PMID- 29110392
OWN - NLM
STAT- MEDLINE
DCOM- 20181211
LR  - 20211204
IS  - 1463-1326 (Electronic)
IS  - 1462-8902 (Linking)
VI  - 20
IP  - 3
DP  - 2018 Mar
TI  - Na(+) /H(+) exchanger 3 blockade ameliorates type 2 diabetes mellitus via 
      inhibition of sodium-glucose co-transporter 1-mediated glucose absorption in the 
      small intestine.
PG  - 709-717
LID - 10.1111/dom.13151 [doi]
AB  - AIM: To elucidate the role of Na(+) /H(+) exchanger 3 (NHE3) in sodium-glucose 
      co-transporter 1 (SGLT1)-mediated small intestinal brush border membrane (BBM) 
      glucose absorption and its functional implications in type 2 diabetes mellitus 
      (T2DM). MATERIALS AND METHODS: Human jejunal samples were obtained from patients 
      undergoing gastrectomy. (14) C-glucose absorption was measured by liquid 
      scintillation counting. NHE3 expression was suppressed by siRNA-mediated 
      knockdown or augmented in Caco2 cells. Glucose and insulin tolerance in db/db and 
      m+/db mice was assessed with oral and intraperitoneal glucose tolerance tests, 
      and an intraperitoneal insulin tolerance test. Insulin resistance and beta-cell 
      function were assessed using homeostatic model assessment of insulin resistance 
      and beta-cell function. RESULTS: NHE3 expression was upregulated in db/db mouse 
      jejunal BBM and high-glucose-treated Caco2 cells. NHE3 blockade impaired 
      SGLT1-mediated glucose absorption in human jejunum, m+/db and db/db mouse 
      jejunums, and Caco2 cells, via serum/glucocorticoid-regulated kinase 1 (SGK1). 
      NHE3 knockdown suppressed SGLT1-mediated glucose uptake and reduced mRNA and 
      protein levels of SGK1 and SGLT1, which were conversely enhanced by NHE3 
      overexpression. Chronic S3226 treatment diminished postprandial glucose levels 
      and ameliorated glucose intolerance in db/db mice. CONCLUSION: NHE3 is essential 
      in the modulation of small intestinal BBM glucose absorption. Our findings 
      provide a rationale for future possible clinical application of NHE3 for 
      treatment of T2DM through reducing intestinal glucose uptake and counteracting 
      postprandial hyperglycaemia.
CI  - (c) 2017 John Wiley & Sons Ltd.
FAU - Chan, Leo K Y
AU  - Chan LKY
AD  - School of Biomedical Sciences, Faculty of Medicine, The Chinese University of 
      Hong Kong, Shatin, New Territories, Hong Kong, China.
FAU - Wang, Yi
AU  - Wang Y
AD  - School of Biomedical Sciences, Faculty of Medicine, The Chinese University of 
      Hong Kong, Shatin, New Territories, Hong Kong, China.
FAU - Ng, Enders K W
AU  - Ng EKW
AD  - Department of Surgery, Prince of Wales Hospital, Faculty of Medicine, The Chinese 
      University of Hong Kong, Shatin, New Territories, Hong Kong, China.
FAU - Leung, Po Sing
AU  - Leung PS
AUID- ORCID: 0000-0001-8074-3178
AD  - School of Biomedical Sciences, Faculty of Medicine, The Chinese University of 
      Hong Kong, Shatin, New Territories, Hong Kong, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20171205
PL  - England
TA  - Diabetes Obes Metab
JT  - Diabetes, obesity & metabolism
JID - 100883645
RN  - 0 (Epithelial Sodium Channel Blockers)
RN  - 0 (Glucose Transporter Type 2)
RN  - 0 (Immediate-Early Proteins)
RN  - 0 (Slc2a2 protein, mouse)
RN  - 0 (Slc5a1 protein, mouse)
RN  - 0 (Sodium-Glucose Transporter 1)
RN  - 0 (Sodium-Hydrogen Exchanger 3)
RN  - 7DZO8EB0Z3 (Amiloride)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (serum-glucocorticoid regulated kinase)
RN  - IY9XDZ35W2 (Glucose)
RN  - VW50CE070T (ethylisopropylamiloride)
SB  - IM
MH  - Amiloride/analogs & derivatives/pharmacology
MH  - Animals
MH  - Caco-2 Cells
MH  - Diabetes Mellitus, Type 2/*drug therapy/metabolism
MH  - Dose-Response Relationship, Drug
MH  - Down-Regulation/physiology
MH  - Epithelial Sodium Channel Blockers/pharmacology
MH  - Gene Knockdown Techniques
MH  - Glucose/pharmacokinetics
MH  - Glucose Intolerance/physiopathology
MH  - Glucose Transporter Type 2/metabolism
MH  - Humans
MH  - Hyperglycemia/physiopathology
MH  - Immediate-Early Proteins/metabolism
MH  - Intestinal Absorption/physiology
MH  - Intestinal Mucosa/metabolism
MH  - Intestine, Small/*metabolism
MH  - Male
MH  - Mice, Inbred C57BL
MH  - Postprandial Period
MH  - Protein Serine-Threonine Kinases/metabolism
MH  - Sodium-Glucose Transporter 1/*antagonists & inhibitors/metabolism
MH  - Sodium-Hydrogen Exchanger 3/*antagonists & inhibitors
OTO - NOTNLM
OT  - NHE3 inhibitor
OT  - diabetes
OT  - glucose intolerance
OT  - postprandial hyperglycaemia
EDAT- 2017/11/08 06:00
MHDA- 2018/12/12 06:00
CRDT- 2017/11/08 06:00
PHST- 2017/07/05 00:00 [received]
PHST- 2017/10/12 00:00 [revised]
PHST- 2017/10/29 00:00 [accepted]
PHST- 2017/11/08 06:00 [pubmed]
PHST- 2018/12/12 06:00 [medline]
PHST- 2017/11/08 06:00 [entrez]
AID - 10.1111/dom.13151 [doi]
PST - ppublish
SO  - Diabetes Obes Metab. 2018 Mar;20(3):709-717. doi: 10.1111/dom.13151. Epub 2017 
      Dec 5.