Turning Foes to Friends: Knocking Down Diabetes Associated SGLT2 Transporters and Sustaining Life

Author(s): Ankit Gupta, Sheenu Mittal, Monika, Richa Dhingra, Neelima Dhingra*

Journal Name: Current Diabetes Reviews

Volume 16 , Issue 7 , 2020


Become EABM
Become Reviewer
Call for Editor

Abstract:

Background: The discovery of Sodium-Glucose co-transporter-2 (SGLT2) inhibitors had rewritten the treatment of diabetes mellitus with an impressive fall in the incidence of death and associated complications.

Introduction: The SGLT2 inhibitors by inhibiting the SGLT2 in the proximal nephron, helps in reducing the reabsorption of approximately 90% of the filtered glucose and increased urinary glucose excretion (UGE).

Methods: The literature related to SGLT2 inhibitors has been thoroughly explored from various available public domains and reviewed extensively for this article. Detailed and updated information related to SGLT2 inhibitors with a major focus on the recently approved Ertuglifolzin is structured in this review.

Result: The present review is an effort to understand the management of diabetes mellitus over the past few decades with a special focus on the role of SGLT2 receptor in the causes of therapeutic and preventive strategies for diabetes mellitus. Pragmatic placement of the currently available Canagliflozin, Dapagliflozin, and Empagliflozin as oral antidiabetic agents has been done. Well accommodated stereochemistry and a high docking score of Ertugliflozin in ligand-receptor simulation studies attribute to its high potency.

Conclusion: This review highlights the unique mechanism of SGLT2 Inhibitors coupled with pleiotropic benefits on weight and blood pressure, which make it an attractive choice of therapy to diabetic patients, not controlled by other medications.

Keywords: Diabetes, SGLT2, ertugliflozin, canagliflozin, dapagliflozin, empagliflozin.

[1]
Fowler MJ. Microvascular and Macrovascular Complications of Diabetes. Clin Diabetes 2008; 26: 77-82.
[http://dx.doi.org/10.2337/diaclin.26.2.77]
[2]
Arya SC. Diabetes mellitus in the Arabian Peninsula. Ann Saudi Med 2002; 22(3-4): 258-9.
[http://dx.doi.org/10.5144/0256-4947.2002.258] [PMID: 17159414]
[3]
Xue S, Chen X, Lu J, Jin L. Protective effect of sulfated Achyranthesbidentata polysaccharides on streptozotocin-induced oxidative stress in rats. Carbohydr Polym 2009; 75: 415-9.
[http://dx.doi.org/10.1016/j.carbpol.2008.08.003]
[4]
Warren RE, Frier BM. Hypoglycaemia and cognitive function. Diabetes Obes Metab 2005; 7(5): 493-503.
[http://dx.doi.org/10.1111/j.1463-1326.2004.00421.x] [PMID: 16050942]
[5]
King H, Aubert RE, Herman WH. Global burden of diabetes, 1995-2025: prevalence, numerical estimates, and projections. Diabetes Care 1998; 21(9): 1414-31.
[http://dx.doi.org/10.2337/diacare.21.9.1414] [PMID: 9727886]
[6]
Patlak M. New weapons to combat an ancient disease: treating diabetes. FASEB J 2002; 16(14): 1853.
[http://dx.doi.org/10.1096/fj.02-0974bkt] [PMID: 12468446]
[7]
Tipton CM. Susruta of India, an unrecognized contributor to the history of exercise physiology. J Appl Physiol 2008; 104(6): 1553-6.
[http://dx.doi.org/10.1152/japplphysiol.00925.2007] [PMID: 18356481]
[8]
Frank LL. Diabetes mellitus in the texts of old Hindu medicine (Charaka, Susruta, Vagbhata). Am J Gastroenterol 1957; 27(1): 76-95.
[PMID: 13381732]
[9]
Shaw JE, Zimmet PZ, Alberti KG. Point: impaired fasting glucose: The case for the new American Diabetes Association criterion. Diabetes Care 2006; 29(5): 1170-2.
[http://dx.doi.org/10.2337/dc06-0013] [PMID: 16644659]
[10]
Gillett MJ. International expert committee report on the role of the A1c assay in the diagnosis of diabetes: diabetes care 2009; 32: 1327-34.
[11]
Leese B. Prevention of diabetes mellitus. Report of a WHO Study Group. WHO technical report series 844, Geneva, 1994. No. of pages: 100. ISBN 92-4-120844-9. Health Econ 1995; 4: 331-2.
[http://dx.doi.org/10.1002/hec.4730040411]
[12]
Amos AF, McCarty DJ, Zimmet P. The rising global burden of diabetes and its complications: estimates and projections to the year 2010. Diabet Med 1997; 14(Suppl. 5): S1-S85.
[http://dx.doi.org/10.1002/(SICI)1096-9136(199712)14:5+<S7:AID-DIA522>3.3.CO;2-I] [PMID: 9450510]
[13]
Rathmann W, Giani G. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004; 27(10): 2568-9.
[http://dx.doi.org/10.2337/diacare.27.10.2568] [PMID: 15451946]
[14]
Schalkwijk CG, Stehouwer CD. Vascular complications in diabetes mellitus: the role of endothelial dysfunction. Clin Sci (Lond) 2005; 109(2): 143-59.
[http://dx.doi.org/10.1042/CS20050025] [PMID: 16033329]
[15]
He Z, King GL. Microvascular complications of diabetes. Endocrinol Metab Clin North Am 2004; 33(1): 215-38. xi-xii.
[http://dx.doi.org/10.1016/j.ecl.2003.12.003] [PMID: 15053904]
[16]
Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 2006; 444(7121): 840-6.
[http://dx.doi.org/10.1038/nature05482] [PMID: 17167471]
[17]
Morgan CL, Currie CJ, Stott NC, Smithers M, Butler CC, Peters JR. The prevalence of multiple diabetes-related complications. Diabet Med 2000; 17(2): 146-51.
[http://dx.doi.org/10.1046/j.1464-5491.2000.00222.x] [PMID: 10746486]
[18]
Defronzo RA, Mandarino L, Ferrannini E. Metabolic and Molecular Pathogenesis of Type 2 Diabetes Mellitus. International Textbook of Diabetes Mellitus 2003; 5: 177-269.
[http://dx.doi.org/10.1002/0470862092.d0310]
[19]
Martin BC, Warram JH, Krolewski AS, Bergman RN, Soeldner JS, Kahn CR. Role of glucose and insulin resistance in development of type 2 diabetes mellitus: results of a 25-year follow-up study. Lancet 1992; 340(8825): 925-9.
[http://dx.doi.org/10.1016/0140-6736(92)92814-V] [PMID: 1357346]
[20]
Snel M, Jonker JT, Schoones J, et al. Ectopic fat and insulin resistance: pathophysiology and effect of diet and lifestyle interventions. Int J Endocrinol 2012; 2012983814
[http://dx.doi.org/10.1155/2012/983814] [PMID: 22675355]
[21]
Defronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 2009; 58(4): 773-95.
[http://dx.doi.org/10.2337/db09-9028] [PMID: 19336687]
[22]
Tahrani AA, Barnett AH, Bailey CJ. SGLT inhibitors in management of diabetes. Lancet Diabetes Endocrinol 2013; 1(2): 140-51.
[http://dx.doi.org/10.1016/S2213-8587(13)70050-0] [PMID: 24622320]
[23]
Patidar D. Pharmacology- III (2ndedtn). Meerut: Shree SaiPrakashan 2011; pp. 113-4.
[24]
Vaxillaire M, Froguel P. Monogenic diabetes in the young, pharmacogenetics and relevance to multifactorial forms of type 2 diabetes. Endocr Rev 2008; 29(3): 254-64.
[http://dx.doi.org/10.1210/er.2007-0024] [PMID: 18436708]
[25]
Ley SH, Hamdy O, Mohan V, Hu FB. Prevention and management of type 2 diabetes: dietary components and nutritional strategies. Lancet 2014; 383(9933): 1999-2007.
[http://dx.doi.org/10.1016/S0140-6736(14)60613-9] [PMID: 24910231]
[26]
Vuksan V, Sievenpiper JL. Herbal remedies in the management of diabetes: lessons learned from the study of ginseng. Nutr Metab Cardiovasc Dis 2005; 15(3): 149-60.
[http://dx.doi.org/10.1016/j.numecd.2005.05.001] [PMID: 15955462]
[27]
Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2013; 37.((Supplement_1))
[28]
Krentz AJ, Bailey CJ. Oral antidiabetic agents: current role in type 2 diabetes mellitus. Drugs 2005; 65(3): 385-411.
[http://dx.doi.org/10.2165/00003495-200565030-00005] [PMID: 15669880]
[29]
Clemmensen C, Müller TD, Finan B, Tschöp MH, Dimarchi R. Current and Emerging Treatment Options in Diabetes Care.Metabolic Control Handbook of Experimental Pharmacology. 2015; pp. 437-59.
[http://dx.doi.org/10.1007/164_2015_7]
[30]
Harikumar K, Kumar BK, Hemalatha GJ, Kumar MB. Steven FransisSakyLado SF. A review on diabetes mellitus. Int J Novel Trends Pharm Sci 2015; 5: 201-17.
[31]
White JR Jr. A brief history of the development of diabetes medications. Diabetes Spectr 2014; 27(2): 82-6.
[http://dx.doi.org/10.2337/diaspect.27.2.82] [PMID: 26246763]
[32]
Elkinson S, Scott LJ. Canagliflozin: first global approval. Drugs 2013; 73(9): 979-88.
[http://dx.doi.org/10.1007/s40265-013-0064-9] [PMID: 23729000]
[33]
Idris I, Donnelly R. Sodium-glucose co-transporter-2 inhibitors: an emerging new class of oral antidiabetic drug. Diabetes Obes Metab 2009; 11(2): 79-88.
[http://dx.doi.org/10.1111/j.1463-1326.2008.00982.x] [PMID: 19125776]
[34]
Ferrannini E, Solini A. SGLT2 inhibition in diabetes mellitus: rationale and clinical prospects. Nat Rev Endocrinol 2012; 8(8): 495-502.
[http://dx.doi.org/10.1038/nrendo.2011.243] [PMID: 22310849]
[35]
Wood IS, Trayhurn P. Glucose transporters (GLUT and SGLT): expanded families of sugar transport proteins. Br J Nutr 2003; 89(1): 3-9.
[http://dx.doi.org/10.1079/BJN2002763] [PMID: 12568659]
[36]
Abdul-Ghani MA, Norton L, Defronzo RA. Role of sodium-glucose cotransporter 2 (SGLT 2) inhibitors in the treatment of type 2 diabetes. Endocr Rev 2011; 32(4): 515-31.
[http://dx.doi.org/10.1210/er.2010-0029] [PMID: 21606218]
[37]
Chao EC, Henry RR. SGLT2 inhibition--a novel strategy for diabetes treatment. Nat Rev Drug Discov 2010; 9(7): 551-9.
[http://dx.doi.org/10.1038/nrd3180] [PMID: 20508640]
[38]
Turk E, Kerner CJ, Lostao MP, Wright EM. Membrane topology of the human Na+/glucose cotransporter SGLT1. J Biol Chem 1996; 271(4): 1925-34.
[http://dx.doi.org/10.1074/jbc.271.4.1925] [PMID: 8567640]
[39]
Levitt MF. Book Review Handbook of Renal Therapeutics Renal Function: Mechanisms Preserving Fluid and Solute Balance in Health. N Engl J Med 1983; 309(13): 801-2.
[http://dx.doi.org/10.1056/NEJM198309293091323]
[40]
Lee YJ, Lee YJ, Han HJ. Regulatory mechanisms of Na(+)/glucose cotransporters in renal proximal tubule cells. Kidney Int Suppl 2007; 72(106): S27-35.
[http://dx.doi.org/10.1038/sj.ki.5002383] [PMID: 17653207]
[41]
Malla P, Kumar R, Mahapatra MK, Kumar M. Ramping glucosuria for management of type 2 diabetes mellitus: an emerging cynosure. Med Res Rev 2014; 34(6): 1146-67.
[http://dx.doi.org/10.1002/med.21314] [PMID: 24633706]
[42]
Raja M, Kinne RK. Structural insights into genetic variants of Na(+)/glucose cotransporter SGLT1 causing glucose-galactose malabsorption: vSGLT as a model structure. Cell Biochem Biophys 2012; 63(2): 151-8.
[http://dx.doi.org/10.1007/s12013-012-9352-3] [PMID: 22383112]
[43]
Francis J, Zhang J, Farhi A, Carey H, Geller DS. A novel SGLT2 mutation in a patient with autosomal recessive renal glucosuria. Nephrol Dial Transplant 2004; 19(11): 2893-5.
[http://dx.doi.org/10.1093/ndt/gfh426] [PMID: 15496564]
[44]
Blevins T. Combination therapy for patients with uncontrolled type 2 diabetes mellitus: adding empagliflozin to pioglitazone or pioglitazone plus metformin. Expert Opin Drug Saf 2015; 14(5): 789-93.
[http://dx.doi.org/10.1517/14740338.2015.1020294] [PMID: 25789798]
[45]
Link JT, Sorensen BK. A method for preparing C-glycosides related to phlorizin. Tetrahedron Lett 2000; 41: 9213-7.
[http://dx.doi.org/10.1016/S0040-4039(00)01709-3]
[46]
Meng W, Ellsworth BA, Nirschl AA, et al. Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. J Med Chem 2008; 51(5): 1145-9.
[http://dx.doi.org/10.1021/jm701272q] [PMID: 18260618]
[47]
Nomura S, Sakamaki S, Hongu M, et al. Discovery of canagliflozin, a novel C-glucoside with thiophene ring, as sodium-dependent glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus. J Med Chem 2010; 53(17): 6355-60.
[http://dx.doi.org/10.1021/jm100332n] [PMID: 20690635]
[48]
Stenlöf K, Cefalu WT, Kim KA, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab 2013; 15(4): 372-82.
[http://dx.doi.org/10.1111/dom.12054] [PMID: 23279307]
[49]
Yale JF, Bakris G, Cariou B, et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab 2013; 15(5): 463-73.
[http://dx.doi.org/10.1111/dom.12090] [PMID: 23464594]
[50]
Shah NK, Deeb WE, Choksi R, Epstein BJ. Dapagliflozin: a novel sodium-glucose cotransporter type 2 inhibitor for the treatment of type 2 diabetes mellitus. Pharmacotherapy 2012; 32(1): 80-94.
[http://dx.doi.org/10.1002/PHAR.1010] [PMID: 22392830]
[51]
Nauck MA, Del Prato S, Meier JJ, et al. Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes Care 2011; 34(9): 2015-22.
[http://dx.doi.org/10.2337/dc11-0606] [PMID: 21816980]
[52]
Bailey CJ, Iqbal N, T’joen C, List JF. Dapagliflozin monotherapy in drug-naïve patients with diabetes: a randomized-controlled trial of low-dose range. Diabetes Obes Metab 2012; 14(10): 951-9.
[http://dx.doi.org/10.1111/j.1463-1326.2012.01659.x] [PMID: 22776824]
[53]
Ferrannini E, Ramos SJ, Salsali A, Tang W, List JF. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care 2010; 33(10): 2217-24.
[http://dx.doi.org/10.2337/dc10-0612] [PMID: 20566676]
[54]
Chen Y-Y, Wu T-T, Ho C-Y, et al. Dapagliflozin Prevents NOX- and SGLT2-Dependent Oxidative Stress in Lens Cells Exposed to Fructose-Induced Diabetes Mellitus. Int J Mol Sci 2019; 20(18): 4357-71.
[http://dx.doi.org/10.3390/ijms20184357] [PMID: 31491943]
[55]
Finelli C, Sommella L, Gioia S, La Sala N, Tarantino G. Should visceral fat be reduced to increase longevity? Ageing Res Rev 2013; 12(4): 996-1004.
[http://dx.doi.org/10.1016/j.arr.2013.05.007] [PMID: 23764746]
[56]
Mechatie E. 2014 August; 1FDA approves empagliflozin for adults with type 2 diabetes Clinical Endocrinology News Digital Network.
[57]
McGill JB. The SGLT2 Inhibitor Empagliflozin for the Treatment of Type 2 Diabetes Mellitus: a Bench to Bedside Review. Diabetes Ther 2014; 5(1): 43-63.
[http://dx.doi.org/10.1007/s13300-014-0063-1] [PMID: 24729157]
[58]
Rosenstock J, Seman LJ, Jelaska A, et al. Efficacy and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, as add-on to metformin in type 2 diabetes with mild hyperglycaemia. Diabetes Obes Metab 2013; 15(12): 1154-60.
[http://dx.doi.org/10.1111/dom.12185] [PMID: 23906374]
[59]
Mechatie E. 2014 August; 1FDA approves empagliflozin for adults with type 2 diabetes Clinical Endocrinology News Digital Network.
[60]
Abdul-Ghani MA, DeFronzo RA. Inhibition of renal glucose reabsorption: a novel strategy for achieving glucose control in type 2 diabetes mellitus. Endocr Pract 2008; 14(6): 782-90.
[http://dx.doi.org/10.4158/EP.14.6.782] [PMID: 18996802]
[61]
Markham A. Ertugliflozin: First Global Approval. Drugs 2018; 78(4): 513-9.
[http://dx.doi.org/10.1007/s40265-018-0878-6] [PMID: 29476348]
[62]
Colvin NN. Ertugliflozin (Steglatro): New Drug in the Family. Juniper Online Journal of Case Studies 2018; 5(5)
[63]
Pratley RE, Eldor R, Raji A, et al. Ertugliflozin plus sitagliptin versus either individual agent over 52 weeks in patients with type 2 diabetes mellitus inadequately controlled with metformin: The VERTIS FACTORIAL randomized trial. Diabetes Obes Metab 2018; 20(5): 1111-20.
[http://dx.doi.org/10.1111/dom.13194] [PMID: 29266675]
[64]
Miao Z, Nucci G, Amin N, et al. Pharmacokinetics, metabolism, and excretion of the antidiabetic agent ertugliflozin (PF-04971729) in healthy male subjects. Drug Metab Dispos 2013; 41(2): 445-56.
[http://dx.doi.org/10.1124/dmd.112.049551] [PMID: 23169609]
[65]
Fujimori Y, Katsuno K, Nakashima I, Ishikawa-Takemura Y, Fujikura H, Isaji M. Remogliflozin etabonate, in a novel category of selective low-affinity sodium glucose cotransporter (SGLT2) inhibitors, exhibits antidiabetic efficacy in rodent models. J Pharmacol Exp Ther 2008; 327(1): 268-76.
[http://dx.doi.org/10.1124/jpet.108.140210] [PMID: 18583547]
[66]
Mudaliar S, Armstrong DA, Mavian AA, et al. Remogliflozin etabonate, a selective inhibitor of the sodium-glucose transporter 2, improves serum glucose profiles in type 1 diabetes. Diabetes Care 2012; 35(11): 2198-200.
[http://dx.doi.org/10.2337/dc12-0508] [PMID: 23011728]
[67]
Goodwin NC, Mabon R, Harrison BA, et al. Novel L-xylose derivatives as selective sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes. J Med Chem 2009; 52(20): 6201-4.
[http://dx.doi.org/10.1021/jm900951n] [PMID: 19785435]
[68]
Cariou B, Charbonnel B. Sotagliflozin as a potential treatment for type 2 diabetes mellitus. Expert Opin Investig Drugs 2015; 24(12): 1647-56.
[http://dx.doi.org/10.1517/13543784.2015.1100361] [PMID: 26548423]
[69]
AstellasPharma; Approval of Suglat tablets, a selective SGLT2 inhibitor for treatment of type 2 diabetes, in Japan Press release 2014.January; 17. www.astellas.com/en/corporate/news/detail/approval-of-suglat-tablets-a-s.html
[70]
Poole RM, Dungo RT. Ipragliflozin: first global approval. Drugs 2014; 74(5): 611-7.
[http://dx.doi.org/10.1007/s40265-014-0204-x] [PMID: 24668021]
[71]
Suzuki M, Honda K, Fukazawa M, et al. Tofogliflozin, a potent and highly specific sodium/glucose cotransporter 2 inhibitor, improves glycemic control in diabetic rats and mice. J Pharmacol Exp Ther 2012; 341(3): 692-701.
[http://dx.doi.org/10.1124/jpet.112.191593] [PMID: 22410641]
[72]
Sasaki T, Sugawara M, Fukuda M. Sodium-glucose cotransporter 2 inhibitor-induced changes in body composition and simultaneous changes in metabolic profile: 52-week prospective LIGHT (Luseogliflozin: the Components of Weight Loss in Japanese Patients with Type 2 Diabetes Mellitus) Study. J Diabetes Investig 2019; 10(1): 108-17.
[http://dx.doi.org/10.1111/jdi.12851] [PMID: 29660782]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 16
ISSUE: 7
Year: 2020
Page: [716 - 732]
Pages: 17
DOI: 10.2174/1573399816666200117155016
Price: $65

Article Metrics

PDF: 25
HTML: 4
PRC: 2