Journal article
Potent Sodium/Glucose Cotransporter SGLT1/2 Dual Inhibition Improves Glycemic Control Without Marked Gastrointestinal Adaptation or Colonic Microbiota Changes in Rodents
The Journal of pharmacology and experimental therapeutics, v 365(3), pp 676-687
01 Jun 2018
PMID: 29674332
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The sodium/glucose cotransporters (SGLT1 and SGLT2) transport glucose across the intestinal brush border and kidney tubule. Dual SGLT1/2 inhibition could reduce hyperglycemia more than SGLT2-selective inhibition in patients with type 2 diabetes. However, questions remain about altered gastrointestinal (Gl) luminal glucose and tolerability, and this was evaluated in slc5a1(-/-) mice or with a potent dual inhibitor (compound 8; SGLT1 K-i = 1.5 +/- 0.5 nM 100-fold greater potency than phlorizin; SGLT2 K-i = 0.4 +/- 0.2 nM). (13)C(6)glucose uptake was quantified in slc5a1(-/-) mice and in isolated rat jejunum. Urinary glucose excretion (UGE), blood glucose (Sprague-Dawley rats), glucagon-like peptide 1 (GLP-1), and hemoglobin A1c (HbA1c) levels (Zucker diabetic fatty rats) were measured. Intestinal adaptation and rRNA gene sequencing was analyzed in C57BI/6 mice. The blood C-13(6)-glucose area under the curve (AUC) was reduced in the absence of SGLT1 by 75% (245 +/- 6 vs. 64 +/- 6 mg/dl.h in wild-type vs. slc5a1(-/-) mice) and compound 8 inhibited its transport up to 50% in isolated rat jejunum. Compound 8 reduced glucose excursion more than SGLT2-selective inhibition (e.g., AUC = 129 +/- 3 vs. 249 +/- 5 mg/dl-h for 1 mg/kg compound 8 vs. dapagliflozin) with similar UGE but a lower renal glucose excretion threshold. In Zucker diabetic fatty rats, compound 8 decreased HbA1c and increased total GLP-1 without changes in jejunum SGLT1 expression, mucosal weight, or villus length. Overall, compound 8 (1 mg/kg for 6 days) did not increase cecal glucose concentrations or bacterial diversity in C57BL76 mice. In conclusion, potent dual SGLT1/2 inhibition lowers blood glucose by reducing intestinal glucose absorption and the renal glucose threshold but minimally impacts the intestinal mucosa or luminal microbiota in chow-fed rodents.
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Details
- Title
- Potent Sodium/Glucose Cotransporter SGLT1/2 Dual Inhibition Improves Glycemic Control Without Marked Gastrointestinal Adaptation or Colonic Microbiota Changes in Rodents
- Creators
- Fuyong Du - JanssenSimon A. Hinke - JanssenCassandre Cavanaugh - Baylor College of MedicineDavid Polidori - Baylor College of MedicineNathanial Wallace - Baylor College of MedicineThomas Kirchner - JanssenMatthew Jennis - Baylor College of MedicineWensheng Lang - Baylor College of MedicineGee-Hong Kuo - Janssen R&D LLC, Cardiovasc & Metab Discovery, 1440 McKean Rd,Bldg SH42-2510-A, Spring House, PA 19477 USAMicheal D. Gaul - Baylor College of MedicineJames Lenhard - Baylor College of MedicineKeith Demarest - Baylor College of MedicineNadim J. Ajami - Baylor College of MedicineYin Liang - JanssenPamela J. Hornby - Janssen
- Publication Details
- The Journal of pharmacology and experimental therapeutics, v 365(3), pp 676-687
- Publisher
- Amer Soc Pharmacology Experimental Therapeutics
- Number of pages
- 12
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000433027200022
- Scopus ID
- 2-s2.0-85047213627
- Other Identifier
- 991021931780404721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- Web of Science research areas
- Pharmacology & Pharmacy