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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The kidney contains two Na(+)/glucose cotransporters, called SGLT2 and SGLT1, arranged in series along the length of the proximal tubule. The low-affinity transporter, SGLT2, is responsible for the reabsorption of most of the glucose in the kidney. There is recent interest in SGLT2 as a target for the treatment of type II diabetes using selective inhibitors based on the structure of the phenylglucoside, phlorizin (phloretin-2'-beta-glucoside). In this study, we examined the inhibition of alpha-methyl-d-glucopyranose transport by phlorizin and a new candidate drug, sergliflozin-A [(2-[4-methoxyphenyl]methyl)phenyl beta-d-glucopyranoside], in COS-7 cells expressing hSGLT1 and hSGLT2. Inhibition by phlorizin was competitive, with K(i) values of 0.3 muM in hSGLT1 and 39 nM in hSGLT2. Inhibition by sergliflozin-A was also competitive, with K(i) values of 1 muM in hSGLT1 and 20 nM in hSGLT2. Phloretin [3-(4-hydroxyphenyl)-1-(2,4,6-trihydroxyphenyl)-1-propanone; the aglucone of phlorizin] was a less potent inhibitor, with IC(50) values of 142 muM in hSGLT1 and 25 muM in hSGLT2. Site-directed mutagenesis of residues believed to be in the phlorizin binding site showed that only Cys610 is involved in inhibitor binding in the human transporters. Mutation of Cys610 in hSGLT1 to lysine resulted in an increased IC(50) for all inhibitors. In contrast, mutagenesis of the analogous Cys615 in hSGLT2 produced the opposite effect, a decrease in IC(50) for phlorizin and sergliflozin-A. The differences in the effects of the mutations between hSGLT1 and hSGLT2 suggest that this cysteine holds key residues in place rather than participating directly in inhibitor binding.
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PMID:Inhibitor binding in the human renal low- and high-affinity Na+/glucose cotransporters. 1806 24

The authors' researches have been focused on pathogenic, physiological and biochemical mechanisms in hypertension and diabetes. Studies on hypertension were performed using salt-sensitive hypertensive Dahl rats as compared with the corresponding normotensive rats. Especially, implication with mobilization of electrolytes such as sodium, potassium, calcium and magnesium in hypertension gave rise to provocative to the author. Furthermore, complications of diabetes with hypertension were themes for the authors' researches. Thus, sodium-dependent glucose transport has been studied on sodium-dependent glucose transporters such as SGLT1 and SGLT2 using cell lines of porcelain renal cell, LLC-PK(1), and murine renal cell, NRK-52E. Relationship between magnesium mobilization and NO in hypertension has been explored using renal epithelial cell-lines and salt-sensitive hypertensive Dahl rats in the latter half of the author's research life.
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PMID:[Expression and regulation of renal sodium-cotransporters and -antiporters, and related-transport proteins]. 1852 Jan 36

The low-affinity sodium glucose cotransporter (SGLT2) plays an important role in renal glucose reabsorption and is a remarkable transporter as a molecular target for the treatment of diabetes. We have discovered remogliflozin etabonate, which is a novel category of selective SGLT2 inhibitors. Remogliflozin etabonate is a prodrug based on benzylpyrazole glucoside and is metabolized to its active form, remogliflozin, in the body. We identified remogliflozin to be a potent and highly selective SGLT2 inhibitor by examining COS-7 cells transiently expressing either high-affinity sodium glucose cotransporter (SGLT1) or SGLT2. Orally administered remogliflozin etabonate increased urinary glucose excretion in a dose-dependent manner in both mice and rats. By increasing urinary glucose excretion, remogliflozin etabonate inhibited the increase in plasma glucose after glucose loading without stimulating insulin secretion in normal rats. Remogliflozin etabonate also showed antihyperglycemic effects in both streptozotocin-induced diabetic rats in oral glucose tolerance and in db/db mice in the fed condition. Chronic treatment with remogliflozin etabonate reduced the levels of fasting plasma glucose and glycated hemoglobin, and it ameliorated glucosuria in db/db mice. In high-fat diet-fed Goto-Kakizaki rats, remogliflozin etabonate improved hyperglycemia, hyperinsulinemia, hypertriglyceridemia, and insulin resistance. This study demonstrates that treatment with remogliflozin etabonate exhibits antidiabetic efficacy in several rodent models and suggests that remogliflozin etabonate may be a new and useful drug for the treatment of diabetes.
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PMID:Remogliflozin etabonate, in a novel category of selective low-affinity sodium glucose cotransporter (SGLT2) inhibitors, exhibits antidiabetic efficacy in rodent models. 1858 47

Diabetes-mediated changes in mRNA expressions of kidney glucose transporters SGLT1 and SGLT2 were investigated in Zucker rats. SGLTs expressions in pre-diabetic obese rats were similar to leans. SGLT1 and SGLT2 levels in diabetic obese rats were 1.6 (P<0.03) and 4.8 (P<0.002) folds higher than age-matched leans, respectively.
Diabetes Res Clin Pract 2009 Jan
PMID:Enhanced expressions of sodium-glucose cotransporters in the kidneys of diabetic Zucker rats. 1909 25

The low-affinity sodium glucose cotransporter (SGLT2) is responsible for most of the glucose reabsorption in the kidney and has been highlighted as a novel therapeutic target for the treatment of diabetes. We discovered sergliflozin etabonate, a novel selective SGLT2 inhibitor, and found that selective inhibition of SGLT2 increased urinary glucose excretion and consequently decreased plasma glucose levels. In this report, we examined the antihyperglycemic effects of sergliflozin etabonate in normal and diabetic rats in comparison with those of a sulfonylurea (gliclazide) and an alpha-glucosidase inhibitor (voglibose). Sergliflozin etabonate increased urinary glucose excretion in a dose-dependent manner, and inhibited the increase in plasma glucose after sucrose loading independently of insulin secretion in normal rats. Sergliflozin etabonate also improved postprandial hyperglycemia in neonatal streptozotocin-induced diabetic rats; whereas gliclazide did not improve it. In rats with mild or moderate streptozotocin-induced diabetes, the degree of the antihyperglycemic effects of sergliflozin etabonate correlated with the severity of the diabetic condition. Sergliflozin etabonate did not affect the plasma glucose level of normal rats as seen with gliclazide. Chronic treatment with sergliflozin etabonate reduced the levels of glycated hemoglobin and fasting plasma glucose, and improved the glycemic response after glucose loading in Zucker fatty rats. In addition, sergliflozin etabonate did not affect the body weight or food intake. These data indicate that sergliflozin etabonate could improve glycemic control without its use resulting in insulin secretion, hypoglycemia, and body weight gain, and may provide a unique approach to the treatment of diabetes.
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PMID:Sergliflozin etabonate, a selective SGLT2 inhibitor, improves glycemic control in streptozotocin-induced diabetic rats and Zucker fatty rats. 1928 9

The kidneys play a major role in the regulation of glucose in humans, reabsorbing 99% of the plasma glucose that filters through the renal glomeruli tubules. The glucose transporter, SGLT2, which is found primarily in the S1 segment of the proximal renal tubule, is essential to this process, accounting for 90% of the glucose reabsorption in the kidney. Evidence has suggested that selective inhibition of SGLT2 induces glucosuria in a dose-dependent manner and may have beneficial effects on glucose regulation in individuals with type II diabetes. Preclinical data with SGLT2 inhibitors, such as dapagliflozin and sergliflozin, show that these compounds are highly selective inhibitors for SGLT2, have beneficial effects on the glucose utilization rate, and reduce hyperglycemia while having no hypoglycemic adverse effects. Clinical research remains to be carried out on the long-term effects of glucosuria and other potential effects of this class of drug. Nonetheless, these compounds represent a very promising approach for the treatment of diabetes.
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PMID:Renal sodium-glucose transport: role in diabetes mellitus and potential clinical implications. 1994 14

Sodium-glucose cotransporters (SGLTs) in the kidney, may be involved in hypertension, diabetes and salt sensitivity. We evaluate the effect of losartan on blood pressure (BP) and SGLT2 expression in diabetic rats with high or normal salt diet. Losartan prevented an increase in BP and SGLT2 expression in diabetic rats.
Diabetes Res Clin Pract 2009 Dec
PMID:Effect of treatment with losartan on salt sensitivity and SGLT2 expression in hypertensive diabetic rats. 1980 Jul 6

Dapagliflozin (BMS-512148), a specific inhibitor of the sodium-glucose cotransporter SGLT2, is under development by AstraZeneca plc and Bristol-Myers Squibb Co for the potential oral treatment of type 2 diabetes mellitus (T2DM); a fixed-dose combination of dapagliflozin and metformin is also being developed by the companies for the potential treatment of diabetes mellitus. Phlorizin, a naturally occurring O-glucoside, inhibits renal glucose transport and induces glucosuria in rodent models of diabetes; however, phlorizin inhibits other glucose transporters in addition to SGLT2 and thus is not suitable for oral administration. The chemical synthesis of more specific SGLT2 inhibitors led to the identification of dapagliflozin, a C-aryl glucoside that was highly selective for SGLT2 compared with SGLT1. In phase II clinical trials in patients with T2DM, once-daily dapagliflozin induced dose-dependent increases in glucosuria and efficiently reduced HbA1c, fasting and postprandial glucose levels. Dapagliflozin was not associated with significant hypoglycemic episodes or weight gain; rather, the caloric losses related to renal glucose wasting induced a net weight loss. In addition, the diuretic effect observed with dapagliflozin may help to control hypertension, an associated finding in patients with T2DM. The major adverse effect associated with dapagliflozin appears to be an increased occurrence of mycotic genital infections.
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PMID:Dapagliflozin, an oral sodium glucose cotransporter type 2 inhibitor for the treatment of type 2 diabetes mellitus. 1994 22

Insulin causes inotropic effects via Ca(2+)-dependent and Ca(2+)-independent pathways. The latter one is potentially glucose dependent. We examined inotropic responses and signal transduction of insulin in human atrial myocardium of diabetic and nondiabetic patients to test for the role of glucose transporters. Experiments were performed in isolated atrial myocardium of 88 patients undergoing cardiac surgery and 28 ventricular muscle samples of explanted hearts. Influence of insulin (0.02 micromol/L) on isometric twitch force was examined with and without blocking glucose transporter (GLUT) 4 translocation (latrunculin), sodium-coupled glucose transporter (SGLT) 1 (phlorizin, T-1095A), or PI3-kinase (wortmannin). Experiments were performed in Tyrode solution containing glucose or pyruvate as energetic substrate. Messenger RNA expression of glucose transporters (GLUT1, GLUT4, SGLT1, SGLT2) was analyzed in atrial and ventricular myocardium of both diabetic and nondiabetic patients. Developed force increases after insulin (to 117.8% +/- 2.4% and 115.8% +/- 1.9%) in trabeculae from patients with and without diabetes. Inotropic effect was reduced after displacing glucose with pyruvate as well as after PI3-kinase inhibition (to 103% +/- 2%) or inhibition of glucose transporters GLUT4 (to 105% +/- 2%) and SGLT1 (phlorizin to 106% +/- 2%, T-1095A to 105% +/- 2%), without differences between the 2 groups. In glucose-free pyruvate-containing solution, only inhibition of PI3-kinase but not blocking glucose transporters resulted in further inhibitory effects. Messenger RNA expression did not show significant differences between patients with or without diabetes. Insulin exerts positive inotropic effects in human atrial myocardium. These effects are mediated via a PI3-kinase-sensitive and a glucose-transport-sensitive pathway. Differences in functional effects or messenger RNA expression of glucose transporters were not detectable between patients with and without diabetes.
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PMID:Glucose-transporter-mediated positive inotropic effects in human myocardium of diabetic and nondiabetic patients. 2004 49

Plasma glucose is continuously filtered through the glomerulus and then is reabsorbed via the transcellular transport system of proximal tubules in the kidney. The glucose reabsorption system in the kidney is mediated by sodium-dependent glucose cotransporters (SGLTs). Most of filtered glucose is reabsorbed by the low affinity, high capacity SGLT2 located in the proximal renal tubule. SGLT2 inhibitors, such as T-1095, enhance urinary glucose excretion and consequently lower blood glucose levels independent of insulin action. The principle behind SGLT inhibition involves the amelioration of diabetic conditions without increasing body weight and the risk of hypoglycemia. A number of SGLT2 inhibitors are being developed for the treatment of diabetes. This review offers the summary of structure-activity relationships (SARs) and pharmacological profiles of T-1095 and diverse SGLT2 inhibitors.
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PMID:Renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for new anti-diabetic agent. 2018 Jul 60


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