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- Title
Overexpression of PPAR in pancreatic β-cells exacerbates glucose intolerance in diet-induced obese mice.
- Authors
Uy, Christopher E.; Hogh, K-Lynn N.; Baker, Robert; Asadi, Ali; Fraser, Jordie; Riedel, Michael; Kieffer, Timothy J.; Gray, Sarah L.
- Abstract
Lipotoxicity is one mechanism implicated in beta-cell dysfunction during the development of obesity-induced type 2 diabetes (T2D). Peroxisome proliferator-activated receptor gamma (PPARg) is a transcription factor involved in lipid uptake and storage. We hypothesize that localized overexpression of lipogenic PPAR gamma in pancreatic beta-cells will aggravate the effects of obesity induced lipotoxicity and impair glucose homeostasis. In MIN6 cells, we have successfully overexpressed PPAR gamma utilizing an adeno-associated viral vector (dsAAV8) and have shown induction in PPAR gamma target genes. Additionally, we have overexpressed PPAR gamma in the pancreatic beta-cells of obese (16wks HFD) C57B/6 mice using the dsAAV8 virus. Changes in carbohydrate metabolism were monitored regularly through bi-weekly measurement of 4-hour fasted blood glucose and monthly measurement of oral glucose tolerance (OGTT), insulin tolerance (ITT), glucose-stimulated insulin secretion (GSIS), and plasma insulin levels. Islet morphology was also assessed at the end of the study. In vivo, pancreatic beta-cell specific overexpression of PPAR gamma impairs glucose tolerance compared to obese controls This disruption in glucose homesostasis is not associated with changes in insulin sensitivity, and instead may be associated with reduced beta-cell mass.This study demonstrates that targeted delivery of PPAR gamma to the beta-cell specifically aggravates the lipotoxic effects of obesity on beta-cell function providing a useful in vivo model to elucidate the mechanisms involved in beta-cell lipotoxicity in obesity-induced T2D.
- Publication
UBC Medical Journal, 2011, Vol 2, Issue 2, p31
- ISSN
1920-7425
- Publication type
Academic Journal