KGA-2727, a Novel Selective Inhibitor of a High-Affinity Sodium Glucose Cotransporter (SGLT1), Exhibits Antidiabetic Efficacy in Rodent Models

Shibazaki, Toshihide; Tomae, Masaki; Ishikawa-Takemura, Yukiko; Fushimi, Nobuhiko; Itoh, Fumiaki; Yamada, Mitsuhiko; Isaji, Masayuki

doi:10.1124/jpet.112.193045

Cited by 76 publications

(76 citation statements)

References 40 publications

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“…Glucose stimulates GLP-1 secretion from the gastrointestinal (GI) tract, and there is an increasing body of evidence that SGLT1 is a sensor linking glucose to incretin release (Moriya et al, 2009;Gorboulev et al, 2012). However, the observation that the SGLT1 inhibitor increased portal GLP-1 levels after intestinal glucose infusion contradicts this hypothesis (Shibazaki et al, 2012). The relative contributions of SGLT1 in glucose-induced GLP-1 secretion remain controversial.…”

Section: Introductionmentioning

confidence: 64%

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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Section: Introductionmentioning

confidence: 64%

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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“…Glucagon-like peptide-1 has been shown to normalize fasting hyperglycemia and has been investigated as a potential treatment of diabetes (Meier et al, 2004). Thus, these findings suggest the notion that partial inhibition of SGLT1 might represent a novel and attractive therapeutic strategy in the treatment of diabetes (Shibazaki et al, 2012). Natural products provide an important resource in the search for new drugs to prevent metabolic disorders and as new therapeutic approaches (Moller, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…For example, glucose uptake is enhanced in brushborder membrane vesicles on the duodenum of patients with diabetes and the enhancement is due to increased expression of SGLT1 mRNA and protein levels (Dyer et al, 2002). It should be noted that the increased circulating glucagon-like peptide-1 level was found in mice and human studies with partial SGLT1 inhibition (Shibazaki et al, 2012;Powell et al, 2013). Glucagon-like peptide-1 has been shown to normalize fasting hyperglycemia and has been investigated as a potential treatment of diabetes (Meier et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

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An Essential Role of cAMP Response Element Binding Protein in Ginsenoside Rg1-Mediated Inhibition of Na⁺/Glucose Cotransporter 1 Gene Expression

Wang

Huang

et al. 2015

Mol Pharmacol

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The Na 1 /glucose cotransporter 1 (SGLT1) is responsible for glucose uptake in intestinal epithelial cells. It has been shown that the intestinal SGLT1 level is significantly increased in diabetic individuals and positively correlated with the pathogenesis of diabetes. The development of targeted therapeutics that can reduce the intestinal SGLT1 expression level is, therefore, important. In this study, we showed that ginsenoside Rg1 effectively decreased intestinal glucose uptake through inhibition of SGLT1 gene expression in vivo and in vitro. Transient transfection analysis of the SGLT1 promoter revealed an essential cAMP response element (CRE) that confers the Rg1-mediated inhibition of SGLT1 gene expression. Chromatin immunoprecipitation assay and targeted CRE-binding protein (CREB) silencing demonstrated that Rg1 reduced the promoter binding of CREB and CREB binding protein associated with an inactivated chromatin status. In addition, further studies showed that the epidermal growth factor receptor (EGFR) signaling pathway also plays an essential role in the inhibitory effect of Rg1; taken together, our study demonstrates the involvement of the EGFR-CREB signaling pathway in the Rg1-mediated downregulation of SGLT1 expression, which offers a potential strategy in the development of antihyperglycemic and antidiabetic treatments.

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“…Area under curve (AUC) was calculated for OGTT by trapezoidal rule. On the day of sacrifice, PTAE was orally fed to the respective treated group 30 min before glucose administration, glucose at the dose of 1g/kg was then fed orally 19,20 . Then the animals were sacrificed.…”

Section: Group I: Control Animals Fed With Normal Dietmentioning

confidence: 99%

Untitled

2016

IJPSR

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Objective: This study was aimed to evaluate the role of GLP-1, GIP in the hypoglycemic activity of Phlogacanthus thyrsiflorus Nees. Materials and Methods: We have evaluated the influence of Phlogacanthus thyrsiflorus Nees, a traditionally used antidiabetic medicinal plant on some metabolic parameters, glucose homeostasis, insulin production, glucagon like peptide 1 (GLP1) and gastric Inhibitory Polypeptide (GIP) in high fat diet fed (HFD) obese mice and High fat diet + streptozotocin (HFD + STZ) induced diabetic mice. Oral glucose tolerance test (OGTT) was done to study the glucose homeostasis in both HFD fed obese mice and HFD + STZ induced diabetic mice. Effect of P. thyrsiflorus on pancreatic beta cells was assessed using histological studies. Results: Phlogacanthus thyrsiflorus aqueous extract (PTAE) treatment lowered the blood glucose levels in HFD fed obese mice and HFD + STZ induced diabetic mice significantly. PTAE treatment reduced the weight gain in HFD fed obese mice and prevented the constant weight loss in HFD+STZ induced diabetic mice. PTAE treatment decreased the food intake significantly in HFD fed obese mice. PTAE treatment improved the glucose tolerance and the lipid profile in HFD fed obese mice. PTAE treatment decreased the insulin level in HFD fed obese mice and increased the insulin level in HFD + STZ induced diabetic mice. PTAE treatment increased the GLP -1 level and decreased the GIP level significantly in both HFD fed obese mice and HFD + STZ induced diabetic mice. Histological studies of pancreas showed that P.thyrsiflorus helps normalizing the pancreatic histoarchitecture. Conclusion: This study states that the hyperglycaemic activity of the P.thyrsiflorus is due to the modulation of the enteroinsular axis in the Hypoglycemic mice. However the study also revealed the doubtful role of GIP as incretins and its role in diabetes treatment.

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KGA-2727, a Novel Selective Inhibitor of a High-Affinity Sodium Glucose Cotransporter (SGLT1), Exhibits Antidiabetic Efficacy in Rodent Models

Abstract: The high-affinity sodium glucose cotransporter (SGLT1) plays a critical role in glucose absorption from the gastrointestinal tract. We have developed 3-(3-{4-[3-(␤-D-glucopyranosyloxy)-5-isopropyl-

Cited by 76 publications

References 40 publications

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

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

An Essential Role of cAMP Response Element Binding Protein in Ginsenoside Rg1-Mediated Inhibition of Na⁺/Glucose Cotransporter 1 Gene Expression

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KGA-2727, a Novel Selective Inhibitor of a High-Affinity Sodium Glucose Cotransporter (SGLT1), Exhibits Antidiabetic Efficacy in Rodent Models

Abstract: The high-affinity sodium glucose cotransporter (SGLT1) plays a critical role in glucose absorption from the gastrointestinal tract. We have developed 3-(3-{4-[3-(␤-D-glucopyranosyloxy)-5-isopropyl-

Cited by 76 publications

References 40 publications

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

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

An Essential Role of cAMP Response Element Binding Protein in Ginsenoside Rg1-Mediated Inhibition of Na+/Glucose Cotransporter 1 Gene Expression

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An Essential Role of cAMP Response Element Binding Protein in Ginsenoside Rg1-Mediated Inhibition of Na⁺/Glucose Cotransporter 1 Gene Expression