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V-ATPase blockade reduces renal gluconeogenesis and improves insulin secretion in type 2 diabetic rats


Vacuolar H+-adenosine triphosphatase (V-ATPase) stimulates vesicular acidification that may activate cytoplasmic enzymes, hormone secretion and membrane recycling of transporters. We investigated the effect of blockade of V-ATPase by bafilomycin B1 on renal gluconeogenesis, mitochondrial enzymes, and insulin secretion in type 2 diabetic rats. Spontaneous type 2 diabetic Torii rats were treated with intraperitoneal injection of bafilomycin B1 for 1 week, and the kidneys were examined after 24 h of starvation in metabolic cages. The renal expression and activity of V-ATPase were increased in the brush border membrane of the proximal tubules in diabetic rats. The blockade of V-ATPase by bafilomycin B1 reduced renal V-ATPase activity and urinary ammonium in diabetic rats. Treatment with bafilomycin suppressed the enhanced renal gluconeogenesis enzymes and mitochondrial electron transport enzymes in type 2 diabetic rats and reduced the renal cytoplasmic glucose levels. The insulin index and pancreatic insulin granules were decreased in diabetic rats with increased V-ATPase expression in islet cells, and treatment with bafilomycin B1 reversed these changes and increased the insulin secretion index. Hepatosteatosis in type 2 diabetic rats was ameliorated by bafilomycin treatment. As a consequence, treatment with bafilomycin B1 significantly decreased the plasma glucose level after 24 h of starvation in diabetic rats. In conclusion, a V-ATPase inhibitor improved plasma glucose levels in type 2 diabetes by inhibiting renal mitochondrial gluconeogenesis and improving insulin secretion.

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This work was partly supported by Grants-in-Aid for scientific research from the Japan Society for the Promotion of Science to AT (C15K09285) and research donations by Dr. Naohiko Kobayashi of the Kobayashi Internal Medicine Clinic, as well as a Dokkyo Medical Research Grant & Incentive Award 2018 to JH. We thank Ms. Kyoko Mamada, Mr. Hisato Hirata, Mr. Yoshifumi Machida, Ms. Masako Minato, Ms. Machiko Sakata, Ms. Noriko Oshima, and Mr. Kazumi Akimoto of the Center for Research Support, Dokkyo Medical University, for their support with the animal operations, sample measurements, and immunostaining. We also thank Mr. Kinichi Matsuyama of the Department of Pathology, Dokkyo Medical University for his excellent help with electron microscopy.

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Correspondence to Akihiro Tojo.

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Hirao, J., Tojo, A., Hatakeyama, S. et al. V-ATPase blockade reduces renal gluconeogenesis and improves insulin secretion in type 2 diabetic rats. Hypertens Res 43, 1079–1088 (2020).

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