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      Sigmoidal kinetics define porcine intestinal segregation of electrogenic monosaccharide transport systems as having multiple transporter population involvement

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          Abstract

          Kinetic characterization of electrogenic sodium‐dependent transport in Ussing chambers of d‐glucose and d‐galactose demonstrated sigmoidal/Hill kinetics in the porcine jejunum and ileum, with the absence of transport in the distal colon. In the jejunum, a high‐affinity, super‐low‐capacity (Ha/ sLc) kinetic system accounted for glucose transport, and a low‐affinity, low‐capacity (La/Lc) kinetic system accounted for galactose transport. In contrast, the ileum demonstrated a high‐affinity, super‐high‐capacity (Ha/ sHc) glucose transport and a low‐affinity, high‐capacity (La/Hc) galactose transport systems. Jejunal glucose transport was not inhibited by dapagliflozin, but galactose transport was inhibited. Comparatively, ileal glucose and galactose transport were both sensitive to dapagliflozin. Genomic and gene expression analyses identified 10 of the 12 known SLC5A family members in the porcine jejunum, ileum, and distal colon. Dominant SGLT1 ( SLC5A1) and SGLT3 ( SLC5A4) expression was associated with the sigmoidal Ha/ sLc glucose and La/Lc galactose transport systems in the jejunum. Comparatively, the dominant expression of SGLT1 ( SLC5A1) in the ileum was only associated with Ha glucose and La galactose kinetic systems. However, the sigmoidal kinetics and overall high capacity (Hc) of transport is unlikely accounted for by SGLT1 ( SLC5A1) alone. Finally, the absence of transport and lack of pharmacological inhibition in the colon was associated with the poor expression of SLC5A genes. Altogether, the results demonstrated intestinal segregation of monosaccharide transport fit different sigmoidal kinetic systems. This reveals multiple transporter populations in each system, supported by gene expression profiles and pharmacological inhibition. Overall, this work demonstrates a complexity to transporter involvement in intestinal electrogenic monosaccharide absorption systems not previously defined.

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          Most cited references38

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          SGLT2 inhibition--a novel strategy for diabetes treatment.

          Inhibiting sodium-glucose co-transporters (SGLTs), which have a key role in the reabsorption of glucose in the kidney, has been proposed as a novel therapeutic strategy for diabetes. Genetic mutations in the kidney-specific SGLT2 isoform that result in benign renal glycosuria, as well as preclinical and clinical studies with SGLT2 inhibitors in type 2 diabetes, support the potential of this approach. These investigations indicate that elevating renal glucose excretion by suppressing SGLT2 can reduce plasma glucose levels, as well as decrease weight. Although data from ongoing Phase III trials of these agents are needed to more fully assess safety, results suggest that the beneficial effects of SGLT2 inhibition might be achieved without exerting significant side effects--an advantage over many current diabetes medications. This article discusses the role of SGLT2 in glucose homeostasis and the evidence available so far on the therapeutic potential of blocking these transporters in the treatment of diabetes.
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            Glucose transporters (GLUT and SGLT): expanded families of sugar transport proteins.

            The number of known glucose transporters has expanded considerably over the past 2 years. At least three, and up to six, Na+-dependent glucose transporters (SGLT1-SGLT6; gene name SLC5A) have been identified. Similarly, thirteen members of the family of facilitative sugar transporters (GLUT1-GLUT12 and HMIT; gene name SLC2A) are now recognised. These various transporters exhibit different substrate specificities, kinetic properties and tissue expression profiles. The number of distinct gene products, together with the presence of several different transporters in certain tissues and cells (for example, GLUT1, GLUT4, GLUT5, GLUT8, GLUT12 and HMIT in white adipose tissue), indicates that glucose delivery into cells is a process of considerable complexity.
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              Dapagliflozin, a novel SGLT2 inhibitor, induces dose-dependent glucosuria in healthy subjects.

              Dapagliflozin selectively inhibits renal glucose reabsorption by inhibiting sodium-glucose cotransporter-2 (SGLT2). It was developed as an insulin-independent treatment approach for type 2 diabetes mellitus (T2DM). The safety, tolerability, pharmacokinetics, and pharmacodynamics of the drug were evaluated in single-ascending-dose (SAD; 2.5-500 mg) and multiple-ascending-dose (MAD; 2.5-100 mg daily for 14 days) studies in healthy subjects. Dapagliflozin exhibited dose-proportional plasma concentrations with a half-life of approximately 17 h. The amount of glucosuria was also dose-dependent. Cumulative amounts of glucose excreted on day 1, relating to doses from 2.5-100 mg (MAD), ranged from 18 to 62 g; day 14 values were comparable to day 1 values, with no apparent changes in glycemic parameters. Doses of approximately 20-50 mg provided close-to-maximal SGLT2 inhibition for at least 24 h. Dapagliflozin demonstrates pharmacokinetic (PK) characteristics and dose-dependent glucosuria that are sustained over 24 h, which indicates that it is suitable for administration in once-daily doses and suggests that further investigation of its efficacy in T2DM patients is warranted.
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                Author and article information

                Contributors
                matthew.loewen@usask.ca
                Journal
                Physiol Rep
                Physiol Rep
                10.1002/(ISSN)2051-817X
                PHY2
                physreports
                Physiological Reports
                John Wiley and Sons Inc. (Hoboken )
                2051-817X
                06 May 2019
                May 2019
                : 7
                : 9 ( doiID: 10.1002/phy2.2019.7.issue-9 )
                : e14090
                Affiliations
                [ 1 ] Department of Veterinary Biomedical Sciences Western College of Veterinary Medicine University of Saskatchewan Saskatoon Saskatchewan Canada
                Author notes
                [*] [* ] Correspondence

                Matthew E. Loewen, Department of Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, 52 Campus Drive, Saskatoon, Saskatchewan, Canada S7N 5B4.

                Tel: 306‐966‐4005

                Fax: 306‐966‐7376

                E‐mail: matthew.loewen@ 123456usask.ca

                Author information
                https://orcid.org/0000-0002-1090-3807
                Article
                PHY214090
                10.14814/phy2.14090
                6503033
                31062524
                6ea064ba-e218-4aa2-ac04-b0d04dc8bed3
                © 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 16 March 2019
                : 09 April 2019
                : 10 April 2019
                Page count
                Figures: 5, Tables: 4, Pages: 15, Words: 5843
                Funding
                Funded by: Natural Sciences and Engineering Research Council of Canada
                Award ID: 371364‐2010
                Categories
                Original Research
                Original Research
                Custom metadata
                2.0
                phy214090
                May 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.2.1 mode:remove_FC converted:06.05.2019

                gastrointestinal tract,glucose absorption,porcine,sigmoidal,sodium‐dependent glucose transporter (sglt)

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