Effect of Canagliflozin on Renal Threshold for Glucose, Glycemia, and Body Weight in Normal and Diabetic Animal Models

Liang, Yin; Akita, Keiichi; Ueta, Kiichiro; Matsushita, Yasuyuki; Kuriyama, Chiaki; Martin, Tonya; Du, Fuyong; Liu, Yi; Xu, June; Conway, Bruce R.; Conway, Jamie; Polidori, David; Ways, Kirk; Demarest, Keith T.

doi:10.1371/journal.pone.0030555

Cited by 215 publications

(173 citation statements)

References 40 publications

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“…Subcutaneous ASPC-1 tumors produced in the upper thigh or lower flank of NSG mice were monitored for up to 4 wk during treatment with 30 mg/kg canagliflozin or dapagliflozin. The protocol for SGLT2 inhibitors was the one developed for inhibiting renal SGLT2 in mice and patients with diabetes (27)(28)(29)(30). As a positive control, we included treatment with the anticancer drug gemcitabine.…”

Section: Is Sglt Functional Activity Correlated With Sglt Expression mentioning

confidence: 99%

Functional expression of sodium-glucose transporters in cancer

Scafoglio

Hirayama

Kepe

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

260

249

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Glucose is a major metabolic substrate required for cancer cell survival and growth. It is mainly imported into cells by facilitated glucose transporters (GLUTs). Here we demonstrate the importance of another glucose import system, the sodium-dependent glucose transporters (SGLTs), in pancreatic and prostate adenocarcinomas, and investigate their role in cancer cell survival. Three experimental approaches were used: (i) immunohistochemical mapping of SGLT1 and SGLT2 distribution in tumors; (ii) measurement of glucose uptake in fresh isolated tumors using an SGLT-specific radioactive glucose analog, α-methyl-, which is not transported by GLUTs; and (iii) measurement of in vivo SGLT activity in mouse models of pancreatic and prostate cancer using Me4FDG-PET imaging. We found that SGLT2 is functionally expressed in pancreatic and prostate adenocarcinomas, and provide evidence that SGLT2 inhibitors block glucose uptake and reduce tumor growth and survival in a xenograft model of pancreatic cancer. We suggest that Me4FDG-PET imaging may be used to diagnose and stage pancreatic and prostate cancers, and that SGLT2 inhibitors, currently in use for treating diabetes, may be useful for cancer therapy.SGLT2 | pancreatic cancer | prostate cancer | SGLT2-inhibitors P ancreatic cancer is the fourth-leading cause of cancer-related death in the United States (behind only lung, colon, and breast cancers), with 46,420 estimated new cases in 2014 and a mortality that almost equals incidence (39,590 estimated deaths in 2014); the overall 5-y survival rate is only 7% (seer.cancer.gov/statfacts/html/ pancreas.html). Prostate cancer is the most frequent cancer in men in the United States, with 233,000 estimated new cases in 2014. Despite widespread adoption of screening programs, prostate cancer is still the second-leading cause of cancer-related death in men, second only to lung cancer (seer.cancer.gov/statfacts/html/prost.

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Section: Is Sglt Functional Activity Correlated With Sglt Expression mentioning

confidence: 99%

Functional expression of sodium-glucose transporters in cancer

Scafoglio

Hirayama

Kepe

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

260

249

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“…We conducted studies in two obese type 2 diabetes models: the BKS.Cg-Dock7 m+/+ Lepr db /J (db/db), presenting a common murine model used for antidiabetes drug testing (14,15), and the Tallyho/JngJ, recapitulating broader aspects of human "diabesity" (16 At the age of 3 weeks, mice were started on a high-fat diet (Ssniff Spezialdiäten, Soest, Germany) containing palm fat (13.5% of fat), sunflower oil (13.5%), starch (30%), saccharose (10%), casein (20%), lignocellulose (5%), mineral plus vitamin mix (5 and 2%, respectively), safflower oil (0.5%), and linseed oil (0.5). Pharmacological studies were started in 8-week-old db/db and wild-type (wt) references, diabetic 9-week-old Tallyho/JngJ males, or, in the case of one study, chronically diabetic 22-week-old Tallyho/JngJ males.…”

Section: Animals and Pharmacological Treatmentmentioning

confidence: 99%

Metformin Supports the Antidiabetic Effect of a Sodium Glucose Cotransporter 2 Inhibitor by Suppressing Endogenous Glucose Production in Diabetic Mice

et al. 2014

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Combined use of metformin and a sodium glucose cotransporter 2 inhibitor (SGLT2I) is a promising treatment strategy for type 2 diabetes. The mechanism by which combination treatment provides better glycemic control than metformin or SGLT2I monotherapy remains elusive. Therefore, we investigated the physiological mechanism by which both compounds lower blood glucose concentrations in diabetic mice. We compared the potential of metformin and the SGLT2I AVE2268 alone or in combination to mitigate hyperglycemia and modulate glucose fluxes in db/db and diabetic Tallyho/JngJ mice. SGLT2I treatment alone elicited a rapid decline in circulating blood glucose levels, which appeared to induce endogenous glucose production. Supplementation of metformin dampened this counterresponse, and therefore, combination therapy more efficiently maintained glycemic control. Finally, combination treatment blunted postprandial glucose excursions and improved HbA(1c) levels within 2 weeks. We conclude that coapplication of metformin enhances the glucose-lowering actions of SGLT2I by restraining endogenous glucose production, which may provide long-term improvement of glycemic control in type 2 diabetic patients

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“…Chronic phlorizin administration restored insulin secretion and normalized β-cell volume and gene expression [18][19][20] . Long-term studies of canagliflozin and dapagliflozin treatment yielded similar results [21,22] . These data indicate that long-term treatment with SGLT2 inhibitors in animal models of T2DM can protect β-cell function.…”

Section: Acta Pharmacologica Sinica Npgmentioning

confidence: 78%

SHR3824, a novel selective inhibitor of renal sodium glucose cotransporter 2, exhibits antidiabetic efficacy in rodent models

et al. 2014

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Aim: The sodium glucose cotransporter 2 (SGLT2) plays an important role in renal glucose reabsorption, thus serves as a new target for the treatment of diabetes. The purpose of this study was to evaluate SHR3824 as a novel selective SGLT2 inhibitor and to characterize its in vivo effects on glucose homeostasis. The effects of chronic administration of SHR3824 on peripheral insulin sensitivity and pancreatic β-cell function were also investigated. Methods: The in vitro potency and selectivity of SHR3824 were assessed in HEK293 cells transfected with human SGLT2 or SGLT1. Acute and multi-dose studies were performed on ICR mice, GK rats and db/db mice to assess the ability of SHR3824 to enhance urinary glucose excretion and improve blood glucose levels. 2-Deoxyglucose uptake and insulin immunohistochemical staining were performed in the soleus muscle and pancreas, respectively, of db/db mice. A selective SGLT2 inhibitor BMS512148 (dapagliflozin) was taken as positive control. Results: SHR3824 potently inhibited human SGLT2 in vitro, but exerted much weak inhibition on human SGLT1 (the IC 50 values of SHR3824 against human SGLT2 and SGLT1 were 2.38 and 4324 nmol/L, respectively). Acute oral administration of SHR3824 (0.3, 1.0, 3.0 mg/kg) dose-dependently improved glucose tolerance in ICR mice, and reduced hyperglycemia by increasing urinary glucose excretion in GK rats and db/db mice. Chronic oral administration of SHR3824 (0.3, 1.0, 3.0 mg·kg -1 ·d -1 ) dose-dependently reduced blood glucose and HbA1c levels in GK rats and db/db mice, and significantly increased insulin-stimulated glucose uptake in the soleus muscles and enhanced insulin staining in the islet cells of db/db mice. Conclusion: SHR3824 is a potent and selective SGLT2 inhibitor and exhibits antidiabetic efficacy in several rodent models, suggesting its potential as a new therapeutic agent for the treatment of type 2 diabetes.

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Effect of Canagliflozin on Renal Threshold for Glucose, Glycemia, and Body Weight in Normal and Diabetic Animal Models

Cited by 215 publications

References 40 publications

Functional expression of sodium-glucose transporters in cancer

Functional expression of sodium-glucose transporters in cancer

Metformin Supports the Antidiabetic Effect of a Sodium Glucose Cotransporter 2 Inhibitor by Suppressing Endogenous Glucose Production in Diabetic Mice

SHR3824, a novel selective inhibitor of renal sodium glucose cotransporter 2, exhibits antidiabetic efficacy in rodent models

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