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Inhibition of Renal Glucose Reabsorption As a Novel Treatment for Diabetes Patients

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Inhibition of Renal Glucose Reabsorption As a Novel Treatment for Diabetes Patients ARTIGO DE REVISÃO | REVIEW ARTICLE Inhibition of renal glucose reabsorption as a novel treatment for diabetes patients Inibição da reabsorção renal de glicose como uma nova forma de tratamento para pacientes com diabetes Autores ABSTRACT RESUMO Eugenio Cersosimo1 Carolina Solis-Herrera1 The importance of the kidney in gluco- A importância do rim na homeostase de Curtis Triplitt1 se homeostasis has been recognized for glicose é reconhecida desde há muitos many years. Recent observations indi- anos. Observações recentes, indicando cating a greater role of renal glucose um papel maior do metabolismo renal 1 University of Texas Health metabolism in various physiologic and da glicose em várias condições fisiológi- Science Center San Antonio, pathologic conditions have rekindled cas e patológicas, reavivaram o interesse Texas. no manuseio renal de glicose como um the interest in renal glucose handling as alvo em potencial para o tratamento do a potential target for the treatment of diabetes. A enorme capacidade das célu- diabetes. The enormous capacity of the las tubulares proximais para reabsorver a proximal tubular cells to reabsorb the carga total de glicose filtrada, utilizando o filtered glucose load entirely, utilizing sistema de co-transporte de sódio e glicose the sodium-glucose co-transporter sys- (SGLT), tornou-se o foco de atenção. Es- tem (primarily SGLT-2), became the fo- tudos originais realizados em animais ex- cus of attention. Original studies con- perimentais com o uso do inibidor não-es- ducted in experimental animals with pecífico da SGLT florizina, demonstraram the nonspecific SGLT inhibitor phlo- que a hiperglicemia após pancreatectomia rizin showed that hyperglycemia after diminuiu como resultado de glicosúria for- çada. Posteriormente, foram desenvolvidas pancreatectomy decreased as a result of diversas substâncias com propriedades forced glycosuria. Subsequently, several mais seletivas de inibição da SGLT-2 ("se- compounds with more selective SGLT-2 gunda geração"). Vários agentes foram inhibition properties (“second-gene- usados em ensaios pré-clínicos e clínicos, ration”) were developed. Some agents e alguns já foram aprovados para uso co- made it into pre-clinical and clinical mercial no tratamento da diabetes tipo 2. trials and a few have already been ap- Em geral, os dados clinicos mostram que proved for commercial use in the treat- um período de 6 meses de tratamento com ment of type 2 diabetes. In general, a inibidores da SGLT-2 é seguido por uma 6-month period of therapy with SGLT- taxa de excreção de glicose urinária média 2 inhibitors is followed by a mean uri- de ~ 80 g/dia, acompanhado por uma que- da na glicemia de jejum e pós-prandial e nary glucose excretion rate of ~80 g/day com redução média na HbA1C de - 1.0%. accompanied by a decline in fasting and Também foram relatados perda concomi- postprandial glucose with average de- tante no peso corpóreo e uma leve mas creases in HgA1C ~1.0%. Concomi- consistente queda da pressão arterial. Em tant body weight loss and a mild but contraste, eventos adversos transitórios Data de submissão: 30/11/2013. consistent drop in blood pressure also como poliúria, sede com desidratação e Data de aprovação: 06/01/2014. have been reported. In contrast, tran- hipotensão ocasional foram descritos na sient polyuria, thirst with dehydration fase inicial de tratamento. Além disso, um aumento significativo na ocorrência Correspondência para: and occasional hypotension have been Eugenio Cersosimo. described early in the treatment. In de infecções urogenitais, particularmente Associate Professor of Medicine, addition, a significant increase in the em mulheres, foi documentado com o Medical Director for Clinical uso de inibidores da SGLT-2. Os efeitos Research, Texas Diabetes Institute. occurrence of uro-genital infections, 7703 Floyd Curl Drive, MC 7886 cardiovasculares, renais e ósseo/minerais San Antonio, TX, USA. particularly in women has been docu- 78229-3900. a longo prazo destes agentes ainda são E-mail: [email protected] mented with the use of SGLT-2 inhibi- desconhecidos. Conclusão: Os inibidores [email protected] tors. Conclusion: Although long-term da SGLT-2, se usados de forma criteriosa e Phone: 1 (210) 567 6691 or (210) 358 7200. Fax: 1 (210) 358 7235. cardiovascular, renal and bone/mineral em pacientes adequados, representam uma effects are unknown SGLT-2 inhibitors, opção terapêutica única, que explora um DOI: 10.5935/0101-2800.20140014 80 Inhibition of Renal Glucose Reabsorption in Diabetes if used with caution and in the proper patient novo mecanismo de ação anti-hiperglicêmico indepen- provide a unique insulin-independent therapeutic dente da insulina. Estão portanto indicados, tanto na option in the management of obese type 2 diabetes monoterapia ou em combinação com outros agentes patients. no tratamento de pacientes obesos com diabetes tipo 2. Keywords: diabetes mellitus, type 2/therapy; glycosuria; Palavras-chave: diabetes mellitus tipo 2/terapia; kidney, sodium-glucose transporter 2. glicosúria; rim; transportador 2 de glucose-sódio. INTRODUCTION enzymatic activity for concomitant glucose utiliza- tion, storage or oxidation has ever been identified in The importance of the kidney in glucose homeostasis proximal tubules.14 has been recognized for many years.1,2 A critical observation indicating that the renal contribution Figure 1. Schematic representation of the nephron showing the to glucose regulation and counter-regulation might heterogeneity of glucose handling by the kidney. Plasma glucose is perhaps be of greater significance than previous- freely filtered at the glomerulus and completely reabsorbed in the proximal tubules. The SGLT-2 transporters located at the luminal ly anticipated was reported in the early 1990’s.3 membrane of cells in the S1 and S2 segments are responsible for This publication rekindled the interest in the role 90% of total glucose re-uptake. The SGLT-1 transporters located downstream in the S3 segment of the proximal tubules account of the kidney in glucose metabolism and several for the remainder 10% of the glucose load reabsorbed into the studies in animals4-6 and humans7-10 subsequently renal interstitial fluid. The process of renal gluconeogenesis occurs exclusively in the proximal tubular cells, whereas glucose utilization is demonstrated the potential impact of renal glucose limited to the distal nephron. Glycogen synthesis and storage, as well handling in various physiologic and pathologic con- as complete glucose oxidation are detected only in cells of the distal nephron and, partial oxidation (anaerobic glycolysis) with formation ditions. Concomitantly, the pharmacological deve- and release of lactate is a characteristic of the hypoxic medullary lopment of new agents capable of inhibiting renal regions of the kidney. glucose reabsorption was accelerated and has now reached clinical relevance. As a result, the kidney has become an additional target for anti-diabetic medications. Renal glucose handling includes free glomerular fil- tration with complete proximal tubular reabsorption into the renal interstitial fluid space. Renal gluconeo- genesis that takes place in the proximal tubular cells adds a small fraction to the glucose load that exchan- ges with the peri-tubular capillaries along the proximal nephron. In the distal nephron, glucose extracted can be either stored in the form of glycogen or oxidized to In contrast, the distal nephron has sufficient generate energy. In turn, no glucose is excreted in the biochemical capability to metabolize the glucose urine and nearly all filtered glucose load perfusing the extracted from the peri-tubular fluid and, the renal distal nephron is restored to the peripheral circulation, medulla is in fact an obligatory site for glucose oxi- after mixing in the renal vein with the remainder 80% dation.13,14 Because most of the energy required by the 11 of unfiltered blood. mega-transport tubular activity is supplied primarily The evidence for the heterogeneity of glucose from the oxidation of fatty acids, glucose sparing by handling within the nephron (Figure 1) is substantiated the kidney is enabled and represents a critical aspect in 1,12-15 by numerous reports in the literature. Several the maintenance of whole-body glucose homeostasis. studies have defined the molecular structure and the enormous enzymatic and transport capacity of the RENAL GLUCOSE TRANSPORT AND METABOLISM renal tubules. The sodium-glucose co-transport sys- Various glucose transmembrane transport systems and tem (SGLT) is located at the luminal membrane of intracellular metabolic pathways have been well charac- 15 the proximal renal tubular cells. These cells con- terized in the kidney. Most information is derived from tain specific enzymes that enable glucose synthesis in vitro cell preparations16-18 and renal perfusion studies 1,12 de novo [renal gluconeogenesis], although no using experimental animal models.19-21 Analogous 81 J Bras Nefrol 2014;36(1):80-92 Inhibition of Renal Glucose Reabsorption in Diabetes findings have been reported in a few studies conducted This same system is also utilized to carry amino in human kidney.22,23 Glucose is actively transported acids from the lumen into the proximal tubular cells. from the lumen to the tubular cells essentially by two The SGLT-2 transport activity across the luminal transmembrane proteins: one with high capacity-low membrane is driven by an electro-chemical gradient, affinity termed sodium-glucose transport SGLT-2 and which
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