H+-ATPase blockade reduced renal gluconeogenesis and plasma glucose in a diabetic rat model

Abstract

Vacuolar H+-adenosine triphosphatase (ATPase) plays important roles in urinary acid excretion, vesicular acidification to activate enzymes, and the membrane recycling of transporters in the kidney. As acidosis stimulates renal gluconeogenesis, we investigated the effect of blockade of H+-ATPase on renal gluconeogenesis in diabetic rats. Diabetes mellitus was induced by a single injection of streptozotocin, and a group of DM rats was treated with bafilomycin B1 intraperitoneally for 8 days. In diabetic rats, the renal expression and activity of H+-ATPase were increased with elevated urinary ammonium excretion. The blockade of H+-ATPase by bafilomycin B1 reduced the renal H+-ATPase activity and urinary ammonium excretion in diabetic rats. Treatment with bafilomycin suppressed the enhancement of the renal gluconeogenesis enzymes phosphoenol pyruvate carboxykinase and glucose-6-phosphatase in diabetic rats and reduced the renal cytoplasmic glucose levels, whereas hepatic gluconeogenesis did not change significantly. After a 24-h starvation period, bafilomycin decreased the plasma glucose level to a normal level in diabetic rats. The suppression of renal gluconeogenesis by an H+-ATPase inhibitor may therefore be a new therapeutic target for the treatment of diabetes mellitus.

Effect of Insulin on Proximal Tubules Handling of Glucose: A Systematic Review

“…Insulin action on the sympathetic system can, indirectly, modulate SGLT2, hence changing glucose handling [22]. In addition, renal gluconeogenesis is enhanced in diabetes [4,14,46,67,110,[173][174][175][176][177] and is inhibited by insulin [4,179], which could influence glucose reabsorption through SGLT2 [21,22].…”

“…Renal gluconeogenesis is enhanced in STZ rats [4,14,46,67,110,173], in murine model knockout for IRecs [174] or IRS1 plus IRS2 [4], in a mix model of high-fat diet plus STZ [175], and in T2D murine models [176,177] demonstrating the essential insulin role.…”

“…Reports of SGLT1 protein [80,84,103] and mRNA [83-85, 92, 93, 98] contents in PTs of T1D murine models are also contradictory while in T2D models only mRNA expression seems to be upregulated [22,90,92,98,100,[103][104][105][106]. SGLT2 has been studied in many models of diabetes, and the results suggest increased protein [32,67,84,85,90,94,99,[107][108][109][110][111] and mRNA [22,32,83,85,100,104,[106][107][108][109]112] contents and activity [108] despite some controversial results [85,93,98,100,105,113].…”

Adipocytes control food intake and weight regain via Vacuolar-type H+ ATPase

“…Eleven-week old male WT C57BL/6 J or KO mice were individually housed and acclimatized to IP injections with 0.9% NaCl for 3 days and then randomized to receive daily bafilomycin B1 (100 nmol/kg) 76 or vehicle (5% DMSO in 0.9% NaCl) injections ∼1 h before the onset of dark period. GTT was performed on day 3 and an ITT on day 7 after a 6 h fast.…”

“…Nine-week old male C57BL/6 mice were fed HFD for 9 weeks and were switched to a LFD for 3 weeks. The mice were switched back to HFD and then randomized to receive IP injections for either bafilomycin B1 (100 nmol/kg) 76 or vehicle (5% DMSO in 0.9% NaCl) ∼1 h before the onset of dark period. Food was measured daily while body weight was measured every 2 days for 3 weeks.…”