Indiana University-Purdue University Indianapolis (IUPUI) / Type 1 and Type 2 diabetes (T1D/T2D) share a common etiology that involves an
increase in oxidative stress that leads to dysfunction and subsequent β cell death.
Lipoxygenases are enzymes that catalyze the oxygenation of polyunsaturated fatty acids
to form lipid metabolites involved in a variety of biological functions including cellular
oxidative stress response. On the other hand, Interleukin 6 (IL-6) signaling has been
demonstrated to be protective in islets. In this study, we explored the effect of
lipoxygenase enzymes 12-Lipoxygenase, 12/15 Lipoxygenase and IL-6 on β cell function
and survival in mice using both STZ and high-fat diet (HFD) models of diabetes. Alox12-/-
mice showed greater impairment in glucose tolerance following STZ and HFD compared
to wild-type mice (WT), whereas Alox15-/- were protected against dysglycemia. These
findings were accompanied by evidence of islet oxidative stress in Alox12-/- mice and
reduced oxidative stress in Alox15-/- mice, consistent with alterations in the expression of
antioxidant response enzymes in islets from these mice. Additionally, islets from Alox12-/-
mice showed a compensatory increase in Alox15 gene expression and treatment of these
mice with the 12/15-lipoxygenase inhibitor ML-351 rescued the dysglycemic phenotype.
IL-6 was able to significantly attenuate the generation of reactive oxygen species by
proinflammatory cytokines in human pancreatic islets. Furthermore, we find that IL-6
regulates the master antioxidant response protein NRF2. Collectively these results show
that loss of Alox12 activates a compensatory increase in Alox15 that sensitizes β cells to
oxidative stress and signaling by IL-6 is required for maximal antioxidant response under
conditions of increased ROS formation, such as obesity.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/19948 |
| Date | 06 1900 |
| Creators | Conteh, Abass M. |
| Contributors | Mirmira, Raghavendra G., Linnemann, Amelia K., Anderson, Ryan M., Considine, Robert V., Harrington, Maureen A. |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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