Long-term treatment with sergliflozin etabonate improves disturbed glucose metabolism in KK-Ay mice

Katsuno, Kenji; Fujimori, Yoshikazu; Ishikawa-Takemura, Yukiko; Isaji, Masayuki

doi:10.1016/j.ejphar.2009.07.001

Cited by 34 publications

(41 citation statements)

References 37 publications

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“…These results were consistent with our findings in SGLT2 knockout mice (Powell et al, 2013a). In comparison, KKA y mice treated with the SGLT2 inhibitors T-1095 [3-(benzo[b]furan-5-yl)-29,69-dihydroxy-49-methylpropiophenone 29-O-(6-O-methoxycarbonyl-b-D-glucopyranoside)] or sergliflozin showed a slight but significant decrease in weight gain, which was associated with a slight increase in food consumption in the sergliflozin-treated mice (Oku et al, 1999;Katsuno et al, 2009). In general, our studies of LX4211-treated rats and dogs show less weight gain despite increased food consumption, results that are consistent with studies of rats with diet-induced obesity where weight loss associated with long-term dapagliflozin treatment was partially offset by increased food consumption (Devenny et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Effect of LX4211 on Glucose Homeostasis and Body Composition in Preclinical Models

Powell

DaCosta

Smith

et al. 2014

J Pharmacol Exp Ther

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Treatments that lower blood glucose levels and body weight should benefit patients with type 2 diabetes mellitus (T2DM). We developed LX4211 [(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol], an orally available small molecule that decreases postprandial glucose excursions by inhibiting intestinal sodium/glucose cotransporter 1 (SGLT1) and increases urinary glucose excretion (UGE) by inhibiting renal SGLT2. In clinical studies of patients with T2DM, LX4211 appears to act through dual SGLT1/SGLT2 inhibition to improve glycemic control and promote weight loss. Here, we present preclinical studies that explored the ability of LX4211 to improve glycemic control and promote weight loss. We found that 1) LX4211 inhibited in vitro glucose transport mediated by mouse, rat, and dog SGLT1 and SGLT2; 2) a single daily LX4211 dose markedly increased UGE for .24 hours in mice, rats, and dogs; and 3) in the KK.Cg-Ay/J heterozygous (KKA y ) mouse model of T2DM, LX4211 lowered A1C and postprandial glucose concentrations while increasing postprandial glucagon-like peptide 1 concentrations. Also, long-term LX4211 treatment 1) decreased oral glucose tolerance test (OGTT) glucose excursions, increased OGTT 30-minute insulin concentrations and increased pancreatic insulin content in KKA y mice; and 2) decreased weight gain in dogs and rats but not in KKA y mice while increasing food consumption in dogs, rats, and KKA y mice; in these KKA y mice, calories lost through UGE were completely offset by calories gained through hyperphagia. These findings suggest that LX4211 improves glycemic control by dual SGLT1/SGLT2 inhibition in mice as in humans, and that the LX4211-mediated weight loss observed in patients with T2DM may be attenuated by LX4211-mediated hyperphagia in some of these individuals.

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Section: Discussionmentioning

confidence: 99%

Effect of LX4211 on Glucose Homeostasis and Body Composition in Preclinical Models

Powell

DaCosta

Smith

et al. 2014

J Pharmacol Exp Ther

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“…Sodium-glucose cotransporter 2 (SGLT2) inhibitors offer an antidiabetic effect by increasing the urinary glucose excretion and subsequently lowering the plasma glucose without inducing excessive insulin secretion. [9] Both animal studies and clinical trials have revealed the efficacy and safety of SGLT2 inhibition for T2D. [10–14] Canagliflozin is a new SGLT2 inhibitor.…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of canagliflozin in patients with type 2 diabetes

et al. 2016

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“…In animal (20,32) and clinical studies with type 2 diabetic patients (3,36), it has been shown that SGLT2 inhibition leads to weight loss. Increased urinary Na ϩ and glucose excretion under the SGLT2 inhibitor therapy induces osmotic diuresis, which contributes to weight loss.…”

Section: Mesangial Index Fraction [%]mentioning

confidence: 99%

The SGLT2 inhibitor empagliflozin ameliorates early features of diabetic nephropathy in BTBR ob/ob type 2 diabetic mice with and without hypertension

Gembardt

Bartaun

Jarzebska

et al. 2014

American Journal of Physiology-Renal Physiology

171

122

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. The SGLT2 inhibitor empagliflozin ameliorates early features of diabetic nephropathy in BTBR ob/ob type 2 diabetic mice with and without hypertension. Am J Physiol Renal Physiol 307: F317-F325, 2014. First published June 18, 2014 doi:10.1152/ajprenal.00145.2014.-Diabetic nephropathy is the leading cause of end-stage renal disease in humans in the Western world. The recent development of Na ϩ -glucose cotransporter 2 (SGLT2) inhibitors offers a new antidiabetic therapy via enhanced glucose excretion. Whether this strategy exerts beneficial effects on the development of type 2 diabetic nephropathy is still largely unclear. We investigated the effects of the specific SGLT2 inhibitor empagliflozin in BTBR.Cg-LepϽobϾ/WiscJ (BTBR ob/ob) mice, which spontaneously develop type 2 diabetic nephropathy. In the first experiment, BTBR ob/ob mice received either a diet containing 300 ppm empagliflozin or equicaloric placebo chow for 12 wk. In the second experiment, BTBR ob/ob mice received 1 g·kg body wt Ϫ1 ·day Ϫ1ANG II to induce arterial hypertension and were separated into the same two diet groups for 6 wk. In both experiments, empagliflozin treatment enhanced glucosuria, thereby lowering blood glucose. Independently of hypertension, empagliflozin reduced albuminuria in diabetic mice. However, empagliflozin treatment affected diabetesrelated glomerular hypertrophy, markers of renal inflammation, and mesangial matrix expansion only in BTBR ob/ob mice without hypertension. In summary, empagliflozin demonstrated significant antihyperglycemic effects, differentially ameliorating early features of diabetic nephropathy in BTBR ob/ob mice with and without hypertension.

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Long-term treatment with sergliflozin etabonate improves disturbed glucose metabolism in KK-Ay mice

Cited by 34 publications

References 37 publications

Effect of LX4211 on Glucose Homeostasis and Body Composition in Preclinical Models

Effect of LX4211 on Glucose Homeostasis and Body Composition in Preclinical Models

Efficacy and safety of canagliflozin in patients with type 2 diabetes

The SGLT2 inhibitor empagliflozin ameliorates early features of diabetic nephropathy in BTBR ob/ob type 2 diabetic mice with and without hypertension

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