UCP2 in pancreatic beta-cells : a radical way to short circuit glucose sensing?
Year: 2005
Type: dissertation
Abstract: Uncoupling proteins (UCPs) catalyse proton transport across the mitochondrial inner membrane, thereby uncoupling oxidative phosphorylation. UCP2 is expressed in several mammalian tissues including pancreatic β-cells. Since UCP2 activity uncouples the processes that link glucose metabolism (oxidation) to insulin secretion (phosphorylation), it is expected to attenuate glucose-stimulated insulin secretion (GSIS). Published studies using UCP2 over-expressing and UCP2 ablated β-cells support this hypothesis. Therefore, identifying regulators of β-cell UCP2 activity may help develop novel ways to treat type II diabetes. Furthermore, β-cells present a valuable system with which to study UCP2 activity in situ. Studies using isolated mitochondria have demonstrated that the superoxide radical and particular reactive alkenals activate UCP2, and that novel, mitochondrially-targeted antioxidants (mito-antioxidants) prevent activation of UCP2 by superoxide. Mito-antioxidants and reactive alkenals are thus useful tools to investigate pancreatic β-cell UCP2 activity in situ. I hypothesised that endogenously produced superoxide activates UCP2 in β-cells to negatively regulate GSIS, and tested this hypothesis by measuring UCP2 activity in isolated β-cell mitochondria and GSIS in intact β-cells. Mito-antioxidants prevented superoxide-activation of UCP2 in isolated β-cell mitochondria but, surprisingly, did not potentiate GSIS. These unexpected findings suggested that either UCP2 was endogenously inactive, or endogenous UCP2 activity is not inhibited by mito-antioxidants. I sought to distinguish between these possibilities using UCP2 overexpressing β-cells, and by investigating isolated mitochondria in which UCP2 appeared to be endogenously active. Certain reactive alkenals both activated UCP2 in β cell mitochondria and attenuated GSIS in intact cells, suggesting that may attenuate insulin secretion physiologically, or provide valuable tools to probe UCP2 activity in cells.
Author: Green, K
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7043572144