Abstract
Background: Type-2 diabetes mellitus accounts for 80-90% of diabetic patients. So far, the treatment of diabetes mainly aims at elevating insulin level and lowering glucose level in the peripheral blood and mitigating insulin resistance. Physiologically, insulin secretion from pancreatic β cells is delicately regulated. Thus, how insulin-related therapies could titrate blood glucose appropriately and avoid the occurrence of hypoglycemia remains an important issue for decades. Similar question is addressed on how to attenuate vascular complication in diabetic subjects.
Methods: We overviewed the evolution of each class of anti-diabetic drugs that have been used in clinical practice, focusing on their mechanisms, clinical results and cautions.
Results: Glucagon-like peptide-1 receptor agonists stimulate β cells for insulin secretion in response to diet but not in fasting stage, which make them superior than conventional insulinsecretion stimulators. DPP-4 inhibitors suppress glucagon-like peptide-1 degradation. Sodium/ glucose co-transporter 2 inhibitors enhance glucose clearance through urine excretion. The appearance of these new drugs provides new information about glycemic control. We update the clinical findings of Glucagon-like peptide-1 receptor agonists, DPP-4 inhibitors and Sodium/glucose cotransporter 2 inhibitors in glycemic control and the risk or progression of cardiovascular disease in diabetic patients. Stem cell therapy might be an alternative tool for diabetic patients to improve β cell regeneration and peripheral ischemia. We summarize the clinical results of mesenchymal stem cells transplanted into patients with diabetic limb and foot.
Conclusion: A stepwise intensification of dual and triple therapy for individual diabetic patient is required to achieve therapeutic target.
Keywords: Type-2 diabetes mellitus, insulin, pancreatic β cells, glucose homeostasis, insulin resistance, stem cells.
[1]
Giovannucci, E.; Harlan, D.M.; Archer, M.C.; Bergenstal, R.M.; Gapstur, S.M.; Habel, L.A.; Pollak, M.; Regensteiner, J.G.; Yee, D. Diabetes and cancer: a consensus report. Diabetes Care, 2010, 33(7), 1674-1685.
[2]
Xu, Y.; Wang, L.; He, J.; Bi, Y.; Li, M.; Wang, T.; Wang, L.; Jiang, Y.; Dai, M.; Lu, J.; Xu, M.; Li, Y.; Hu, N.; Li, J.; Mi, S.; Chen, C.S.; Li, G.; Mu, Y.; Zhao, J.; Kong, L.; Chen, J.; Lai, S.; Wang, W.; Zhao, W.; Ning, G. Prevalence and control of diabetes in Chinese adults. JAMA, 2013, 310(9), 948-959.
[3]
Collaboration, N.C.D.R.F. Effects of diabetes definition on global surveillance of diabetes prevalence and diagnosis: a pooled analysis of 96 population-based studies with 331,288 participants. Lancet Diabetes Endocrinol., 2015, 3(8), 624-637.
[4]
Danaei, G.; Finucane, M.M.; Lu, Y.; Singh, G.M.; Cowan, M.J.; Paciorek, C.J.; Lin, J.K.; Farzadfar, F.; Khang, Y.H.; Stevens, G.A.; Rao, M.; Ali, M.K.; Riley, L.M.; Robinson, C.A.; Ezzati, M. National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2·7 million participants. Lancet, 2011, 378(9785), 31-40.
[5]
Yu, K.; Zhao, D.; Feng, Y.M. Targeting obesity for the treatment of type 2 diabetes mellitus. J. Cytol. Histol., 2014, 5, 2.
[6]
Meier, J.J.; Butler, A.E.; Saisho, Y.; Monchamp, T.; Galasso, R.; Bhushan, A.; Rizza, R.A.; Butler, P.C. Beta-cell replication is the primary mechanism subserving the postnatal expansion of beta-cell mass in humans. Diabetes, 2008, 57(6), 1584-1594.
[7]
Freemantle, N.; Balkau, B.; Danchin, N.; Wang, E.; Marre, M.; Vespasiani, G.; Kawamori, R.; Home, P.D. Factors influencing initial choice of insulin therapy in a large international non-interventional study of people with type 2 diabetes. Diabetes Obes. Metab., 2012, 14(10), 901-909.
[8]
Klonoff, D.; Nayberg, I.; Erbstein, F.; Cali, A.; Brulle-Wohlhueter, C.; Haak, T. Usability of the Gla-300 injection device compared with three other commercialized disposable insulin pens: results of an interview-based survey. J. Diabetes Sci. Technol., 2015, 9(4), 936-938.
[9]
Solomon, T.P.; Haus, J.M.; Kelly, K.R.; Rocco, M.; Kashyap, S.R.; Kirwan, J.P. Improved pancreatic β-cell function in type 2 diabetic patients after lifestyle-induced weight loss is related to glucose-dependent insulinotropic polypeptide. Diabetes Care, 2010, 33(7), 1561-1566.
[10]
McCall, A.L. Insulin therapy and hypoglycemia. Endocrinol. Metab. Clin. North Am., 2012, 41(1), 57-87.
[11]
Hartman, I. Insulin analogs: impact on treatment success, satisfaction, quality of life, and adherence. Clin. Med. Res., 2008, 6(2), 54-67.
[12]
Vila-Carriles, W.H.; Zhao, G.; Bryan, J. Defining a binding pocket for sulfonylureas in ATP-sensitive potassium channels. FASEB J., 2007, 21(1), 18-25.
[13]
Zeffren, J.L.; Sherry, S. Effects of prolonged tolbutamide therapy on hepatic function and serum cholesterol of adult diabetic patients. Metabolism, 1957, 6(6 Pt 1), 504-508.
[14]
Gangji, A.S.; Cukierman, T.; Gerstein, H.C.; Goldsmith, C.H.; Clase, C.M. A systematic review and meta-analysis of hypoglycemia and cardiovascular events: a comparison of glyburide with other secretagogues and with insulin. Diabetes Care, 2007, 30(2), 389-394.
[15]
Klepzig, H.; Kober, G.; Matter, C.; Luus, H.; Schneider, H.; Boedeker, K.H.; Kiowski, W.; Amann, F.W.; Gruber, D.; Harris, S.; Burger, W. Sulfonylureas and ischaemic preconditioning; a double-blind, placebo-controlled evaluation of glimepiride and glibenclamide. Eur. Heart J., 1999, 20(6), 439-446.
[16]
Chen, L.L.; Liao, Y.F.; Zeng, T.S.; Yu, F.; Li, H.Q.; Feng, Y. Effects of metformin plus gliclazide compared with metformin alone on circulating endothelial progenitor cell in type 2 diabetic patients. Endocrine, 2010, 38(2), 266-275.
[17]
Jennings, P.E.; Belch, J.J. Free radical scavenging activity of sulfonylureas: a clinical assessment of the effect of gliclazide. Metabolism, 2000, 49(2)(Suppl. 1), 23-26.
[18]
He, F.; Li, Y.; Zeng, C.; Xia, C.; Xiong, Y.; Zhang, H.; Huang, S.; Liu, M. Contribution of cytochrome P450 isoforms to gliquidone metabolism in rats and human. Xenobiotica, 2014, 44(3), 229-234.
[19]
Nakamura, I.; Oyama, J.; Komoda, H.; Shiraki, A.; Sakamoto, Y.; Taguchi, I.; Hiwatashi, A.; Komatsu, A.; Takeuchi, M.; Yamagishi, S.; Inoue, T.; Node, K. Possible effects of glimepiride beyond glycemic control in patients with type 2 diabetes: a preliminary report. Cardiovasc. Diabetol., 2014, 13, 15.
[20]
Yao, H.; Feng, J.; Zheng, Q.; Wei, Y.; Wang, S.; Feng, W. The effects of gliclazide, methylcobalamin, and gliclazide+methylcobalamin combination therapy on diabetic peripheral neuropathy in rats. Life Sci., 2016, 161, 60-68.
[21]
Tankova, T.; Koev, D.; Dakovska, L.; Kirilov, G. The effect of repaglinide on insulin secretion and oxidative stress in type 2 diabetic patients. Diabetes Res. Clin. Pract., 2003, 59(1), 43-49.
[22]
Del Guerra, S.; Grupillo, M.; Masini, M.; Lupi, R.; Bugliani, M.; Torri, S.; Boggi, U.; Del Chiaro, M.; Vistoli, F.; Mosca, F.; Del Prato, S.; Marchetti, P. Gliclazide protects human islet beta-cells from apoptosis induced by intermittent high glucose. Diabetes Metab. Res. Rev., 2007, 23(3), 234-238.
[23]
Ma, Z.J.; Chen, R.; Ren, H.Z.; Guo, X.; Chen, J.G.; Chen, L.M. Endothelial nitric oxide synthase (eNOS) 4b/a polymorphism and the risk of diabetic nephropathy in type 2 diabetes mellitus: A meta-analysis. Meta Gene, 2013, 2, 50-62.
[24]
Takahashi, A.; Nagashima, K.; Hamasaki, A.; Kuwamura, N.; Kawasaki, Y.; Ikeda, H.; Yamada, Y.; Inagaki, N.; Seino, Y. Sulfonylurea and glinide reduce insulin content, functional expression of K(ATP) channels, and accelerate apoptotic beta-cell death in the chronic phase. Diabetes Res. Clin. Pract., 2007, 77(3), 343-350.
[25]
Li, Y.; Xu, L.; Shen, J.; Ran, J.; Zhang, Y.; Wang, M.; Yan, L.; Cheng, H.; Fu, Z. Effects of short-term therapy with different insulin secretagogues on glucose metabolism, lipid parameters and oxidative stress in newly diagnosed Type 2 Diabetes Mellitus. Diabetes Res. Clin. Pract., 2010, 88(1), 42-47.
[26]
Hu, S.; Wang, S.; Dunning, B.E. Tissue selectivity of antidiabetic agent nateglinide: study on cardiovascular and beta-cell K(ATP) channels. J. Pharmacol. Exp. Ther., 1999, 291(3), 1372-1379.
[27]
Yamada, S.; Watanabe, M.; Funae, O.; Atsumi, Y.; Suzuki, R.; Yajima, K.; Nakamura, Y.; Kawai, T.; Oikawa, Y.; Shimada, A. Effect of combination therapy of a rapid-acting insulin secretagogue (glinide) with premixed insulin in type 2 diabetes mellitus. Intern. Med., 2007, 46(23), 1893-1897.
[28]
De Lima, J.G.; Nóbrega, L.H.C. Endocrinology and diabetes: a problem-oriented approach, 2014, 375-384.
[29]
Black, C.; Donnelly, P.; McIntyre, L.; Royle, P.L.; Shepherd, J.P.; Thomas, S. Meglitinide analogues for type 2 diabetes mellitus. Cochrane Database Syst. Rev., 2007, (2)CD004654
[30]
Herzlinger, S.; Abrahamson, M.J. Treating Type 2 Diabetes Mellitus. In:Principles of Diabetes Mellitus; Poretsky, L., Ed.; Springer: Boston, MA, 2010, pp. 731-747.
[31]
Gumieniczek, A.; Komsta, L.; Chehab, M.R. Effects of two oral antidiabetics, pioglitazone and repaglinide, on aconitase inactivation, inflammation and oxidative/nitrosative stress in tissues under alloxan-induced hyperglycemia. Eur. J. Pharmacol., 2011, 659(1), 89-93.
[32]
Hu, S. Interaction of nateglinide with K(ATP) channel in beta-cells underlies its unique insulinotropic action. Eur. J. Pharmacol., 2002, 442(1-2), 163-171.
[33]
Wang, L.; Guo, L.; Zhang, L.; Zhou, Y.; He, Q.; Zhang, Z.; Wang, M. Effects of glucose load and nateglinide intervention on endothelial function and oxidative stress. J. Diabetes Res., 2013, 2013849295
[34]
Kodani, N.; Saisho, Y.; Tanaka, K.; Kawai, T.; Itoh, H. Effects of mitiglinide, a short-acting insulin secretagogue, on daily glycemic variability and oxidative stress markers in Japanese patients with type 2 diabetes mellitus. Clin. Drug Investig., 2013, 33(8), 563-570.
[36]
Montrose-Rafizadeh, C.; Egan, J.M.; Roth, J. Incretin hormones regulate glucose-dependent insulin secretion in RIN 1046-38 cells: mechanisms of action. Endocrinology, 1994, 135(2), 589-594.
[37]
Clark, A.L.; Urano, F. Endoplasmic reticulum stress in beta cells and autoimmune diabetes. Curr. Opin. Immunol., 2016, 43, 60-66.
[38]
Berchtold, L.A.; Prause, M.; Størling, J.; Mandrup-Poulsen, T. Cytokines and Pancreatic β-Cell Apoptosis. Adv. Clin. Chem., 2016, 75, 99-158.
[39]
Malhotra, J.D.; Kaufman, R.J. Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword? Antioxid. Redox Signal., 2007, 9(12), 2277-2293.
[40]
An, F.M.; Chen, S.; Xu, Z.; Yin, L.; Wang, Y.; Liu, A.R.; Yao, W.B.; Gao, X.D. Glucagon-like peptide-1 regulates mitochondrial biogenesis and tau phosphorylation against advanced glycation end product-induced neuronal insult: Studies in vivo and in vitro. Neuroscience, 2015, 300, 75-84.
[41]
Shimoda, M.; Kanda, Y.; Hamamoto, S.; Tawaramoto, K.; Hashiramoto, M.; Matsuki, M.; Kaku, K. The human glucagon-like peptide-1 analogue liraglutide preserves pancreatic beta cells via regulation of cell kinetics and suppression of oxidative and endoplasmic reticulum stress in a mouse model of diabetes. Diabetologia, 2011, 54(5), 1098-1108.
[42]
Langlois, A.; Dal, S.; Vivot, K.; Mura, C.; Seyfritz, E.; Bietiger, W.; Dollinger, C.; Peronet, C.; Maillard, E.; Pinget, M.; Jeandidier, N.; Sigrist, S. Improvement of islet graft function using liraglutide is correlated with its anti-inflammatory properties. Br. J. Pharmacol., 2016, 173(24), 3443-3453.
[43]
Hamamoto, S.; Kanda, Y.; Shimoda, M.; Tatsumi, F.; Kohara, K.; Tawaramoto, K.; Hashiramoto, M.; Kaku, K. Vildagliptin preserves the mass and function of pancreatic β cells via the developmental regulation and suppression of oxidative and endoplasmic reticulum stress in a mouse model of diabetes. Diabetes Obes. Metab., 2013, 15(2), 153-163.
[44]
Lee, J.; Hong, S.W.; Park, S.E.; Rhee, E.J.; Park, C.Y.; Oh, K.W.; Park, S.W.; Lee, W.Y. Exendin-4 attenuates endoplasmic reticulum stress through a SIRT1-dependent mechanism. Cell Stress Chaperones, 2014, 19(5), 649-656.
[45]
Batchuluun, B.; Inoguchi, T.; Sonoda, N.; Sasaki, S.; Inoue, T.; Fujimura, Y.; Miura, D.; Takayanagi, R. Metformin and liraglutide ameliorate high glucose-induced oxidative stress via inhibition of PKC-NAD(P)H oxidase pathway in human aortic endothelial cells. Atherosclerosis, 2014, 232(1), 156-164.
[46]
Shiraki, A.; Oyama, J.; Komoda, H.; Asaka, M.; Komatsu, A.; Sakuma, M.; Kodama, K.; Sakamoto, Y.; Kotooka, N.; Hirase, T.; Node, K. The glucagon-like peptide 1 analog liraglutide reduces TNF-α-induced oxidative stress and inflammation in endothelial cells. Atherosclerosis, 2012, 221(2), 375-382.
[47]
Gao, H.; Zeng, Z.; Zhang, H.; Zhou, X.; Guan, L.; Deng, W.; Xu, L. The Glucagon-like peptide-1 analogue liraglutide inhibits oxidative stress and inflammatory response in the liver of rats with diet-induced non-alcoholic fatty liver disease. Biol. Pharm. Bull., 2015, 38(5), 694-702.
[48]
Whalley, N.M.; Pritchard, L.E.; Smith, D.M.; White, A. Processing of proglucagon to GLP-1 in pancreatic α-cells: is this a paracrine mechanism enabling GLP-1 to act on β-cells? J. Endocrinol., 2011, 211(1), 99-106.
[49]
Mangmool, S.; Hemplueksa, P.; Parichatikanond, W.; Chattipakorn, N. Epac is required for GLP-1R-mediated inhibition of oxidative stress and apoptosis in cardiomyocytes. Mol. Endocrinol., 2015, 29(4), 583-596.
[50]
Avogaro, A.; Vigili de Kreutzenberg, S.; Fadini, G.P. Cardiovascular actions of GLP-1 and incretin-based pharmacotherapy. Curr. Diab. Rep., 2014, 14(5), 483.
[51]
Kim, M.; Platt, M.J.; Shibasaki, T.; Quaggin, S.E.; Backx, P.H.; Seino, S.; Simpson, J.A.; Drucker, D.J. GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure. Nat. Med., 2013, 19(5), 567-575.
[52]
Xu, F.; Lin, B.; Zheng, X.; Chen, Z.; Cao, H.; Xu, H.; Liang, H.; Weng, J. GLP-1 receptor agonist promotes brown remodelling in mouse white adipose tissue through SIRT1. Diabetologia, 2016, 59(5), 1059-1069.
[53]
Tsutsumi, Y.M.; Tsutsumi, R.; Hamaguchi, E.; Sakai, Y.; Kasai, A.; Ishikawa, Y.; Yokoyama, U.; Tanaka, K. Exendin-4 ameliorates cardiac ischemia/reperfusion injury via caveolae and caveolins-3. Cardiovasc. Diabetol., 2014, 13, 132.
[54]
Ye, Y.; Birnbaum, Y. Cyclic AMP-mediated pleiotropic effects of glucagon-like peptide-1 receptor activation. Focus on “Exendin-4 attenuates high glucose-induced cardiomyocyte apoptosis via inhibition of endoplasmic reticulum stress and activation of SERCA2a”. Am. J. Physiol. Cell Physiol., 2013, 304(6), C505-C507.
[55]
Ying, Y.; Zhu, H.; Liang, Z.; Ma, X.; Li, S. GLP1 protects cardiomyocytes from palmitate-induced apoptosis via Akt/GSK3b/b-catenin pathway. J. Mol. Endocrinol., 2015, 55(3), 245-262.
[56]
Gastaldelli, A.; Gaggini, M.; Daniele, G.; Ciociaro, D.; Cersosimo, E.; Tripathy, D.; Triplitt, C.; Fox, P.; Musi, N.; DeFronzo, R.; Iozzo, P. Exenatide improves both hepatic and adipose tissue insulin resistance: A dynamic positron emission tomography study. Hepatology, 2016, 64(6), 2028-2037.
[57]
Skrivanek, Z.; Gaydos, B.L.; Chien, J.Y.; Geiger, M.J.; Heathman, M.A.; Berry, S.; Anderson, J.H.; Forst, T.; Milicevic, Z.; Berry, D. Dose-finding results in an adaptive, seamless, randomized trial of once-weekly dulaglutide combined with metformin in type 2 diabetes patients (AWARD-5). Diabetes Obes. Metab., 2014, 16(8), 748-756.
[58]
Weinstock, R.S.; Guerci, B.; Umpierrez, G.; Nauck, M.A.; Skrivanek, Z.; Milicevic, Z. Safety and efficacy of once-weekly dulaglutide versus sitagliptin after 2 years in metformin-treated patients with type 2 diabetes (AWARD-5): a randomized, phase III study. Diabetes Obes. Metab., 2015, 17(9), 849-858.
[59]
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.
[60]
Karagiannis, T.; Paschos, P.; Paletas, K.; Matthews, D.R.; Tsapas, A. Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: systematic review and meta-analysis. BMJ, 2012, 344e1369
[61]
Gerstein, H.C.; Miller, M.E.; Byington, R.P. Effects of intensive glucose lowering in type 2 diabetes. Kardiol. Pol., 2008, 66(9), 1013-1019.
[62]
Gallwitz, B.; Rosenstock, J.; Rauch, T.; Bhattacharya, S.; Patel, S.; von Eynatten, M.; Dugi, K.A.; Woerle, H.J. 2-year efficacy and safety of linagliptin compared with glimepiride in patients with type 2 diabetes inadequately controlled on metformin: a randomised, double-blind, non-inferiority trial. Lancet, 2012, 380(9840), 475-483.
[63]
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.
[64]
Nauck, M.A. Incretin-based therapies for type 2 diabetes mellitus: properties, functions, and clinical implications. Am. J. Med., 2011, 124(1)(Suppl.), S3-S18.
[65]
Ferdinand, K.C.; Botros, F.T.; Atisso, C.M.; Sager, P.T. Cardiovascular safety for once-weekly dulaglutide in type 2 diabetes: a pre-specified meta-analysis of prospectively adjudicated cardiovascular events. Cardiovasc. Diabetol., 2016, 15, 38.
[66]
Pfeffer, M.A.; Claggett, B.; Diaz, R.; Dickstein, K.; Gerstein, H.C.; Køber, L.V.; Lawson, F.C.; Ping, L.; Wei, X.; Lewis, E.F.; Maggioni, A.P.; McMurray, J.J.; Probstfield, J.L.; Riddle, M.C.; Solomon, S.D.; Tardif, J.C. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N. Engl. J. Med., 2015, 373(23), 2247-2257.
[67]
Marso, S.P.; Daniels, G.H.; Brown-Frandsen, K.; Kristensen, P.; Mann, J.F.; Nauck, M.A.; Nissen, S.E.; Pocock, S.; Poulter, N.R.; Ravn, L.S.; Steinberg, W.M.; Stockner, M.; Zinman, B.; Bergenstal, R.M.; Buse, J.B. Liraglutide and cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med., 2016, 375(4), 311-322.
[68]
Scirica, B.M.; Bhatt, D.L.; Braunwald, E.; Steg, P.G.; Davidson, J.; Hirshberg, B.; Ohman, P.; Frederich, R.; Wiviott, S.D.; Hoffman, E.B.; Cavender, M.A.; Udell, J.A.; Desai, N.R.; Mosenzon, O.; McGuire, D.K.; Ray, K.K.; Leiter, L.A.; Raz, I. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N. Engl. J. Med., 2013, 369(14), 1317-1326.
[69]
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.
[70]
Green, J.B.; Bethel, M.A.; Armstrong, P.W.; Buse, J.B.; Engel, S.S.; Garg, J.; Josse, R.; Kaufman, K.D.; Koglin, J.; Korn, S.; Lachin, J.M.; McGuire, D.K.; Pencina, M.J.; Standl, E.; Stein, P.P.; Suryawanshi, S.; Van de Werf, F.; Peterson, E.D.; Holman, R.R. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med., 2015, 373(3), 232-242.
[71]
Gier, B.; Matveyenko, A.V.; Kirakossian, D.; Dawson, D.; Dry, S.M.; Butler, P.C. Chronic GLP-1 receptor activation by exendin-4 induces expansion of pancreatic duct glands in rats and accelerates formation of dysplastic lesions and chronic pancreatitis in the Kras(G12D) mouse model. Diabetes, 2012, 61(5), 1250-1262.
[72]
Butler, P.C.; Matveyenko, A.V.; Dry, S.; Bhushan, A.; Elashoff, R. Glucagon-like peptide-1 therapy and the exocrine pancreas: innocent bystander or friendly fire? Diabetologia, 2010, 53(1), 1-6.
[73]
Zhou, G.; Myers, R.; Li, Y.; Chen, Y.; Shen, X.; Fenyk-Melody, J.; Wu, M.; Ventre, J.; Doebber, T.; Fujii, N.; Musi, N.; Hirshman, M.F.; Goodyear, L.J.; Moller, D.E. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest., 2001, 108(8), 1167-1174.
[74]
Gunton, J.E.; Delhanty, P.J.; Takahashi, S.; Baxter, R.C. Metformin rapidly increases insulin receptor activation in human liver and signals preferentially through insulin-receptor substrate-2. J. Clin. Endocrinol. Metab., 2003, 88(3), 1323-1332.
[75]
Geerling, J.J.; Boon, M.R.; van der Zon, G.C.; van den Berg, S.A.; van den Hoek, A.M.; Lombès, M.; Princen, H.M.; Havekes, L.M.; Rensen, P.C.; Guigas, B. Metformin lowers plasma triglycerides by promoting VLDL-triglyceride clearance by brown adipose tissue in mice. Diabetes, 2014, 63(3), 880-891.
[76]
Mannucci, E.; Tesi, F.; Bardini, G.; Ognibene, A.; Petracca, M.G.; Ciani, S.; Pezzatini, A.; Brogi, M.; Dicembrini, I.; Cremasco, F.; Messeri, G.; Rotella, C.M. Effects of metformin on glucagon-like peptide-1 levels in obese patients with and without Type 2 diabetes. Diabetes Nutr. Metab., 2004, 17(6), 336-342.
[77]
Forslund, K.; Hildebrand, F.; Nielsen, T.; Falony, G.; Le Chatelier, E.; Sunagawa, S.; Prifti, E.; Vieira-Silva, S.; Gudmundsdottir, V.; Pedersen, H.K.; Arumugam, M.; Kristiansen, K.; Voigt, A.Y.; Vestergaard, H.; Hercog, R.; Costea, P.I.; Kultima, J.R.; Li, J.; Jørgensen, T.; Levenez, F.; Dore, J.; Nielsen, H.B.; Brunak, S.; Raes, J.; Hansen, T.; Wang, J.; Ehrlich, S.D.; Bork, P.; Pedersen, O.; Pedersen, O. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature, 2015, 528(7581), 262-266.
[78]
Cheang, W.S.; Tian, X.Y.; Wong, W.T.; Lau, C.W.; Lee, S.S.; Chen, Z.Y.; Yao, X.; Wang, N.; Huang, Y. Metformin protects endothelial function in diet-induced obese mice by inhibition of endoplasmic reticulum stress through 5′ adenosine monophosphate-activated protein kinase-peroxisome proliferator-activated receptor δ pathway. Arterioscler. Thromb. Vasc. Biol., 2014, 34(4), 830-836.
[79]
Stephenne, X.; Foretz, M.; Taleux, N.; van der Zon, G.C.; Sokal, E.; Hue, L.; Viollet, B.; Guigas, B. Metformin activates AMP-activated protein kinase in primary human hepatocytes by decreasing cellular energy status. Diabetologia, 2011, 54(12), 3101-3110.
[80]
González-Barroso, M.M.; Anedda, A.; Gallardo-Vara, E.; Redondo-Horcajo, M.; Rodríguez-Sánchez, L.; Rial, E. Fatty acids revert the inhibition of respiration caused by the antidiabetic drug metformin to facilitate their mitochondrial β-oxidation. Biochim. Biophys. Acta, 2012, 1817(10), 1768-1775.
[81]
An, H.; He, L. Current understanding of metformin effect on the control of hyperglycemia in diabetes. J. Endocrinol., 2016, 228(3), R97-R106.
[82]
Li, C.L.; Pan, C.Y.; Lu, J.M.; Zhu, Y.; Wang, J.H.; Deng, X.X.; Xia, F.C.; Wang, H.Z.; Wang, H.Y. Effect of metformin on patients with impaired glucose tolerance. Diabet. Med., 1999, 16(6), 477-481.
[83]
Blumer, I.; Hadar, E.; Hadden, D.R.; Jovanovič, L.; Mestman, J.H.; Murad, M.H.; Yogev, Y. Diabetes and pregnancy: an endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab., 2013, 98(11), 4227-4249.
[84]
Kedikova, S.; Sirakov, M.; Boyadzhieva, M. [Metformin efficiency for the adolescent PCOS treatment]. Akush. Ginekol. (Sofiia), 2012, 51(6), 6-10.
[85]
Bucher, K.G.; Wiltz, S.A. Alternatives to metformin for patients with PCOS. Am. Fam. Physician, 2016, 94(5), 378-379.
[86]
Farmer, R.E.; Ford, D.; Forbes, H.J.; Chaturvedi, N.; Kaplan, R.; Smeeth, L.; Bhaskaran, K. Metformin and cancer in type 2 diabetes: a systematic review and comprehensive bias evaluation. Int. J. Epidemiol., 2016.
[87]
Bannister, C.A.; Holden, S.E.; Jenkins-Jones, S.; Morgan, C.L.; Halcox, J.P.; Schernthaner, G.; Mukherjee, J.; Currie, C.J. Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls. Diabetes Obes. Metab., 2014, 16(11), 1165-1173.
[88]
Clark, M.; Thomaseth, K.; Dirikolu, L.; Ferguson, D.C.; Hoenig, M. Effects of pioglitazone on insulin sensitivity and serum lipids in obese cats. J. Vet. Intern. Med., 2014, 28(1), 166-174.
[89]
Schoenberg, K.M.; Perfield, K.L.; Farney, J.K.; Bradford, B.J.; Boisclair, Y.R.; Overton, T.R. Effects of prepartum 2,4-thiazolidinedione on insulin sensitivity, plasma concentrations of tumor necrosis factor-α and leptin, and adipose tissue gene expression. J. Dairy Sci., 2011, 94(11), 5523-5532.
[90]
Saitoh, Y.; Chun-ping, C.; Noma, K.; Ueno, H.; Mizuta, M.; Nakazato, M. Pioglitazone attenuates fatty acid-induced oxidative stress and apoptosis in pancreatic beta-cells. Diabetes Obes. Metab., 2008, 10(7), 564-573.
[91]
Ricote, M.; Li, A.C.; Willson, T.M.; Kelly, C.J.; Glass, C.K. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature, 1998, 391(6662), 79-82.
[92]
Gupta, S.; Gupta, K.; Ravi, R.; Mehta, V.; Banerjee, S.; Joshi, S.; Saboo, B. Pioglitazone and the risk of bladder cancer: An Indian retrospective cohort study. Indian J. Endocrinol. Metab., 2015, 19(5), 639-643.
[93]
Tuccori, M.; Filion, K.B.; Yin, H.; Yu, O.H.; Platt, R.W.; Azoulay, L. Pioglitazone use and risk of bladder cancer: population based cohort study. BMJ, 2016, 352, i1541.
[94]
Standl, E.; Schnell, O. Alpha-glucosidase inhibitors 2012 - cardiovascular considerations and trial evaluation. Diab. Vasc. Dis. Res., 2012, 9(3), 163-169.
[95]
Van, D.L.; Floris, A; Lucassen, P.L. α-Glucosidase inhibitors
for patients with type 2 diabetes. Diabetes Care, 2005, 28(7), 1840-author reply 1841.
[96]
DeGeeter, M.; Williamson, B. Alternative agents in type 1 diabetes in addition to insulin therapy: metformin, alpha-glucosidase inhibitors, pioglitazone, GLP-1 agonists, DPP-IV inhibitors, and SGLT-2 inhibitors. J. Pharm. Pract., 2016, 29(2), 144-159.
[97]
Sahdeo, S.; Tomilov, A.; Komachi, K.; Iwahashi, C.; Datta, S.; Hughes, O.; Hagerman, P.; Cortopassi, G. High-throughput screening of FDA-approved drugs using oxygen biosensor plates reveals secondary mitofunctional effects. Mitochondrion, 2014, 17, 116-125.
[98]
Kobayashi, H.; Yasuda, S.; Bao, N.; Iwasa, M.; Kawamura, I.; Yamada, Y.; Yamaki, T.; Sumi, S.; Ushikoshi, H.; Nishigaki, K.; Takemura, G.; Fujiwara, T.; Fujiwara, H.; Minatoguchi, S. Postinfarct treatment with oxytocin improves cardiac function and remodeling via activating cell-survival signals and angiogenesis. J. Cardiovasc. Pharmacol., 2009, 54(6), 510-519.
[99]
Chiasson, J.L.; Josse, R.G.; Gomis, R.; Hanefeld, M.; Karasik, A.; Laakso, M. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. JAMA, 2003, 290(4), 486-494.
[100]
Moritoh, Y.; Takeuchi, K.; Asakawa, T.; Kataoka, O.; Odaka, H. Chronic administration of alogliptin, a novel, potent, and highly selective dipeptidyl peptidase-4 inhibitor, improves glycemic control and beta-cell function in obese diabetic ob/ob mice. Eur. J. Pharmacol., 2008, 588(2-3), 325-332.
[101]
Patel, H.; Royall, P.G.; Gaisford, S.; Williams, G.R.; Edwards, C.H.; Warren, F.J.; Flanagan, B.M.; Ellis, P.R.; Butterworth, P.J. Structural and enzyme kinetic studies of retrograded starch: Inhibition of α-amylase and consequences for intestinal digestion of starch. Carbohydr. Polym., 2017, 164, 154-161.
[102]
Gopal, S.S.; Lakshmi, M.J.; Sharavana, G.; Sathaiah, G.; Sreerama, Y.N.; Baskaran, V. Lactucaxanthin - a potential anti-diabetic carotenoid from lettuce (Lactuca sativa) inhibits α-amylase and α-glucosidase activity in vitro and in diabetic rats. Food Funct., 2017, 8(3), 1124-1131.
[103]
Rasouli, H.; Hosseini-Ghazvini, S.M.; Adibi, H.; Khodarahmi, R. Differential α-amylase/α-glucosidase inhibitory activities of plant-derived phenolic compounds: a virtual screening perspective for the treatment of obesity and diabetes. Food Funct., 2017, 8(5), 1942-1954.
[104]
de Sales, P.M.; de Souza, P.M.; Dartora, M.; Resck, I.S.; Simeoni, L.A.; Fonseca-Bazzo, Y.M.; de Oliveira Magalhaes, P.; Silveira, D. Pouteria torta epicarp as a useful source of alpha-amylase inhibitor in the control of type 2 diabetes. Food Chem. Toxicol., 2017, 109(Pt. 2), 962-969.
[105]
Vasilakou, D.; Karagiannis, T.; Athanasiadou, E.; Mainou, M.; Liakos, A.; Bekiari, E.; Sarigianni, M.; Matthews, D.R.; Tsapas, A. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann. Intern. Med., 2013, 159(4), 262-274.
[106]
Ishibashi, Y.; Matsui, T.; Yamagishi, S. Tofogliflozin, A highly selective inhibitor of SGLT2 blocks proinflammatory and proapoptotic effects of glucose overload on proximal tubular cells partly by suppressing oxidative stress generation. Horm. Metab. Res., 2016, 48(3), 191-195.
[107]
Hatanaka, T.; Ogawa, D.; Tachibana, H.; Eguchi, J.; Inoue, T.; Yamada, H.; Takei, K.; Makino, H.; Wada, J. Inhibition of SGLT2 alleviates diabetic nephropathy by suppressing high glucose-induced oxidative stress in type 1 diabetic mice. Pharmacol. Res. Perspect., 2016, 4(4)e00239
[108]
Maeda, S.; Matsui, T.; Takeuchi, M.; Yamagishi, S. Sodium-glucose cotransporter 2-mediated oxidative stress augments advanced glycation end products-induced tubular cell apoptosis. Diabetes Metab. Res. Rev., 2013, 29(5), 406-412.
[109]
Yokono, M.; Takasu, T.; Hayashizaki, Y.; Mitsuoka, K.; Kihara, R.; Muramatsu, Y.; Miyoshi, S.; Tahara, A.; Kurosaki, E.; Li, Q.; Tomiyama, H.; Sasamata, M.; Shibasaki, M.; Uchiyama, Y. SGLT2 selective inhibitor ipragliflozin reduces body fat mass by increasing fatty acid oxidation in high-fat diet-induced obese rats. Eur. J. Pharmacol., 2014, 727, 66-74.
[110]
Tahara, A.; Kurosaki, E.; Yokono, M.; Yamajuku, D.; Kihara, R.; Hayashizaki, Y.; Takasu, T.; Imamura, M.; Li, Q.; Tomiyama, H.; Kobayashi, Y.; Noda, A.; Sasamata, M.; Shibasaki, M. Effects of SGLT2 selective inhibitor ipragliflozin on hyperglycemia, hyperlipidemia, hepatic steatosis, oxidative stress, inflammation, and obesity in type 2 diabetic mice. Eur. J. Pharmacol., 2013, 715(1-3), 246-255.
[111]
Bailey, C.J. The current drug treatment landscape for diabetes and perspectives for the future. Clin. Pharmacol. Ther., 2015, 98(2), 170-184.
[112]
Chao, E.C.; Henry, R.R. SGLT2 inhibition--a novel strategy for diabetes treatment. Nat. Rev. Drug Discov., 2010, 9(7), 551-559.
[113]
Zaccardi, F.; Webb, D.R.; Htike, Z.Z.; Youssef, D.; Khunti, K.; Davies, M.J. Efficacy and safety of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes mellitus: systematic review and network meta-analysis. Diabetes Obes. Metab., 2016, 18(8), 783-794.
[114]
Zinman, B.; Wanner, C.; Lachin, J.M.; Fitchett, D.; Bluhmki, E.; Hantel, S.; Mattheus, M.; Devins, T.; Johansen, O.E.; Woerle, H.J.; Broedl, U.C.; Inzucchi, S.E. Empagliflozin, Cardiovascular outcomes, and mortality in type 2 diabetes. N. Engl. J. Med., 2015, 373(22), 2117-2128.
[115]
Frías, J.P.; Guja, C.; Hardy, E.; Ahmed, A.; Dong, F.; Öhman, P.; Jabbour, S.A. Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol., 2016, 4(12), 1004-1016.
[116]
Xie, R.; Everett, L.J.; Lim, H.W.; Patel, N.A.; Schug, J.; Kroon, E.; Kelly, O.G.; Wang, A.; D’Amour, K.A.; Robins, A.J.; Won, K.J.; Kaestner, K.H.; Sander, M. Dynamic chromatin remodeling mediated by polycomb proteins orchestrates pancreatic differentiation of human embryonic stem cells. Cell Stem Cell, 2013, 12(2), 224-237.
[117]
Rezania, A.; Bruin, J.E.; Riedel, M.J.; Mojibian, M.; Asadi, A.; Xu, J.; Gauvin, R.; Narayan, K.; Karanu, F.; O’Neil, J.J.; Ao, Z.; Warnock, G.L.; Kieffer, T.J. Maturation of human embryonic stem cell-derived pancreatic progenitors into functional islets capable of treating pre-existing diabetes in mice. Diabetes, 2012, 61(8), 2016-2029.
[118]
Pagliuca, F.W.; Millman, J.R.; Gürtler, M.; Segel, M.; Van Dervort, A.; Ryu, J.H.; Peterson, Q.P.; Greiner, D.; Melton, D.A. Generation of functional human pancreatic β cells in vitro. Cell, 2014, 159(2), 428-439.
[119]
Zhang, D.; Jiang, W.; Liu, M.; Sui, X.; Yin, X.; Chen, S.; Shi, Y.; Deng, H. Highly efficient differentiation of human ES cells and iPS cells into mature pancreatic insulin-producing cells. Cell Res., 2009, 19(4), 429-438.
[120]
Shaer, A.; Azarpira, N.; Karimi, M.H.; Soleimani, M.; Dehghan, S. Differentiation of human-induced pluripotent stem cells into insulin-producing clusters by MicroRNA-7. Exp. Clin. Transplant., 2016, 14(5), 555-563.
[121]
Lin, T.; Ambasudhan, R.; Yuan, X.; Li, W.; Hilcove, S.; Abujarour, R.; Lin, X.; Hahm, H.S.; Hao, E.; Hayek, A.; Ding, S. A chemical platform for improved induction of human iPSCs. Nat. Methods, 2009, 6(11), 805-808.
[122]
Enderami, S.E.; Mortazavi, Y.; Soleimani, M.; Nadri, S.; Biglari, A.; Mansour, R.N. Generation of insulin-producing cells from human induced pluripotent stem cells using a stepwise differentiation protocol optimized with platelet-rich plasma. J. Cell. Physiol., 2017, 232(10), 2878-2886.
[123]
Roscioni, S.S.; Migliorini, A.; Gegg, M.; Lickert, H. Impact of islet architecture on β-cell heterogeneity, plasticity and function. Nat. Rev. Endocrinol., 2016, 12(12), 695-709.
[124]
Quaranta, P.; Antonini, S.; Spiga, S.; Mazzanti, B.; Curcio, M.; Mulas, G.; Diana, M.; Marzola, P.; Mosca, F.; Longoni, B. Co-transplantation of endothelial progenitor cells and pancreatic islets to induce long-lasting normoglycemia in streptozotocin-treated diabetic rats. PLoS One, 2014, 9(4)e94783
[125]
Li, X.Y.; Zheng, Z.H.; Li, X.Y.; Guo, J.; Zhang, Y.; Li, H.; Wang, Y.W.; Ren, J.; Wu, Z.B. Treatment of foot disease in patients with type 2 diabetes mellitus using human umbilical cord blood mesenchymal stem cells: response and correction of immunological anomalies. Curr. Pharm. Des., 2013, 19(27), 4893-4899.
[126]
Liu, X.; Zheng, P.; Wang, X.; Dai, G.; Cheng, H.; Zhang, Z.; Hua, R.; Niu, X.; Shi, J.; An, Y. A preliminary evaluation of efficacy and safety of Wharton’s jelly mesenchymal stem cell transplantation in patients with type 2 diabetes mellitus. Stem Cell Res. Ther., 2014, 5(2), 57.
[127]
Lee, H.C.; An, S.G.; Lee, H.W.; Park, J.S.; Cha, K.S.; Hong, T.J.; Park, J.H.; Lee, S.Y.; Kim, S.P.; Kim, Y.D.; Chung, S.W.; Bae, Y.C.; Shin, Y.B.; Kim, J.I.; Jung, J.S. Safety and effect of adipose tissue-derived stem cell implantation in patients with critical limb ischemia: a pilot study. Circ. J., 2012, 76(7), 1750-1760.
[128]
Flouzat-Lachaniette, C.H.; Heyberger, C.; Bouthors, C.; Roubineau, F.; Chevallier, N.; Rouard, H.; Hernigou, P. Osteogenic progenitors in bone marrow aspirates have clinical potential for tibial non-unions healing in diabetic patients. Int. Orthop., 2016, 40(7), 1375-1379.
[129]
Lu, D.; Chen, B.; Liang, Z.; Deng, W.; Jiang, Y.; Li, S.; Xu, J.; Wu, Q.; Zhang, Z.; Xie, B.; Chen, S. Comparison of bone marrow mesenchymal stem cells with bone marrow-derived mononuclear cells for treatment of diabetic critical limb ischemia and foot ulcer: a double-blind, randomized, controlled trial. Diabetes Res. Clin. Pract., 2011, 92(1), 26-36.
[130]
Wang, Q.; Zhang, W.; He, G.; Sha, H.; Quan, Z. Method for in vitro differentiation of bone marrow mesenchymal stem cells into endothelial progenitor cells and vascular endothelial cells. Mol. Med. Rep., 2016, 14(6), 5551-5555.
[131]
Si, Y.; Zhao, Y.; Hao, H.; Liu, J.; Guo, Y.; Mu, Y.; Shen, J.; Cheng, Y.; Fu, X.; Han, W. Infusion of mesenchymal stem cells ameliorates hyperglycemia in type 2 diabetic rats: identification of a novel role in improving insulin sensitivity. Diabetes, 2012, 61(6), 1616-1625.
[132]
Al-Shabrawey, M.; Bartoli, M.; El-Remessy, A.B.; Ma, G.; Matragoon, S.; Lemtalsi, T.; Caldwell, R.W.; Caldwell, R.B. Role of NADPH oxidase and Stat3 in statin-mediated protection against diabetic retinopathy. Invest. Ophthalmol. Vis. Sci., 2008, 49(7), 3231-3238.
[133]
Rojas, M.; Zhang, W.; Xu, Z.; Lemtalsi, T.; Chandler, P.; Toque, H.A.; Caldwell, R.W.; Caldwell, R.B. Requirement of NOX2 expression in both retina and bone marrow for diabetes-induced retinal vascular injury. PLoS One, 2013, 8(12)e84357
[134]
Bentley, K.; Franco, C.A.; Philippides, A.; Blanco, R.; Dierkes, M.; Gebala, V.; Stanchi, F.; Jones, M.; Aspalter, I.M.; Cagna, G.; Weström, S.; Claesson-Welsh, L.; Vestweber, D.; Gerhardt, H. The role of differential VE-cadherin dynamics in cell rearrangement during angiogenesis. Nat. Cell Biol., 2014, 16(4), 309-321.
[135]
Fu, J.; Lee, K.; Chuang, P.Y.; Liu, Z.; He, J.C. Glomerular endothelial cell injury and cross talk in diabetic kidney disease. Am. J. Physiol. Renal Physiol., 2015, 308(4), F287-F297.
[136]
Ulker, E.; Parker, W.H.; Raj, A.; Qu, Z.C.; May, J.M. Ascorbic acid prevents VEGF-induced increases in endothelial barrier permeability. Mol. Cell. Biochem., 2016, 412(1-2), 73-79.
[137]
Blinder, K.J.; Dugel, P.U.; Chen, S.; Jumper, J.M.; Walt, J.G.; Hollander, D.A.; Scott, L.C. Anti-VEGF treatment of diabetic macular edema in clinical practice: effectiveness and patterns of use (ECHO Study Report 1). Clin. Ophthalmol., 2017, 11, 393-401.
[138]
Babapoor-Farrokhran, S.; Jee, K.; Puchner, B.; Hassan, S.J.; Xin, X.; Rodrigues, M.; Kashiwabuchi, F.; Ma, T.; Hu, K.; Deshpande, M.; Daoud, Y.; Solomon, S.; Wenick, A.; Lutty, G.A.; Semenza, G.L.; Montaner, S.; Sodhi, A. Angiopoietin-like 4 is a potent angiogenic factor and a novel therapeutic target for patients with proliferative diabetic retinopathy. Proc. Natl. Acad. Sci. USA, 2015, 112(23), E3030-E3039.
[139]
Abu El-Asrar, A.M.; Ahmad, A.; Bittoun, E.; Siddiquei, M.M.; Mohammad, G.; Mousa, A.; De Hertogh, G.; Opdenakker, G. Differential expression and localization of human tissue inhibitors of metalloproteinases in proliferative diabetic retinopathy. Acta Ophthalmol., 2018, 96(1), e27-e37.
[140]
Xu, W.; Mu, Y.; Zhao, J.; Zhu, D.; Ji, Q.; Zhou, Z.; Yao, B.; Mao, A.; Engel, S.S.; Zhao, B.; Bi, Y.; Zeng, L.; Ran, X.; Lu, J.; Ji, L.; Yang, W.; Jia, W.; Weng, J. Efficacy and safety of metformin and sitagliptin based triple antihyperglycemic therapy (STRATEGY): a multicenter, randomized, controlled, non-inferiority clinical trial. Sci. China Life Sci., 2017, 60(3), 225-238.
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