Skip to Main Content
 

Global Search Box

 
 
 

ETD Abstract Container

Abstract Header

Stress Reducing, Protective Activities, and Working Mechanisms of α-PGG and 6Cl- TGQ in Pancreatic β-cells.

Cottrill, David
http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1614345333101552

Abstract Details

2021, Doctor of Philosophy (PhD), Ohio University, Biological Sciences (Arts and Sciences).
Type 2 diabetes (T2DM) is a global epidemic affecting 422 million people. It is characterized by a progressive loss of insulin sensitivity, increasing hyperglycemia, and other deleterious physiological effects. Pancreatic β-cells are endocrine cells responsible for secretion of the hormone insulin in response to a meal. Glucose transporter 2 (GLUT2) is a transport protein responsible for glucose uptake by β-cells, and therefore serves as a “sensor” of blood glucose levels. Increases in glucose uptake trigger the secretion of the hormone insulin. Insulin then travels through the blood stream and binds to the insulin receptor located on insulin sensitive cells such as fat and muscle, triggering the uptake of glucose from the blood and restoring glucose homeostasis. Recent research has indicated that β-cell dysfunction and loss because of hyperglycemic conditions is a significant contributor to the progression of T2D, making preservation of these cells a highly active area of research. Naturally occurring compound α-PGG and its synthetic derivative 6Cl-TGQ have previously been identified as insulin-mimetic compounds that bind to the insulin receptor and trigger glucose uptake both in vitro and in vivo. During in vivo characterization, it was also found that they lost their blood glucose lowering effects and inhibited endogenous insulin secretion. Further investigation found that this effect was a result of the compounds inhibiting glucose transport in pancreatic β-cells, a process coupled to insulin secretion. In this study, we hypothesized that the glucose uptake inhibition could provide a protective effect for β-cells from hyperglycemia induced oxidative stress and cell death. Given the demonstrated insulin receptor (IR) activity of these compounds, we first conducted tests to confirm the target for these effects was direct glucose transport inhibition separate from the IR. In silico docking analysis confirmed that each compound could bind to the central channel of GLUT2, the primary glucose transporter in rodent β- cells. Glucose uptake assays utilizing insulin revealed no significant activity, and glucose stimulated insulin secretion assays utilizing S961, an IR antagonist, do not diminish the effect of α-PGG/TGQ, indicating that the reductions in glucose uptake are separate from IR activity. Metabolic activity of hyperglycemic stressed rat INS-1 832/13 β cells was reduced below control levels in Seahorse experiments with α-PGG /TGQ treatment, and untargeted metabolomics analysis indicated that α-PGG /TGQ were targeting glucose metabolism. This was met with concomitant reductions in intracellular ROS and makers of oxidative stress m-tyrosine/3-nitrotyrosine and intracellular MDA content. Activity of cellular oxidative defense enzymes catalase and superoxide dismutase were reduced with α-PGG and TGQ, indicating that the primary means behind reductions in ROS were decreases in glucose uptake and metabolism. By reducing oxidative stress, α-PGG and TGQ increased viability of hyperglycemic INS-832/13 cells in a manner separate from their IR activity. Due to TGQ’s greater specificity for the IR, its overall effect tended to be less than that of α-PGG. This in conjunction with our insulin and S961 experiments suggest that these different activities of α-PGG and TGQ can be separated and further refined through future structure activity relationship studies.
Xiaozhuo Chen, Ph.D (Committee Chair)
Stephen Bergmeier, Ph.D (Committee Member)
Craig Nunemaker, Ph.D (Committee Member)
Sarah Wyatt, Ph.D (Committee Member)
133 p.
Biology; Biomedical Research; Cellular Biology; Molecular Biology
diabetes; beta-cells; tannins; hyperglycemia; glucose uptake; glucotoxicity

Recommended Citations

Citations

  • Cottrill, D. (2021). Stress Reducing, Protective Activities, and Working Mechanisms of α-PGG and 6Cl- TGQ in Pancreatic β-cells. [Doctoral dissertation, Ohio University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1614345333101552

    APA Style (7th edition)

  • Cottrill, David. Stress Reducing, Protective Activities, and Working Mechanisms of α-PGG and 6Cl- TGQ in Pancreatic β-cells. 2021. Ohio University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1614345333101552.

    MLA Style (8th edition)

  • Cottrill, David. "Stress Reducing, Protective Activities, and Working Mechanisms of α-PGG and 6Cl- TGQ in Pancreatic β-cells." Doctoral dissertation, Ohio University, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1614345333101552

    Chicago Manual of Style (17th edition)

ohiou1614345333101552
310
© 2021, all rights reserved.
This open access ETD is published by Ohio University and OhioLINK.