Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Pathology and Laboratory Medicine

Supervisor

Wang, Rennian

Affiliation

The University of Western Ontario, Children's Health Research Institute

Abstract

Type 2 diabetes mellitus (T2DM) progression increases oxidative stress which contributes to beta cell compensation and eventual dysfunction. To investigate the role of antioxidant N-acetyl-L-cysteine (NAC) on beta cell function and pancreatic stellate cell activation (aSMA+) during early and late stages of compensation, NAC was used for preventative (p) and intervention (i) treatments in C57BL/6N mice fed a 60% kcal high-fat diet (HFD) for 8 or 22 weeks. Significantly improved glucose tolerance was observed at 22 weeks following pNAC treatment in HFD mice. Although 22-week HFD mice displayed hyperinsulinemia, beta cell hypertrophy, decreased beta cell PDX-1 nuclear localization, and increased intra-islet aSMA+ cells, HFD mice with iNAC treatment normalized beta cell mass and insulin secretion, improved nuclear PDX-1 labeling, and decreased intra- islet aSMA+ staining. In conclusion, NAC treatment prevented beta cell over-compensation associated dysfunction and improved metabolic outcomes in diet-induced obesity T2DM mouse models.

Summary for Lay Audience

Type 2 diabetes mellitus (T2DM) is a progressive disease that occurs in multiple stages, with each stage causing increased levels of stress on cells responsible for lowering blood sugar through the hormone insulin. Early in T2DM, the body requires more insulin production. Insulin-producing cells can keep up with this demand for a short period of time by increasing their size and number. However, the increased demand for insulin causes insulin-producing cells to develop complications, which eventually leads to their failure. The drug N-acetyl-L-cysteine (NAC) has been shown to decrease a type of stress found in T2DM insulin-producing cells. This study determined whether decreasing the stress using NAC could help protect the insulin-producing cells, and when it was most effective. When NAC was given to mice that demonstrated T2DM progression, their insulin-producing cells were partially protected from developing dysfunction when compared to insulin-producing cells from T2DM mice not treated with NAC. These cells increased markers of their ability to produce and release insulin, did not increase in size, and did not overproduce insulin, suggesting they were functioning more like the normal insulin-producing cells rather than those experiencing T2DM. However, no significant improvement was found in overall blood sugar levels from T2DM mice treated with NAC. When NAC was given to mice one week before T2DM started, significant improvements in blood sugar levels and improvements in the size of the insulin-producing cell area were found. In conclusion, NAC may be able to protect insulin-producing cells from the dysfunction associated with overcompensation during T2DM, as well as whole-body metabolic changes when taken early enough and for a long-time duration.

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