Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The bulk of glucose that is filtered by the renal glomerulus is reabsorbed by the glucose transporters of the proximal convoluted tubular epithelium. However, it has been difficult to investigate this in diseases such as type 2 diabetes because of the inability to isolate primary renal cells from patients without a renal biopsy. We report here a method for the immunomagnetic isolation and novel primary culture of human exfoliated proximal tubular epithelial cells (HEPTECs) from fresh urine. The primary isolates are highly enriched and differentiated and express characteristic proximal tubular phenotypic markers. They continue to express the proximal tubular markers CD13/aminopeptidase-N, sodium glucose cotransporter (SGLT) 2, and alkaline phosphatase through up to six subsequent subcultures in a similar way to human proximal cells isolated from renal biopsies. In a hyperglycemic environment, HEPTECs isolated from patients with type 2 diabetes expressed significantly more SGLT2 and the facilitative glucose transporter GLUT2 than cells from healthy individuals. We also demonstrated a markedly increased renal glucose uptake in HEPTECs isolated from patients with type 2 diabetes compared with healthy control subjects. Our findings indicate for the first time in a human cellular model that increased renal glucose transporter expression and activity is associated with type 2 diabetes.
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PMID:Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. 1630 58

Mutations in Na(+)-glucose transporters (SGLT)-2 and hepatocyte nuclear factor (HNF)-1alpha genes have been related to renal glycosuria and maturity-onset diabetes of the young 3, respectively. However, the expression of these genes have not been investigated in type 1 and type 2 diabetes. Here in kidney of diabetic rats, we tested the hypotheses that SGLT2 mRNA expression is altered; HNF-1alpha is involved in this regulation; and glycemic homeostasis is a related mechanism. The in vivo binding of HNF-1alpha into the SGLT2 promoter region in renal cortex was confirmed by chromatin immunoprecipitation assay. SGLT2 and HNF-1alpha mRNA expression (by Northern and RT-PCR analysis) and HNF-1 binding activity of nuclear proteins (by EMSA) were investigated in diabetic rats and treated or not with insulin or phlorizin (an inhibitor of SGLT2). Results showed that diabetes increases SGLT2 and HNF-1alpha mRNA expression (~50%) and binding of nuclear proteins to a HNF-1 consensus motif (~100%). Six days of insulin or phlorizin treatment restores these parameters to nondiabetic-rat levels. Moreover, both treatments similarly reduced glycemia, despite the differences in plasma insulin and urinary glucose concentrations, highlighting the plasma glucose levels as involved in the observed modulations. This study shows that SGLT2 mRNA expression and HNF-1alpha expression and activity correlate positively in kidney of diabetic rats. It also shows that diabetes-induced changes are reversed by lowering glycemia, independently of insulinemia. Our demonstration that HNF-1alpha binds DNA that encodes SGLT2 supports the hypothesis that HNF-1alpha, as a modulator of SGLT2 expression, may be involved in diabetic kidney disease.
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PMID:Na(+) -glucose transporter-2 messenger ribonucleic acid expression in kidney of diabetic rats correlates with glycemic levels: involvement of hepatocyte nuclear factor-1alpha expression and activity. 1796 40

AVE2268, a substituted glycopyranoside, is an orally active and selective inhibitor of sodium-dependent glucose transporter 2 (SGLT2; IC50 = 13 nmol/L). Investigation of the pharmacological profile of AVE2268 on urinary glucose excretion (UGE) and blood glucose after glucose challenge (po or Intraperitoneal) was performed in mice and rats. AVE2268 caused a dose-dependent increase of UGE in mice (ID30 = 79 +/- 8.1 mg/kg p.o.) and rats (ID30 = 39.8 +/- 4.0 mg/kg p.o.). AVE2268 in mice was more potent to decrease blood glucose ascent when glucose was given intraperitoneally (ID50 = 13.2 +/- 3.9 mg/ kg), compared to orally administered glucose (ID50 = 26.1 +/- 3.9 mg/kg), showing that AVE2268 has no effects on SGLT 1 in the gut in vivo, which is in accordance with ist very low affinity to the SGLT 1 in vitro (IC50 >10,000 nmol/L). During an oral glucose tolerance test, AVE2268 dose-dependently increased UGE, with subsequent decreases of AUC and blood glucose. A highly significant inverse correlation between AUC and UGE was found (p < 0.001). The increase in UGE is linked to the inhibition of SGLT2 only. This profile renders AVE2268 as a new antidiabetic drug for the treatment of type 2 diabetes.
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PMID:Effects of AVE2268, a substituted glycopyranoside, on urinary glucose excretion and blood glucose in mice and rats. 1913 8

The full significance of the kidney's role in glucose homeostasis is now well recognized. For example, it is now known that renal gluconeogenesis contributes substantially to total-body glucose release in the postabsorptive state. The kidney contributes to glucose homeostasis by filtering and reabsorbing glucose. Under normal circumstances, glucose filtered by glomeruli is completely reabsorbed, but glucosuria may occur under conditions of hyperglycemia or reduced reabsorptive capacity. The sodium-glucose cotransporter SGLT2 (encoded by the SLC5A2 gene), which is expressed almost exclusively in proximal tubules, mediates approximately 90% of active renal glucose reabsorption. This transporter can be blocked by SGLT2 inhibitors, a class of compound that may prove effective in managing type 2 diabetes. The glucosuria induced by these compounds has a naturally occurring parallel in familial renal glucosuria (FRG), a condition in which SGLT2 mutations reduce renal reabsorptive capacity. Interestingly, the chronic glucosuria of patients with FRG does not appear to be associated with other pathological changes, and patients with FRG are mostly asymptomatic. This suggests that glucosuria is not intrinsically detrimental. Selective SGLT2 inhibitors are currently in clinical trials.
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PMID:Glucose control by the kidney: an emerging target in diabetes. 1970 67

In the last few years, the type 2 sodium glucose co-transporters (SGLT2) have been the subject of particular attention as a new, potent group of anti-diabetic drugs. SGLT2 inhibitors block glucose reabsorption in the kidneys, which prompts urinary excretion of glucose and results in lowering of its plasma levels. Although this group of medications is still under investigation, their efficacy in the treatment of type 2 diabetes mellitus (T2D) is very promising, with some of these inhibitors currently undergoing clinical trials.
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PMID:Inhibitors of type 2 sodium glucose co-transporters--a new strategy for diabetes treatment. 1990

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

Four members of two glucose transporter families, SGLT1, SGLT2, GLUT1, and GLUT2, are differentially expressed in the kidney, and three of them have been shown to be necessary for normal glucose resorption from the glomerular filtrate. Mutations in SGLT1 are associated with glucose-galactose malabsorption, SGLT2 with familial renal glucosuria (FRG), and GLUT2 with Fanconi-Bickel syndrome. Patients with FRG have decreased renal tubular resorption of glucose from the urine in the absence of hyperglycemia and any other signs of tubular dysfunction. Glucosuria in these patients can range from <1 to >150 g/1.73 m(2) per d. The majority of patients do not seem to develop significant clinical problems over time, and further description of specific disease sequelae in these individuals is reviewed. SGLT2, a critical transporter in tubular glucose resorption, is located in the S1 segment of the proximal tubule, and, as such, recent attention has been given to SGLT2 inhibitors and their utility in patients with type 2 diabetes, who might benefit from the glucose-lowering effect of such compounds. A natural analogy is made of SGLT2 inhibition to observations with inactivating mutations of SGLT2 in patients with FRG, the hereditary condition that results in benign glucosuria. This review provides an overview of renal glucose transport physiology, FRG and its clinical course, and the potential of SGLT2 inhibition as a therapeutic target in type 2 diabetes.
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PMID:Familial renal glucosuria and SGLT2: from a mendelian trait to a therapeutic target. 1996 50

The kidney plays a major role in glucose homeostasis because of its role in gluconeogenesis and the glomerular filtration and reabsorption of glucose in the proximal convoluted tubules. Approximately 180 g of glucose is filtered daily in the glomeruli of a normal healthy adult. Typically, all of this glucose is reabsorbed with <1% being excreted in the urine. The transport of glucose from the tubule into the tubular epithelial cells is accomplished by sodium-glucose co-transporters (SGLTs). SGLTs encompass a family of membrane proteins that are responsible for the transport of glucose, amino acids, vitamins, ions and osmolytes across the brush-border membrane of proximal renal tubules as well as the intestinal epithelium. SGLT2 is a high-capacity, low-affinity transporter expressed chiefly in the kidney. It accounts for approximately 90% of glucose reabsorption in the kidney and has thus become the focus of a great deal of interest in the field of diabetes mellitus. SGLT2 inhibitors block the reabsorption of filtered glucose leading to glucosuria. This mechanism of action holds potential promise for patients with type 2 diabetes mellitus (T2DM) in terms of improvements in glycaemic control. In addition, the glucosuria associated with SGLT2 inhibition is associated with caloric loss, thus providing a potential benefit of weight loss. Dapagliflozin is the SGLT2 inhibitor with the most clinical data available to date, with other SGLT2 inhibitors currently in the developmental pipeline. Dapagliflozin has demonstrated sustained, dose-dependent glucosuria over 24 hours with once-daily dosing in clinical trials. Although long-term safety data are lacking, studies to date have generally found dapagliflozin to be safe and well tolerated. Concerns related to SGLT2 inhibition include the fact that by their very nature they cause glucose elevation in the urine that can theoretically lead to urinary tract and genital infections, electrolyte imbalances and increased urinary frequency. Although studies to date have been promising in terms of these and other concerns, longer-term studies evaluating the usual safety and efficacy outcomes will need to be conducted. Similarly, head-to-head comparator trials are needed to determine the role of SGLT2 inhibitors in relation to the many other therapeutic options available for the treatment of T2DM. If significant reductions in haemoglobin A(1c) are associated with SGLT2 inhibitor therapy, and these agents are determined to be safe and well tolerated in the long term, they could become a major breakthrough in the T2DM treatment armamentarium.
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PMID:Sodium-glucose co-transport inhibitors: progress and therapeutic potential in type 2 diabetes mellitus. 2020 82

Derivatives of a novel scaffold, C-phenyl 1-thio-D-glucitol, were prepared and evaluated for sodium-dependent glucose cotransporter (SGLT) 2 and SGLT1 inhibition activities. Optimization of substituents on the aromatic rings afforded five compounds with potent and selective SGLT2 inhibition activities. The compounds were evaluated for in vitro human metabolic stability, human serum protein binding (SPB), and Caco-2 permeability. Of them, (1S)-1,5-anhydro-1-[5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio-D-glucitol (3p) exhibited potent SGLT2 inhibition activity (IC(50) = 2.26 nM), with 1650-fold selectivity over SGLT1. Compound 3p showed good metabolic stability toward cryo-preserved human hepatic clearance, lower SPB, and moderate Caco-2 permeability. Since 3p should have acceptable human pharmacokinetics (PK) properties, it could be a clinical candidate for treating type 2 diabetes. We observed that compound 3p exhibits a blood glucose lowering effect, excellent urinary glucose excretion properties, and promising PK profiles in animals. Phase II clinical trials of 3p (TS-071) are currently ongoing.
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PMID:(1S)-1,5-anhydro-1-[5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio-D-glucitol (TS-071) is a potent, selective sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for type 2 diabetes treatment. 2030 2

Inhibiting sodium-glucose co-transporters (SGLTs), which have a key role in the reabsorption of glucose in the kidney, has been proposed as a novel therapeutic strategy for diabetes. Genetic mutations in the kidney-specific SGLT2 isoform that result in benign renal glycosuria, as well as preclinical and clinical studies with SGLT2 inhibitors in type 2 diabetes, support the potential of this approach. These investigations indicate that elevating renal glucose excretion by suppressing SGLT2 can reduce plasma glucose levels, as well as decrease weight. Although data from ongoing Phase III trials of these agents are needed to more fully assess safety, results suggest that the beneficial effects of SGLT2 inhibition might be achieved without exerting significant side effects--an advantage over many current diabetes medications. This article discusses the role of SGLT2 in glucose homeostasis and the evidence available so far on the therapeutic potential of blocking these transporters in the treatment of diabetes.
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PMID:SGLT2 inhibition--a novel strategy for diabetes treatment. 2050 40


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