Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.152
Filtrar
2.
Rev Assoc Med Bras (1992) ; 66Suppl 1(Suppl 1): s17-s24, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31939531

RESUMO

Type 2 diabetes mellitus is an important public health problem, with a significant impact on cardiovascular morbidity and mortality and an important risk factor for chronic kidney disease. Various hypoglycemic therapies have proved to be beneficial to clinical outcomes, while others have failed to provide an improvement in cardiovascular and renal failure, only reducing blood glucose levels. Recently, sodium-glucose cotransporter-2 (SGLT2) inhibitors, represented by the empagliflozin, dapagliflozin, and canagliflozin, have been showing satisfactory and strong results in several clinical trials, especially regarding the reduction of cardiovascular mortality, reduction of hospitalization due to heart failure, reduction of albuminuria, and long-term maintenance of the glomerular filtration rate. The benefit from SGLT2 inhibitors stems from its main mechanism of action, which occurs in the proximal tubule of the nephron, causing glycosuria, and a consequent increase in natriuresis. This leads to increased sodium intake by the juxtaglomerular apparatus, activating the tubule glomerular-feedback and, finally, reducing intraglomerular hypertension, a frequent physiopathological condition in kidney disease caused by diabetes. In addition, this class of medication presents an appropriate safety profile, and its most frequently reported complication is an increase in the incidence of genital infections. Thus, these hypoglycemic agents gained space in practical recommendations for the management of type 2 diabetes mellitus and should be part of the initial therapeutic approach to provide, in addition to glycemic control, cardiovascular outcomes, and the renoprotection in the long term.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Nefropatias/prevenção & controle , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Transportador 2 de Glucose-Sódio/farmacologia , Compostos Benzidrílicos/uso terapêutico , Canagliflozina/uso terapêutico , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/mortalidade , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/prevenção & controle , Taxa de Filtração Glomerular , Glucose/metabolismo , Glucosídeos/uso terapêutico , Humanos , Hipoglicemiantes/uso terapêutico , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/fisiopatologia , Nefropatias/etiologia , Nefropatias/metabolismo , Transportador 2 de Glucose-Sódio/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
3.
Life Sci ; 240: 117090, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31765648

RESUMO

Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are a relatively newer class of anti-hyperglycemic medications that reduce blood glucose by inhibition of renal glucose re-uptake, thereby increasing urinary glucose excretion. Although glycosuria is the primary mechanism of action of these agents, there is some evidence suggesting they can reduce insulin resistance and induce peripheral insulin sensitivity. Identifying the molecular mechanisms by which these medications improve glucose homeostasis can help us to develop newer forms of SGLT2i with lesser side effects. We have reviewed the molecular mechanisms and signaling pathways by which SGLT2i therapy improve insulin sensitivity and ameliorates insulin resistance.


Assuntos
Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/metabolismo , Hipoglicemiantes/farmacologia , Resistência à Insulina , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Transportador 2 de Glucose-Sódio/metabolismo , Animais , Humanos , Hipoglicemiantes/uso terapêutico
4.
J Ethnopharmacol ; 248: 112268, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-31593813

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Phyllanthus emblica Linn. (Syn. Emblica officinalis Gaertn.), has been used to cure many ailments of human beings. Literature survey demonstrates that it has many pharmacological activities i.e. antidiabetic, antioxidant, anti-microbial, antifungal, antiallergic, antiviral, and anticancer properties. AIM OF THE STUDY: The present study aimed to identify the novel plant-derived antidiabetic compounds from P. emblica to understand the molecular basis of antidiabetic activities. MATERIAL AND METHODS: Text mining analysis of P. emblica and its disease association was carried out using server DLAD4U. Due to the highest score of P. emblica with diabetes, the virtual screening of a phytochemical library of P. emblica against three targets of diabetes was carried out. After that FAF-Drug4, admetSAR and DruLiTo servers were used for drug-likeness prediction. Additionally, pharmacophore modeling was also carried out to understand the antidiabetic activity of screened compounds. RESULTS: The docking scores, drug-likeness and pharmacophore studies found that Ellagic acid, Estradiol, Sesamine, Kaempferol, Zeatin, Quercetin, and Leucodelphinidin are potential antidiabetic compounds. CONCLUSIONS: Our study shows that phytochemicals of P. emblica are very potential antidiabetic candidates. Using the modern techniques these molecules could be used to develop an effective antidiabetic drugs from a natural resource.


Assuntos
Peptídeo 1 Semelhante ao Glucagon/metabolismo , Hipoglicemiantes/farmacologia , PPAR gama/metabolismo , Phyllanthus emblica , Compostos Fitoquímicos/farmacologia , Transportador 2 de Glucose-Sódio/metabolismo , Simulação por Computador , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Hipoglicemiantes/farmacocinética , Modelos Biológicos , Simulação de Acoplamento Molecular , Compostos Fitoquímicos/farmacocinética , Fitoterapia
5.
Cell Mol Biol (Noisy-le-grand) ; 65(7): 55-59, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31880518

RESUMO

To investigate the effect of polydatin on glucose transporter, blood glucose homeostasis and renal injury in streptozotocin (STZ)-induced diabetic rats. The in vitro inhibitory effect of polydatin on sodium-glucose cotransporter-1 (SGLT1) and 2 (SGLT2) was determined using HEK293 cells. The inhibitory effect of polydatin on GLUT1 and GLUT4 was evaluated using 3T3-L1 adipocytes. Streptozotocin-induced diabetic rats were used for this study. Fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c), urea nitrogen, serum creatinine and urinary protein were determined using biochemical analyzer. Histopathological examination was performed on renal tissue. Serum levels of interleukin 1ß (IL-1ß), tumor necrosis factor α (TNF-α), monocyte chemoattractant protein 1 (MCP-1) and C-reactive protein (CRP) were also determined. Polydatin significantly inhibited SGLT1/2 and exhibited high selectivity for both GLUT1 and GLUT4. It significantly and dose-dependently decreased hyperglycemia, enhanced urine glucose excretion in the diabetic rats. The polydatin treatment significantly ameliorated symptoms of DN such as polyuria, polydipsia and hyperphagia. The hypoglycemic effect of polydatin was maintained throughout the treatment period. In addition,the levels of IL-1ß, TNF-α, MCP-1 and CRP were significantly reduced in treated group. Treatment with polydatin significantly ameliorated most of the structural and morphological changes induced by STZ. Moreover, the levels of urinary protein, serum creatinine and urea nitrogen were significantly reduced after treatment with polydatin.  As a potential dual inhibitor of SGLT1/2, polydatin has high selectivity for GLUT1 and GLUT4. Its long-term administration delays the development of DN, protects renal function and ameliorates renal tissue injury.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Glucosídeos/uso terapêutico , Hiperglicemia/tratamento farmacológico , Estilbenos/uso terapêutico , Células 3T3-L1 , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Células HEK293 , Humanos , Hiperglicemia/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Camundongos , Transportador 1 de Glucose-Sódio/metabolismo , Transportador 2 de Glucose-Sódio/metabolismo
7.
Cell Physiol Biochem ; 53(5): 865-886, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31724838

RESUMO

BACKGROUND/AIMS: Heart failure is characterized by chronic low-grade vascular inflammation, which in itself can lead to endothelial dysfunction. Clinical trials showed reductions in heart failure-related hospitalizations of type 2 diabetic patients using sodium glucose co-transporter 2 inhibitors (SGLT2i's). Whether and how SGLT2i's directly affect the endothelium under inflammatory conditions is not completely understood. The aim of the study was to investigate whether the SGLT2i Empagliflozin (EMPA) and Dapagliflozin (DAPA) reduce tumor necrosis factor α (TNFα) induced endothelial inflammation in vitro. METHODS: Human coronary arterial endothelial cells (HCAECs) and human umbilical vein endothelial cells (HUVECs) were (pre-)incubated with 1 µM EMPA or DAPA and subsequently exposed to 10 ng/ml TNFα. ROS and NO were measured using live cell imaging. Target proteins were either determined by infrared western blotting or fluorescence activated cell sorting (FACS). The connection between Cav-1 and eNOS was determined by co-immunoprecipitation. RESULTS: Nitric oxide (NO) bioavailability was reduced by TNFα and both EMPA and DAPA restored NO levels in TNFα-stimulated HCAECs. Intracellular ROS was increased by TNFα, and this increase was completely abolished by EMPA and DAPA in HCAECs by means of live cell imaging. eNOS signaling was significantly disturbed after 24 h when cells were exposed to TNFα for 24h, yet the presence of both SGLT2is did not prevent this disruption. TNFα-induced enhanced permeability at t=24h was unaffected in HUVECs by EMPA. Similarly, adhesion molecule expression (VCAM-1 and ICAM-1) was elevated after 4h TNFα (1.5-5.5 fold increase of VCAM-1 and 4-12 fold increase of ICAM-1) but were unaffected by EMPA and DAPA in both cell types. Although we detected expression of SGLT2 protein levels, the fact that we could not silence this expression by means of siRNA and the mRNA levels of SGLT2 were not detectable in HCAECs, suggests aspecificity or our SGLT2 antibody and absence of SGLT2 in our cells. CONCLUSION: These data suggest that EMPA and DAPA rather restore NO bioavailability by inhibiting ROS generation than by affecting eNOS expression or signaling, barrier function and adhesion molecules expression in TNFα-induced endothelial cells. Furthermore, the observed effects cannot be ascribed to the inhibition of SGLT2 in endothelial cells.


Assuntos
Compostos Benzidrílicos/farmacologia , Regulação para Baixo/efeitos dos fármacos , Glucosídeos/farmacologia , Óxido Nítrico/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Vasos Coronários/citologia , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Permeabilidade/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transportador 2 de Glucose-Sódio/genética , Transportador 2 de Glucose-Sódio/metabolismo , Molécula 1 de Adesão de Célula Vascular
8.
Biol Pharm Bull ; 42(10): 1707-1712, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31582658

RESUMO

Recent clinical studies indicate that sodium-glucose cotransporter 2 (SGLT2) inhibitors exhibit a renoprotective effect. While studies at the single nephron level suggest that direct effects of SGLT2 inhibitors on renal hemodynamics may be a possible mechanism underlying their renoprotective effect, few studies have focused on such direct effects at the whole-kidney level. In the present study, we investigated the acute and direct effect of SGLT2 inhibition on creatinine clearance, an index of whole-kidney glomerular filtration rate (GFR), in a rat model of type 2 diabetes. Twelve to fifteen-week-old male Spontaneously Diabetic Torii (SDT) fatty rats and Sprague-Dawley rats were used as diabetic animals and non-diabetic controls, respectively. Under general anesthesia, baseline urine samples were collected from the left and right ureters for 1 h. The selective SGLT2 inhibitor ipragliflozin or vehicle was subsequently administered intravenously and post-drug urine was collected for 1 h. Baseline and post-drug blood samples were collected immediately before baseline urine collection and immediately after post-drug urine collection, respectively. Plasma glucose, urine volume, urinary glucose and albumin excretion were measured, and creatinine clearance was calculated. Blood pressure and heart rate were monitored continuously throughout the experiment. A single intravenous injection of ipragliflozin increased both urine output and glucose excretion, but reduced creatinine clearance without affecting systemic blood pressure. These results suggest that SGLT2 inhibition directly reduced whole-kidney GFR, most likely due to a reduction in intraglomerular pressure, by altering local renal hemodynamics, which may contribute to the renoprotective effects demonstrated in clinical studies.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Taxa de Filtração Glomerular/efeitos dos fármacos , Glucosídeos/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Tiofenos/uso terapêutico , Animais , Glicemia/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Cloretos/sangue , Creatinina/sangue , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/fisiopatologia , Nefropatias Diabéticas/prevenção & controle , Glucosídeos/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Masculino , Ratos Sprague-Dawley , Sódio/sangue , Transportador 2 de Glucose-Sódio , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Tiofenos/farmacologia
9.
Eur J Med Chem ; 184: 111773, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31630053

RESUMO

Gliflozins constitute an important class of compounds useful as sodium glucose co-transporter (SGLT2) inhibitors to treat type-II diabetes. They act by blocking sodium-glucose transport protein 2 which is responsible for re-absorption of glucose in the proximal convoluted tubule (PCT) of kidney and thus its inhibition reduces blood glucose level. There are a number of gliflozins which have been approved by drug regulatory bodies like FDA, EMA and PMDA whereas some others are in pipeline in their late developmental phases. The present review article offers a detailed account of synthetic strategies employed for the synthesis, alternate synthetic routes along with Structure Activity Relationship (SAR) studies of well-established as well as newly developed SGLT2 inhibitors.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/farmacologia , Hipoglicemiantes/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Transportador 2 de Glucose-Sódio/metabolismo , Animais , Diabetes Mellitus Tipo 2/metabolismo , Relação Dose-Resposta a Droga , Glucosídeos/síntese química , Glucosídeos/química , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Estrutura Molecular , Inibidores do Transportador 2 de Sódio-Glicose/síntese química , Inibidores do Transportador 2 de Sódio-Glicose/química , Relação Estrutura-Atividade
10.
Int J Mol Sci ; 20(18)2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31491943

RESUMO

PURPOSE: Cataracts in patients with diabetes mellitus (DM) are a major cause of blindness in developed and developing countries. This study aims to examine whether the generation of reactive oxygen species (ROS) via the increased expression of glucose transporters (GLUTs) and the receptor for advanced glycation end products (RAGE) influences the cataract development in DM. METHODS: Lens epithelial cells (LECs) were isolated during cataract surgery from patients without DM or with DM, but without diabetic retinopathy. In a rat model, fructose (10% fructose, 8 or 12 weeks) with or without dapagliflozin (1.2 mg/day, 2 weeks) treatment did induce DM, as verified by blood pressure and serum parameter measurements. Immunofluorescence stainings and immunoblottings were used to quantify the protein levels. Endogenous O2˙¯ production in the LECs was determined in vivo with dihydroethidium stainings. RESULTS: We investigated that GLUT levels in LECs differed significantly, thus leading to the direct enhancement of RAGE-associated superoxide generation in DM patients with cataracts. Superoxide production was significantly higher in LECs from rats with fructose-induced type 2 DM, whereas treatment with the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin prevented this effect in fructose-fed rats. Protein expression levels of the sodium/glucose cotransporter 2 (SGLT2), GLUT1, GLUT5, the nicotinamide adenine dinucleotide phosphate reduced form (NADPH) oxidase subunit p67-phox, NOX2/4 and RAGE were upregulated in fructose-fed animals, whereas dapagliflozin treatment reversed these effects. CONCLUSIONS: In rats with fructose-induced DM, dapagliflozin downregulates RAGE-induced NADPH oxidase expression in LECs via the inactivation of GLUTs and a reduction in ROS generation. These novel findings suggest that the SGLT2 inhibitor dapagliflozin may be a candidate for the pharmacological prevention of cataracts in patients with DM.


Assuntos
Cristalino/citologia , Cristalino/metabolismo , NADPH Oxidases/genética , Estresse Oxidativo/genética , Transportador 2 de Glucose-Sódio/genética , Idoso , Animais , Diabetes Mellitus/etiologia , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patologia , Modelos Animais de Doenças , Feminino , Frutose/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , NADPH Oxidases/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Transportador 2 de Glucose-Sódio/metabolismo
11.
Molecules ; 24(18)2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31540429

RESUMO

Studies have indicated that Na+-d-glucose co-transporter (SGLT) inhibitors had anti-proliferative activity by attenuating the uptake of glucose in several tumor cell lines. In this study, the molecular docking showed that, trilobatin, one of the dihydrochalcones from leaves of Lithocarpus polystachyus Rehd., might be a novel inhibitor of SGLT1 and SGLT2, which evidently attenuated the uptake of glucose in vitro and in vivo. To our surprise, we observed that trilobatin did not inhibit, but promoted the proliferation of human hepatoblastoma HepG2 and Huh 7 cells when it was present at high concentrations. At the same time, incubation with high concentrations of trilobatin arrested the cell cycle at S phase in HepG2 cells. We also found that treatment with trilobatin had no significant effect on the expression of hepatitis B x-interacting protein (HBXIP) and hepatocyte nuclear factor (HNF)-4α, the two key regulators of hepatocyte proliferation. Taken together, although trilobatin worked as a novel inhibitor of SGLTs to attenuate the uptake of glucose, it also selectively induced the cell proliferation of HepG2 cells, suggesting that not all the SGLT inhibitors inhibited the proliferation of tumor cells, and further studies are needed to assess the anti-cancer potentials of new glucose-lowering agents.


Assuntos
Carcinoma Hepatocelular/metabolismo , Proliferação de Células/efeitos dos fármacos , Neoplasias Hepáticas/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Transportador 1 de Glucose-Sódio/antagonistas & inibidores , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Transportador 2 de Glucose-Sódio , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Carcinoma Hepatocelular/patologia , Flavonoides , Células Hep G2 , Fator 4 Nuclear de Hepatócito/metabolismo , Humanos , Neoplasias Hepáticas/patologia , Proteínas de Neoplasias/metabolismo , Polifenóis , Ratos , Inibidores do Transportador 2 de Sódio-Glicose/química
12.
Med Hypotheses ; 130: 109270, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31383344

RESUMO

Idiopathic oedema is a syndrome affecting primarily women that is characterized by frustrating intermittent fluid retention, with hallmarks of obesity, periodic oedema, anxiety, and a susceptibility to develop type 2 diabetes. Management is typically reassurance and weight control, with no known drug class proven to provide consistent relief. We hypothesise that sodium-glucose cotransporter 2 inhibition is a logical intervention in the treatment of idiopathic oedema, having effects on obesity, blood pressure, impaired glucose tolerance, sympathetic overdrive, and reduction in swelling - the most common and distressing complaint. Sodium-glucose cotransporter 2 inhibition by promoting greater electrolyte-free, but glucose driven, water clearance with preferential fluid clearance from the interstitial space, without compromising intravascular volume, may provide symptomatic relief of swelling and bloating. The consequent weight reduction secondary to caloric loss from renal glycosuria and decreased adiposity would prevent disease progression of type 2 diabetes or pre-diabetes. With diminished adrenergic output from central and peripheral autonomic influences, reduction of blood pressure occurs, and by similar mechanisms, anxiety may be reduced.


Assuntos
Edema/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Transportador 2 de Glucose-Sódio/metabolismo , Ansiedade/complicações , Sistema Nervoso Autônomo , Compostos Benzidrílicos/farmacologia , Pressão Sanguínea , Estudos Cross-Over , Eletrólitos , Feminino , Intolerância à Glucose , Glucosídeos/farmacologia , Hemodinâmica , Humanos , Modelos Teóricos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Perda de Peso
13.
Expert Opin Investig Drugs ; 28(9): 811-820, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31402716

RESUMO

Introduction: More than 424 million adults have diabetes mellitus (DM). This number is expected to increase to 626 million by 2045. The majority (90-95%) of people with DM has type 2-diabetes (T2DM). The continued prevalence of DM and associated complications has prompted investigators to find new therapies. One of the most recent additions to the anti-diabetic armamentarium are inhibitors of sodium-glucose co-transporters 1 and 2 (SGLT1, SGLT2). Areas covered: The authors review the status of SGLT2 inhibitors for the treatment of T2DM and place an emphasis on those agents in early phase clinical trials. Data and information were retrieved from American Diabetes Association, Diabetes UK, ClinicalTrials.gov, PubMed, and Scopus websites. The keywords used in the search were T2DM, SGLT1, SGLT2, and clinical trials. Expert opinion: The benefits of SGLT inhibitors include reductions in serum glycated hemoglobin (HbA1c), body weight, blood pressure and cardiovascular and renal events. However, SGLT inhibitors increase the risk of genitourinary tract infections, diabetic ketoacidosis, and bone fractures. The development of SGLT inhibitors with fewer side effects and as combination therapies are the key to maximizing the therapeutic effects of this important class of anti-diabetic drug.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Transportador 1 de Glucose-Sódio/antagonistas & inibidores , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Adulto , Animais , Diabetes Mellitus Tipo 2/fisiopatologia , Desenvolvimento de Medicamentos/métodos , Hemoglobina A Glicada/metabolismo , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacologia , Transportador 1 de Glucose-Sódio/metabolismo , Transportador 2 de Glucose-Sódio/efeitos dos fármacos , Transportador 2 de Glucose-Sódio/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos
14.
Internist (Berl) ; 60(9): 903-911, 2019 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-31375850

RESUMO

BACKGROUND: Inhibitors of sodium-glucose cotransporters type 2 (SGLT-2) are a class of oral antidiabetic drugs with a novel specific mode of action in the kidneys. OBJECTIVE: The effects of SGLT-2 inhibitors on cardiovascular (CV) and renal endpoints in outcome trials with type 2 diabetes patients. MATERIAL AND METHODS: Differential analysis and interpretation of the results of outcome trials with the SGLT-2 inhibitors empagliflozin, canagliflozin and dapagliflozin in type 2 diabetes mellitus. RESULTS: In the EMPA-REG OUTCOME trial, empagliflozin demonstrated a significant reduction in major cardiac adverse events (MACE), hospitalization for heart failure (HHI), renal endpoints, CV and total mortality vs. placebo in >7000 patients with type 2 diabetes and established CV disease over 3.1 years. In the CANVAS program, canagliflozin demonstrated a significant reduction of MACE, HHI and renal endpoints vs. placebo in >10,000 patients with type 2 diabetes and high CV risk over 2.4 years. In the CREDENCE trial, canagliflozin demonstrated a significant reduction of a combined renal endpoint and CV endpoints vs. placebo in >4000 patients with type 2 diabetes and established kidney disease with albuminuria over 2.6 years. In the DECLARE-TIMI 58 trial, dapagliflozin demonstrated a significant reduction in a combined endpoint of CV death and HHI vs. placebo in >17,000 patients with type 2 diabetes and established CV disease or with multiple CV risk factors over 3.1 years. CONCLUSION: Outcome trials with SGLT-2 inhibitors have collectively demonstrated cardioprotective and nephroprotective effects in patients with type 2 diabetes and high CV risk. The use of SGLT-2 inhibitors is recommended in current guidelines and consensus statements as primary combination partners for metformin in patients with type 2 diabetes and established CV disease, high CV risk, heart failure or kidney disease.


Assuntos
Canagliflozina/uso terapêutico , Doenças Cardiovasculares/fisiopatologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/terapia , Nefropatias/fisiopatologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Canagliflozina/efeitos adversos , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Hipoglicemiantes/uso terapêutico , Guias de Prática Clínica como Assunto , Transportador 2 de Glucose-Sódio/efeitos dos fármacos , Transportador 2 de Glucose-Sódio/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Resultado do Tratamento
15.
Diabetes Metab Syndr ; 13(5): 2927-2932, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31425958

RESUMO

BACKGROUND: The risks of hypoglycemia, dehydration and kidney injury may theoretically be aggravated by people with type 2 diabetes treated with Insulin and SGLT2 inhibitors during Ramadan. Data on safety and efficacy of SGLT2-I in people with type 2 diabetes treated with insulin is scanty. We aimed to assess the impact of SGLT2 inhibitors during Ramadan in high-risk patients with type 2 diabetes treated with insulin, on hypoglycemia, glycemic control and kidney function. METHODS: This is a prospective interventional study on high-risk diabetes patients who insisted on fasting. All patients were treated with insulin ±â€¯SGLT2I. All patients received a FGMS and Ramadan focused education. All patients attended clinic before and post Ramadan where they were advised on treatment modification as well as biometric and biochemical measurements. RESULTS: 95 patients enrolled in the study and 49 of them were on SGLT2i. There was a no significant change in creatinine in both groups. FGMS showed an improvement in the sensor-calculated HbA1c from 7.3 ±â€¯1.5 to 6.8 ±â€¯1.1 and from 8 ±â€¯1.6 to 7.7 ±â€¯1.5 in the SGLT2 group and the non-SGT2i groups, respectively. The hypoglycemia was predominantly reported during Ramadan between 12:00 to 18:00 h, while in pre-Ramadan readings was during 2400-0600 and 1200-1800 slots. CONCLUSIONS: This is the first study that assesses the use of SGLT2i along with insulin during Ramadan, using FGMS in high-risk patients with type 2 diabetes under optimal care. There was minimal interruption of fasting, significant improvement in glycemic control, and no significant change in the kidney function after Ramadan.


Assuntos
Automonitorização da Glicemia/estatística & dados numéricos , Glicemia/análise , Diabetes Mellitus Tipo 2/sangue , Hipoglicemia/prevenção & controle , Insulina/uso terapêutico , Qualidade de Vida , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Adolescente , Adulto , Idoso , Biomarcadores/análise , Automonitorização da Glicemia/instrumentação , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Seguimentos , Humanos , Hipoglicemiantes/uso terapêutico , Islamismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Transportador 2 de Glucose-Sódio/química , Emirados Árabes Unidos/epidemiologia , Adulto Jovem
16.
Curr Top Med Chem ; 19(20): 1818-1849, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31456521

RESUMO

Type 2 diabetes mellitus is one of the most common forms of the disease worldwide. Hyperglycemia and insulin resistance play key roles in type 2 diabetes mellitus. Renal glucose reabsorption is an essential feature in glycaemic control. Kidneys filter 160 g of glucose daily in healthy subjects under euglycaemic conditions. The expanding epidemic of diabetes leads to a prevalence of diabetes-related cardiovascular disorders, in particular, heart failure and renal dysfunction. Cellular glucose uptake is a fundamental process for homeostasis, growth, and metabolism. In humans, three families of glucose transporters have been identified, including the glucose facilitators GLUTs, the sodium-glucose cotransporter SGLTs, and the recently identified SWEETs. Structures of the major isoforms of all three families were studied. Sodium-glucose cotransporter (SGLT2) provides most of the capacity for renal glucose reabsorption in the early proximal tubule. A number of cardiovascular outcome trials in patients with type 2 diabetes have been studied with SGLT2 inhibitors reducing cardiovascular morbidity and mortality. The current review article summarises these aspects and discusses possible mechanisms with SGLT2 inhibitors in protecting heart failure and renal dysfunction in diabetic patients. Through glucosuria, SGLT2 inhibitors reduce body weight and body fat, and shift substrate utilisation from carbohydrates to lipids and, possibly, ketone bodies. These pleiotropic effects of SGLT2 inhibitors are likely to have contributed to the results of the EMPA-REG OUTCOME trial in which the SGLT2 inhibitor, empagliflozin, slowed down the progression of chronic kidney disease and reduced major adverse cardiovascular events in high-risk individuals with type 2 diabetes. This review discusses the role of SGLT2 in the physiology and pathophysiology of renal glucose reabsorption and outlines the unexpected logic of inhibiting SGLT2 in the diabetic kidney.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Nefropatias/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Transportador 2 de Glucose-Sódio/metabolismo , Doenças Cardiovasculares/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Nefropatias/metabolismo
17.
Eur J Pharmacol ; 860: 172537, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31310751

RESUMO

The widely used db/db mouse as a model of diabetic nephropathy (DN) only mimics the early changes in human DN with a slow disease progression. Since high protein diet (HPD) has been reported to affect progression of nephropathy in both humans and mice, we investigated whether HPD could accelerate nephropathy in db/db mice. Diabetic (C57BLKS-Leprdb/db) and non-diabetic (C57BLKS-Leprdb/+) mice were fed either HPD (60 kcal% protein) or control diet (22 kcal% protein), from 7 to 22 weeks of age. In db/db mice, HPD was found to significantly increase all measured readouts of renal injury including albuminuria, renal hypertrophy, mesangial expansion and expression of a panel of DN related markers, including KIM-1, Ki67 and Collagen III, which increased on both gene and protein levels. Furthermore, HPD activated the Renin-angiotensin system significantly and increased hyperfiltration, measured as reduced plasma Cystatin C. Usefulness of the HPD db/db mouse as a model for faster drug efficacy studies was investigated in a 5-week treatment study with the SGLT2 inhibitor, dapagliflozin. Expectedly, dapagliflozin normalised blood glucose levels and improved glucose intolerance in both HPD and control diet mice. Only HPD db/db mice, not the control diet db/db mice, showed clear hyperfiltration that was significantly reduced with dapagliflozin treatment at both 2 and 4 weeks of treatment. In conclusion, these studies confirm that HPD can significantly accelerate progression of nephropathy in db/db mice, and that this model could be useful for rapid evaluation of drug targets with potential to ameliorate features of DN, especially glomerular hyperfiltration.


Assuntos
Compostos Benzidrílicos/farmacologia , Nefropatias Diabéticas/induzido quimicamente , Nefropatias Diabéticas/tratamento farmacológico , Dieta Rica em Proteínas/efeitos adversos , Glucosídeos/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Transportador 2 de Glucose-Sódio/metabolismo , Animais , Compostos Benzidrílicos/uso terapêutico , Biomarcadores/sangue , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/fisiopatologia , Progressão da Doença , Regulação da Expressão Gênica/efeitos dos fármacos , Glucosídeos/uso terapêutico , Rim/efeitos dos fármacos , Rim/fisiopatologia , Camundongos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Fatores de Tempo
18.
Eur J Med Chem ; 180: 398-416, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31325786

RESUMO

In this work, aiming at finding a novel, potent, and selective sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor with good pharmacokinetic profiles for the treatment of diabetes, we focus on modifying the sugar moiety of SGLT2 inhibitors, which dominates the binding with glucose binding site of hSGLT, via removing the C-6 hydroxy group to adjust the physicochemical properties and target-recognition manners of SGLT2 inhibitors. In addition, tofogliflozin containing a special O-spiroketal C-arylglucoside scaffold, displayed good efficacy and bioavailability both in animals and in humans. Therefore, a series of 6-deoxy O-spiroketal C-arylglucosides as novel SGLT2 inhibitors were designed, synthesized, and evaluated in this work. The structure-activity relationship (SAR) research on this novel series and a comprehensive in vitro and in vivo biological evaluation afforded compound 39 with high in vitro hSGLT2 inhibitory activity (IC50 = 4.5 nM), good pharmacokinetic profiles, and more remarkable efficacy in C57BL/6J mice and Sprague-Dawley rats than marketed drug tofogliflozin.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Desenho de Fármacos , Inibidores do Transportador 2 de Sódio-Glicose/síntese química , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Transportador 2 de Glucose-Sódio/metabolismo , Animais , Compostos Benzidrílicos/síntese química , Compostos Benzidrílicos/química , Compostos Benzidrílicos/farmacologia , Relação Dose-Resposta a Droga , Glucosídeos/síntese química , Glucosídeos/química , Glucosídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Inibidores do Transportador 2 de Sódio-Glicose/química , Compostos de Espiro/síntese química , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Relação Estrutura-Atividade
20.
Diabetes Metab Syndr ; 13(2): 1679-1683, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31336541

RESUMO

Diabetes mellitus prevalence is increasing worldwide leading to increased morbidity and mortality through diabetes related microvascular and macrovascular disease. The treatment of hypertension has been shown to be a major therapeutic intervention for the prevention of cardiovascular events and other diabetes related complications in diabetes. Sodium-glucose co-transporter inhibitors (SGLT2i) are newly introduced anti-diabetes drugs that lower blood glucose by the inhibition of glucose reuptake and the induction of glycosuria. However, there is increasing evidence showing their cardiovascular benefit beyond the improvement of glycemic control. Here we review the latest findings on the effect of SGLT2i on blood pressure in diabetes.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Transportador 2 de Glucose-Sódio/química , Humanos , Prognóstico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA