An Insight into the Development of Potential Antidiabetic Agents along
with their Therapeutic Targets

Siddhita      Tiwari; Paranjeet      Kaur; Deepali      Gupta; Saumik      Chaudhury; Manish      Chaudhary; Amit      Mittal; Shubham      Kumar; Sanjeev   Kumar   Sahu
Abstract

Diabetes is a metabolic disorder that has been reported to increase the mortality rate worldwide. About 40 million people across the globe suffer from diabetes, with people living in developing countries being affected the most due to this deadly disease. Although the therapeutic management of hyperglycaemia can treat diabetes, metabolic disorders associated with this disease are a greater challenge in its treatment. Hence, potential strategies to treat hyperglycaemia and its side effects are needed. In this review, we have summarized several therapeutic targets, like dipeptidyl peptidase-4 (DPP-4), glucagon receptor antagonists, glycogen phosphorylase or fructose-1,6- biphosphatase inhibitors, SGLT inhibitors, 11beta-HSD-1 inhibitors, glucocorticoids receptor antagonists, glucose-6-phosphatase and glycogen phosphorylase inhibitors. These targets can help in designing and developing novel antidiabetic agents.
Keywords: Type-2 diabetes, hyperglycaemia, metabolic syndrome, therapeutic targets, pancreas, antidiabetic agents.
Graphical Abstract

[1]
Diagnosis and classification of diabetes mellitus. Diabetes Care,  2010, 33(Suppl. 1), S62-S69.
 [http://dx.doi.org/10.2337/dc10-S062] [PMID: 20042775]

[2]
Sarwar, N.; Gao, P.; Seshasai, S.R.; Gobin, R.; Kaptoge, S.; Di Angelantonio, E.; Ingelsson, E.; Lawlor, D.A.; Selvin, E.; Stampfer, M.; Stehouwer, C.D. Emerging risk factors collaboration diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet,  2010, 375(9733), 2215-2222.
 [http://dx.doi.org/10.1016/S0140-6736(10)60484-9]

[3]
Saran, R.; Robinson, B.; Abbott, K.C.; Agodoa, L.Y.; Albertus, P.; Ayanian, J.; Balkrishnan, R.; Bragg-Gresham, J.; Cao, J.; Chen, J.L.; Cope, E. US renal data system 2016 annual data report: epidemiology of kidney disease in the United States., American journal of kidney diseases, 2017. 1; 69(3), A7-8.
 [http://dx.doi.org/10.1053/j.ajkd.2018.01.002]

[4]
Bourne, R.R.A.; Stevens, G.A.; White, R.A.; Smith, J.L.; Flaxman, S.R.; Price, H.; Jonas, J.B.; Keeffe, J.; Leasher, J.; Naidoo, K.; Pesudovs, K.; Resnikoff, S.; Taylor, H.R. Causes of vision loss worldwide, 1990–2010: a systematic analysis. Lancet Glob. Health,  2013, 1(6), e339-e349.
 [http://dx.doi.org/10.1016/S2214-109X(13)70113-X] [PMID: 25104599]

[5]
Gale, J. India’s diabetes epidemic cuts down millions who escape poverty. Bloomberg. Retrieved.,  2012, Jun, 8. [India’s Diabetes Epidemic Cuts Down Millions Who Escape Poverty - Bloomberg.]

[6]
Saeedi, P.; Petersohn, I.; Salpea, P.; Malanda, B.; Karuranga, S.; Unwin, N.; Colagiuri, S.; Guariguata, L.; Motala, A.A.; Ogurtsova, K.; Shaw, J.E.; Bright, D.; Williams, R. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and  2045: Results from the International Diabetes Federation Diabetes Atlas, 9th edition.  In: Diabetes Res. Clin. Pract; , 2019; 157, p. 107843.
 [http://dx.doi.org/10.1016/j.diabres.2019.107843] [PMID: 31518657]

[7]
Adeghate, E.; Schattner, P.; Dunn, E. An update on the etiology and epidemiology of diabetes mellitus. Ann. N. Y. Acad. Sci.,  2006, 1084(1), 1-29.
 [http://dx.doi.org/10.1196/annals.1372.029] [PMID: 17151290]

[8]
Scheen, A.J. Pathophysiology of type 2 diabetes. Acta Clin. Belg.,  2003, 58(6), 335-341.
 [http://dx.doi.org/10.1179/acb.2003.58.6.001] [PMID: 15068125]

[9]
Marchetti, P.; Dotta, F.; Lauro, D.; Purrello, F. An overview of pancreatic beta-cell defects in human type 2 diabetes: Implications for treatment. Regul. Pept.,  2008, 146(1-3), 4-11.
 [http://dx.doi.org/10.1016/j.regpep.2007.08.017] [PMID: 17889380]

[10]
Gunasekaran, U.; Gannon, M. Type 2 diabetes and the aging pancreatic beta cell. Aging,  2011, 3(6), 565-575.
 [http://dx.doi.org/10.18632/aging.100350] [PMID: 21765202]

[11]
Del Guerra, S.; Lupi, R.; Marselli, L.; Masini, M.; Bugliani, M.; Sbrana, S.; Torri, S.; Pollera, M.; Boggi, U.; Mosca, F.; Del Prato, S.; Marchetti, P. Functional and molecular defects of pancreatic islets in human type 2 diabetes. Diabetes,  2005, 54(3), 727-735.
 [http://dx.doi.org/10.2337/diabetes.54.3.727] [PMID: 15734849]

[12]
Lo, J.C.; Ljubicic, S.; Leibiger, B.; Kern, M.; Leibiger, I.B.; Moede, T.; Kelly, M.E.; Chatterjee Bhowmick, D.; Murano, I.; Cohen, P.; Banks, A.S.; Khandekar, M.J.; Dietrich, A.; Flier, J.S.; Cinti, S.; Blüher, M.; Danial, N.N.; Berggren, P.O.; Spiegelman, B.M. Adipsin is an adipokine that improves β cell function in diabetes. Cell,  2014, 158(1), 41-53.
 [http://dx.doi.org/10.1016/j.cell.2014.06.005] [PMID: 24995977]

[13]
Gómez-Banoy, N.; Guseh, J.S.; Li, G.; Rubio-Navarro, A.; Chen, T.; Poirier, B.; Putzel, G.; Rosselot, C.; Pabón, M.A.; Camporez, J.P.; Bhambhani, V.; Hwang, S.J.; Yao, C.; Perry, R.J.; Mukherjee, S.; Larson, M.G.; Levy, D.; Dow, L.E.; Shulman, G.I.; Dephoure, N.; Garcia-Ocana, A.; Hao, M.; Spiegelman, B.M.; Ho, J.E.; Lo, J.C. Adipsin preserves beta cells in diabetic mice and associates with protection from type 2 diabetes in humans. Nat. Med.,  2019, 25(11), 1739-1747.
 [http://dx.doi.org/10.1038/s41591-019-0610-4] [PMID: 31700183]

[14]
Zhang, B.B.; Moller, D.E. New approaches in the treatment of type 2 diabetes. Curr. Opin. Chem. Biol.,  2000, 4(4), 461-467.
 [http://dx.doi.org/10.1016/S1367-5931(00)00103-4] [PMID: 10959776]

[15]
Moller, D.E. New drug targets for type 2 diabetes and the metabolic syndrome. Nature,  2001, 414(6865), 821-827.
 [http://dx.doi.org/10.1038/414821a] [PMID: 11742415]

[16]
Chehade, J.M.; Mooradian, A.D. A rational approach to drug therapy of type 2 diabetes mellitus. Drugs,  2000, 60(1), 95-113.
 [http://dx.doi.org/10.2165/00003495-200060010-00006] [PMID: 10929931]

[17]
Drivsholm, T.; de Fine Olivarius, N.; Nielsen, A.B.S.; Siersma, V. Symptoms, signs and complications in newly diagnosed type 2 diabetic patients, and their relationship to glycaemia, blood pressure and weight. Diabetologia,  2005, 48(2), 210-214.
 [http://dx.doi.org/10.1007/s00125-004-1625-y] [PMID: 15650820]

[18]
Liu, Q.; Chen, L.; Hu, L.; Guo, Y.; Shen, X. Small molecules from natural sources, targeting signaling pathways in diabetes. Biochim. Biophys. Acta. Gene Regul. Mech.,  2010, 1799(10-12), 854-865.
 [http://dx.doi.org/10.1016/j.bbagrm.2010.06.004] [PMID: 20601278]

[19]
Randle, P.J.; Garland, P.B.; Hales, C.N.; Newsholme, E.A. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet,  1963, 281(7285), 785-789.
 [http://dx.doi.org/10.1016/S0140-6736(63)91500-9] [PMID: 13990765]

[20]
Nguyen, N.D.T.; Le, L.T. Targeted proteins for diabetes drug design. Advances in Natural Sciences: Nanoscience and Nanotechnology,  2012, 3, 013001.

[21]
Ahmed, I.; Adeghate, E.; Sharma, A.K.; Pallot, D.J.; Singh, J. Effects of Momordica charantia fruit juice on islet morphology in the pancreas of the streptozotocin-diabetic rat. Diabetes Res. Clin. Pract.,  1998, 40(3), 145-151.
 [http://dx.doi.org/10.1016/S0168-8227(98)00022-9] [PMID: 9716917]

[22]
Porte, D., Jr; Kahn, S.E. Mechanisms for hyperglycemia in type II diabetes mellitus: Therapeutic implications for sulfonylurea treatment—an update. Am. J. Med.,  1991, 90(6), S8-S14.
 [http://dx.doi.org/10.1016/0002-9343(91)90412-Q] [PMID: 1872310]

[23]
Pillay, T.S.; Makgoba, M.W. Molecular mechanisms of insulin resistance. S. Afr. Med. J.,  1991, 79(10), 607-613.
 [PMID: 2028355]

[24]
Schinner, S.; Scherbaum, W.A.; Bornstein, S.R.; Barthel, A. Molecular mechanisms of insulin resistance. Diabet. Med.,  2005, 22(6), 674-682.
 [http://dx.doi.org/10.1111/j.1464-5491.2005.01566.x] [PMID: 15910615]

[25]
Yuan, S.; Liu, Y.; Zhu, L. Vascular complications of diabetes mellitus. Clin. Exp. Pharmacol. Physiol.,  1999, 26(12), 977-978.
 [http://dx.doi.org/10.1046/j.1440-1681.1999.03172.x] [PMID: 10626065]

[26]
Miki, T.; Yuda, S.; Kouzu, H.; Miura, T. Diabetic cardiomyopathy: pathophysiology and clinical features. Heart Fail. Rev.,  2013, 18(2), 149-166.
 [http://dx.doi.org/10.1007/s10741-012-9313-3] [PMID: 22453289]

[27]
Voulgari, C.; Tentolouris, N.; Papadogiannis, D. Diabetic cardiomyopathy: from the pathophysiology of the cardiac myocytes to current diagnosis and management strategies. Vasc. Health Risk Manag.,  2010, 6, 883-903.
 [http://dx.doi.org/10.2147/VHRM.S11681] [PMID: 21057575]

[28]
Asghar, O.; Al-Sunni, A.; Khavandi, K.; Khavandi, A.; Withers, S.; Greenstein, A.; Heagerty, A.M.; Malik, R.A. Diabetic cardiomyopathy. Clin. Sci. (Lond.),  2009, 116(10), 741-760.
 [http://dx.doi.org/10.1042/CS20080500] [PMID: 19364331]

[29]
Adeghate, E. Molecular and cellular basis of the aetiology and management of diabetic cardiomyopathy: A short review. Mol. Cell. Biochem.,  2004, 261(1), 187-191.
 [http://dx.doi.org/10.1023/B:MCBI.0000028755.86521.11] [PMID: 15362503]

[30]
Rossing, K.; Christensen, P.K.; Hovind, P.; Tarnow, L.; Rossing, P.; Parving, H.H. Progression of nephropathy in type 2 diabetic patients. Kidney Int.,  2004, 66(4), 1596-1605.
 [http://dx.doi.org/10.1111/j.1523-1755.2004.00925.x] [PMID: 15458456]

[31]
Ayodele, O.E.; Alebiosu, C.O.; Salako, B.L. Diabetic nephropathy--a review of the natural history, burden, risk factors and treatment. J. Natl. Med. Assoc.,  2004, 96(11), 1445-1454.
 [PMID: 15586648]

[32]
Campbell, R.C.; Ruggenenti, P.; Remuzzi, G. Proteinuria in diabetic nephropathy: Treatment and evolution. Curr. Diab. Rep.,  2003, 3(6), 497-504.
 [http://dx.doi.org/10.1007/s11892-003-0014-0] [PMID: 14611747]

[33]
Ruggenenti, P.; Perna, A.; Mosconi, L.; Pisoni, R.; Remuzzi, G. Urinary protein excretion rate is the best independent predictor of ESRF in non-diabetic proteinuric chronic nephropathies. Kidney Int.,  1998, 53(5), 1209-1216.
 [http://dx.doi.org/10.1046/j.1523-1755.1998.00874.x] [PMID: 9573535]

[34]
Lewis, E.J.; Hunsicker, L.G.; Bain, R.P.; Rohde, R.D. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N. Engl. J. Med.,  1993, 329(20), 1456-1462.
 [http://dx.doi.org/10.1056/NEJM199311113292004] [PMID: 8413456]

[35]
Wilmer, W.A.; Hebert, L.A.; Lewis, E.J.; Rohde, R.D.; Whittier, F.; Cattran, D.; Levey, A.S.; Lewis, J.B.; Spitalewitz, S.; Blumenthal, S.; Bain, R.P. Remission of nephrotic syndrome in type 1 diabetes: Long-term follow-up of patients in the Captopril Study. Am. J. Kidney Dis.,  1999, 34(2), 308-314.
 [http://dx.doi.org/10.1016/S0272-6386(99)70360-4] [PMID: 10430979]

[36]
Gall, M.A.; Nielsen, F.S.; Smidt, U.M.; Parving, H.H. The course of kidney function in Type 2 (non-insulin-dependent) diabetic patients with diabetic nephropathy. Diabetologia,  1993, 36(10), 1071-1078.
 [http://dx.doi.org/10.1007/BF02374501] [PMID: 8243857]

[37]
Lewis, E.J.; Hunsicker, L.G.; Clarke, W.R.; Berl, T.; Pohl, M.A.; Lewis, J.B.; Ritz, E.; Atkins, R.C.; Rohde, R.; Raz, I. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N. Engl. J. Med.,  2001, 345(12), 851-860.
 [http://dx.doi.org/10.1056/NEJMoa011303] [PMID: 11565517]

[38]
Brenner, B.M.; Cooper, M.E.; de Zeeuw, D.; Keane, W.F.; Mitch, W.E.; Parving, H.H.; Remuzzi, G.; Snapinn, S.M.; Zhang, Z.; Shahinfar, S. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N. Engl. J. Med.,  2001, 345(12), 861-869.
 [http://dx.doi.org/10.1056/NEJMoa011161] [PMID: 11565518]

[39]
Parving, H.H.; Hovind, P.; Rossing, K.; Andersen, S. Evolving strategies for renoprotection: diabetic nephropathy. Curr. Opin. Nephrol. Hypertens.,  2001, 10(4), 515-522.
 [http://dx.doi.org/10.1097/00041552-200107000-00006] [PMID: 11458033]

[40]
Rossing, K.; Schjoedt, K.J.; Smidt, U.M.; Boomsma, F.; Parving, H.H. Beneficial effects of adding spironolactone to recommended antihypertensive treatment in diabetic nephropathy: A randomized, double-masked, cross-over study. Diabetes Care,  2005, 28(9), 2106-2112.
 [http://dx.doi.org/10.2337/diacare.28.9.2106] [PMID: 16123474]

[41]
Campbell, R.; Sangalli, F.; Perticucci, E.; Aros, C.; Viscarra, C.; Perna, A.; Remuzzi, A.; Bertocchi, F.; Fagiani, L.; Remuzzi, G.; Ruggenenti, P. Effects of combined ACE inhibitor and angiotensin II antagonist treatment in human chronic nephropathies. Kidney Int.,  2003, 63(3), 1094-1103.
 [http://dx.doi.org/10.1046/j.1523-1755.2003.00832.x] [PMID: 12631093]

[42]
Control, T.D.; Group, C.D.R. Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial. Kidney Int.,  1995, 47(6), 1703-1720.
 [http://dx.doi.org/10.1038/ki.1995.236] [PMID: 7643540]

[43]
Epstein, M. Aldosterone as a mediator of progressive renal disease: Pathogenetic and clinical implications. Am. J. Kidney Dis.,  2001, 37(4), 677-688.
 [http://dx.doi.org/10.1016/S0272-6386(01)80115-3] [PMID: 11273866]

[44]
Orth, S.R.; Hallan, S.I. Smoking: a risk factor for progression of chronic kidney disease and for cardiovascular morbidity and mortality in renal patients--absence of evidence or evidence of absence? Clin. J. Am. Soc. Nephrol.,  2008, 3(1), 226-236.
 [http://dx.doi.org/10.2215/CJN.03740907] [PMID: 18003763]

[45]
Chuahirun, T.; Wesson, D.E. Cigarette smoking predicts faster progression of type 2 established diabetic nephropathy despite ACE inhibition. Am. J. Kidney Dis.,  2002, 39(2), 376-382.
 [http://dx.doi.org/10.1053/ajkd.2002.30559] [PMID: 11840380]

[46]
Dronavalli, S.; Duka, I.; Bakris, G.L. The pathogenesis of diabetic nephropathy. Nat. Clin. Pract. Endocrinol. Metab.,  2008, 4(8), 444-452.
 [http://dx.doi.org/10.1038/ncpendmet0894] [PMID: 18607402]

[47]
Giuliari, G.P. Diabetic retinopathy: Current and new treatment options. Curr. Diabetes Rev.,  2012, 8(1), 32-41.
 [http://dx.doi.org/10.2174/157339912798829188] [PMID: 22352446]

[48]
Shah, C. Diabetic retinopathy: A comprehensive review. Indian J. Med. Sci.,  2008, 62(12), 500-519.
 [http://dx.doi.org/10.4103/0019-5359.48562] [PMID: 19265246]

[49]
Nathan, D.M.; Genuth, S.; Lachin, J.; Cleary, P.; Crofford, O.; Davis, M.; Rand, L.; Siebert, C. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N. Engl. J. Med.,  1993, 329(14), 977-986.
 [http://dx.doi.org/10.1056/NEJM199309303291401] [PMID: 8366922]

[50]
Group, U.P.D.S. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ,  1998, 317(7160), 703-713.
 [http://dx.doi.org/10.1136/bmj.317.7160.703] [PMID: 9732337]

[51]
Group, U.P.D.S. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet,  1998, 352(9131), 837-853.
 [http://dx.doi.org/10.1016/S0140-6736(98)07019-6] [PMID: 9742976]

[52]
Group, U.P.D.S. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet,  1998, 352(9131), 854-865.
 [http://dx.doi.org/10.1016/S0140-6736(98)07037-8] [PMID: 9742977]

[53]
Patel, A.; MacMahon, S.; Chalmers, J.; Neal, B.; Billot, L.; Woodward, M.; Marre, M.; Cooper, M.; Glasziou, P.; Grobbee, D.; Hamet, P.; Harrap, S.; Heller, S.; Liu, L.; Mancia, G.; Mogensen, C.E.; Pan, C.; Poulter, N.; Rodgers, A.; Williams, B.; Bompoint, S.; de Galan, B.E.; Joshi, R.; Travert, F. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N. Engl. J. Med.,  2008, 358(24), 2560-2572.
 [http://dx.doi.org/10.1056/NEJMoa0802987] [PMID: 18539916]

[54]
Holman, R.R.; Paul, S.K.; Bethel, M.A.; Neil, H.A.W.; Matthews, D.R. Long-term follow-up after tight control of blood pressure in type 2 diabetes. N. Engl. J. Med.,  2008, 359(15), 1565-1576.
 [http://dx.doi.org/10.1056/NEJMoa0806359] [PMID: 18784091]

[55]
Schmidt, W.E.; Siegel, E.G.; Creutzfeldt, W. Glucagon-like peptide-1 but not glucagon-like peptide-2 stimulates insulin release from isolated rat pancreatic islets. Diabetologia,  1985, 28(9), 704-707.
 [http://dx.doi.org/10.1007/BF00291980] [PMID: 3905480]

[56]
Takeda, J.; Seino, Y.; Tanaka, K.; Fukumoto, H.; Kayano, T.; Takahashi, H.; Mitani, T.; Kurono, M.; Suzuki, T.; Tobe, T. Sequence of an intestinal cDNA encoding human gastric inhibitory polypeptide precursor. Proc. Natl. Acad. Sci.,  1987, 84(20), 7005-7008.
 [http://dx.doi.org/10.1073/pnas.84.20.7005] [PMID: 2890159]

[57]
Wilkinson, C.P.; Ferris, F.L., III; Klein, R.E.; Lee, P.P.; Agardh, C.D.; Davis, M.; Dills, D.; Kampik, A.; Pararajasegaram, R.; Verdaguer, J.T. Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Ophthalmology,  2003, 110(9), 1677-1682.
 [http://dx.doi.org/10.1016/S0161-6420(03)00475-5] [PMID: 13129861]

[58]
Gillies, M.; Sutter, F.; Simpson, J.; Larsson, J.; Ali, H.; Zhu, M. Intravitreal triamcinolone for refractory diabetic macular edema: Two-year results of a double-masked, placebo-controlled, randomized clinical trial. Ophthalmology,  2006, 113(9), 1533-1538.
 [http://dx.doi.org/10.1016/j.ophtha.2006.02.065] [PMID: 16828501]

[59]
Bakri, S.J.; Beer, P.M. The effect of intravitreal triamcinolone acetonide on intraocular pressure; Slack Incorporated Thorofare: NJ, 2003, pp. 386-390.

[60]
Michels, S.; Rosenfeld, P.J.; Puliafito, C.A.; Marcus, E.N. Venkatraman, AS Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration: Twelve-week results of an uncontrolled open-label clinical study. Ophthalmology,  2005, 112, 1035-1047.

[61]
Avery, R.L.; Pieramici, D.J.; Rabena, M.D.; Castellarin, A.A.; Ma’an, A.N. Giust, MJ Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology,  2006, 113, 363-372.

[62]
Spaide, R.F.; Laud, K.; Fine, H.F.; Klancnik, J.M., Jr; Meyerle, C.B.; Yannuzzi, L.A.; Sorenson, J.; Slakter, J.; Fisher, Y.L.; Cooney, M.J. Intravitreal bevacizumab treatment of choroidal neovascularization secondary to age-related macular degeneration. Retina,  2006, 26(4), 383-390.
 [http://dx.doi.org/10.1097/01.iae.0000238561.99283.0e] [PMID: 16603955]

[63]
de Laey, J.J. Complications of photocoagulation for diabetic retinopathy. Diabete Metab.,  1993, 19(5), 430-435.
 [PMID: 8056122]

[64]
Ferris, F.L., III; Kleiner, R.C.; Elman, M.J.; Murphy, R.P. Transient severe visual loss after panretinal photocoagulation. Am. J. Ophthalmol.,  1988, 106(3), 298-306.
 [http://dx.doi.org/10.1016/S0002-9394(14)76621-8] [PMID: 3421291]

[65]
Lewis, H.; Schachat, A.P.; Haimann, M.H.; Haller, J.A.; Quinlan, P.; Von Fricken, M.A.; Fine, S.L.; Murphy, R.P. Choroidal neovascularization after laser photocoagulation for diabetic macular edema. Ophthalmology,  1990, 97(4), 503-511.
 [http://dx.doi.org/10.1016/S0161-6420(90)32574-5] [PMID: 1691477]

[66]
Giuliari, G.P.; Guel, D.A.; Cortez, M.A.; Cortez, R.T. Selective and pan-blockade agents in the anti-angiogenic treatment of proliferative diabetic retinopathy: A literature summary. Can. J. Ophthalmol.,  2010, 45(5), 501-508.
 [http://dx.doi.org/10.3129/i10-023] [PMID: 20648074]

[67]
Giuliari, G.; Guel, D.; Gonzalez, V. Pegaptanib sodium for the treatment of proliferative diabetic retinopathy and diabetic macular edema. Curr. Diabetes Rev.,  2009, 5(1), 33-38.
 [http://dx.doi.org/10.2174/157339909787314158] [PMID: 19199896]

[68]
Fong, D.S.; Aiello, L.; Gardner, T.W.; King, G.L.; Blankenship, G.; Cavallerano, J.D.; Ferris, F.L., III; Klein, R.; Association, A.D. Retinopathy in diabetes. Diabetes Care,  2004, 27(S1), s84-s87.
 [http://dx.doi.org/10.2337/diacare.27.2007.S84] [PMID: 14693935]

[69]
Haller, J.A.; Qin, H.; Apte, R.S.; Beck, R.R.; Bressler, N.M.; Browning, D.J.; Danis, R.P.; Glassman, A.R.; Googe, J.M.; Kollman, C.; Lauer, A.K.; Peters, M.A.; Stockman, M.E. Vitrectomy outcomes in eyes with diabetic macular edema and vitreomacular traction. Ophthalmology,  2010, 117(6), 1087-1093.e3.
 [http://dx.doi.org/10.1016/j.ophtha.2009.10.040] [PMID: 20299105]

[70]
Said, G. Diabetic neuropathy—a review. Nat. Clin. Pract. Neurol.,  2007, 3(6), 331-340.
 [http://dx.doi.org/10.1038/ncpneuro0504] [PMID: 17549059]

[71]
Martin, C.L.; Albers, J.; Herman, W.H.; Cleary, P.; Waberski, B.; Greene, D.A.; Stevens, M.J.; Feldman, E.L. Neuropathy among the diabetes control and complications trial cohort 8 years after trial completion. Diabetes Care,  2006, 29(2), 340-344.
 [http://dx.doi.org/10.2337/diacare.29.02.06.dc05-1549] [PMID: 16443884]

[72]
Giurini, J.M.; Rosenblum, B.I.; Lyons, T.E. Management of the diabetic foot. Clinical Management of Diabetic Neuropathy; Springer, 1998, pp. 303-318.
 [http://dx.doi.org/10.1007/978-1-4612-1816-6_19]

[73]
Navarro, X.; Sutherland, D.E.R.; Kennedy, W.R. Long-term effects of pancreatic transplantation on diabetic neuropathy. Ann. Neurol.,  1997, 42(5), 727-736.
 [http://dx.doi.org/10.1002/ana.410420509] [PMID: 9392572]

[74]
Said, G.; Lacroix, C.; Lozeron, P.; Ropert, A.; Planté, V.; Adams, D. Inflammatory vasculopathy in multifocal diabetic neuropathy. Brain,  2003, 126(2), 376-385.
 [http://dx.doi.org/10.1093/brain/awg029] [PMID: 12538404]

[75]
Ozougwu, O.; Obimba, K.; Belonwu, C.; Unakalamba, C. The pathogenesis and pathophysiology of type 1 and type 2 diabetes mellitus. J. Physiol. Pathophysiol.,  2013, 4(4), 46-57.
 [http://dx.doi.org/10.5897/JPAP2013.0001]

[76]
Prabhakar, P.; Doble, M. A target based therapeutic approach towards diabetes mellitus using medicinal plants. Curr. Diabetes Rev.,  2008, 4(4), 291-308.
 [http://dx.doi.org/10.2174/157339908786241124] [PMID: 18991598]

[77]
Bastaki, S. Diabetes mellitus and its treatment. Dubai Diabetes And Endocrinology Journal.,  2005, 13(3), 111-134.

[78]
Shlossman, M.; Knowler, W.C.; Pettitt, D.J.; Genco, R.J. Type 2 diabetes mellitus and periodontal disease. J. Am. Dent. Assoc.,  1990, 121(4), 532-536.
 [http://dx.doi.org/10.14219/jada.archive.1990.0211] [PMID: 2212346]

[79]
Kim, Y.D.; Park, K.G.; Lee, Y.S.; Park, Y.Y.; Kim, D.K.; Nedumaran, B.; Jang, W.G.; Cho, W.J.; Ha, J.; Lee, I.K.; Lee, C.H.; Choi, H.S. Metformin inhibits hepatic gluconeogenesis through AMP-activated protein kinase-dependent regulation of the orphan nuclear receptor SHP. Diabetes,  2008, 57(2), 306-314.
 [http://dx.doi.org/10.2337/db07-0381] [PMID: 17909097]

[80]
Collier, C.A.; Bruce, C.R.; Smith, A.C.; Lopaschuk, G.; Dyck, D.J. Metformin counters the insulin-induced suppression of fatty acid oxidation and stimulation of triacylglycerol storage in rodent skeletal muscle. Am. J. Physiol. Endocrinol. Metab.,  2006, 291(1), E182-E189.
 [http://dx.doi.org/10.1152/ajpendo.00272.2005] [PMID: 16478780]

[81]
Chiniwala, N.; Jabbour, S. Management of diabetes mellitus in the elderly. Curr. Opin. Endocrinol. Diabetes Obes.,  2011, 18(2), 148-152.
 [http://dx.doi.org/10.1097/MED.0b013e3283444ba0] [PMID: 21522002]

[82]
Van Staa, T.; Abenhaim, L.; Monette, J. Rates of hypoglycemia in users of sulfonylureas. J. Clin. Epidemiol.,  1997, 50(6), 735-741.
 [http://dx.doi.org/10.1016/S0895-4356(97)00024-3] [PMID: 9250272]

[83]
Shorr, R.I.; Ray, W.A.; Daugherty, J.R.; Griffin, M.R. Individual sulfonylureas and serious hypoglycemia in older people. J. Am. Geriatr. Soc.,  1996, 44(7), 751-755.
 [http://dx.doi.org/10.1111/j.1532-5415.1996.tb03729.x] [PMID: 8675920]

[84]
Fuhlendorff, J.; Rorsman, P.; Kofod, H.; Brand, C.L.; Rolin, B.; MacKay, P.; Shymko, R.; Carr, R.D. Stimulation of insulin release by repaglinide and glibenclamide involves both common and distinct processes. Diabetes,  1998, 47(3), 345-351.
 [http://dx.doi.org/10.2337/diabetes.47.3.345] [PMID: 9519738]

[85]
Blicklé, J.F. Meglitinide analogues: a review of clinical data focused on recent trials. Diabetes Metab.,  2006, 32(2), 113-120.
 [http://dx.doi.org/10.1016/S1262-3636(07)70257-4] [PMID: 16735959]

[86]
Yki-Järvinen, H. Thiazolidinediones. N. Engl. J. Med.,  2004, 351(11), 1106-1118.
 [http://dx.doi.org/10.1056/NEJMra041001] [PMID: 15356308]

[87]
Yoon, K.H.; Lee, J.H.; Kim, J.W.; Cho, J.H.; Choi, Y.H.; Ko, S.H.; Zimmet, P.; Son, H.Y. Epidemic obesity and type 2 diabetes in Asia. Lancet,  2006, 368(9548), 1681-1688.
 [http://dx.doi.org/10.1016/S0140-6736(06)69703-1] [PMID: 17098087]

[88]
Coniff, R.F.; Shapiro, J.A.; Seaton, T.B.; Bray, G.A. Multicenter, placebo-controlled trial comparing acarbose (BAY g 5421) with placebo, tolbutamide, and tolbutamide-plus-acarbose in non-insulin-dependent diabetes mellitus. Am. J. Med.,  1995, 98(5), 443-451.
 [http://dx.doi.org/10.1016/S0002-9343(99)80343-X] [PMID: 7733122]

[89]
Kim, W.; Egan, J.M. The role of incretins in glucose homeostasis and diabetes treatment. Pharmacol. Rev.,  2008, 60(4), 470-512.
 [http://dx.doi.org/10.1124/pr.108.000604] [PMID: 19074620]

[90]
Group, E.T.D.R.S.R. Treatment techniques and clinical guidelines for photocoagulation of diabetic macular edema. Early Treatment Diabetic Retinopathy Study Report Number 2. Ophthalmology,  1987, 94(7), 761-774.
 [http://dx.doi.org/10.1016/S0161-6420(87)33527-4] [PMID: 3658348]

[91]
Brown, J.C.; Dryburgh, J.R.; Ross, S.A.; Dupre, J. Identification and actions of gastric inhibitory polypeptide. Recent Prog. Horm. Res.,  1975, 31, 487-532.
 [http://dx.doi.org/10.1016/b978-0-12-571131-9]

[92]
Dupre, J.; Ross, S.A.; Watson, D.; Brown, J.C. Stimulation of insulin secretion by gastric inhibitory polypeptide in man. J. Clin. Endocrinol. Metab.,  1973, 37(5), 826-828.
 [http://dx.doi.org/10.1210/jcem-37-5-826] [PMID: 4749457]

[93]
Yip, R.G.C.; Wolfe, M.M. GIF biology and fat metabolism. Life Sci.,  1999, 66(2), 91-103.
 [http://dx.doi.org/10.1016/S0024-3205(99)00314-8] [PMID: 10666005]

[94]
Lynn, F.C.; Pamir, N.; Ng, E.H.C.; McIntosh, C.H.S.; Kieffer, T.J.; Pederson, R.A. Defective glucose-dependent insulinotropic polypeptide receptor expression in diabetic fatty Zucker rats. Diabetes,  2001, 50(5), 1004-1011.
 [http://dx.doi.org/10.2337/diabetes.50.5.1004] [PMID: 11334402]

[95]
Ross, S.A.; Brown, J.C.; Dupré, J. Hypersecretion of gastric inhibitory polypeptide following oral glucose in diabetes mellitus. Diabetes,  1977, 26(6), 525-529.
 [http://dx.doi.org/10.2337/diab.26.6.525] [PMID: 324834]

[96]
Vilsbøll, T.; Krarup, T.; Deacon, C.F.; Madsbad, S.; Holst, J.J. Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes,  2001, 50(3), 609-613.
 [http://dx.doi.org/10.2337/diabetes.50.3.609] [PMID: 11246881]

[97]
Zhou, J.; Livak, M.F.A.; Bernier, M.; Muller, D.C.; Carlson, O.D.; Elahi, D.; Maudsley, S.; Egan, J.M. Ubiquitination is involved in glucose-mediated downregulation of GIP receptors in islets. Am. J. Physiol. Endocrinol. Metab.,  2007, 293(2), E538-E547.
 [http://dx.doi.org/10.1152/ajpendo.00070.2007] [PMID: 17505054]

[98]
Drucker, D.J.; Nauck, M.A. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet,  2006, 368(9548), 1696-1705.
 [http://dx.doi.org/10.1016/S0140-6736(06)69705-5] [PMID: 17098089]

[99]
Bell, G.I.; Santerre, R.F.; Mullenbach, G.T. Hamster preproglucagon contains the sequence of glucagon and two related peptides. Nature,  1983, 302(5910), 716-718.
 [http://dx.doi.org/10.1038/302716a0] [PMID: 6835407]

[100]
Zhu, X.; Zhou, A.; Dey, A.; Norrbom, C.; Carroll, R.; Zhang, C.; Laurent, V.; Lindberg, I.; Ugleholdt, R.; Holst, J.J.; Steiner, D.F. Disruption of PC1/3 expression in mice causes dwarfism and multiple neuroendocrine peptide processing defects. Proc. Natl. Acad. Sci.,  2002, 99(16), 10293-10298.
 [http://dx.doi.org/10.1073/pnas.162352599] [PMID: 12145326]

[101]
Group, E.T.D.R.S.R. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch. Ophthalmol.,  1985, 103(12), 1796-1806.
 [http://dx.doi.org/10.1001/archopht.1985.01050120030015] [PMID: 2866759]

[102]
Doyle, M.E.; Egan, J.M. Mechanisms of action of glucagon-like peptide 1 in the pancreas. Pharmacol. Ther.,  2007, 113(3), 546-593.
 [http://dx.doi.org/10.1016/j.pharmthera.2006.11.007] [PMID: 17306374]

[103]
Holz, G.G., IV; Kühtreiber, W.M.; Habener, J.F. Pancreatic beta-cells are rendered glucose-competent by the insulinotropic hormone glucagon-like peptide-1(7-37). Nature,  1993, 361(6410), 362-365.
 [http://dx.doi.org/10.1038/361362a0] [PMID: 8381211]

[104]
Zander, M.; Madsbad, S.; Madsen, J.L.; Holst, J.J. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and β-cell function in type 2 diabetes: a parallel-group study. Lancet,  2002, 359(9309), 824-830.
 [http://dx.doi.org/10.1016/S0140-6736(02)07952-7] [PMID: 11897280]

[105]
Abbas, G.; Haq, Q.M.I.; Hamaed, A.; Al-Sibani, M.; Hussain, H. Glucagon and glucagon-like peptide-1 receptors: Promising therapeutic targets for an effective management of diabetes mellitus. Curr. Pharm. Des.,  2020, 26(4), 501-508.
 [http://dx.doi.org/10.2174/1381612826666200131143231] [PMID: 32003684]

[106]
Kaushal, S.; Chopra, S.C.; Arora, S. Exenatide: An incretin-mimetic agent. Indian J. Pharmacol.,  2006, 38(1), 76.
 [http://dx.doi.org/10.4103/0253-7613.19864]

[107]
Samat, AG; Bhargava, A; Reddy, V A review of exenatide in the treatment of type 2 diabetes mellitus clinical medicine insights: therapeutics 2: CMT. 2010, S3489

[108]
Triplitt, C.; Chiquette, E. Exenatide: from the Gila monster to the pharmacy. J. Am. Pharm. Assoc.,  2006, 46(1), 44-55.
 [http://dx.doi.org/10.1331/154434506775268698] [PMID: 16529340]

[109]
Fala, L. Tanzeum (Albiglutide): a once-weekly GLP-1 receptor agonist subcutaneous injection approved for the treatment of patients with type 2. diabetes. Am. Health Drug Benefits, ,  2015, 8(Spec Feature), 126-130.
 [PMID: 26629277]

[110]
Werner, U.; Haschke, G.; Herling, A.W.; Kramer, W. Pharmacological profile of lixisenatide: A new GLP-1 receptor agonist for the treatment of type 2 diabetes. Regul. Pept.,  2010, 164(2-3), 58-64.
 [http://dx.doi.org/10.1016/j.regpep.2010.05.008] [PMID: 20570597]

[111]
Mannucci, E.; Lamanna, C. Incretins and the specific mechanism of action of liraglutide, the first applicable human glucagon-like peptide 1 analog in the treatment of type 2 diabetes. J. Receptor Ligand Channel Res.,  2010, 3, 105.
 [http://dx.doi.org/10.2147/JRLCR.S6345]

[112]
Sanford, M. Dulaglutide: first global approval. Drugs,  2014, 74(17), 2097-2103.
 [http://dx.doi.org/10.1007/s40265-014-0320-7] [PMID: 25367716]

[113]
Deacon, C.F. Dipeptidyl peptidase 4 inhibitors in the treatment of type 2 diabetes mellitus. Nat. Rev. Endocrinol.,  2020, 16(11), 642-653.
 [http://dx.doi.org/10.1038/s41574-020-0399-8] [PMID: 32929230]

[114]
Ahrén, B. DPP-4 inhibitors. Best Pract. Res. Clin. Endocrinol. Metab.,  2007, 21(4), 517-533.
 [http://dx.doi.org/10.1016/j.beem.2007.07.005] [PMID: 18054733]

[115]
Scott, L.J. Sitagliptin: a review in type 2 diabetes. Drugs,  2017, 77(2), 209-224.
 [http://dx.doi.org/10.1007/s40265-016-0686-9] [PMID: 28078647]

[116]
Dhillon, S. Sitagliptin. Drugs,  2010, 70(4), 489-512.
 [http://dx.doi.org/10.2165/11203790-000000000-00000] [PMID: 20205490]

[117]
Plosker, G.L. Sitagliptin: a review of its use in patients with type 2 diabetes mellitus. Drugs,  2014, 74(2), 223-242.
 [http://dx.doi.org/10.1007/s40265-013-0169-1] [PMID: 24407560]

[118]
Scherer, P.E.; Hill, J.A. Obesity, diabetes, and cardiovascular diseases: a compendium; Am Heart Assoc, 2016, pp. 1703-1705.

[119]
Association, A.D. 8. Cardiovascular disease and risk management. Diabetes Care,  2016, 39(Suppl. 1), S60-S71.
 [http://dx.doi.org/10.2337/dc16-S011] [PMID: 26696684]

[120]
Ahrén, B. What mediates the benefits associated with dipeptidyl peptidase-IV inhibition? Diabetologia,  2005, 48(4), 605-607.
 [http://dx.doi.org/10.1007/s00125-005-1706-6] [PMID: 15770467]

[121]
Ahrén, B.; Schweizer, A.; Dejager, S.; Villhauer, E.B.; Dunning, B.E.; Foley, J.E. Mechanisms of action of the dipeptidyl peptidase-4 inhibitor vildagliptin in humans. Diabetes Obes. Metab.,  2011, 13(9), 775-783.
 [http://dx.doi.org/10.1111/j.1463-1326.2011.01414.x] [PMID: 21507182]

[122]
Pratley, R.E.; Schweizer, A.; Rosenstock, J.; Foley, J.E.; Banerji, M.A.; Pi-Sunyer, F.X.; Mills, D.; Dejager, S. Robust improvements in fasting and prandial measures of β-cell function with vildagliptin in drug-naïve patients: analysis of pooled vildagliptin monotherapy database. Diabetes Obes. Metab.,  2008, 10(10), 931-938.
 [http://dx.doi.org/10.1111/j.1463-1326.2007.00835.x] [PMID: 18093207]

[123]
Ahrén, B.; Pacini, G.; Tura, A.; Foley, J.; Schweizer, A. Improved meal-related insulin processing contributes to the enhancement of B-cell function by the DPP-4 inhibitor vildagliptin in patients with type 2 diabetes. Horm. Metab. Res.,  2007, 39(11), 826-829.
 [http://dx.doi.org/10.1055/s-2007-991172] [PMID: 17992639]

[124]
El-Ouaghlidi, A.; Rehring, E.; Holst, J.J.; Schweizer, A.; Foley, J.; Holmes, D.; Nauck, M.A. The dipeptidyl peptidase 4 inhibitor vildagliptin does not accentuate glibenclamide-induced hypoglycemia but reduces glucose-induced glucagon-like peptide 1 and gastric inhibitory polypeptide secretion. J. Clin. Endocrinol. Metab.,  2007, 92(11), 4165-4171.
 [http://dx.doi.org/10.1210/jc.2006-1932] [PMID: 17698900]

[125]
He, Y.L.; Wang, Y.; Bullock, J.M.; Deacon, C.F.; Holst, J.J.; Dunning, B.E.; Ligueros-Saylan, M.; Foley, J.E. Pharmacodynamics of vildagliptin in patients with type 2 diabetes during OGTT. J. Clin. Pharmacol.,  2007, 47(5), 633-641.
 [http://dx.doi.org/10.1177/0091270006299137] [PMID: 17442688]

[126]
Vardarli, I.; Nauck, M.A.; Köthe, L.D.; Deacon, C.F.; Holst, J.J.; Schweizer, A.; Foley, J.E. Inhibition of DPP-4 with vildagliptin improved insulin secretion in response to oral as well as “isoglycemic” intravenous glucose without numerically changing the incretin effect in patients with type 2 diabetes. J. Clin. Endocrinol. Metab.,  2011, 96(4), 945-954.
 [http://dx.doi.org/10.1210/jc.2010-2178] [PMID: 21239518]

[127]
Scheen, A.J. Linagliptin for the treatment of type 2 diabetes (pharmacokinetic evaluation). Expert Opin. Drug Metab. Toxicol.,  2011, 7(12), 1561-1576.
 [http://dx.doi.org/10.1517/17425255.2011.628986] [PMID: 22022857]

[128]
Cobble, M.E.; Frederich, R. Saxagliptin for the treatment of type 2 diabetes mellitus: assessing cardiovascular data. Cardiovasc. Diabetol.,  2012, 11(1), 6.
 [http://dx.doi.org/10.1186/1475-2840-11-6] [PMID: 22248301]

[129]
Pratley, R.E. Alogliptin: a new, highly selective dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes. Expert Opin. Pharmacother.,  2009, 10(3), 503-512.
 [http://dx.doi.org/10.1517/14656560802694713] [PMID: 19191685]

[130]
White, W.B.; Cannon, C.P.; Heller, S.R.; Nissen, S.E.; Bergenstal, R.M.; Bakris, G.L.; Perez, A.T.; Fleck, P.R.; Mehta, C.R.; Kupfer, S.; Wilson, C.; Cushman, W.C.; Zannad, F. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N. Engl. J. Med.,  2013, 369(14), 1327-1335.
 [http://dx.doi.org/10.1056/NEJMoa1305889] [PMID: 23992602]

[131]
Saisho, Y. Alogliptin benzoate for management of type 2 diabetes. Vasc. Health Risk Manag.,  2015, 11, 229-243.
 [http://dx.doi.org/10.2147/VHRM.S68564] [PMID: 25914541]

[132]
Seino, Y.; Fujita, T.; Hiroi, S.; Hirayama, M.; Kaku, K. Efficacy and safety of alogliptin in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, dose-ranging comparison with placebo, followed by a long-term extension study. Curr. Med. Res. Opin.,  2011, 27(9), 1781-1792.
 [http://dx.doi.org/10.1185/03007995.2011.599371] [PMID: 21806314]

[133]
Li, L.; Li, X.; Xu, L.; Sheng, Y.; Huang, J.; Zheng, Q. Systematic evaluation of dose accumulation studies in clinical pharmacokinetics. Curr. Drug Metab.,  2013, 14(5), 605-615.
 [http://dx.doi.org/10.2174/13892002113149990002] [PMID: 23701162]

[134]
Pattzi, H.M.R.; Pitale, S.; Alpizar, M.; Bennett, C.; O’Farrell, A.M.; Li, J.; Cherrington, J.M.; Guler, H.P.; Group, P.P.S. Dutogliptin, a selective DPP4 inhibitor, improves glycaemic control in patients with type 2 diabetes: A 12-week, double-blind, randomized, placebo-controlled, multicentre trial. Diabetes Obes. Metab.,  2010, 12(4), 348-355.
 [http://dx.doi.org/10.1111/j.1463-1326.2010.01195.x] [PMID: 20380656]

[135]
Johnson, K. Dutogliptin, a dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes mellitus. Curr. Opin. Investig. Drugs,  2010, 11, 455-463.

[136]
Dreyer, C.; Krey, G.; Keller, H.; Givel, F.; Helftenbein, G.; Wahli, W. Control of the peroxisomal β-oxidation pathway by a novel family of nuclear hormone receptors. Cell,  1992, 68(5), 879-887.
 [http://dx.doi.org/10.1016/0092-8674(92)90031-7] [PMID: 1312391]

[137]
Grygiel-Górniak, B. Peroxisome proliferator-activated receptors and their ligands: nutritional and clinical implications - a review. Nutr. J.,  2014, 13(1), 17.
 [http://dx.doi.org/10.1186/1475-2891-13-17] [PMID: 24524207]

[138]
Jay, M.; Ren, J. Peroxisome proliferator-activated receptor (PPAR) in metabolic syndrome and type 2 diabetes mellitus. Curr. Diabetes Rev.,  2007, 3(1), 33-39.
 [http://dx.doi.org/10.2174/157339907779802067] [PMID: 18220654]

[139]
Tai, E.S.; Collins, D.; Robins, S.J.; O’Connor, J.J., Jr; Bloomfield, H.E.; Ordovas, J.M.; Schaefer, E.J.; Brousseau, M.E. The L162V polymorphism at the peroxisome proliferator activated receptor alpha locus modulates the risk of cardiovascular events associated with insulin resistance and diabetes mellitus: The Veterans Affairs HDL Intervention Trial (VA-HIT). Atherosclerosis,  2006, 187(1), 153-160.
 [http://dx.doi.org/10.1016/j.atherosclerosis.2005.08.034] [PMID: 16221474]

[140]
Pourcet, B.; Fruchart, J.C.; Staels, B.; Glineur, C. Selective PPAR modulators, dual and pan PPAR agonists: Multimodal drugs for the treatment of Type 2 diabetes and atherosclerosis. Expert Opin. Emerg. Drugs,  2006, 11(3), 379-401.
 [http://dx.doi.org/10.1517/14728214.11.3.379] [PMID: 16939380]

[141]
Dowarah, J.; Singh, V.P. Anti-diabetic drugs recent approaches and advancements. Bioorg. Med. Chem.,  2020, 28(5), 115263.
 [http://dx.doi.org/10.1016/j.bmc.2019.115263] [PMID: 32008883]

[142]
Etgen, G.J.; Oldham, B.A.; Johnson, W.T.; Broderick, C.L.; Montrose, C.R.; Brozinick, J.T.; Misener, E.A.; Bean, J.S.; Bensch, W.R.; Brooks, D.A.; Shuker, A.J.; Rito, C.J.; McCarthy, J.R.; Ardecky, R.J.; Tyhonas, J.S.; Dana, S.L.; Bilakovics, J.M.; Paterniti, J.R., Jr; Ogilvie, K.M.; Liu, S.; Kauffman, R.F. A tailored therapy for the metabolic syndrome: the dual peroxisome proliferator-activated receptor-α/γ agonist LY465608 ameliorates insulin resistance and diabetic hyperglycemia while improving cardiovascular risk factors in preclinical models. Diabetes,  2002, 51(4), 1083-1087.
 [http://dx.doi.org/10.2337/diabetes.51.4.1083] [PMID: 11916929]

[143]
Chakrabarti, R.; Vikramadithyan, R.K.; Misra, P.; Hiriyan, J.; Raichur, S.; Damarla, R.K.; Gershome, C.; Suresh, J.; Rajagopalan, R. Ragaglitazar: a novel PPAR α & PPAR γ agonist with potent lipid-lowering and insulin-sensitizing efficacy in animal models. Br. J. Pharmacol.,  2003, 140(3), 527-537.
 [http://dx.doi.org/10.1038/sj.bjp.0705463] [PMID: 12970088]

[144]
Mamnoor, P.; Hegde, P.; Datla, S.; Damarla, R.; Rajagopalan, R.; Chakrabarti, R. Antihypertensive effect of ragaglitazar: A novel PPARα and γ dual activator. Pharmacol. Res.,  2006, 54(2), 129-135.
 [http://dx.doi.org/10.1016/j.phrs.2006.03.020] [PMID: 16651004]

[145]
Zhang, B.C.; Li, W.M.; Li, X.K.; Zhu, M.Y.; Che, W.L.; Xu, Y.W. Tesaglitazar ameliorates non-alcoholic fatty liver disease and atherosclerosis development in diabetic low-density lipoprotein receptor-deficient mice. Exp. Ther. Med.,  2012, 4(6), 987-992.
 [http://dx.doi.org/10.3892/etm.2012.713] [PMID: 23226761]

[146]
Buse, J.B.; Rubin, C.J.; Frederich, R.; Viraswami-Appanna, K.; Lin, K.C.; Montoro, R.; Shockey, G.; Davidson, J.A. Muraglitazar, a dual (α/γ) PPAR activator: A randomized, double-blind, placebo-controlled, 24-week monotherapy trial in adult patients with type 2 diabetes. Clin. Ther.,  2005, 27(8), 1181-1195.
 [http://dx.doi.org/10.1016/j.clinthera.2005.08.005] [PMID: 16199244]

[147]
Kim, S.G.; Kim, D.M.; Woo, J.T.; Jang, H.C.; Chung, C.H.; Ko, K.S.; Park, J.H.; Park, Y.S.; Kim, S.J.; Choi, D.S. Efficacy and safety of lobeglitazone monotherapy in patients with type 2 diabetes mellitus over 24-weeks: A multicenter, randomized, double-blind, parallel-group, placebo controlled trial. PLoS One,  2014, 9(4), e92843.
 [http://dx.doi.org/10.1371/journal.pone.0092843] [PMID: 24736628]

[148]
Jang, J.Y.; Bae, H.; Lee, Y.J.; Choi, Y.I.; Kim, H.J.; Park, S.B.; Suh, S.W.; Kim, S.W.; Han, B.W. Structural basis for the enhanced anti-diabetic efficacy of lobeglitazone on PPARγ. Sci. Rep.,  2018, 8(1), 31.
 [http://dx.doi.org/10.1038/s41598-017-18274-1]

[149]
Mittermayer, F.; Caveney, E.; De Oliveira, C.; Gourgiotis, L.; Puri, M.; Tai, L.J.; Turner, J.R. Addressing unmet medical needs in type 2 diabetes: a narrative review of drugs under development. Curr. Diabetes Rev.,  2015, 11(1), 17-31.
 [http://dx.doi.org/10.2174/1573399810666141224121927] [PMID: 25537454]

[150]
Lee, H.S.; Chang, M.; Lee, J.E.; Kim, W.; Hwang, I.C.; Kim, D.H.; Park, H.K.; Choi, H.J.; Jo, W.; Cha, S.W.; Son, W.C. Carcinogenicity study of CKD-501, a novel dual peroxisome proliferator-activated receptors α and γ agonist, following oral administration to Sprague Dawley rats for 94–101weeks. Regul. Toxicol. Pharmacol.,  2014, 69(2), 207-216.
 [http://dx.doi.org/10.1016/j.yrtph.2014.04.003] [PMID: 24747398]

[151]
Kim, S.H.; Kim, S.G.; Kim, D.M.; Woo, J.T.; Jang, H.C.; Chung, C.H.; Ko, K.S.; Park, J.H.; Park, Y.S.; Kim, S.J.; Choi, D.S. Safety and efficacy of lobeglitazone monotherapy in patients with type 2 diabetes mellitus over 52 weeks: An open-label extension study. Diabetes Res. Clin. Pract.,  2015, 110(3), e27-e30.
 [http://dx.doi.org/10.1016/j.diabres.2015.09.009] [PMID: 26458774]

[152]
Shin, D.; Kim, T.E.; Yoon, S.H.; Cho, J.Y.; Shin, S.G.; Jang, I.J.; Yu, K.S. Assessment of the pharmacokinetics of co-administered metformin and lobeglitazone, a thiazolidinedione antihyperglycemic agent, in healthy subjects. Curr. Med. Res. Opin.,  2012, 28(7), 1213-1220.
 [http://dx.doi.org/10.1185/03007995.2012.703131] [PMID: 22697273]

[153]
Wright, E.M. Renal Na+-glucose cotransporters. Am. J. Physiol. Renal Physiol.,  2001, 280(1), F10-F18.
 [http://dx.doi.org/10.1152/ajprenal.2001.280.1.F10] [PMID: 11133510]

[154]
Lee, Y.J.; Lee, Y.J.; Han, H.J. Regulatory mechanisms of Na+/glucose cotransporters in renal proximal tubule cells. Kidney Int.,  2007, 72(106), S27-S35.
 [http://dx.doi.org/10.1038/sj.ki.5002383] [PMID: 17653207]

[155]
Nauck, M. Update on developments with SGLT2 inhibitors in the management of type 2 diabetes. Drug Des. Devel. Ther.,  2014, 8, 1335-1380.
 [http://dx.doi.org/10.2147/DDDT.S50773] [PMID: 25246775]

[156]
Handlon, A.L. Sodium glucose co-transporter 2 (SGLT2) inhibitors as potential antidiabetic agents. Expert Opin. Ther. Pat.,  2005, 15, 1531-1540.

[157]
Kong, Y.K.; Song, K.S.; Jung, M.E.; Kang, M.; Kim, H.J.; Kim, M.J. Discovery of GCC5694A: A potent and selective sodium glucose co-transporter 2 inhibitor for the treatment of type 2 diabetes. Bioorg. Med. Chem. Lett.,  2022, 56, 128466.
 [http://dx.doi.org/10.1016/j.bmcl.2021.128466] [PMID: 34813882]

[158]
Washburn, W.N. Sodium glucose co-transporter 2 (SGLT2) inhibitors: novel antidiabetic agents. Expert Opin. Ther. Pat.,  2012, 22, 483-494.

[159]
Rosenstock, J.; Aggarwal, N.; Polidori, D.; Zhao, Y.; Arbit, D.; Usiskin, K.; Capuano, G.; Canovatchel, W.; Group, C.D.S. Dose-ranging effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to metformin in subjects with type 2 diabetes. Diabetes Care,  2012, 35(6), 1232-1238.
 [http://dx.doi.org/10.2337/dc11-1926] [PMID: 22492586]

[160]
Polidori, D.; Mari, A.; Ferrannini, E. Canagliflozin, a sodium glucose co-transporter 2 inhibitor, improves model-based indices of beta cell function in patients with type 2 diabetes. Diabetologia,  2014, 57(5), 891-901.
 [http://dx.doi.org/10.1007/s00125-014-3196-x] [PMID: 24585202]

[161]
Devineni, D.; Curtin, C.R.; Marbury, T.C.; Smith, W.; Vaccaro, N.; Wexler, D.; Vandebosch, A.; Rusch, S.; Stieltjes, H.; Wajs, E. Effect of hepatic or renal impairment on the pharmacokinetics of canagliflozin, a sodium glucose co-transporter 2 inhibitor. Clin. Ther.,  2015, 37, 610-628.
 [http://dx.doi.org/10.1016/j.clinthera.2014.12.013]

[162]
Yale, J.F.; Bakris, G.; Cariou, B.; Yue, D.; David-Neto, E.; Xi, L.; Figueroa, K.; Wajs, E.; Usiskin, K.; Meininger, G. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes. Metab.,  2013, 15(5), 463-473.
 [http://dx.doi.org/10.1111/dom.12090] [PMID: 23464594]

[163]
Saeed, M.A.; Narendran, P. Dapagliflozin for the treatment of type 2 diabetes: a review of the literature. Drug Des. Devel. Ther.,  2014, 8, 2493-2505.
 [PMID: 25525338]

[164]
Coppenrath, V.A.; Hydery, T. Dapagliflozin/Saxagliptin fixed-dose tablets: a new sodium-glucose cotransporter 2 and dipeptidyl peptidase 4 combination for the treatment of type 2 diabetes. Ann. Pharmacother.,  2018, 52(1), 78-85.
 [http://dx.doi.org/10.1177/1060028017731111] [PMID: 28884600]

[165]
Plosker, G.L. Dapagliflozin: a review of its use in patients with type 2 diabetes. Drugs,  2014, 74(18), 2191-2209.
 [http://dx.doi.org/10.1007/s40265-014-0324-3] [PMID: 25389049]

[166]
Henry, R.R.; Rosenstock, J.; Edelman, S.; Mudaliar, S.; Chalamandaris, A.G.; Kasichayanula, S.; Bogle, A.; Iqbal, N.; List, J.; Griffen, S.C. Exploring the potential of the SGLT2 inhibitor dapagliflozin in type 1 diabetes: a randomized, double-blind, placebo-controlled pilot study. Diabetes Care,  2015, 38(3), 412-419.
 [http://dx.doi.org/10.2337/dc13-2955] [PMID: 25271207]

[167]
Levine, M.J. Empagliflozin for type 2 diabetes mellitus: an overview of phase 3 clinical trials. Curr. Diabetes Rev.,  2017, 13(4), 405-423.
 [PMID: 27296042]

[168]
Scheen, A.J. Empagliflozin (Jardiance):Nw Sglt2 Cotransporter Inhibitor For Treating Type 2 Diabetes. Rev. Med. Liege,  2015, 70(9), 472-479.
 [PMID: 26638450]

[169]
Komiya, C.; Tsuchiya, K.; Shiba, K.; Miyachi, Y.; Furuke, S.; Shimazu, N.; Yamaguchi, S.; Kanno, K.; Ogawa, Y. Ipragliflozin improves hepatic steatosis in obese mice and liver dysfunction in type 2 diabetic patients irrespective of body weight reduction. PLoS One,  2016, 11(3), e0151511.
 [http://dx.doi.org/10.1371/journal.pone.0151511] [PMID: 26977813]

[170]
Kashiwagi, A.; Takahashi, H.; Ishikawa, H.; Yoshida, S.; Kazuta, K.; Utsuno, A.; Ueyama, E. A randomized, double-blind, placebo-controlled study on long-term efficacy and safety of ipragliflozin treatment in patients with type 2 diabetes mellitus and renal impairment: results of the Long-Term ASP1941 Safety Evaluation in Patients with Type 2 Diabetes with Renal Impairment (LANTERN) study. Diabetes Obes. Metab.,  2015, 17(2), 152-160.
 [http://dx.doi.org/10.1111/dom.12403] [PMID: 25347938]

[171]
Ferrannini, E.; Veltkamp, S.A.; Smulders, R.A.; Kadokura, T. Renal glucose handling: Impact of chronic kidney disease and sodium-glucose cotransporter 2 inhibition in patients with type 2 diabetes. Diabetes Care,  2013, 36(5), 1260-1265.
 [http://dx.doi.org/10.2337/dc12-1503] [PMID: 23359360]

[172]
Kakinuma, H.; Oi, T.; Hashimoto-Tsuchiya, Y.; Arai, M.; Kawakita, Y.; Fukasawa, Y.; Iida, I.; Hagima, N.; Takeuchi, H.; Chino, Y.; Asami, J.; Okumura-Kitajima, L.; Io, F.; Yamamoto, D.; Miyata, N.; Takahashi, T.; Uchida, S.; Yamamoto, K. (1S)-1,5-anhydro-1-[5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio-D-glucitol (TS-071) is a potent, selective sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for type 2 diabetes treatment. J. Med. Chem.,  2010, 53(8), 3247-3261.
 [http://dx.doi.org/10.1021/jm901893x] [PMID: 20302302]

[173]
Yamamoto, K.; Uchida, S.; Kitano, K.; Fukuhara, N.; Okumura-Kitajima, L.; Gunji, E.; Kozakai, A.; Tomoike, H.; Kojima, N.; Asami, J.; Toyoda, H.; Arai, M.; Takahashi, T.; Takahashi, K. TS-071 is a novel, potent and selective renal sodium-glucose cotransporter 2 (SGLT2) inhibitor with anti-hyperglycaemic activity. Br. J. Pharmacol.,  2011, 164(1), 181-191.
 [http://dx.doi.org/10.1111/j.1476-5381.2011.01340.x] [PMID: 21410690]

[174]
Seino, Y.; Inagaki, N.; Haneda, M.; Kaku, K.; Sasaki, T.; Fukatsu, A.; Ubukata, M.; Sakai, S.; Samukawa, Y. Efficacy and safety of luseogliflozin added to various oral antidiabetic drugs in Japanese patients with type 2 diabetes mellitus. J. Diabetes Investig.,  2015, 6(4), 443-453.
 [http://dx.doi.org/10.1111/jdi.12316] [PMID: 26221523]

[175]
van de Laar, F.A. Lucassen, P.L.; Akkermans, R.P.; van de Lisdonk, E.H.; Rutten, G.E.; van Weel, C. α-glucosidase inhibitors for patients with type 2 diabetes: results from a Cochrane systematic review and meta-analysis. Diabetes Care,  2005, 28(1), 154-163.
 [http://dx.doi.org/10.2337/diacare.28.1.154] [PMID: 15616251]

[176]
Hossain, U.; Das, A.K.; Ghosh, S.; Sil, P.C. An overview on the role of bioactive α-glucosidase inhibitors in ameliorating diabetic complications. Food Chem. Toxicol.,  2020, 145, 111738.
 [http://dx.doi.org/10.1016/j.fct.2020.111738] [PMID: 32916220]

[177]
Li, Z.; Zhao, L.; Yu, L.; Yang, J. Head-to-Head comparison of the hypoglycemic efficacy and safety between dipeptidyl peptidase-4 inhibitors and α-glucosidase inhibitors in patients with type 2 diabetes mellitus: a meta-analysis of randomized controlled trials. Front. Pharmacol.,  2019, 10, 777.
 [http://dx.doi.org/10.3389/fphar.2019.00777] [PMID: 31354492]

[178]
Usman, B.; Sharma, N.; Satija, S.; Mehta, M.; Vyas, M.; Khatik, G.L.; Khurana, N.; Hansbro, P.M.; Williams, K.; Dua, K. Recent developments in alpha-glucosidase inhibitors for management of type-2 diabetes: An update. Curr. Pharm. Des.,  2019, 25(23), 2510-2525.
 [http://dx.doi.org/10.2174/1381612825666190717104547] [PMID: 31333110]

[179]
Lebovitz, H.E. alpha-Glucosidase inhibitors. Endocrinol. Metab. Clin. North Am.,  1997, 26(3), 539-551.
 [http://dx.doi.org/10.1016/S0889-8529(05)70266-8] [PMID: 9314014]

[180]
Khalifa, M.M.; Sakr, H.M.; Ibrahim, A.; Mansour, A.M.; Ayyad, R.R. Design and synthesis of new benzylidene-quinazolinone hybrids as potential anti-diabetic agents: in vitro α-glucosidase inhibition, and docking studies. J. Mol. Struct.,  2022, 1250, 131768.
 [http://dx.doi.org/10.1016/j.molstruc.2021.131768]

[181]
Klochkov, V.G.; Bezsonova, E.N.; Dubar, M.; Melekhina, D.D.; Temnov, V.V.; Zaryanova, E.V.; Lozinskaya, N.A.; Babkov, D.A.; Spasov, A.A. Towards multi-target antidiabetic agents: in vitro and in vivo evaluation of 3,5-disubstituted indolin-2-one derivatives as novel α-glucosidase inhibitors. Bioorg. Med. Chem. Lett.,  2022, 55, 128449.
 [http://dx.doi.org/10.1016/j.bmcl.2021.128449] [PMID: 34780899]

[182]
Smith, D.L., Jr; Orlandella, R.M.; Allison, D.B.; Norian, L.A. Diabetes medications as potential calorie restriction mimetics—a focus on the alpha-glucosidase inhibitor acarbose. Geroscience,  2021, 43(3), 1123-1133.
 [http://dx.doi.org/10.1007/s11357-020-00278-x] [PMID: 33006707]

[183]
Zhao, B.; Wu, F.; Han, X.; Zhou, W.; Shi, Q.; Wang, H. Protective effects of acarbose against insulitis in multiple low-dose streptozotocin-induced diabetic mice. Life Sci.,  2020, 263, 118490.
 [http://dx.doi.org/10.1016/j.lfs.2020.118490] [PMID: 32979357]

[184]
Dabhi, A.S.; Bhatt, N.R.; Shah, M.J. Voglibose: An alpha glucosidase inhibitor. J. Clin. Diagn. Res.,  2013, 7(12), 3023-3027.
 [PMID: 24551718]

[185]
Sels, J.P.J.E.; Huijberts, M.S.P.; Wolffenbuttel, B.H.R. Miglitol, a new α-glucosidase inhibitor. Expert Opin. Pharmacother.,  1999, 1(1), 149-156.
 [http://dx.doi.org/10.1517/14656566.1.1.149] [PMID: 11249557]

[186]
Scott, L.J.; Spencer, C.M. Miglitol. Drugs,  2000, 59(3), 521-549.
 [http://dx.doi.org/10.2165/00003495-200059030-00012] [PMID: 10776834]

[187]
Asensio, C.; Muzzin, P.; Rohner-Jeanrenaud, F. Role of glucocorticoids in the physiopathology of excessive fat deposition and insulin resistance. Int. J. Obes.,  2004, 28(S4), S45-S52.
 [http://dx.doi.org/10.1038/sj.ijo.0802856] [PMID: 15592486]

[188]
Ogg, D.; Elleby, B.; Norström, C.; Stefansson, K.; Abrahmsén, L.; Oppermann, U.; Svensson, S. The crystal structure of guinea pig 11β-hydroxysteroid dehydrogenase type 1 provides a model for enzyme-lipid bilayer interactions. J. Biol. Chem.,  2005, 280(5), 3789-3794.
 [http://dx.doi.org/10.1074/jbc.M412463200] [PMID: 15542590]

[189]
Odermatt, A.; Atanasov, A.G.; Balazs, Z.; Schweizer, R.A.S.; Nashev, L.G.; Schuster, D.; Langer, T. Why is 11β-hydroxysteroid dehydrogenase type 1 facing the endoplasmic reticulum lumen? Mol. Cell. Endocrinol.,  2006, 248(1-2), 15-23.
 [http://dx.doi.org/10.1016/j.mce.2005.11.040] [PMID: 16412558]

[190]
Saito, R.; Miki, Y.; Abe, T.; Miyauchi, E.; Abe, J.; Nanamiya, R.; Inoue, C.; Sato, I.; Sasano, H. 11β hydroxysteroid dehydrogenase 1: a new marker for predicting response to immune-checkpoint blockade therapy in non-small-cell lung carcinoma. Br. J. Cancer,  2020, 123(1), 61-71.
 [http://dx.doi.org/10.1038/s41416-020-0837-3] [PMID: 32336752]

[191]
Davani, B.; Portwood, N.; Bryzgalova, G.; Reimer, M.K.; Heiden, T.; Östenson, C.G.; Okret, S.; Ahren, B.; Efendic, S.; Khan, A. Aged transgenic mice with increased glucocorticoid sensitivity in pancreatic β-cells develop diabetes. Diabetes,  2004, 53(Suppl. 1), S51-S59.
 [http://dx.doi.org/10.2337/diabetes.53.2007.S51] [PMID: 14749266]

[192]
Ming, LJ; Yin, ACY Therapeutic effects of glycyrrhizic acid., Natural product communications, 2013. 8, 1934578X1300800335.
 [http://dx.doi.org/10.1177/1934578X1300800335]

[193]
Liu, Y.; Nakagawa, Y.; Wang, Y.; Liu, L.; Du, H.; Wang, W.; Ren, X.; Lutfy, K.; Friedman, T.C. Reduction of hepatic glucocorticoid receptor and hexose-6-phosphate dehydrogenase expression ameliorates diet-induced obesity and insulin resistance in mice. J. Mol. Endocrinol.,  2008, 41(2), 53-64.
 [http://dx.doi.org/10.1677/JME-08-0004] [PMID: 18524870]

[194]
Ghosh, D.; Pletnev, V.Z.; Zhu, D.W.; Wawrzak, Z.; Duax, W.L.; Pangborn, W.; Labrie, F.; Lin, S.X. Structure of human estrogenic 17β-hydroxysteroid dehydrogenase at 2.20 å resolution. Structure,  1995, 3(5), 503-513.
 [http://dx.doi.org/10.1016/S0969-2126(01)00183-6] [PMID: 7663947]

[195]
Lin, S.X.; Han, Q.; Azzi, A.; Zhu, D-W.; Gongloff, A.; Campbell, R.L. 3D-structure of human estrogenic 17β-HSD1: Binding with various steroids. J. Steroid Biochem. Mol. Biol.,  1999, 69(1-6), 425-429.
 [http://dx.doi.org/10.1016/S0960-0760(99)00062-X] [PMID: 10419021]

[196]
Ahmad, F.; Goldstein, B.J. Increased abundance of specific skeletal muscle protein-tyrosine phosphatases in a genetic model of insulin-resistant obesity and diabetes mellitus. Metabolism,  1995, 44(9), 1175-1184.
 [http://dx.doi.org/10.1016/0026-0495(95)90012-8] [PMID: 7666792]

[197]
Dadke, S.S.; Li, H.C.; Kusari, A.B.; Begum, N.; Kusari, J. Elevated expression and activity of protein-tyrosine phosphatase 1B in skeletal muscle of insulin-resistant type II diabetic Goto-Kakizaki rats. Biochem. Biophys. Res. Commun.,  2000, 274(3), 583-589.
 [http://dx.doi.org/10.1006/bbrc.2000.3188] [PMID: 10924321]

[198]
Lam, N.T.; Covey, S.D.; Lewis, J.T.; Oosman, S.; Webber, T.; Hsu, E.C.; Cheung, A.T.; Kieffer, T.J. Leptin resistance following over-expression of protein tyrosine phosphatase 1B in liver. J. Mol. Endocrinol.,  2006, 36(1), 163-174.
 [http://dx.doi.org/10.1677/jme.1.01937] [PMID: 16461936]

[199]
Stuible, M.; Doody, K.M.; Tremblay, M.L. PTP1B and TC-PTP: regulators of transformation and tumorigenesis. Cancer Metastasis Rev.,  2008, 27(2), 215-230.
 [http://dx.doi.org/10.1007/s10555-008-9115-1] [PMID: 18236007]

[200]
Dadke, S.; Chernoff, J. Protein-tyrosine phosphatase 1B mediates the effects of insulin on the actin cytoskeleton in immortalized fibroblasts. J. Biol. Chem.,  2003, 278(42), 40607-40611.
 [http://dx.doi.org/10.1074/jbc.M306772200] [PMID: 12902327]

[201]
Bandyopadhyay, D.; Kusari, A.; Kenner, K.A.; Liu, F.; Chernoff, J.; Gustafson, T.A.; Kusari, J. Protein-tyrosine phosphatase 1B complexes with the insulin receptor in vivo and is tyrosine-phosphorylated in the presence of insulin. J. Biol. Chem.,  1997, 272(3), 1639-1645.
 [http://dx.doi.org/10.1074/jbc.272.3.1639] [PMID: 8999839]

[202]
Kenner, K.A.; Anyanwu, E.; Olefsky, J.M.; Kusari, J. Protein-tyrosine phosphatase 1B is a negative regulator of insulin- and insulin-like growth factor-I-stimulated signaling. J. Biol. Chem.,  1996, 271(33), 19810-19816.
 [http://dx.doi.org/10.1074/jbc.271.33.19810] [PMID: 8702689]

[203]
Zhou, J.; Neidigh, J.; Espinosa, R.; LeBeau, M.; McClain, D. Glutamine: fructose-6-phosphate amidotransferase: chromosomal localization and tissue distribution of mRNA. Hum. Genet.,  1995, 96, 99-101.
 [http://dx.doi.org/10.1007/BF00214194] [PMID: 7607664]

[204]
Johnson, T.O.; Ermolieff, J.; Jirousek, M.R. Protein tyrosine phosphatase 1B inhibitors for diabetes. Nat. Rev. Drug Discov.,  2002, 1(9), 696-709.
 [http://dx.doi.org/10.1038/nrd895] [PMID: 12209150]

[205]
Love, D.C.; Hanover, J.A. The hexosamine signaling pathway: deciphering the “O-GlcNAc code”. Sci. STKE,  2005, 2005(312), re13-re13.
 [http://dx.doi.org/10.1126/stke.3122005re13] [PMID: 16317114]

[206]
McKnight, G.L.; Mudri, S.L.; Mathewes, S.L.; Traxinger, R.R.; Marshall, S.; Sheppard, P.O.; O’Hara, P.J. Molecular cloning, cDNA sequence, and bacterial expression of human glutamine:fructose-6-phosphate amidotransferase. J. Biol. Chem.,  1992, 267(35), 25208-25212.
 [http://dx.doi.org/10.1016/S0021-9258(19)74026-5] [PMID: 1460020]

[207]
García-Salcedo, J.A.; Gijón, P.; Nolan, D.P.; Tebabi, P.; Pays, E. A chromosomal SIR2 homologue with both histone NAD-dependent ADP-ribosyltransferase and deacetylase activities is involved in DNA repair in Trypanosoma brucei. EMBO J.,  2003, 22(21), 5851-5862.
 [http://dx.doi.org/10.1093/emboj/cdg553] [PMID: 14592982]

[208]
Zhou, J.; Neidigh, J.L.; Espinosa, R., III; LeBeau, M.M.; McClain, D.A. Human glutamine: Fructose-6-phosphate amidotransferase: characterization of mRNA and chromosomal assignment to 2p13. Hum. Genet.,  1995, 96(1), 99-101.
 [http://dx.doi.org/10.1007/BF00214194] [PMID: 7607664]

[209]
Vyas, B.; Silakari, O.; Singh Bahia, M.; Singh, B. Glutamine: fructose-6-phosphate amidotransferase (GFAT): Homology modelling and designing of new inhibitors using pharmacophore and docking based hierarchical virtual screening protocol. SAR QSAR Environ. Res.,  2013, 24(9), 733-752.
 [http://dx.doi.org/10.1080/1062936X.2013.797493] [PMID: 23767808]

[210]
Nguyen Vo, T.H.; Tran, N.; Nguyen, D.; Le, L. An in silico study on antidiabetic activity of bioactive compounds in Euphorbia thymifolia Linn. Springerplus,  2016, 5(1), 1359.
 [http://dx.doi.org/10.1186/s40064-016-2631-5] [PMID: 27588252]

[211]
Natarajan, A.; Sugumar, S.; Bitragunta, S.; Balasubramanyan, N. Molecular docking studies of (4Z, 12Z)-cyclopentadeca-4, 12-dienone from Grewia hirsuta with some targets related to type 2 diabetes. BMC Complement. Altern. Med.,  2015, 15(1), 73.
 [http://dx.doi.org/10.1186/s12906-015-0588-5] [PMID: 25885803]

[212]
Fridlyand, L.E.; Philipson, L.H. Pancreatic beta cell G-protein coupled receptors and second messenger interactions: a systems biology computational analysis. PLoS One,  2016, 11(5), e0152869.
 [http://dx.doi.org/10.1371/journal.pone.0152869] [PMID: 27138453]

[213]
Ashcroft, F.M.; Rorsman, P. Electrophysiology of the pancreatic β-cell. Prog. Biophys. Mol. Biol.,  1989, 54(2), 87-143.
 [http://dx.doi.org/10.1016/0079-6107(89)90013-8] [PMID: 2484976]

[214]
Gilon, P.; Henquin, J-C. Mechanisms and physiological significance of the cholinergic control of pancreatic β-cell function. Endocr. Rev.,  2001, 22(5), 565-604.
 [PMID: 11588141]

[215]
Amisten, S.; Salehi, A.; Rorsman, P.; Jones, P.M.; Persaud, S.J. An atlas and functional analysis of G-protein coupled receptors in human islets of Langerhans. Pharmacol. Ther.,  2013, 139(3), 359-391.
 [http://dx.doi.org/10.1016/j.pharmthera.2013.05.004] [PMID: 23694765]

[216]
Fyfe, M.C.T.; McCormack, J.G.; Overton, H.A.; Procter, M.J.; Reynet, C. GPR119 agonists as potential new oral agents for the treatment of type 2 diabetes and obesity. Expert Opin. Drug Discov.,  2008, 3(4), 403-413.
 [http://dx.doi.org/10.1517/17460441.3.4.403] [PMID: 23489096]

[217]
Overton, H.A.; Fyfe, M.C.T.; Reynet, C. GPR119, a novel G protein-coupled receptor target for the treatment of type 2 diabetes and obesity. Br. J. Pharmacol.,  2008, 153, S76-S81.
 [http://dx.doi.org/10.1038/sj.bjp.0707529] [PMID: 18037923]

[218]
Jones, R.M.; Leonard, J.N.; Buzard, D.J.; Lehmann, J. GPR119 agonists for the treatment of type 2 diabetes. Expert Opin. Ther. Pat.,  2009, 19, 1339-1359.
 [http://dx.doi.org/10.1517/13543770903153878]

[219]
Zhang, Y.; Xiao, M.; Niu, G.; Tan, H. Mechanisms of oleic acid deterioration in insulin secretion: Role in the pathogenesis of type 2 diabetes. Life Sci.,  2005, 77(17), 2071-2081.
 [http://dx.doi.org/10.1016/j.lfs.2004.12.047] [PMID: 15935394]

[220]
Wang, Y.; Yu, Z.; Xiao, W.; Lu, S.; Zhang, J. Allosteric binding sites at the receptor–lipid bilayer interface: novel targets for GPCR drug discovery. Drug Discov. Today,  2021, 26(3), 690-703.
 [http://dx.doi.org/10.1016/j.drudis.2020.12.001] [PMID: 33301977]

[221]
Flock, G.; Holland, D.; Seino, Y.; Drucker, D.J. GPR119 regulates murine glucose homeostasis through incretin receptor-dependent and independent mechanisms. Endocrinology,  2011, 152(2), 374-383.
 [http://dx.doi.org/10.1210/en.2010-1047] [PMID: 21068156]

[222]
Yoshida, S.; Ohishi, T.; Matsui, T.; Tanaka, H.; Oshima, H.; Yonetoku, Y.; Shibasaki, M. The role of small molecule GPR119 agonist, AS1535907, in glucose-stimulated insulin secretion and pancreatic β-cell function. Diabetes Obes. Metab.,  2011, 13(1), 34-41.
 [http://dx.doi.org/10.1111/j.1463-1326.2010.01315.x] [PMID: 21114601]

[223]
Fell, J.; McVean, M.; Aicher, T.; Boyd, S.; Larsen, P.; Neitzel, N.; Williams, L.; Pratt, S.; Fischer, J.; Hinklin, R. AR-7947, A GPR119 agonist with durable reductions in post-prandial and fasted blood glucose in preclinical models of type 2 diabetes. Diabetologia; Springer: New York, 10013 USA, 2011, pp. S363-S363, 

[224]
Risérus, U.; Willett, W.C.; Hu, F.B. Dietary fats and prevention of type 2 diabetes. Prog. Lipid Res.,  2009, 48(1), 44-51.
 [http://dx.doi.org/10.1016/j.plipres.2008.10.002] [PMID: 19032965]

[225]
Nolan, C.J.; Madiraju, M.S.R.; Delghingaro-Augusto, V.; Peyot, M.L.; Prentki, M. Fatty acid signaling in the β-cell and insulin secretion. Diabetes,  2006, 55(Suppl. 2), S16-S23.
 [http://dx.doi.org/10.2337/db06-S003] [PMID: 17130640]

[226]
Shenoy, P.; Bandawane, D.; Chaudhari, P. G-Protein coupled receptors-a potential new drug target to combat diabetic syndrome: an overview. Int. J. Pharm. Sci. Res.,  2011, 2, 2490.

[227]
Matschinsky, F.M.; Magnuson, M.A.; Zelent, D.; Jetton, T.L.; Doliba, N.; Han, Y.; Taub, R.; Grimsby, J. The network of glucokinase-expressing cells in glucose homeostasis and the potential of glucokinase activators for diabetes therapy. Diabetes,  2006, 55(1), 1-12.
 [http://dx.doi.org/10.2337/diabetes.55.01.06.db05-0926] [PMID: 16380470]

[228]
Matschinsky, F.M. Assessing the potential of glucokinase activators in diabetes therapy. Nat. Rev. Drug Discov.,  2009, 8(5), 399-416.
 [http://dx.doi.org/10.1038/nrd2850] [PMID: 19373249]

[229]
Pal, M. Medicinal chemistry approaches for glucokinase activation to treat type 2 diabetes. Curr. Med. Chem.,  2009, 16(29), 3858-3874.
 [http://dx.doi.org/10.2174/092986709789177993] [PMID: 19747136]

[230]
Matschinsky, F.M. Banting Lecture 1995. A lesson in metabolic regulation inspired by the glucokinase glucose sensor paradigm. Diabetes,  1996, 45(2), 223-241.
 [http://dx.doi.org/10.2337/diab.45.2.223] [PMID: 8549869]

[231]
Grimsby, J.; Matschinsky, F.; Grippo, J. Discovery and actions of glucokinase activators. Frontiers in Diabetes,  2004, 16, 360-378.

[232]
Johnson, D.; Shepherd, R.M.; Gill, D.; Gorman, T.; Smith, D.M.; Dunne, M.J. Glucose-dependent modulation of insulin secretion and intracellular calcium ions by GKA50, a glucokinase activator. Diabetes,  2007, 56(6), 1694-1702.
 [http://dx.doi.org/10.2337/db07-0026] [PMID: 17360975]

[233]
Ineedi, S.; Kandasamy, A.D.; Veeranjaneyulu, A.; Kumar, V. G-protein coupled receptors for free fatty acids as novel targets for type 2 diabetes. Pharmacologyonline,  2009, 2, 17-28.

[234]
Kim, J.E.; Kim, J.S.; Jo, M.J.; Cho, E.; Ahn, S.Y.; Kwon, Y.J.; Ko, G.J. The roles and associated mechanisms of adipokines in development of metabolic syndrome. Molecules,  2022, 27(2), 334.
 [http://dx.doi.org/10.3390/molecules27020334] [PMID: 35056647]

[235]
Tafere, G.G.; Wondafrash, D.Z.; Zewdie, K.A.; Assefa, B.T.; Ayza, M.A. Plasma adipsin as a biomarker and its implication in type 2 diabetes mellitus. Diabetes Metab. Syndr. Obes.,  2020, 13, 1855-1861.
 [http://dx.doi.org/10.2147/DMSO.S253967] [PMID: 32547147]

[236]
Yang, L.; Qiu, Y.; Ling, W.; Liu, Z.; Yang, L.; Wang, C.; Peng, X.; Wang, L.; Chen, J. Anthocyanins regulate serum adipsin and visfatin in patients with prediabetes or newly diagnosed diabetes: A randomized controlled trial. Eur. J. Nutr.,  2021, 60(4), 1935-1944.
 [http://dx.doi.org/10.1007/s00394-020-02379-x] [PMID: 32930848]

[237]
Li, Y.; Zou, W.; Brestoff, J.R.; Rohatgi, N.; Wu, X.; Atkinson, J.P.; Harris, C.A.; Teitelbaum, S.L. Fat-produced adipsin regulates inflammatory arthritis. Cell Rep.,  2019, 27, 2809-2816.
 [http://dx.doi.org/10.1016/j.celrep.2019.05.032]

[238]
Saleh, J.; Al-Maqbali, M.; Abdel-Hadi, D. Role of complement and complement-related adipokines in regulation of energy metabolism and fat storage. Compr. Physiol.,  2019, 9(4), 1411-1429.
 [http://dx.doi.org/10.1002/cphy.c170037] [PMID: 31688967]

[239]
Marrazzo, G.; Barbagallo, I.; Galvano, F. Role of dietary and endogenous antioxidants in diabetes. Crit. Rev. Food Sci. Nutr.,  2014, 54, 1599-1616.

[240]
Sandouk, T.; Reda, D.; Hofmann, C. Antidiabetic agent pioglitazone enhances adipocyte differentiation of 3T3-F442A cells. Am. J. Physiol. Cell Physiol.,  1993, 264(6), C1600-C1608.
 [http://dx.doi.org/10.1152/ajpcell.1993.264.6.C1600] [PMID: 8333508]

[241]
Samal, B.; Sun, Y.; Stearns, G.; Xie, C.; Suggs, S.; McNiece, I. Cloning and characterization of the cDNA encoding a novel human pre-B-cell colony-enhancing factor. Mol. Cell. Biol.,  1994, 14(2), 1431-1437.
 [PMID: 8289818]

[242]
Fukuhara, A.; Matsuda, M.; Nishizawa, M.; Segawa, K.; Tanaka, M.; Kishimoto, K.; Matsuki, Y.; Murakami, M.; Ichisaka, T.; Murakami, H.; Watanabe, E.; Takagi, T.; Akiyoshi, M.; Ohtsubo, T.; Kihara, S.; Yamashita, S.; Makishima, M.; Funahashi, T.; Yamanaka, S.; Hiramatsu, R.; Matsuzawa, Y.; Shimomura, I. Visfatin: a protein secreted by visceral fat that mimics the effects of insulin. Science,  2005, 307(5708), 426-430.
 [http://dx.doi.org/10.1126/science.1097243] [PMID: 15604363]

[243]
Chen, M.P.; Chung, F.M.; Chang, D.M.; Tsai, J.C.R.; Huang, H.F.; Shin, S.J.; Lee, Y.J. Elevated plasma level of visfatin/pre-B cell colony-enhancing factor in patients with type 2 diabetes mellitus. J. Clin. Endocrinol. Metab.,  2006, 91(1), 295-299.
 [http://dx.doi.org/10.1210/jc.2005-1475] [PMID: 16234302]

[244]
Berndt, J.; Klöting, N.; Kralisch, S.; Kovacs, P.; Fasshauer, M.; Schön, M.R.; Stumvoll, M.; Blüher, M. Plasma visfatin concentrations and fat depot-specific mRNA expression in humans. Diabetes,  2005, 54(10), 2911-2916.
 [http://dx.doi.org/10.2337/diabetes.54.10.2911] [PMID: 16186392]

[245]
Kieswich, J.; Sayers, S.R.; Silvestre, M.F.; Harwood, S.M.; Yaqoob, M.M.; Caton, P.W. Monomeric eNAMPT in the development of experimental diabetes in mice: a potential target for type 2 diabetes treatment. Diabetologia,  2016, 59(11), 2477-2486.
 [http://dx.doi.org/10.1007/s00125-016-4076-3] [PMID: 27541013]

[246]
Sayers, S.R.; Beavil, R.L.; Fine, N.H.F.; Huang, G.C.; Choudhary, P.; Pacholarz, K.J.; Barran, P.E.; Butterworth, S.; Mills, C.E.; Cruickshank, J.K.; Silvestre, M.P.; Poppitt, S.D.; McGill, A.T.; Lavery, G.G.; Hodson, D.J.; Caton, P.W. Structure-functional changes in eNAMPT at high concentrations mediate mouse and human beta cell dysfunction in type 2 diabetes. Diabetologia,  2020, 63(2), 313-323.
 [http://dx.doi.org/10.1007/s00125-019-05029-y] [PMID: 31732790]

[247]
Garten, A.; Schuster, S.; Penke, M.; Gorski, T.; de Giorgis, T.; Kiess, W. Physiological and pathophysiological roles of NAMPT and NAD metabolism. Nat. Rev. Endocrinol.,  2015, 11(9), 535-546.
 [http://dx.doi.org/10.1038/nrendo.2015.117] [PMID: 26215259]

[248]
Pei, L.; Wan, T.; Wang, S.; Ye, M.; Qiu, Y.; Jiang, R.; Pang, N.; Huang, Y.; Zhou, Y.; Jiang, X.; Ling, W.; Zhang, Z.; Yang, L. Cyanidin-3-O-β-glucoside regulates the activation and the secretion of adipokines from brown adipose tissue and alleviates diet induced fatty liver. Biomed. Pharmacother.,  2018, 105, 625-632.
 [http://dx.doi.org/10.1016/j.biopha.2018.06.018] [PMID: 29898429]

[249]
Hieronymus, L.; Griffin, S. Role of amylin in type 1 and type 2 diabetes. Diabetes Educ.,  2015, 41(1)(Suppl.), 47S-56S.
 [http://dx.doi.org/10.1177/0145721715607642] [PMID: 26424675]

[250]
Götz, J.; Lim, Y.A.; Eckert, A. Lessons from two prevalent amyloidoses—what amylin and Aβ have in common. Front. Aging Neurosci.,  2013, 5, 38.
 [http://dx.doi.org/10.3389/fnagi.2013.00038] [PMID: 23964237]

[251]
Mack, C.M.; Soares, C.J.; Wilson, J.K.; Athanacio, J.R.; Turek, V.F.; Trevaskis, J.L.; Roth, J.D.; Smith, P.A.; Gedulin, B.; Jodka, C.M.; Roland, B.L.; Adams, S.H.; Lwin, A.; Herich, J.; Laugero, K.D.; Vu, C.; Pittner, R.; Paterniti, J.R., Jr; Hanley, M.; Ghosh, S.; Parkes, D.G. Davalintide (AC2307), a novel amylin-mimetic peptide: enhanced pharmacological properties over native amylin to reduce food intake and body weight. Int. J. Obes.,  2010, 34(2), 385-395.
 [http://dx.doi.org/10.1038/ijo.2009.238] [PMID: 19935749]

[252]
Mack, C.M.; Smith, P.A.; Athanacio, J.R.; Xu, K.; Wilson, J.K.; Reynolds, J.M.; Jodka, C.M.; Lu, M.G.W.; Parkes, D.G. Glucoregulatory effects and prolonged duration of action of davalintide: a novel amylinomimetic peptide. Diabetes Obes. Metab.,  2011, 13(12), 1105-1113.
 [http://dx.doi.org/10.1111/j.1463-1326.2011.01465.x] [PMID: 21733060]

[253]
Association, A.D. Standards of medical care in diabetes--2014. Diabetes Care,  2014, 37(Suppl. 1), S14-S80.
 [http://dx.doi.org/10.2337/dc14-S014] [PMID: 24357209]

[254]
Westermark, P.; Engström, U.; Johnson, K.H.; Westermark, G.T.; Betsholtz, C. Islet amyloid polypeptide: Pinpointing amino acid residues linked to amyloid fibril formation. Proc. Natl. Acad. Sci. USA,  1990, 87(13), 5036-5040.
 [http://dx.doi.org/10.1073/pnas.87.13.5036] [PMID: 2195544]

[255]
Sakurai, H.; Dobbs, R.E.; Unger, R.H. The role of glucagon in the pathogenesis of the endogenous hyperglycemia of diabetes mellitus. Metabolism,  1975, 24(11), 1287-1297.
 [http://dx.doi.org/10.1016/0026-0495(75)90067-0] [PMID: 1186499]

[256]
Mathiesen, D.S.; Bagger, J.I.; Knop, F.K. Long-acting amylin analogues for the management of obesity. Curr. Opin. Endocrinol. Diabetes Obes.,  2022, 29(2), 183-190.
 [http://dx.doi.org/10.1097/MED.0000000000000716] [PMID: 35066542]

[257]
Montgomery, M.K.; Bayliss, J.; Devereux, C.; Bezawork-Geleta, A.; Roberts, D.; Huang, C.; Schittenhelm, R.B.; Ryan, A.; Townley, S.L.; Selth, L.A.; Biden, T.J.; Steinberg, G.R.; Samocha-Bonet, D.; Meex, R.C.R.; Watt, M.J. SMOC1 is a glucose-responsive hepatokine and therapeutic target for glycemic control. Sci. Transl. Med.,  2020, 12(559), eaaz8048.
 [http://dx.doi.org/10.1126/scitranslmed.aaz8048] [PMID: 32878981]

[258]
Matthew, W.; Ruth, M. Methods and compositions for improving glucose metabolism; Google Patents 2020. (WO2017070744A1)

[259]
Tang, W.J. Targeting insulin-degrading enzyme to treat type 2 diabetes mellitus. Trends Endocrinol. Metab.,  2016, 27(1), 24-34.
 [http://dx.doi.org/10.1016/j.tem.2015.11.003] [PMID: 26651592]

[260]
Deprez-Poulain, R.; Hennuyer, N.; Bosc, D.; Liang, W.G.; Enée, E.; Marechal, X.; Charton, J.; Totobenazara, J.; Berte, G.; Jahklal, J.; Verdelet, T.; Dumont, J.; Dassonneville, S.; Woitrain, E.; Gauriot, M.; Paquet, C.; Duplan, I.; Hermant, P.; Cantrelle, F.X.; Sevin, E.; Culot, M.; Landry, V.; Herledan, A.; Piveteau, C.; Lippens, G.; Leroux, F.; Tang, W.J.; van Endert, P.; Staels, B.; Deprez, B. Catalytic site inhibition of insulin-degrading enzyme by a small molecule induces glucose intolerance in mice. Nat. Commun.,  2015, 6(1), 8250.
 [http://dx.doi.org/10.1038/ncomms9250] [PMID: 26394692]

[261]
Nunes da Rocha, M.; Marinho, M.M.; Magno Rodrigues Teixeira, A.; Marinho, E.S.; dos Santos, H.S. Predictive ADMET study of rhodanine-3-acetic acid chalcone derivatives. J. Indian Chem. Soc.,  2022, 99(7), 100535.
 [http://dx.doi.org/10.1016/j.jics.2022.100535]
Cite As
Endocrine, Metabolic & Immune Disorders - Drug Targets

An Insight into the Development of Potential Antidiabetic Agents along with their Therapeutic Targets

Abstract

Graphical Abstract
