Elizabeth R (2013) Recent advances in understanding the anti-diabetic actions of dietary flavonoids. J Nutr Biochem 24:1777-89
Jia, Zhenquan; Zhen, Wei; Velayutham Anandh Babu, Pon et al. (2013) Phytoestrogen genistein protects against endothelial barrier dysfunction in vascular endothelial cells through PKA-mediated suppression of RhoA signaling. Endocrinology 154:727-37
Fu, Zhuo; Gilbert, Elizabeth R; Liu, Dongmin (2013) Regulation of insulin synthesis and secretion and pancreatic Beta-cell dysfunction in diabetes. Curr Diabetes Rev 9:25-53
Gilbert, Elizabeth R; Liu, Dongmin (2013) Anti-diabetic functions of soy isoflavone genistein: mechanisms underlying its effects on pancreatic *-cell function. Food Funct 4:200-12
Fu, Zhuo; Yuskavage, Julia; Liu, Dongmin (2013) Dietary flavonol epicatechin prevents the onset of type 1 diabetes in nonobese diabetic mice. J Agric Food Chem 61:4303-9