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

Abstract

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.

• Authors: Jun Hirao, Akihiro Tojo, Saaya Hatakeyama, Hiroshi Satonaka, Toshihiko Ishimitsu
• Journal: Hypertension research : official journal of the Japanese Society of Hypertension (Hypertens Res) Vol. 43 Issue 10 Pg. 1079-1088 (10 2020) ISSN: 1348-4214 [Electronic] England
• PMID: 32382157 (Publication Type: Journal Article)

Chemical References

• Blood Glucose
• Macrolides
• bafilomycin B1
• Vacuolar Proton-Translocating ATPases

Topics

• Animals
• Blood Glucose (drug effects)
• Diabetes Mellitus, Experimental (drug therapy)
• Diabetes Mellitus, Type 2 (drug therapy)
• Drug Evaluation, Preclinical
• Gluconeogenesis (drug effects)
• Insulin Resistance
• Insulin Secretion (drug effects)
• Kidney (drug effects, enzymology)
• Lipid Metabolism (drug effects)
• Liver (drug effects)
• Macrolides (pharmacology, therapeutic use)
• Male
• Pancreas (drug effects)
• Rats
• Vacuolar Proton-Translocating ATPases (antagonists & inhibitors, metabolism)