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Life Sci ; 232: 116622, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31271767


AIMS: This study was designed to compare the effects of empagliflozin monotherapy and its combination with metformin on glucose and lipid modulations in T2DM mice. MAIN METHODS: Nine-week-old male C57BLKS/J db/db mice (n = 32) were used as T2DM model, and their age-matched C57BLKS/J db/m mice (n = 8) were used as normal control. A total of 32 db/db mice were randomly divided into four groups (n = 8/group): the DMT1 group, treated with metformin (250 mg/kg/day); the DMT2 group, treated with metformin (250 mg/kg/day) plus empagliflozin (10 mg/kg/day); the DMT3 group, treated with empagliflozin (10 mg/kg/day); the T2DM control group (DM), received 0.5% Natrosol. The db/m mice received same administration as DM group. KEY FINDINGS: After four-week treatments, compared with T2DM control (DM), the empagliflozin or its combination with metformin dramatically increased the levels of plasma HDL-C (139.6% and 154.9%, respectively), with significant decrease in plasma TC (22.9% and 13.7%, respectively) and plasma TG (26% and 19.7%, respectively) and in hepatic TG (30.3% and 28.6%, respectively). The protein expressions of SREBP1c (75.3% and 54.0%, respectively) and APOC-III (51.2% and 50.2%, respectively) were reduced, while CPT1A (304.0% and 221.4%, respectively) and ApoA1 levels (90.0% and 85.3%, respectively) were enhanced. Although both interventions improve above-mentioned lipid homeostasis, there were no statistic differences between two groups (p > 0.05). SIGNIFICANCE: Our study demonstrated that current dose of combination therapy may have no higher amelioration than empagliflozin monotherapy for glucose and lipid metabolism in male T2DM mice when it followed a treatment shorter than that expected during clinical treatment.

Compostos Benzidrílicos/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/farmacologia , Animais , Compostos Benzidrílicos/metabolismo , Glicemia/efeitos dos fármacos , Modelos Animais de Doenças , Quimioterapia Combinada/métodos , Glucose/metabolismo , Glucosídeos/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Metformina/metabolismo , Metformina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Inibidores do Transportador 2 de Sódio-Glicose/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Resultado do Tratamento
Life Sci ; 231: 116538, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31176776


Apoptosis is a complicated process that involves activation of a series of intracellular signaling. Tissue injuries from diabetes mellitus mostly occur as a consequence of higher rate of apoptosis process due to activation of a series of molecular mechanisms. Several classes of anti-hyperglycaemic agents have been developed which could potentially modulate the apoptotic process resulting in fewer tissue damages. Novel types of anti-hyperglycaemic medications such as sodium glucose cotransporters-2 inhibitors, glucagon like peptide-1 receptor agonists and dipeptidyl peptidase 4 inhibitors have shown to provide potent anti-hyperglycaemic effects, but their influences on diabetes-induced apoptotic injuries is largely unknown. Therefore, in the current study, we reviewed the published data about the possible effects of these anti-hyperglycaemic agents on apoptosis in diabetic milieu as well as in cancer cells.

Apoptose/efeitos dos fármacos , Hipoglicemiantes/metabolismo , Hipoglicemiantes/farmacologia , Glicemia/efeitos dos fármacos , Surdez/tratamento farmacológico , Surdez/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Inibidores da Dipeptidil Peptidase IV/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Peptídeos Semelhantes ao Glucagon/agonistas , Humanos , Doenças Mitocondriais/tratamento farmacológico , Doenças Mitocondriais/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
Life Sci ; 230: 19-27, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31125563


AIMS: We investigated the effect of the selective sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor ipragliflozin on cardiac dysfunction and histopathology in a non-diabetic rat model of cardiomyopathy. MAIN METHODS: Ipragliflozin was mixed with chow (0.01%, w/w) and administered to male DahlS.Z-Leprfa/Leprfa (DS/obese) rats for 8 weeks. Male DahlS.Z-Lepr+/Lepr+ (DS/lean) rats of the same age were used as controls. Systolic blood pressure (SBP) and heart rate (HR) were measured every 4 weeks. After 8 weeks of treatment, echocardiography and histopathological examinations were performed. Further, the effect of ipragliflozin on blood and urine parameters were investigated. KEY FINDINGS: In the DS/obese rats, ipragliflozin delayed the age-related increase in SBP without affecting HR, reduced left ventricular (LV) mass and intraventricular septal thickness in echocardiography, and ameliorated hypertrophy of cardiomyocytes and LV fibrosis in histopathological examination. Although ipragliflozin significantly increased both urine volume and urinary glucose excretion in DS/obese rats, it did not alter plasma glucose levels. SIGNIFICANCE: Ipragliflozin prevented LV hypertrophy and fibrosis in non-diabetic DS/obese rats without affecting plasma glucose levels. These findings suggest that SGLT2 inhibitors have a cardio-protective effect in non-diabetic patients with cardiomyopathy.

Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/patologia , Glucosídeos/farmacologia , Tiofenos/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Ecocardiografia , Fibrose/tratamento farmacológico , Fibrose/prevenção & controle , Glucosídeos/metabolismo , Coração/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Hipertrofia Ventricular Esquerda/prevenção & controle , Hipoglicemiantes/farmacologia , Masculino , Síndrome Metabólica/fisiopatologia , Obesidade , Ratos , Ratos Endogâmicos Dahl , Transportador 2 de Glucose-Sódio/efeitos dos fármacos , Transportador 2 de Glucose-Sódio/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Sístole/efeitos dos fármacos , Tiofenos/metabolismo
Artigo em Inglês | MEDLINE | ID: mdl-31030051


Ertugliflozin is a potent and selective inhibitor of sodium-dependent glucose cotransporters 2 (SGLT2) and used as a monotherapy to improve glycemic control in adult patients with type 2 diabetes. In this study, ertugliflozin binding to human serum albumin (HSA) was investigated by multispectroscopic and computer simulations. The fluorescence spectra demonstrated that the quenching mechanism of ertugliflozin and HSA was static quenching. Thermodynamic parameters indicated that hydrogen bonding and van der Waals forces played a key role in the binding. Fluorescence competition experiments and molecular docking revealed that ertugliflozin bound to HSA sites II. In three-dimensional fluorescence, circular dichroism spectroscopy, and molecular dynamics simulation, ertugliflozin did not affect the basic skeleton structure of HSA but slightly increased the α-helical structure content and changed the microenvironment around amino acid residues. Results provide valuable information on the basis of the interaction of ertugliflozin with HSA.

Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Albumina Sérica Humana/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/metabolismo , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Conformação Proteica/efeitos dos fármacos , Albumina Sérica Humana/química , Termodinâmica
Nat Commun ; 9(1): 5245, 2018 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-30532032


Sodium-dependent glucose transporters (SGLTs) exploit sodium gradients to transport sugars across the plasma membrane. Due to their role in renal sugar reabsorption, SGLTs are targets for the treatment of type 2 diabetes. Current therapeutics are phlorizin derivatives that contain a sugar moiety bound to an aromatic aglycon tail. Here, we develop structural models of human SGLT1/2 in complex with inhibitors by combining computational and functional studies. Inhibitors bind with the sugar moiety in the sugar pocket and the aglycon tail in the extracellular vestibule. The binding poses corroborate mutagenesis studies and suggest a partial closure of the outer gate upon binding. The models also reveal a putative Na+ binding site in hSGLT1 whose disruption reduces the transport stoichiometry to the value observed in hSGLT2 and increases inhibition by aglycon tails. Our work demonstrates that subtype selectivity arises from Na+-regulated outer gate closure and a variable region in extracellular loop EL5.

Glucose/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/metabolismo , Sódio/metabolismo , Simportadores/metabolismo , Regulação Alostérica , Animais , Sítios de Ligação , Feminino , Humanos , Oócitos/efeitos dos fármacos , Oócitos/metabolismo , Oócitos/fisiologia , Florizina/metabolismo , Florizina/farmacologia , Ligação Proteica , Transportador 1 de Glucose-Sódio/genética , Transportador 1 de Glucose-Sódio/metabolismo , Transportador 2 de Glucose-Sódio/genética , Transportador 2 de Glucose-Sódio/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Simportadores/antagonistas & inibidores , Simportadores/genética , Xenopus laevis
J Pharmacol Exp Ther ; 365(3): 676-687, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29674332


The sodium/glucose cotransporters (SGLT1 and SGLT2) transport glucose across the intestinal brush border and kidney tubule. Dual SGLT1/2 inhibition could reduce hyperglycemia more than SGLT2-selective inhibition in patients with type 2 diabetes. However, questions remain about altered gastrointestinal (GI) luminal glucose and tolerability, and this was evaluated in slc5a1-/- mice or with a potent dual inhibitor (compound 8; SGLT1 Ki = 1.5 ± 0.5 nM 100-fold greater potency than phlorizin; SGLT2 Ki = 0.4 ± 0.2 nM). 13C6-glucose uptake was quantified in slc5a1-/- mice and in isolated rat jejunum. Urinary glucose excretion (UGE), blood glucose (Sprague-Dawley rats), glucagon-like peptide 1 (GLP-1), and hemoglobin A1c (HbA1c) levels (Zucker diabetic fatty rats) were measured. Intestinal adaptation and rRNA gene sequencing was analyzed in C57Bl/6 mice. The blood 13C6-glucose area under the curve (AUC) was reduced in the absence of SGLT1 by 75% (245 ± 6 vs. 64 ± 6 mg/dl⋅h in wild-type vs. slc5a1-/- mice) and compound 8 inhibited its transport up to 50% in isolated rat jejunum. Compound 8 reduced glucose excursion more than SGLT2-selective inhibition (e.g., AUC = 129 ± 3 vs. 249 ± 5 mg/dl⋅h for 1 mg/kg compound 8 vs. dapagliflozin) with similar UGE but a lower renal glucose excretion threshold. In Zucker diabetic fatty rats, compound 8 decreased HbA1c and increased total GLP-1 without changes in jejunum SGLT1 expression, mucosal weight, or villus length. Overall, compound 8 (1 mg/kg for 6 days) did not increase cecal glucose concentrations or bacterial diversity in C57BL/6 mice. In conclusion, potent dual SGLT1/2 inhibition lowers blood glucose by reducing intestinal glucose absorption and the renal glucose threshold but minimally impacts the intestinal mucosa or luminal microbiota in chow-fed rodents.

Glicemia/metabolismo , Colo/efeitos dos fármacos , Colo/microbiologia , Microbiota/efeitos dos fármacos , Transportador 1 de Glucose-Sódio/antagonistas & inibidores , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Transportador 2 de Glucose-Sódio/metabolismo , Animais , Biodiversidade , Colo/metabolismo , Masculino , Camundongos , Ratos , Inibidores do Transportador 2 de Sódio-Glicose/metabolismo