Canagliflozin potentiates GLP-1 secretion and lowers the peak of GIP secretion in rats fed a high-fat high-sucrose diet

Hira, Tohru; Koga, Toshiki; Sasaki, Kazuyo; Hara, Hiroshi

doi:10.1016/j.bbrc.2017.08.031

Cited by 17 publications

(13 citation statements)

References 27 publications

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“…Intestinal sodium glucose cotransporter-1 inhibition was reported to enhance glucagon-like peptide-1 (GLP-1) secretion in normal and diabetic rodents 21) . Especially, Canagliflozin was reported to potentiate GLP-1 secretion and lower the peak of GLP -1 secretion in DM rats 22,23) . The effect of combined treatment with Canagliflozin and teneligliptin could be more useful than either DPP4 or SGLT2 therapy alone.…”

Section: Discussionmentioning

confidence: 99%

Effect of Canagliflozin on endothelial function in diabetic patients with suspected coronary artery disease: retrospective preliminary pilot study

2018

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Background: Sodium-glucose transporter-2 inhibitor (SGLT2) is reported to have anti-atherosclerotic effects in experiment. However, the effect of SGLT2 on endothelial function (ECF) in humans is not fully investigated. Method and Results: We measured ECF in 11 diabetic patients with coronary artery disease (CAD) and poor control of diabetics (HbA1c >7%; 75 8 years old) by simultaneously measuring brachial artery flow-mediated dilation (FMD) and EndoPAT2000 (measuring RHI). FMD and RHI were measured before and after mean periods of 4-week treatment of Canagliflozin (100 mg per every other day).

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Section: Discussionmentioning

confidence: 99%

Effect of Canagliflozin on endothelial function in diabetic patients with suspected coronary artery disease: retrospective preliminary pilot study

2018

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“…In a rodent model, Hara et al demonstrated that oral administration of canagliflozin suppresses GIP secretion, by inhibiting SGLT-1 in the upper part of the intestine, and reduces the excursion of blood glucose under hyperglycemic conditions (OGTT), by increasing total GLP-1 levels. Interestingly, the action of canagliflozin on GLP-1-producing cells may be determined by increased glucose delivery to the lower part of the small intestine [51]. Since this increase in GLP-1 is not observed with more SGLT-2 selective inhibitors, such as empagliflozin [52], it is safe to assume that the increase in GLP-1 is a consequence of intestinal SGLT-1 and subsequent delayed glucose absorption.…”

Section: Intestinal Sglt-1mentioning

confidence: 99%

Sotagliflozin, the first dual SGLT inhibitor: current outlook and perspectives

Cefalo

Cinti

Moffa

et al. 2019

Cardiovasc Diabetol

123

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Sotagliflozin is a dual sodium-glucose co-transporter-2 and 1 (SGLT2/1) inhibitor for the treatment of both type 1 (T1D) and type 2 diabetes (T2D). Sotagliflozin inhibits renal sodium-glucose co-transporter 2 (determining significant excretion of glucose in the urine, in the same way as other, already available SGLT-2 selective inhibitors) and intestinal SGLT-1, delaying glucose absorption and therefore reducing post prandial glucose. Well-designed clinical trials, have shown that sotagliflozin (as monotherapy or add-on therapy to other anti-hyperglycemic agents) improves glycated hemoglobin in adults with T2D, with beneficial effects on bodyweight and blood pressure. Similar results have been obtained in adults with T1D treated with either continuous subcutaneous insulin infusion or multiple daily insulin injections, even after insulin optimization. A still ongoing phase 3 study is currently evaluating the effect of sotagliflozin on cardiovascular outcomes (ClinicalTrials.gov NCT03315143). In this review we illustrate the advantages and disadvantages of dual SGLT 2/1 inhibition, in order to better characterize and investigate its mechanisms of action and potentialities.

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“…SGLT2-selective inhibitors, such as canagliflozin, can also be associated with increased GLP-1 secretion due to a transient inhibition of SGLT1 at high local luminal concentrations (Polidori et al, 2013b). The enhancement of GLP-1 release by canagliflozin is due to the increase in SCFA in the distal intestine (Hira et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Potent Sodium/Glucose Cotransporter SGLT1/2 Dual Inhibition Improves Glycemic Control Without Marked Gastrointestinal Adaptation or Colonic Microbiota Changes in Rodents

Hinke

Cavanaugh

et al. 2018

J Pharmacol Exp Ther

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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 (GI) luminal glucose and tolerability, and this was evaluated in slc5a1 mice or with a potent dual inhibitor (compound 8; SGLT1 = 1.5 ± 0.5 nM 100-fold greater potency than phlorizin; SGLT2 = 0.4 ± 0.2 nM). C-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 C57Bl/6 mice. The blood C-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 C57BL/6 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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Canagliflozin potentiates GLP-1 secretion and lowers the peak of GIP secretion in rats fed a high-fat high-sucrose diet

Cited by 17 publications

References 27 publications

Effect of Canagliflozin on endothelial function in diabetic patients with suspected coronary artery disease: retrospective preliminary pilot study

Effect of Canagliflozin on endothelial function in diabetic patients with suspected coronary artery disease: retrospective preliminary pilot study

Sotagliflozin, the first dual SGLT inhibitor: current outlook and perspectives

Potent Sodium/Glucose Cotransporter SGLT1/2 Dual Inhibition Improves Glycemic Control Without Marked Gastrointestinal Adaptation or Colonic Microbiota Changes in Rodents

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