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

Hirao, Jun; Tojo, Akihiro; Hatakeyama, S.; Saito, Hiroshi; Ishimitsu, Toshihiko

doi:10.1038/s41440-020-0450-0

Cited by 11 publications

(7 citation statements)

References 27 publications

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“…To this point, recent studies have shown increased apical V-ATPase expression and activity in the proximal tubule epithelial cells of diabetic rats, together with a decrease in insulin-containing secretory granules and insulin secretion by the pancreas. Furthermore, intraperitoneal injection of these diabetic rats with bafilomycin increased insulin secretion and reduced plasma glucose levels ( 154 ).…”

Section: Diabetesmentioning

confidence: 99%

The H⁺-ATPase (V-ATPase): from proton pump to signaling complex in health and disease

Eaton

Merkulova

Brown

2021

American Journal of Physiology-Cell Physiology

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A primary function of the H+-ATPase (or V-ATPase) is to create an electrochemical proton gradient across eukaryotic cell membranes, which energizes fundamental cellular processes. Its activity notably allows for the acidification of intracellular vesicles and organelles, which is necessary for many essential cell biological events to occur. In addition, many specialized cell types in various organ systems such as the kidney, bone, male reproductive tract, inner ear, olfactory mucosa, and more, use plasma membrane V-ATPases to perform specific activities that depend on extracellular acidification. However, it is increasingly apparent that V-ATPases are central players in many normal and pathophysiological processes that directly influence human health in many different, and sometimes unexpected ways. These include cancer, neurodegenerative diseases, diabetes, and sensory perception, as well as energy and nutrient sensing functions within cells. This review first covers the well-established role of the V-ATPase as a transmembrane proton pump in the plasma membrane and intracellular vesicles, and outlines factors contributing to its physiological regulation in different cell types. This is followed by a discussion of the more recently emerging unconventional roles for the V-ATPase, such as its role as a protein interaction hub involved in cell signaling, and the (patho)physiological implications of these interactions. Finally, the central importance of endosomal acidification and V-ATPase activity on viral infection will be discussed in the context of the current COVID-19 pandemic.

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Section: Diabetesmentioning

confidence: 99%

The H⁺-ATPase (V-ATPase): from proton pump to signaling complex in health and disease

Eaton

Merkulova

Brown

2021

American Journal of Physiology-Cell Physiology

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“…PPI drugs, such as omeprazole, the other drug used in this study, increase endogenous gastrin levels, and gastrin was reported to stimulate β-cell regeneration and improve glucose tolerance in 95% pancreatectomized rats ( 28 ). Furthermore, a PPI could simultaneously increase insulin secretion by inhibiting the V-ATPase proton pump in β-cell insulin granules ( 29 ). Combination of GLP-1 with gastrin ( 30 ), as well as the combination of a DPP-4i and a PPI ( 31 ), have been reported to increase islet β-cell mass and restore normoglycemia in NOD mice with autoimmune diabetes.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of combination therapy with GABA, a DPP-4i and a PPI as an adjunct to insulin therapy in patients with type 1 diabetes

et al. 2023

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IntroductionThe purpose of this retrospective clinic chart review study was to determine the potential of a combination therapy (CT) consisting of γ-aminobutyric acid (GABA), a dipeptidyl peptidase-4 inhibitor (DPP-4i), and a proton pump inhibitor (PPI) to improve glycemic control as an adjunct to insulin therapy in patients with type 1 diabetes (T1D).Research design and methodsNineteen patients with T1D on insulin therapy were treated with additional CT in oral form. Fasting blood glucose (FBG), HbA1c, insulin dose-adjusted HbA1c (IDA-A1c), daily insulin dose, insulin/weight ratio (IWR), and fasting plasma C-peptide were measured after 26-42 weeks of treatments.ResultsFBG, HbA1c, IDA-A1c, insulin dose and IWR were all significantly decreased while plasma C-peptide was significantly increased by the CT. Treatment outcomes were further analyzed by separation of the 19 patients into two groups. One group started on the CT within 12 months of insulin treatment (early therapy, 10 patients) and another group started on this therapy only after 12 months of insulin treatment (late therapy, 9 patients). FBG, IDA-A1c, insulin dose, and IWR decreased significantly in both the early and late CT groups, however to a better extent in the early therapy group. Moreover, plasma C-peptide increased significantly only in the early therapy group, and 7 of the 10 patients in this group were able to discontinue insulin treatment while maintaining good glycemic control to study end compared with none of the 9 patients in the late therapy group.ConclusionThese results support the concept that the combination of GABA, a DPP-4i and a PPI as an adjunct to insulin therapy improves glycemic control in patients with T1D, and that the insulin dose required for glycemic control can be reduced or even eliminated in some patients receiving this novel therapy.

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“…Its insulin responsivity suggests a recent, specialized role in the regulation of IR complexes and insulin clearance through its tyrosine dephosphorylation activity, possibly complementing the activity of CEACAM1/FASN complexes. Of equal interest, the insulin index and pancreatic insulin granules were recently found to have decreased in diabetic rats with increased V-ATPase expression in their islet cells, inhibition of V-ATPase inhibited renal gluconeogenesis enzymes, and improved insulin secretion [93], further linking the network view and co-functionality with islets.…”

Section: From Ppin To a T2d Disease Modulementioning

confidence: 99%

Insulin’s Discovery: New Insights on Its Hundredth Birthday: From Insulin Action and Clearance to Sweet Networks

Leroux

Boutchueng-Djidjou

Faure

2021

IJMS

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In 2021, the 100th anniversary of the isolation of insulin and the rescue of a child with type 1 diabetes from death will be marked. In this review, we highlight advances since the ingenious work of the four discoverers, Frederick Grant Banting, John James Rickard Macleod, James Bertram Collip and Charles Herbert Best. Macleoad closed his Nobel Lecture speech by raising the question of the mechanism of insulin action in the body. This challenge attracted many investigators, and the question remained unanswered until the third part of the 20th century. We summarize what has been learned, from the discovery of cell surface receptors, insulin action, and clearance, to network and precision medicine.

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

Cited by 11 publications

References 27 publications

The H⁺-ATPase (V-ATPase): from proton pump to signaling complex in health and disease

The H⁺-ATPase (V-ATPase): from proton pump to signaling complex in health and disease

Efficacy of combination therapy with GABA, a DPP-4i and a PPI as an adjunct to insulin therapy in patients with type 1 diabetes

Insulin’s Discovery: New Insights on Its Hundredth Birthday: From Insulin Action and Clearance to Sweet Networks

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

Cited by 11 publications

References 27 publications

The H+-ATPase (V-ATPase): from proton pump to signaling complex in health and disease

The H+-ATPase (V-ATPase): from proton pump to signaling complex in health and disease

Efficacy of combination therapy with GABA, a DPP-4i and a PPI as an adjunct to insulin therapy in patients with type 1 diabetes

Insulin’s Discovery: New Insights on Its Hundredth Birthday: From Insulin Action and Clearance to Sweet Networks

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Product

Resources

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The H⁺-ATPase (V-ATPase): from proton pump to signaling complex in health and disease

The H⁺-ATPase (V-ATPase): from proton pump to signaling complex in health and disease