Inhibidores del cotransportador de sodio-glucosa tipo 2: Efecto de los mecanismos moleculares en el miocardio / Sodium-glucose cotransporter 2 inhibitors: Effect of molecular mechanisms on the myocardium

Resumen Los receptores del cotransportador de sodio-glucosa han demostrado una gran relevancia en la función miocárdica. Los receptores tipo 1 se encuentran en el miocardio en valores bajos, sin embargo, se elevan en patologías cardiacas por medio de distintos mecanismos moleculares. Por otra parte, los receptores tipo 2 están ausentes en el miocardio. Los fármacos que inhiben este receptor tienen beneficio cardiovascular evidente en estudios clínicos y experimentales, principalmente en pacientes con diabetes mellitus tipo 2 e insuficiencia cardiaca, en los que se ha demostrado una reducción de la mortalidad por causas cardiovasculares y reducción en hospitalización por insuficiencia cardiaca. Existen interrogantes sobre el mecanismo de acción directo de este grupo antihiperglicemiantes sobre el cardiomiocito y se han desarrollado hipótesis y teorías para explicar este efecto. El objetivo de este artículo es revisar y analizar los diferentes mecanismos metabólicos, estructurales, funcionales y mitocondriales en un contexto molecular de los inhibidores del cotransportador sodio-glucosa tipo 2. La acción fisiopatológica del receptor tipo 1 en el miocardio también es importante y se encuentran en desarrollo estudios clínicos para establecer el efecto de su inhibición a nivel cardíaco.

Abstract Sodium-glucose cotransporter receptors have demonstrated relevance in myocardial function. Type 1 receptors are found in the myocardium in low values, however, they are elevated in cardiac pathologies by means of different molecular mechanisms. On the other hand, type 2 receptors are absent in the myocardium. The drugs that inhibit this receptor have been shown to have a cardiovascular benefit demonstrated in clinical and experimental studies, mainly in patients with type 2 diabetes mellitus and heart failure, presenting a reduction in mortality due to cardiovascular causes and a reduction in hospitalization due to heart failure. Due to the above, many questions arise about the mechanism of direct action of this antihyperglycemic group on cardiomyocyte, which is why they have been developed from hypotheses and theories to clarify this action by medicines. The objective of this article is to analyze the different metabolic, structural, functional and mitochondrial mechanisms in a molecular context of the inhibitors of the sodium-glucose cotransporter type 2. On the other hand, to analyze the pathophysiological action of the type 1 receptor in the myocardium, since that future clinical studies will be developed to establish the effect with its inhibition at the cardiac level.

Immunohistochemical expressionof sodium-dependent glucose transporter - 2 (SGLT-2) in clear cell renal carcinoma: possible prognostic implications

ABSTRACT Purpose: Glucose is a major energy resource for tumor cell survival and growth, and its influx into cells is mainly carried out by facilitative glucose transporters (GLUTs). Sodium - dependent glucose transporters (SGLTs) have been highlighted as playing important roles in diabetic treatment. However, their potential roles in cancer remain unclear. We examined expression patterns of SGLTs in tumor tissues together with conventional pathological variables to determine prognostic significance in patients with renal cell carcinoma (RCC). Materials and Methods: Nephrectomy specimens were obtained from 68 patients. GLUT - 1, - 2 and SGLT - 1, - 2 expression in tumor and adjacent normal tissues were analyzed by immunohistochemical staining, and intensity was quantified using an image analyzer. Results: The four glucose transporters evaluated were broadly distributed in tumor tissues as well as throughout the normal parenchyma. There was no significant correlation between transporter expression and conventional pathological variables. However, increased SGLT - 2 expression was significantly associated with shorter overall survival (p < 0.01), regardless of metastatic status. Conclusions: We propose possible prognostic significance of SGLT - 2 expression in human RCC. Given that glucose is a major energy resource for tumor cells and that glucose transport is largely mediated by SGLT, SGLT - 2 may serve as a possible therapeutic target in RCC.

The Potential Cardioprotective Mechanism of Sodium-Glucose Cotransporter 2 Inhibitors / 임상당뇨병

The potential mechanism by which sodium-glucose cotransporter 2 (SGLT2) inhibitors prevent cardiovascular disease (CVD) is being widely investigated. Improved insulin resistance, along with decreased body fat mass associated with SGLT2 inhibitor treatment is consistent with previously well-established factors contributing to the prevention of CVD. These factors are responsible for reduction of oxidative stress as well as improvement of systemic inflammation. Because heart failure was one of the most dramatically improved cardiovascular events in various clinical trials and because SGLT2 inhibitors promote osmotic diuresis and natriuresis, hemodynamic changes are considered as a critical mechanism responsible for the cardioprotective effect of SGLT2 inhibitors. Restored tubuloglomerular feedback by SGLT2 inhibitors might play a role in renoprotection, which in turn, leads to fewer CVDs. Finally, blood ketone body increments in response to SGLT2 inhibition might act as a “super-fuel” for salvaging the failing diabetic heart.

Efectos renales y nefroprotección inducidos por el inhibidor del SGLT2 Empagliflozina en pacientes con diabetes mellitus: revisión de la literatura / Renal effects and nephroprotection induced by SGLT2 inhibitor Empagliflozin in patients with Diabetes Mellitus: a literature review

La insuficiencia renal es una comorbilidad frecuente en pacientes con diabetes mellitus (DM) e incrementa en ellos el riesgo cardiovascular; la hiperglucemia crónica en pacientes con DM induce una gran cantidad de alteraciones directas e indirectas en la estructura y la función renal, y constituye el principal factor para el desarrollo de la nefropatía diabética y la enfermedad renal terminal. En la presente revisión, se exponen los resultados de los estudios en los que se ha demostrado la alta tolerabilidad de empagliflozina en pacientes diabéticos con insuficiencia renal concomitante en estadios I a III. Empagliflozina, mediante la inhibición de SGLT2, ofrece una terapia novedosa con efectos benéficos no sólo sobre el control glucémico, sino también beneficios cardiovasculares y renales, los cuales han sido demostrados en el estudio EMPA-REG OUTCOME y continúan en evaluación en otros estudios

Chronic kidney disease is a frequent comorbidity in patients with diabetes mellitus (DM) and it increases their cardiovascular risk; chronic hyperglycemia in patients with DM leads to direct and indirect disorders in kidney's structure and function, and it is the principal risk factor for the development of diabetic nephropathy and end-stage renal disease. In the current review, results of studies are exposed in which high tolerability of empagliflozin is exposed in diabetic patients with kidney disease. Empagliflozin by inhibiting SGLT2 provides a novel therapy with benefic effects, not only in glycemic control, but it also has cardiovascular and renal benefits, which they have been demonstrated in the EMPA-REG OUTCOME trial, and continue in evaluation in other studies

A Case of Isolated Glycosuria Mediated by an SLC5A2 Gene Mutation and Characterized by Postprandial Heavy Glycosuria Without Salt Wasting

Familial renal glycosuria (FRG) is an inherited disorder characterized by persistent glycosuria in the absence of hyperglycemia. It is caused by mutations in the sodium-glucose co-transporter, leading to increase in the renal excretion of glucose and sodium. However, there have been no studies on the role of fasting and postprandial changes in the urinary sodium excretion in patients with FRG. We report a case of renal glycosuria, which was confirmed by a SLC5A2 mutation via gene sequencing, and compared the postprandial urinary glucose and sodium excretion. A 26-year-old man sometimes experienced glycosuria on routine screening; however, other laboratory findings were normal. His fasting and postprandial urinary glucose excretion levels were 295mg/dL and 2,170mg/dL, respectively. The fasting and postprandial urinary sodium excretion levels were 200mEq/L and 89mEq/L, respectively. In patients with FRG, excessive diuresis might be prevented by a compensatory mechanism that reduces postprandial sodium excretion.

Inhibition of renal glucose reabsorption as a novel treatment for diabetes patients / Inibicao da reabsorcao renal de glicose como uma nova forma de tratamento para pacientes com diabetes

The importance of the kidney in glucose homeostasis has been recognized for many years. Recent observations indicating a greater role of renal glucose metabolism in various physiologic and pathologic conditions have rekindled the interest in renal glucose handling as a potential target for the treatment of diabetes. The enormous capacity of the proximal tubular cells to reabsorb the filtered glucose load entirely, utilizing the sodium-glucose co-transporter system (primarily SGLT-2), became the focus of attention. Original studies conducted in experimental animals with the nonspecific SGLT inhibitor phlorizin showed that hyperglycemia after pancreatectomy decreased as a result of forced glycosuria. Subsequently, several compounds with more selective SGLT-2 inhibition properties (“second-generation”) were developed. Some agents made it into pre-clinical and clinical trials and a few have already been approved for commercial use in the treatment of type 2 diabetes. In general, a 6-month period of therapy with SGLT-2 inhibitors is followed by a mean urinary glucose excretion rate of ~80 g/day accompanied by a decline in fasting and postprandial glucose with average decreases in HgA1C ~1.0%. Concomitant body weight loss and a mild but consistent drop in blood pressure also have been reported. In contrast, transient polyuria, thirst with dehydration and occasional hypotension have been described early in the treatment. In addition, a significant increase in the occurrence of uro-genital infections, particularly in women has been documented with the use of SGLT-2 inhibitors. Conclusion: Although long-term cardiovascular, renal and bone/mineral effects are unknown SGLT-2 inhibitors, if used with caution and in the proper patient provide a unique insulin-independent therapeutic option in the management of obese type 2 diabetes patients. .

A importância do rim na homeostase de glicose é reconhecida desde há muitos anos. Observações recentes, indicando um papel maior do metabolismo renal da glicose em várias condições fisiológicas e patológicas, reavivaram o interesse no manuseio renal de glicose como um alvo em potencial para o tratamento do diabetes. A enorme capacidade das células tubulares proximais para reabsorver a carga total de glicose filtrada, utilizando o sistema de co-transporte de sódio e glicose (SGLT), tornou-se o foco de atenção. Estudos originais realizados em animais experimentais com o uso do inibidor não-específico da SGLT florizina, demonstraram que a hiperglicemia após pancreatectomia diminuiu como resultado de glicosúria forçada. Posteriormente, foram desenvolvidas diversas substâncias com propriedades mais seletivas de inibição da SGLT-2 ("segunda geração"). Vários agentes foram usados em ensaios pré-clínicos e clínicos, e alguns já foram aprovados para uso comercial no tratamento da diabetes tipo 2. Em geral, os dados clinicos mostram que um período de 6 meses de tratamento com inibidores da SGLT-2 é seguido por uma taxa de excreção de glicose urinária média de ~ 80 g/dia, acompanhado por uma queda na glicemia de jejum e pós-prandial e com redução média na HbA1C de - 1.0%. Também foram relatados perda concomitante no peso corpóreo e uma leve mas consistente queda da pressão arterial. Em contraste, eventos adversos transitórios como poliúria, sede com desidratação e hipotensão ocasional foram descritos na fase inicial de tratamento. Além disso, um aumento significativo na ocorrência de infecções urogenitais, particularmente em mulheres, foi documentado com o uso de inibidores da SGLT-2. Os efeitos ...

Glucose and other hexoses transporters in marine invertebrates: a mini review

Glucose and related hexoses are very important metabolic substrates. Their most important function is to provide quick fuel for most organisms in all three kingdoms because they are the first substrate for energy production in the form of ATP through glycolysis and the subsequent metabolic pathways. In this paper we review the current information about how glucose and related hexoses are transported across biological membranes to carry out their function either as a metabolic molecule or as energy store in marine invertebrate organisms. In these animals, there are two sugar transport systems that are mediated by the sodium/solute symporter family proteins (SGLT) and the major facilitative super-family proteins (GLUT). The most studied sugar transporters in marine invertebrates are involved with dietary sugar uptake, such as SGLT1, SGLT4, GLUT2 and GLUT5, however more studies need to be done to extend the knowledge about these and other sugar transporters involved in metabolic processes.

kidneys as an emerging target for the treatment of diabetes mellitus: What we know, thought we knew and hope to gain

Glucose filtered by kidneys is reabsorbed into the proximal tubule through the sodium-coupled glucose co-transporter [GLT2] This promotes urinary excretion of glucose and results in lowering of plasma glucose level. Administration of agents [.g. dapagliflozin] hat inhibits SGLT2 transporter have shown to be associated with improvement in hyperglycaemia without clinically persistent electrolytes disturbances or change in osmolarity. This may suggest that administration of dapagliflozin is effective and safe as treatment for hyperglycaemia. Ongoing clinical trials will reveal the potential benefit and safety of SGLT2 inhibitors as part of the therapy of type 2 diabetes