American Diabetes Association
Moon_et_al-Supplementary_Figures_cx.pdf (47.19 MB)

HIF-2α Preserves Mitochondrial Activity And Glucose Sensing in Compensating Beta Cells in Obesity

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Version 2 2022-05-18, 20:08
Version 1 2022-04-26, 21:26
posted on 2022-05-18, 20:08 authored by Jae-Su Moon, Matthew Riopel, Jong Bae Seo, Vicente Herrero-Aguayo, Roi Isaac, Yun Sok Lee

In obesity, increased mitochondrial metabolism with the accumulation of oxidative stress leads to mitochondrial damage and beta cell dysfunction. In particular, beta cells express anti-oxidant enzymes at relatively low levels and are highly vulnerable to oxidative stress. Early in the development of obesity, beta cells exhibit increased GSIS, in order to compensate for insulin resistance. This increase in beta cell function under the condition of enhanced metabolic stress suggests that beta cells possess a defense mechanism(s) against increased oxidative damage, which may become insufficient or decline at the onset of type 2 diabetes. Here, we show that metabolic stress induces beta cell HIF-2a, which stimulates anti-oxidant gene expression (e.g. Sod2 and Cat) and protects against mitochondrial ROS and subsequent mitochondrial damage. Knockdown of HIF-2a in Min6 cells exaggerated chronic high glucose-induced mitochondrial damage and beta cell dysfunction by increasing mitochondrial ROS levels. Moreover, inducible beta cell HIF-2a KO mice developed more severe beta cell dysfunction and glucose intolerance on high fat diet, along with increased ROS levels and decreased islet mitochondrial mass. Our results provide a previously unknown mechanism for how beta cell defends against increased metabolic stress to promote beta cell compensation in obesity. 


This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (NIH) (DK124298), a UCSD Health Sciences Research Grant (RG084153), a grant from the Janssen Pharmaceuticals. Inc, a grant Cymabay Therapeutics, Inc, and a grant from pH Pharma, LTD.


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