abetes & Di M f e o t a l b a o Ahmed et al., J Diabetes Metab 2014, 5:4 n l r i s u m o DOI: 10.4172/2155-6156.1000358 J Journal of Diabetes and Metabolism ISSN: 2155-6156 Review Article Open Access An Emerging Protagonist: Sodium Glucose Co-transporters (SGLTs) as a Burgeoning Target for the Treatment of Diabetes Mellitus Danish Ahmed1*, Manju Sharma2, Vikas Kumar1 and Yadav Pankajkumar Subhashchandra1 1Department of Pharmaceutical Sciences, Sam Higginbottom Institute of Agriculture, Technology and Sciences (SHIATS)-Deemed University, India 2Department of Pharmacology, JamiaHamdard University, Hamdard Nagar, New Delhi, India Abstract Contemporary therapies to rationalize the hyperglycaemia in type 2 diabetes mellitus (T2DM) generally involve insulin-dependent mechanisms and lose their effectiveness as pancreatic b-cell function decreases to a greater extent. Kidney emerges out as a novel and potential target to trim down the complications of T2DM. The filtered glucose is reabsorbed principally through the sodium glucose co-transporter-2 (SGLT2), a low affinity transport system, which are present at the luminal surface cells that covers the first segment of proximal tubules. Competitive inhibition of SGLT2 therefore represents an innovative therapeutic strategy for the treatment of hyperglycaemia and/or obesity in patients with type 1 or type 2 diabetes by enhancing glucose and energy loss through the urine. Selective inhibitors of SGLT2 reduce glucose reabsorption, causing excess glucose to be eliminated in the urine; this decreases plasma glucose. SGLT2 inhibitors are coupled with osmotic dieresis and loss of weight which aid in reducing the blood pressure. The observation that individuals with familial renal glycosuria maintain normal long- term kidney function provides some encouragement that this mode of action will not adversely affect renal function. This novel mechanism of targeting kidney for the treatment of T2DM is reasonably valuable and is independent of insulin and clutch with the low risk of hypoglycemia. Keywords: SGLT2; Diabetes; Kidney; Hyperglycemia; Type 2 the concentration gradient. Sodium is the major ion present in the diabetes mellitus mammals whose gradient across the cell membrane has been used as thrust. The secondary active transport of sugars, carboxylic acid and the Abbreviations: SGLTs: Sodium-Dependent Glucose Cotransporters; aminoacids rivet the synchronized movement of sodium ions by and T2DM: Type2 Diabetes Mellitus; HbA1c: Glycated Heamoglobin ; large in the same direction as the substrate [6] (Figure 1). FPG: Fasting Plasma Glucose; HRQOL: Health Related Quality of Life; CFU: Colony Forming Units; OADs: Oral Antidiabetic Drugs Kidney is the main organ where active transport of sugar takes place in the early part of the proximal tubule. Research work on the Introduction transport of sugar in the early and late segments of proximal tubule and vesicles demonstrate that the kidney contains two D-glucose co- Diabetes has become an engorgement apprehension worldwide. transporters with the difference in their stoichiometry for sodium in More or less 285 million people all over the world will be suffering the early proximal tubule. There is a mutual translocation of one sugar from diabetes by the end of 2010. WHO estimates that more than 346 and one sodium molecule in the luminal membrane while two sodium million people worldwide have diabetes [1]. This number is likely to ions are transferred with one sugar molecule in the late part of proximal become more than double by 2030 without intervention. Almost 80% of tubule. There is a divergence in the affinity for D-glucose for the two diabetes deaths occur in low- and middle-income countries. The most transporters [7] (Figure 2). common disorder of glucose homeostasis is Type2 Diabetes Mellitus (T2DM). It accounts for 90-96% of all cases of diabetes [2]. Sodium- The transporter in the early part has been identified as SGLT1 at the Dependent Glucose Cotransporters (SGLTs) facilitate the transport of same time the transporter found in the early proximal tubule as SGLT2. glucose against a concentration gradient with synchronized transport The sodium gluocose co-transporter (SGLT2) is a high capacity, low of sodium down a concentration gradient [3]. The anticipation is affinity proximal tubular cell transporter that reabsorbs filtered glucose. that there is about 90% of total renal glucose reabsorption is aided Mutations in this transporter lead to renal glycosuria. In diabeticanimal by SGLT2. Thus a new therapeutic approach without dependence on models, there appears to be up-regulation of the SGLT2 receptors and insulin and appropriate for use in amalgamation with other agents would be preeminent choice for treatment of hyperglycemia in type 2 diabetes mellitus (T2DM). Sodium Glucose co-transporter inhibitors create a center of attention as there is a need of potential therapy for *Corresponding author: Danish Ahmed, Department of Pharmaceutical Sciences, Faculty of Health Sciences, Sam Higginbottom Institute of Agriculture, Technology diabetes mellitus with lesser side effects [4,5]. This review scrutinize the and Sciences (SHIATS)-Deemed University, Allahabad, Uttar Pradesh, India, niceties of various SGLT2 inhibitors Tel: 919580001578; Fax: 91 532 2684190; E-mail: [email protected] The role of SGLT is fundamental in the mutual transfer of sugar Received February 24, 2014; Accepted March 16, 2014; Published March 22, and sodium across the epithelial membrane. The transport of sugar 2014 takes place in the small intestine and the renal tubule through active Citation: Ahmed D, Sharma M, Kumar V, Pankajkumar Y, chandra S (2014) transport. It necessitates the coupling of cellular energy metabolism An Emerging Protagonist: Sodium Glucose Co-transporters (SGLTs) as a to the transepithelial transfer. It is SGLT where the coupling takes Burgeoning Target for the Treatment of Diabetes Mellitus. J Diabetes Metab 5: 358 doi:10.4172/2155-6156.1000358 place. There is no hydrolysis of ATP is engaged as compared to the primary active transport episodes for instance those intervened by ion Copyright: © 2014 Ahmed D, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted translocating ATPases. As an alternative the SGLT exploit the energy use, distribution, and reproduction in any medium, provided the original author and accumulated in an ion gradient for the translocation of sugars against source are credited. J Diabetes Metab ISSN: 2155-6156 JDM, an open access journal Volume 5 • Issue 4 • 1000358 Citation: Ahmed D, Sharma M, Kumar V, Pankajkumar Y, chandra S (2014) An Emerging Protagonist: Sodium Glucose Co-transporters (SGLTs) as a Burgeoning Target for the Treatment of Diabetes Mellitus. J Diabetes Metab 5: 358 doi:10.4172/2155-6156.1000358 Page 2 of 7 acquaintances pave the way for the identification of an identical gene in the kidney [9]. This further allowed the researchers to do mutagenesis Glucose Lumen studies, structural elucidation and the discovery of substrate binding Na+ Basolateral Membrane sites as well as inhibitor binding sites [8]. SGLT2 The extensive research on the membrane topology of the transporter S1 Proximal which was possible only after the acquaintance of the sequence was Tubule Na+ done. The research showed that the N-terminus of thee transporter Glucose is pointing outside of the cell with 14 transmembrane segments. K+ The position of the loop 13-14 is essential after pholrizin binding site requires the loop 13-14. The C-terminus also plays a vital role in the recognition and translocation of the sugar [8]. The N-terminal segments IV-V are implicated in the recognition of sodium as well as GLUT2 glucose binding (Table 1). K+ Blood Na+K+ATPase Pump Glucose Na+ Lateral Intercellular Space Pancreas Fat Cells Insulin Glucagon Insulin + - + Glomerulus Bowmans Capsule Distal Nephron Tubule Liver 90 mg/100 ml Skeletal Proximal Muscle Tubule Collecting Duet Loop of Henle Fasting Plasma Glucose Kidney Figure 2: Normal glucose homeostasis. This outlines the hormonal interactions that are important in regulating normal glucose homeostasis. Normal fasting glucose homeostasis involves the hormonal regulation of glucose utilization and production, as well as the filtration and reabsorption of glucose by the kidney10. Under basa conditions, Kidney glucose uptake by the tissues is matched by glucose production from the liver; this enables fine regulation of glucose at a fixed level. Gluconeogenesis in the liver helps prevent hypoglycaemia. (Reproduced with permission from Edward C. Chao, Copyright @2010, Macmilan Publishers Limited). Figure 1: Reabsorption of glucose from the renal proximal tubules by the sodium glucose cotransporters SGLT2. Almost all of the glucose entering glomeruli in the afferent glomerular arterioles Selectivity for UGE in humans at Reduction in is filtered into the nephron fluid of the proximal renal tubules. Most (up to Compound SGLT2 vs. SGLT1 highest dose; mean HbA1c (%) 90%) of this filtered glucose is reabsorbed in the initial proximal convoluted (Fold) value ± SDa (g/day) segment (S1) by SGLT2 located at the luminal surface of proximal tubular cells. 90.8 ± 16.0 [29] Remaining glucose is reabsorbed from the filtrate in themore distal convoluted ASP1941 255 [28] 58.9 ± 14.6 [31] −0.8 [30] and straight segments by SGLT1. Glucose within the proximal tubular cells is 50 [30] then transported back to the interstitial compartment and thence to the plasma by the facilitative glucose transporters GLUT2 in the S1 segment, respectively. 72.6 ± 35.9 [33] In normal individuals with an average plasma glucose concentration of 5-5.5 BI 10773 >2,500 [32] 88 ± 20.3 [34] NR mmol/L (90-100mg/dL), approximately 160–180 g of glucose is filtered daily, 90.8 [35] with less than 0.5 g/day of glucose appearing in the urine based on Bakris et 129.2 ± 20.8 SE [37] Canagliflozin 414 [36] −0.92 [37] al. and Bays. 113 [38] −0.61 to −0.89 Dapagliflozin 1,200 [39] 70 [22] [16-19] GLUT2mRNA.