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.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Research Project (R01)
Project #
5R01AT007077-03
Application #
8619589
Study Section
Special Emphasis Panel (ZAT1-SM (24))
Program Officer
Hopp, Craig
Project Start
2012-03-01
Project End
2017-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
3
Fiscal Year
2014
Total Cost
$379,887
Indirect Cost
$137,387
Name
Virginia Polytechnic Institute and State University
Department
Nutrition
Type
Schools of Earth Sciences/Natur
DUNS #
003137015
City
Blacksburg
State
VA
Country
United States
Zip Code
24061
Tao, Zhipeng; Zheng, Louise D; Smith, Cayleen et al. (2018) Estradiol signaling mediates gender difference in visceral adiposity via autophagy. Cell Death Dis 9:309
Alkhalidy, Hana; Moore, Will; Wang, Yao et al. (2018) The Flavonoid Kaempferol Ameliorates Streptozotocin-Induced Diabetes by Suppressing Hepatic Glucose Production. Molecules 23:
Luo, Jing; Wang, Aihua; Zhen, Wei et al. (2018) Phytonutrient genistein is a survival factor for pancreatic ?-cells via GPR30-mediated mechanism. J Nutr Biochem 58:59-70
Alkhalidy, Hana; Moore, Will; Wang, Aihua et al. (2018) Kaempferol ameliorates hyperglycemia through suppressing hepatic gluconeogenesis and enhancing hepatic insulin sensitivity in diet-induced obese mice. J Nutr Biochem 58:90-101
Alkhalidy, Hana; Wang, Yao; Liu, Dongmin (2018) Dietary Flavonoids in the Prevention of T2D: An Overview. Nutrients 10:
Wang, Aihua; Luo, Jing; Moore, William et al. (2016) GPR30 regulates diet-induced adiposity in female mice and adipogenesis in vitro. Sci Rep 6:34302
Liu, Longhua; Tao, Zhipeng; Zheng, Louise D et al. (2016) FoxO1 interacts with transcription factor EB and differentially regulates mitochondrial uncoupling proteins via autophagy in adipocytes. Cell Death Discov 2:16066
Jia, Zhenquan; Nallasamy, Palanisamy; Liu, Dongmin et al. (2015) Luteolin protects against vascular inflammation in mice and TNF-alpha-induced monocyte adhesion to endothelial cells via suppressing I?B?/NF-?B signaling pathway. J Nutr Biochem 26:293-302
Alkhalidy, Hana; Moore, William; Zhang, Yanling et al. (2015) Small Molecule Kaempferol Promotes Insulin Sensitivity and Preserved Pancreatic ? -Cell Mass in Middle-Aged Obese Diabetic Mice. J Diabetes Res 2015:532984
Liu, L; Zou, P; Zheng, L et al. (2015) Tamoxifen reduces fat mass by boosting reactive oxygen species. Cell Death Dis 6:e1586

Showing the most recent 10 out of 24 publications