It is demonstrated that glucose fluctuations, such as postprandial hyperglycemia, and hypoglycemia due to diabetes treatment could be implicated in the development of diabetic complications. There is evidence for the involvement of oxidative stress in the pathogenesis of diabetic neuropathy. It has been elucidated that hyperglycemia induced oxidative stress and caused peripheral nerve dysfunction. However, the effects of hypoglycemia and blood glucose fluctuation on diabetic neuropathy remain unclear. In the present study, we investigated the mechanisms of recurrent short-term hypoglycemia and hyperglycemia on apoptosis and oxidative stress in Schwann cells, and we also examined the involvement of polyol pathway and endoplasmic reticulum (ER) stress pathway in these abnormalities. Immortalized adult mouse Schwann cells were exposed to five different glucose treatments over 3 days: 1) normal glucose (NG), 2) constant low glucose (LG), 3) constant high glucose (HG), 4) intermittent low glucose (ILG; 1 h three times per day), 5) intermittent high glucose (IHG; 1 h three times per day). Cell viability was reduced not only HG, but also LG. Furthermore, either IHG or ILG also decreased cell viabilities. TBARS levels were increased by HG, LG, IHG, and ILG. High glucose (HG and IHG) and low glucose (LG and ILG) increased the expression of cleaved caspase-3 and reduced that of Bcl-2. Epalrestat, an aldose reductase inhibitor, as well as 4-PBA, an ER stress inhibitor, recovered cell death and oxidative stress which were induced by LG, HG, ILG and IHG. These results suggest that intermittent hypoglycemia and hyperglycemia enhanced apoptosis and oxidative stress through both polyol pathway and ER stress pathway in Schwann cells, and that not only hyperglycemia, but also hypoglycemia and glucose fluctuations might cause nerve dysfunction in diabetes, resulting in the onset and progression of diabetic neuropathy.
A. Kato: None. Y. Tatsumi: None. H. Yako: None. T. Himeno: None. M. Kondo: None. Y. Kato: Speaker's Bureau; Self; Merck & Co., Inc. H. Kamiya: Speaker's Bureau; Self; Astellas Pharma Inc., Eli Lilly Japan K.K., MSD K.K., Novartis Pharma K.K., Novo Nordisk Oharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi K.K. K. Sango: None. J. Nakamura: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Japan Tobacco Inc., Kissei Pharmaceutical Co., Ltd., Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Kowa Pharmaceu. Co. Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi K.K., Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. K. Kato: None.
Japan Society for the Promotion of Science