Novel Indole-<i>N</i>-glucoside, TA-1887 As a Sodium Glucose Cotransporter 2 Inhibitor for Treatment of Type 2 Diabetes

Nomura, Sumihiro; Yamamoto, Yasuo; Matsumura, Yosuke; Ohba, Kiyomi; Sakamaki, Shigeki; Kimata, Hirotaka; Nakayama, Keiko; Kuriyama, Chiaki; Matsushita, Yasuyuki; Ueta, Kiichiro; Tsuda-Tsukimoto, Minoru

doi:10.1021/ml400339b

Cited by 44 publications

(32 citation statements)

References 22 publications

(32 reference statements)

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“…For analysis, we used TA-1887, an SGLT2i with selectivity for SGLT2 versus SGLT1, similar to canagliflozin. 11 , 12 To determine treatment effects, we evaluated db/db mice (also known as Lepr −/− mice) fed a HF diet as a model of severe diabetes and treated them with or without TA-1887. As reported by others, 13 , 14 in 1st month body weight of TA-1887-treated mice decreased relative to that of untreated mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

Treatment of diabetic mice with the SGLT2 inhibitor TA-1887 antagonizes diabetic cachexia and decreases mortality

et al. 2017

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A favorable effect of an inhibitor of the sodium–glucose cotransporter 2 (SGLT2i) on mortality of diabetic patients was recently reported, although mechanisms underlying that effect remained unclear. Here, we examine SGLT2i effects on survival of diabetic mice and assess factors underlying these outcomes. To examine SGLT2i treatment effects in a model of severe diabetes, we fed genetically diabetic db/db mice a high-fat diet and then assessed outcomes including diabetic complications between SGLT2i TA-1887-treated and control mice. We also compare effects of SGLT2i TA-1887 with those of lowering blood glucose levels via insulin treatment. Untreated db/db mice showed remarkable weight loss, or cachexia, while TA-1887-treated mice did not but rather continued to gain weight at later time points and decreased mortality. TA-1887 treatment prevented pancreatic beta cell death, enhanced preservation of beta cell mass and endogenous insulin secretion, and increased insulin sensitivity. Moreover, TA-1887 treatment attenuated inflammation, oxidative stress, and cellular senescence, especially in visceral white adipose tissue, and antagonized endothelial dysfunction. Insulin treatment of db/db mice also prevented weight loss and antagonized inflammation and oxidative stress. However, insulin treatment had less potent effects on survival and prevention of cellular senescence and endothelial dysfunction than did TA-1887 treatment. SGLT2i treatment prevents diabetic cachexia and death by preserving function of beta cells and insulin target organs and attenuating complications. SGLT2i treatment may be a promising therapeutic strategy for type 2 diabetes patients with morbid obesity and severe insulin resistance.

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Section: Resultsmentioning

confidence: 99%

Treatment of diabetic mice with the SGLT2 inhibitor TA-1887 antagonizes diabetic cachexia and decreases mortality

et al. 2017

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“…A previous report showed that phloridzin reduced glucose-induced GLP-1 release (Moriya et al, 2009). CGMI is reported to have more potent inhibitory activity against SGLT1 than canagliflozin (Nomura et al, 2014). We explored the effects of these compounds on plasma GLP-1 levels and intestinal carbohydrate absorption and evaluated the combined effect of canagliflozin and sitagliptin, a DPP4 inhibitor, in normal and diabetic rodents.…”

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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“…SGLT2 inhibitors have a glucose-lowing effect, but there is little risk of severe hypoglycemia due to SGLT1 reabsorption of glucose which occurs in the distal part of the proximal tubule [3]. One of the reasons the patient did not show severe hypoglycemia might be because she did not take other glucose-lowering agents at the same time which have been reported to induce severe hypoglycemia [6].…”

Section: Discussionmentioning

confidence: 99%

“…Since SGLT2 inhibitors inhibit glucose reabsorption by SGLT2, urine osmotic pressure increases due to increased urinary glucose excretion, causing osmotic diuresis, which affects urine output and body fluid volume [2]. Since these drugs do not directly affect glucose metabolism or insulin secretion in the body, SGLT2 inhibitor monotherapy does not cause severe hypoglycemia [3].…”

Section: Introductionmentioning

confidence: 99%

Severe intoxication caused by sodium-glucose cotransporter 2 inhibitor overdose: a case report

Nakamura

Nakade

Toyama

et al. 2020

BMC Pharmacol Toxicol

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Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors inhibit SGLT2, which is expressed in the proximal renal tubule, and thus reduce blood glucose levels by enabling the urinary excretion of excess glucose. SGLT2 inhibitors have been reported to suppress the complications of diabetes and reduce overall mortality. However, little is known about the types of symptoms that may occur in response to an overdose of an SGLT2 inhibitor. Here, we describe a case of intoxication caused by an overdose of an SGLT2 inhibitor. Case presentation: An otherwise physically healthy adult woman ingested an overdose of ipragliflozin, an SGLT2 inhibitor, and a polypill of olmesartan medoxomil, and azelnidipine in a suicide attempt. Although her blood ipragliflozin concentration was very high (9516.3 ng/mL) upon hospital arrival, her initial blood glucose level was normal, and she did not exhibit symptoms such as hypoglycemia or polyuria. Moderate renal dysfunction associated with an estimated glomerular filtration rate of 42.3 mL/min/1.73 m 2 was observed. Thirty-six hours after ingestion, her blood ipragliflozin concentration decreased to a level equivalent to that observed after a therapeutic dose and her renal function improved almost simultaneously. After improvement in her renal function, the osmotic diuretic effect of the drug progressed. Her blood glucose level declined slightly but was in the normal range due to glucose administration. During the clinical course, fatal hypoglycemia was not observed. Conclusions: Our case showed that an overdose of an SGLT2 inhibitor caused toxic effects on renal function, but severe hypoglycemia was not observed. Additional cases of intoxication from SGLT2 inhibitors alone would be helpful to clarify the mechanism of intoxication.

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Novel Indole-N-glucoside, TA-1887 As a Sodium Glucose Cotransporter 2 Inhibitor for Treatment of Type 2 Diabetes

Cited by 44 publications

References 22 publications

Treatment of diabetic mice with the SGLT2 inhibitor TA-1887 antagonizes diabetic cachexia and decreases mortality

Treatment of diabetic mice with the SGLT2 inhibitor TA-1887 antagonizes diabetic cachexia and decreases mortality

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

Severe intoxication caused by sodium-glucose cotransporter 2 inhibitor overdose: a case report

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