Dataset Information

Interleukin-6 Reduces ?-Cell Oxidative Stress by Linking Autophagy With the Antioxidant Response.

ABSTRACT: Production of reactive oxygen species (ROS) is a key instigator of ?-cell dysfunction in diabetes. The pleiotropic cytokine interleukin 6 (IL-6) has previously been linked to ?-cell autophagy but has not been studied in the context of ?-cell antioxidant response. We used a combination of animal models of diabetes and analysis of cultured human islets and rodent ?-cells to study how IL-6 influences antioxidant response. We show that IL-6 couples autophagy to antioxidant response and thereby reduces ROS in ?-cells and human islets. ?-Cell-specific loss of IL-6 signaling in vivo renders mice more susceptible to oxidative damage and cell death through the selective ?-cell toxins streptozotocin and alloxan. IL-6-driven ROS reduction is associated with an increase in the master antioxidant factor NRF2, which rapidly translocates to the mitochondria to decrease mitochondrial activity and stimulate mitophagy. IL-6 also initiates a robust transient decrease in cellular cAMP levels, likely contributing to the stimulation of mitophagy to mitigate ROS. Our findings suggest that coupling autophagy to antioxidant response in ?-cells leads to stress adaptation that can reduce cellular apoptosis. These findings have implications for ?-cell survival under diabetogenic conditions and present novel targets for therapeutic intervention.

SUBMITTER: Marasco MR

PROVIDER: S-EPMC6054440 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Interleukin-6 Reduces β-Cell Oxidative Stress by Linking Autophagy With the Antioxidant Response.

Marasco Michelle R MR Conteh Abass M AM Reissaus Christopher A CA Cupit John E JE Appleman Evan M EM Mirmira Raghavendra G RG Linnemann Amelia K AK

Diabetes 20180521 8

Production of reactive oxygen species (ROS) is a key instigator of β-cell dysfunction in diabetes. The pleiotropic cytokine interleukin 6 (IL-6) has previously been linked to β-cell autophagy but has not been studied in the context of β-cell antioxidant response. We used a combination of animal models of diabetes and analysis of cultured human islets and rodent β-cells to study how IL-6 influences antioxidant response. We show that IL-6 couples autophagy to antioxidant response and thereby reduc ...[more]

PMID: 29784660

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Project description:Many theories have been advanced to better understand why β cell function and structure relentlessly deteriorate during the course of type 2 diabetes (T2D). These theories include inflammation, apoptosis, replication, neogenesis, autophagy, differentiation, dedifferentiation, and decreased levels of insulin gene regulatory proteins. However, none of these have considered the possibility that endogenous self-repair of existing β cells may be an important factor. To examine this hypothesis, we conducted studies with female Zucker diabetic fatty rats fed a high-fat diet (HFD) for 1, 2, 4, 7, 9, 18, or 28 days, followed by a return to regular chow for 2-3 weeks. Repair was defined as reversal of elevated blood glucose and of inappropriately low blood insulin levels caused by a HFD, as well as reversal of structural damage visualized by imaging studies. We observed evidence of functional β cell damage after a 9-day exposure to a HFD and then repair after 2-3 weeks of being returned to normal chow (blood glucose [BG] = 348 ± 30 vs. 126 ± 3; mg/dl; days 9 vs. 23 day, P < 0.01). After 18- and 28-day exposure to a HFD, damage was more severe and repair was less evident. Insulin levels progressively diminished with 9-day exposure to a HFD; after returning to a regular diet, insulin levels rebounded toward, but did not reach, normal values. Increase in β cell mass was 4-fold after 9 days and 3-fold after 18 days, and there was no increase after 28 days of a HFD. Increases in β cell mass during a HFD were not different when comparing values before and after a return to regular diet within the 9-, 18-, or 28-day studies. No changes were observed in apoptosis or β cell replication. Formation of intracellular markers of oxidative stress, intranuclear translocation of Nrf2, and formation of intracellular antioxidant proteins indicated the participation of HFD/oxidative stress induction of the Nrf2/antioxidant pathway. Flow cytometry-based assessment of β cell volume, morphology, and insulin-specific immunoreactivity, as well as ultrastructural analysis by transmission electron microscopy, revealed that short-term exposure to a HFD produced significant changes in β cell morphology and function that are reversible after returning to regular chow. These results suggest that a possible mechanism mediating the ability of β cells to self-repair after a short-term exposure to a HFD is the activation of the Nrf2/antioxidant pathway.

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Dataset Information

Interleukin-6 Reduces ?-Cell Oxidative Stress by Linking Autophagy With the Antioxidant Response.

Publications

Interleukin-6 Reduces β-Cell Oxidative Stress by Linking Autophagy With the Antioxidant Response.

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