Analysis of the Effect of Canagliflozin on Renal Glucose Reabsorption and Progression of Hyperglycemia in Zucker Diabetic Fatty Rats

Kuriyama, Chiaki; Xu, Jun; Lee, Seunghun Paul; Qi, Jenson; Kimata, Hirotaka; Kakimoto, Tetsuhiro; Nakayama, Keiko; Watanabe, Yoshinori; Taniuchi, Nobuhiko; Hikida, Kumiko; Matsushita, Yasuyuki; Akita, Keiichi; Saito, Akira; Ueta, Kiichiro; Shiotani, Masaharu

doi:10.1124/jpet.114.217992

Cited by 44 publications

(36 citation statements)

References 19 publications

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“…Moreover, a local circulation of canagliflozin through the apical membrane of renal proximal tubules may be facilitated by the SGLT2-mediated reabsorption of canagliflozin with the possible involvement of its efflux transporters. This would retain canagliflozin in the proximity of SGLT2, enabling the recurrent inhibition of SGLT2 from the luminal side, which explains the prolonged drug action beyond the decrease in blood canagliflozin levels Kuriyama et al, 2014). The significance of SGLT2-mediated canagliflozin uptake in pharmacodynamics as well as pharmacokinetics in vivo remains to be investigated.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to antihyperglycemic action, canagliflozin, as a selective SGLT2 inhibitor, exhibits other favorable effects for the treatment of type 2 diabetes mellitus, including loss in body weight and hypotensive effects (Sha et al, 2011;Lavalle-Gonzalez et al, 2013). Among the selective SGLT2 inhibitors currently available for clinical use, a characteristic of canagliflozin is its modest SGLT1 inhibitory action in the intestine at clinical dosage (Grempler et al, 2012;Kuriyama et al, 2014). This is probably because of its relatively low SGLT2/SGLT1 selectivity as well as its relatively high clinical dosage, owing to its high plasma protein binding (Fujita and Inagaki, 2014;Devineni et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Interaction of the Sodium/Glucose Cotransporter (SGLT) 2 inhibitor Canagliflozin with SGLT1 and SGLT2

Ohgaki

Wei

Yamada

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Canagliflozin, a selective sodium/glucose cotransporter (SGLT) 2 inhibitor, suppresses the renal reabsorption of glucose and decreases blood glucose level in patients with type 2 diabetes. A characteristic of canagliflozin is its modest SGLT1 inhibitory action in the intestine at clinical dosage. To reveal its mechanism of action, we investigated the interaction of canagliflozin with SGLT1 and SGLT2. Inhibition kinetics and transporter-mediated uptake were examined in human SGLT1-or SGLT2-expressing cells. Whole-cell patch-clamp recording was conducted to examine the sidedness of drug action. Canagliflozin competitively inhibited SGLT1 and SGLT2, with high potency and selectivity for SGLT2. Inhibition constant (K i ) values for SGLT1 and SGLT2 were 770.5 and 4.0 nM, respectively. 14 C-canagliflozin was suggested to be transported by SGLT2; however, the transport rate was less than that of a-methyl-D-glucopyranoside. Canagliflozin inhibited a-methyl-D-glucopyranoside-induced SGLT1-and SGLT2-mediated inward currents preferentially from the extracellular side and not from the intracellular side. Based on the K i value, canagliflozin is estimated to sufficiently inhibit SGLT2 from the urinary side in renal proximal tubules. The K i value for SGLT1 suggests that canagliflozin suppresses SGLT1 in the small intestine from the luminal side, whereas it does not affect SGLT1 in the heart and skeletal muscle, considering the maximal concentration of plasma-unbound canagliflozin. Similarly, SGLT1 in the kidney would not be inhibited, thereby aiding in the prevention of hypoglycemia. After binding to SGLT2, canagliflozin may be reabsorbed by SGLT2, which leads to the low urinary excretion and prolonged drug action of canagliflozin.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Interaction of the Sodium/Glucose Cotransporter (SGLT) 2 inhibitor Canagliflozin with SGLT1 and SGLT2

Ohgaki

Wei

Yamada

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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“…for each group, and IC 50 values in Tables 1 and 2 were expressed as the geometric mean of two to three experiments (Fleming et al, 1972;Stórustovu and Ebert, 2006;Kuriyama et al, 2014). The area under the curve (AUC) and incremental AUC (DAUC, defined as the AUC occurring above the baseline value) were calculated by the trapezoidal rule.…”

Section: Discussionmentioning

confidence: 99%

“…Canagliflozin, a first-in-class SGLT2 inhibitor with potent antihyperglycemic activity (Nomura et al, 2010;Liang et al, 2012;Cefalu et al, 2013;Kuriyama et al, 2014), has modest SGLT1 inhibitory potency compared with other highly selective SGLT2 inhibitors (Grempler et al, 2012). A recent clinical study of canagliflozin found delayed intestinal glucose absorption accompanied by increased plasma GLP-1 levels in healthy subjects (Polidori et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Intestinal Sodium Glucose Cotransporter 1 Inhibition Enhances Glucagon-Like Peptide-1 Secretion in Normal and Diabetic Rodents

Oguma¹,

Nakayama²,

Kuriyama³

et al. 2015

J Pharmacol Exp Ther

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The sodium glucose cotransporter (SGLT) 1 plays a major role in glucose absorption and incretin hormone release in the gastrointestinal tract; however, the impact of SGLT1 inhibition on plasma glucagon-like peptide-1 (GLP-1) levels in vivo is controversial. We analyzed the effects of SGLT1 inhibitors on GLP-1 secretion in normoglycemic and hyperglycemic rodents using phloridzin, CGMI [3-(4-cyclopropylphenylmethyl)-1-(b-Dglucopyranosyl)-4-methylindole], and canagliflozin. These compounds are SGLT2 inhibitors with moderate SGLT1 inhibitory activity, and their IC 50 values against rat SGLT1 and mouse SGLT1 were 609 and 760 nM for phloridzin, 39.4 and 41.5 nM for CGMI, and 555 and 613 nM for canagliflozin, respectively. Oral administration of these inhibitors markedly enhanced and prolonged the glucose-induced plasma active GLP-1 (aGLP-1) increase in combination treatment with sitagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, in normoglycemic mice and rats. CGMI, the most potent SGLT1 inhibitor among them, enhanced glucose-induced, but not fat-induced, plasma aGLP-1 increase at a lower dose compared with canagliflozin. Both CGMI and canagliflozin delayed intestinal glucose absorption after oral administration in normoglycemic rats. The combined treatment of canagliflozin and a DPP4 inhibitor increased plasma aGLP-1 levels and improved glucose tolerance compared with single treatment in both 8-and 13-week-old Zucker diabetic fatty rats. These results suggest that transient inhibition of intestinal SGLT1 promotes GLP-1 secretion by delaying glucose absorption and that concomitant inhibition of intestinal SGLT1 and DPP4 is a novel therapeutic option for glycemic control in type 2 diabetes mellitus.

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“…However, insulin-sensitivity is not fully restored as shown by the only partially normalized blood glucose values (fasting and non-fasting) and HbA1c values as well as the obvious hyperinsulinemia in the plasma of all ZDF groups. The increase in insulin plasma levels in ZDF rats with different SGLT2i drugs is well documented [25,[46][47][48][49]. Of importance is that empagliflozin was shown to lower blood glucose levels (thereby sparing insulin) in a preclinical model of streptozotocin-induced type 1 diabetes [50] and also in human studies [51,52].…”

Section: Discussionmentioning

confidence: 99%

The SGLT2 Inhibitor Empagliflozin Improves the Primary Diabetic Complications in ZDF Rats

Hanf

Steven

Oelze

et al. 2017

Free Radical Biology and Medicine

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A B S T R A C THyperglycemia associated with inflammation and oxidative stress is a major cause of vascular dysfunction and cardiovascular disease in diabetes. Recent data reports that a selective sodium-glucose co-transporter 2 inhibitor (SGLT2i), empagliflozin (Jardiance ® ), ameliorates glucotoxicity via excretion of excess glucose in urine (glucosuria) and significantly improves cardiovascular mortality in type 2 diabetes mellitus (T2DM). The overarching hypothesis is that hyperglycemia and glucotoxicity are upstream of all other complications seen in diabetes. The aim of this study was to investigate effects of empagliflozin on glucotoxicity, β-cell function, inflammation, oxidative stress and endothelial dysfunction in Zucker diabetic fatty (ZDF) rats. Male ZDF rats were used as a model of T2DM (35 diabetic ZDF-Lepr fa/fa and 16 ZDF-Lepr +/+ controls). Empagliflozin (10 and 30 mg/kg/d) was administered via drinking water for 6 weeks. Treatment with empagliflozin restored glycemic control. Empagliflozin improved endothelial function (thoracic aorta) and reduced oxidative stress in the aorta and in blood of diabetic rats. Inflammation and glucotoxicity (AGE/RAGE signaling) were epigenetically prevented by SGLT2i treatment (ChIP). Linear regression analysis revealed a significant inverse correlation of endothelial function with HbA1c, whereas leukocyte-dependent oxidative burst and C-reactive protein (CRP) were positively correlated with HbA1c. Viability of hyperglycemic endothelial cells was pleiotropically improved by SGLT2i. Empagliflozin reduces glucotoxicity and thereby prevents the development of endothelial dysfunction, reduces oxidative stress and exhibits anti-inflammatory effects in ZDF rats, despite persisting hyperlipidemia and hyperinsulinemia. Our preclinical observations provide insights into the mechanisms by which empagliflozin reduces cardiovascular mortality in humans (EMPA-REG trial).

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Analysis of the Effect of Canagliflozin on Renal Glucose Reabsorption and Progression of Hyperglycemia in Zucker Diabetic Fatty Rats

Cited by 44 publications

References 19 publications

Interaction of the Sodium/Glucose Cotransporter (SGLT) 2 inhibitor Canagliflozin with SGLT1 and SGLT2

Interaction of the Sodium/Glucose Cotransporter (SGLT) 2 inhibitor Canagliflozin with SGLT1 and SGLT2

Intestinal Sodium Glucose Cotransporter 1 Inhibition Enhances Glucagon-Like Peptide-1 Secretion in Normal and Diabetic Rodents

The SGLT2 Inhibitor Empagliflozin Improves the Primary Diabetic Complications in ZDF Rats

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