Autoimmune Polyglandular Syndrome Type 3 Complicated with IgG4-related Disease.

A 52-year-old Japanese woman developed type 1 diabetes mellitus (type 1 DM) at 41 years old. She became complicated with Hashimoto's disease and showed swelling of both submandibular glands, which was diagnosed as IgG4-related disease (IgG4-RD). This is a rare case of a Japanese patient with autoimmune polyglandular syndrome type 3A (APS-3A) coexisting with autoimmune thyroid disease (AITD) and type 1 DM complicated by IgG4-RD. Bilateral submandibular gland resection was successfully performed without steroid therapy. We discuss the possibility that the immunological pathogenic mechanisms of APS-3A and IgG4-RD are related.

Hypoglycemia Induces Mitochondrial Reactive Oxygen Species Production Through Increased Fatty Acid Oxidation and Promotes Retinal Vascular Permeability in Diabetic Mice.

Aims: Hypoglycemia is associated with increased reactive oxygen species (ROS) production and vascular events. We have previously reported that low-glucose (LG) conditions induce mitochondrial ROS (mtROS) production in aortic endothelial cells (ECs). However, the mechanism by which hypoglycemia promotes diabetic retinopathy (DR) is unclear. Blood-retinal barrier (BRB) disruption occurs in the early stages of DR. We hypothesized that the mechanisms underlying hypoglycemia-induced DR are associated with BRB breakdown due to mtROS generation during hypoglycemia. Here, we aimed to determine whether hypoglycemia exacerbated mtROS production and induced BRB disruption. Results: We observed that hypoglycemia induced mtROS production by increasing fatty acid oxidation (FAO), which was suppressed by overexpression of mitochondrial-specific manganese superoxide dismutase (MnSOD) in retinal ECs. Furthermore, FAO blockade decreased the hypoglycemia-induced mtROS production. Recurrent hypoglycemia increased albumin leak in diabetic mice retina, which was suppressed in diabetic vascular endothelial cell-specific MnSOD transgenic (eMnSOD-Tg) mice. Pharmacological FAO blockade also reduced mtROS production, reduced vascular endothelial growth factor (VEGF) production during hypoglycemia, and prevented retinal vascular permeability in diabetic mice. MnSOD overexpression or carnitine palmitoyltransferase I (CPT1) blockade suppressed vascular endothelial-cadherin phosphorylation under LG in retinal ECs. Innovation and Conclusion: Reduction of mtROS and VEGF production via pharmacological FAO and/or CPT1 blockade may prevent hypoglycemia-induced worsening of DR.

Low glucose induces mitochondrial reactive oxygen species via fatty acid oxidation in bovine aortic endothelial cells.

AIMS/INTRODUCTION: Overproduction of reactive oxygen species (ROS) in endothelial cells (ECs) plays a pivotal role in endothelial dysfunction. Mitochondrial ROS (mtROS) is one of the key players in the pathogenesis of diabetic vascular complications. Hypoglycemia is linked to increased ROS production and vascular events; however, the underlying mechanisms remain unclear. In the present study, we aimed to determine whether and how low glucose (LG) mediates mtROS generation in ECs, and to examine the impact of LG-induced mtROS on endothelial dysfunction. MATERIALS AND METHODS: Metabolomic profiling, cellular oxygen consumption rate, mtROS, endothelial nitric oxide synthase phosphorylation, and the expression of vascular cell adhesion molecule-1 or intercellular adhesion molecule-1 were evaluated in bovine aortic ECs. RESULTS: We found that LG increased mtROS generation in ECs; which was suppressed by overexpression of manganese superoxide dismutase. Comprehensive metabolic analysis using capillary electrophoresis-mass spectrometry and oxygen consumption rate assessment showed that the pathway from fatty acid to acetyl-CoA through fatty acid oxidation was upregulated in ECs under LG conditions. In addition, etomoxir, a specific inhibitor of the free fatty acid transporter, decreased LG-induced mtROS production. These results suggested that LG increased mtROS generation through activation of fatty acid oxidation. We further revealed that LG inhibited endothelial nitric oxide synthase phosphorylation, and increased the expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1. These effects were suppressed either by overexpression of manganese superoxide dismutase or by treatment with etomoxir. CONCLUSIONS: The activation of fatty acid oxidation followed by mtROS production could be one of the causes for endothelial dysfunction during hypoglycemia.

Hyperglycemia Induces Cellular Hypoxia through Production of Mitochondrial ROS Followed by Suppression of Aquaporin-1.

We previously proposed that hyperglycemia-induced mitochondrial reactive oxygen species (mtROS) generation is a key event in the development of diabetic complications. Interestingly, some common aspects exist between hyperglycemia and hypoxia-induced phenomena. Thus, hyperglycemia may induce cellular hypoxia, and this phenomenon may also be involved in the pathogenesis of diabetic complications. In endothelial cells (ECs), cellular hypoxia increased after incubation with high glucose (HG). A similar phenomenon was observed in glomeruli of diabetic mice. HG-induced cellular hypoxia was suppressed by mitochondria blockades or manganese superoxide dismutase (MnSOD) overexpression, which is a specific SOD for mtROS. Overexpression of MnSOD also increased the expression of aquaporin-1 (AQP1), a water and oxygen channel. AQP1 overexpression in ECs suppressed hyperglycemia-induced cellular hypoxia, endothelin-1 and fibronectin overproduction, and apoptosis. Therefore, hyperglycemia-induced cellular hypoxia and mtROS generation may promote hyperglycemic damage in a coordinated manner.