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Inhibition of intestinal villus cell Na/K-ATPase mediates altered glucose and NaCl absorption in obesity-associated diabetes and hypertension

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Palaniappan, Balasubramanian, Arthur, Subha, Sundaram, Vijaya Lakshmi, Butts, Molly, Sundaram, Shanmuga, Mani, Kathiresh, Singh, Soudamani, Nepal, Niraj +1 more·2019·The FASEB Journal
DOI 10.1096/fj.201802673rPMC PMC6662973
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Abstract

During obesity, diabetes and hypertension inevitably coexist and cause innumerable health disparities. In the obesity, diabetes, and hypertension triad (ODHT), deregulation of glucose and NaCl homeostasis, respectively, causes diabetes and hypertension. In the mammalian intestine, glucose is primarily absorbed by Naglucose cotransport 1 (SGLT1) and coupled NaCl by the dual operation of Na‐H exchange 3 (NHE3) and Cl‐HCO 3 [down‐regulated in adenoma (DRA) or putative anion transporter 1 (PAT1)] exchange in the brush border membrane (BBM) of villus cells. The basolateral membrane (BLM) Na/K‐ATPase provides the favorable transcellular Na gradient for BBM SGLT1 and NHE3. How these multiple, distinct transport processes may be affected in ODHT is unclear. Here, we show the novel and broad regulation by Na/K‐ATPase of glucose and NaCl absorption in ODHT in multiple species (mice, rats, and humans). In vivo , during obesity inhibition of villus‐cell BLM, Na/K‐ATPase led to compensatory stimulation of BBM SGLT1 and DRA or PAT1, whereas NHE3 was unaffected. Supporting this new cellular adaptive mechanism, direct silencing of BLM Na/K‐ATPase in intestinal epithelial cells resulted in selective stimulation of BBM SGLT1 and DRA or PAT1 but not NHE3. These changes will lead to an increase in glucose absorption, maintenance of traditional coupled NaCl absorption, and a de novo increase in NaCl absorption from the novel coupling of stimulated SGLT1 with DRA or PAT1. Thus, these novel observations provide the pathophysiologic basis for the deregulation of glucose and NaCl homeostasis of diabetes and hypertension, respectively, during obesity. These observations may lead to more efficacious treatment for obesity‐associated diabetes and hypertension.—Palaniappan, B., Arthur, S., Sundaram, V. L., Butts, M., Sundaram, S., Mani, K., Singh, S., Nepal, N., Sundaram, U. Inhibition of intestinal villus cell Na/K‐ATPase mediates altered glucose and NaCl absorption in obesity‐associated diabetes and hypertension. FASEB J. 33, 9323–9333 (2019). www.fasebj.org

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  • Our laboratory has published evidence that compensatory regulation between the two primary Na absorptive pathways may be lost in obesity, leading to enhanced absorption of both Na and glucose and contributing to hypertension and diabetes as complications of obesity.

    “As previously noted, our laboratory has published evidence that the compensatory regulation between the two primary Na absorptive pathways may be lost in obesity, leading to enhanced absorption of both Na and glucose, thus contributing to the pathophysiology of two common complications of obesity: hypertension and diabetes [8].”

    From Regulation of Enterocyte Brush Border Membrane Primary Na-Absorptive Transporters in Human Intestinal Organoid-Derived Monolayers (2024) · cites this paper as [8]

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Cited by

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Authors
Palaniappan, B., Arthur, S., Sundaram, V. L., Butts, M., Sundaram, S., Mani, K., Singh, S., Nepal, N., & Sundaram, U.
Affiliations
Marshall University (US)
ORCID
Venue
The FASEB Journal
Publisher
Wiley
Published
2019-05-20
Volume
33
Issue
8
Pages
9323-9333
ISSN
  • 0892-6638 (ISSN-L)
  • 1530-6860
DOI
10.1096/fj.201802673r
PMC
PMC6662973
OpenAlex
W2946732136
Cited by
21
References
1
Citations by year
2026: 3 · 2025: 4 · 2024: 4 · 2023: 3 · 2022: 3 · 2021: 3 · 2019: 1
FWCI
0.58
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • The FASEB Journal (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • American Gastroenterological Association
  • National Institutes of Health
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK‐067420, DK‐108054)
  • National Institute of General Medical Sciences (P20GM121299‐01A1)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
Keywords
Na+/K+-ATPase, obesity, obesity-related diabetes, hypertension, glucose absorption, NaCl absorption, SGLT1, NHE3, DRA, PAT1, brush border membrane, basolateral membrane, intestinal epithelial cells, compensatory adaptation, sodium homeostasis, chloride homeostasis, intestinal transporters
MeSH terms
Sodium-Potassium-Exchanging ATPase, Animals, Cell Line, Fluorescent Antibody Technique, Glucose, Hypertension, Intestinal Absorption, Intestinal Mucosa, Intestines, Male, Microvilli, Obesity, Sodium Chloride, Blotting, Western, RNA Interference, Rats

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