Anti-Insulin Receptor Antibodies in the Pathology and Therapy of Diabetes Mellitus

Arshida       Ashraf; Abdulrasheed       Palakkott; Mohammed    Akli    Ayoub
doi:10.2174/1573399816666200604122345
Abstract

Diabetes mellitus (DM) is recognized as the most common and the world’s fastest-growing chronic disease with severe complications leading to increased mortality. Many strategies exist for the management of DM and its control, including treatment with insulin and insulin analogs, oral hypoglycemic therapy such as insulin secretion stimulators and insulin sensitizers, and diet and physical training. Over the years, many types of drugs and molecules with an interesting pharmacological diversity have been developed and proposed for their anti-diabetic potential. Such molecules target diverse key receptors, enzymes, and regulatory/signaling proteins known to be directly or indirectly involved in the pathophysiology of DM. Among them, insulin receptor (IR) is undoubtedly the target of choice for its central role in insulin-mediated glucose homeostasis and its utilization by the major insulin-sensitive tissues such as skeletal muscles, adipose tissue, and the liver. In this review, we focus on the implication of antibodies targeting IR in the pathology of DM as well as the recent advances in the development of IR antibodies as promising anti-diabetic drugs. The challenge still entails development of more powerful, highly selective, and safer anti-diabetic drugs.
Keywords: Diabetes, insulin receptor, therapeutic antibodies, autoantibodies, allosteric antibodies, anti-diabetic drug.
[1] 
National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes  1979; 28(12): 1039-57.
[http://dx.doi.org/10.2337/diab.28.12.1039] [PMID:  510803] 
[2] 
Kharroubi AT, Darwish HM. Diabetes mellitus: The epidemic of the century. World J Diabetes  2015; 6(6): 850-67.
[http://dx.doi.org/10.4239/wjd.v6.i6.850] [PMID:  26131326] 
[3] 
Katsarou A, Gudbjörnsdottir S, Rawshani A, et al. Type 1 diabetes mellitus. Nat Rev Dis Primers  2017; 3: 17016.
[http://dx.doi.org/10.1038/nrdp.2017.16] [PMID:  28358037] 
[4] 
Olefsky JM, Garvey WT, Henry RR, Brillon D, Matthaei S, Freidenberg GR. Cellular mechanisms of insulin resistance in non-insulin-dependent (type II) diabetes. Am J Med  1988; 85(5A): 86-105.
[http://dx.doi.org/10.1016/0002-9343(88)90401-9] [PMID:  3057897] 
[5] 
DeFronzo RA, Ferrannini E, Groop L, et al. Type 2 diabetes mellitus. Nat Rev Dis Primers  2015; 1: 15019.
[http://dx.doi.org/10.1038/nrdp.2015.19] [PMID:  27189025] 
[6] 
Haeusler RA, McGraw TE, Accili D. Biochemical and cellular properties of insulin receptor signalling. Nat Rev Mol Cell Biol  2018; 19(1): 31-44.
[http://dx.doi.org/10.1038/nrm.2017.89] [PMID:  28974775] 
[7] 
Taha C, Klip A. The insulin signaling pathway. J Membr Biol  1999; 169(1): 1-12.
[http://dx.doi.org/10.1007/PL00005896] [PMID:  10227847] 
[8] 
Boucher J, Kleinridders A, Kahn CR. Insulin Receptor Signaling in Normal and Insulin-Resistant States 2014.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3941218/
[http://dx.doi.org/10.1101/cshperspect.a009191] 
[9] 
Becker AB, Roth RA. Insulin receptor structure and function in normal and pathological conditions. Annu Rev Med  1990; 41(1): 99-115.
[http://dx.doi.org/10.1146/annurev.me.41.020190.000531] [PMID:  2184752] 
[10] 
Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature  2001; 414(6865): 799-806.
[http://dx.doi.org/10.1038/414799a] [PMID:  11742412] 
[11] 
Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol  2006; 7(2): 85-96.
[http://dx.doi.org/10.1038/nrm1837] [PMID:  16493415] 
[12] 
Galuska D, Ryder J, Kawano Y, Charron MJ, Zierath JR. Insulin signaling and glucose transport in insulin resistant skeletal muscle. Special reference to GLUT4 transgenic and GLUT4 knockout mice. Adv Exp Med Biol  1998; 441: 73-85.
[http://dx.doi.org/10.1007/978-1-4899-1928-1_7] [PMID:  9781315] 
[13] 
Kerru N, Singh-Pillay A, Awolade P, Singh P. Current anti-diabetic agents and their molecular targets: A review. Eur J Med Chem  2018; 152: 436-88.
[http://dx.doi.org/10.1016/j.ejmech.2018.04.061] [PMID:  29751237] 
[14] 
Yunn N-O, Kim J, Kim Y, Leibiger I, Berggren P-O, Ryu SH. Mechanistic understanding of insulin receptor modulation: Implications for the development of anti-diabetic drugs. Pharmacol Ther  2018; 185: 86-98.
[http://dx.doi.org/10.1016/j.pharmthera.2017.12.005] [PMID:  29262294] 
[15] 
Chaudhury A, Duvoor C, Reddy Dendi VS, et al. Clinical Review
of Antidiabetic Drugs: Implications for Type 2 Diabetes Mellitus
Management Front Endocrinol (Lausanne) 2017.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5256065/
[16] 
Vigneri R, Squatrito S, Frittitta L. Selective insulin receptor modulators (SIRM): a new class of antidiabetes drugs? Diabetes  2012; 61(5): 984-5.
[http://dx.doi.org/10.2337/db12-0192] [PMID:  22517652] 
[17] 
Zhang B, Salituro G, Szalkowski D, et al. Discovery of a small molecule insulin mimetic with antidiabetic activity in mice. Science  1999; 284(5416): 974-7.
[http://dx.doi.org/10.1126/science.284.5416.974] [PMID:  10320380] 
[18] 
Manchem VP, Goldfine ID, Kohanski RA, et al. A novel small molecule that directly sensitizes the insulin receptor in vitro and in vivo. Diabetes  2001; 50(4): 824-30.
[http://dx.doi.org/10.2337/diabetes.50.4.824] [PMID:  11289048] 
[19] 
Schlein M, Ludvigsen S, Olsen HB, Andersen AS, Danielsen GM, Kaarsholm NC. Properties of small molecules affecting insulin receptor function. Biochemistry  2001; 40(45): 13520-8.
[http://dx.doi.org/10.1021/bi015672w] [PMID:  11695899] 
[20] 
Laborde E, Manchem VP. Small molecule activators of the insulin receptor: potential new therapeutic agents for the treatment of diabetes mellitus. Curr Med Chem  2002; 9(24): 2231-42.
[http://dx.doi.org/10.2174/0929867023368665] [PMID:  12470244] 
[21] 
Pender C, Goldfine ID, Manchem VP, et al. Regulation of insulin receptor function by a small molecule insulin receptor activator. J Biol Chem  2002; 277(46): 43565-71.
[http://dx.doi.org/10.1074/jbc.M202426200] [PMID:  12213804] 
[22] 
Jung SH, Ha YJ, Shim EK, et al. Insulin-mimetic and insulin-sensitizing activities of a pentacyclic triterpenoid insulin receptor activator. Biochem J  2007; 403(2): 243-50.
[http://dx.doi.org/10.1042/BJ20061123] [PMID:  17201692] 
[23] 
Robinson L, Bajjalieh S, Cairns N, et al. 5-Substituted isophthalamides as insulin receptor sensitizers. Bioorg Med Chem Lett  2008; 18(12): 3492-4.
[http://dx.doi.org/10.1016/j.bmcl.2008.05.031] [PMID:  18513965] 
[24] 
Tsai HJ, Chou S-Y. A novel hydroxyfuroic acid compound as an insulin receptor activator. Structure and activity relationship of a prenylindole moiety to insulin receptor activation. J Biomed Sci  2009; 16: 68.
[http://dx.doi.org/10.1186/1423-0127-16-68] [PMID:  19642985] 
[25] 
He K, Chan C-B, Liu X, et al. Identification of a molecular activator for insulin receptor with potent anti-diabetic effects. J Biol Chem  2011; 286(43): 37379-88.
[http://dx.doi.org/10.1074/jbc.M111.247387] [PMID:  21908618] 
[26] 
Wu M, Dai G, Yao J, Hoyt S, Wang L, Mu J. Potentiation of insulin-mediated glucose lowering without elevated hypoglycemia risk by a small molecule insulin receptor modulator. PLoS One  2015; 10(3)e0122012
[http://dx.doi.org/10.1371/journal.pone.0122012] [PMID:  25799496] 
[27] 
Lin B, Li Z, Park K, et al. Identification of novel orally available small molecule insulin mimetics. J Pharmacol Exp Ther  2007; 323(2): 579-85.
[http://dx.doi.org/10.1124/jpet.107.126102] [PMID:  17687071] 
[28] 
Mukherjee S, Chattopadhyay M, Bhattacharya S, et al. A Small Insulinomimetic Molecule Also Improves Insulin Sensitivity in Diabetic Mice. PLoS One  2017; 12(1)e0169809
[http://dx.doi.org/10.1371/journal.pone.0169809] [PMID:  28072841] 
[29] 
Pillutla RC, Hsiao KC, Beasley JR, et al. Peptides identify the critical hotspots involved in the biological activation of the insulin receptor. J Biol Chem  2002; 277(25): 22590-4.
[http://dx.doi.org/10.1074/jbc.M202119200] [PMID:  11964401] 
[30] 
Schäffer L, Brissette RE, Spetzler JC, et al. Assembly of high-affinity insulin receptor agonists and antagonists from peptide building blocks. Proc Natl Acad Sci USA  2003; 100(8): 4435-9.
[http://dx.doi.org/10.1073/pnas.0830026100] [PMID:  12684539] 
[31] 
Jensen M, Hansen B, De Meyts P, Schäffer L, Ursø B. Activation of the insulin receptor by insulin and a synthetic peptide leads to divergent metabolic and mitogenic signaling and responses. J Biol Chem  2007; 282(48): 35179-86.
[http://dx.doi.org/10.1074/jbc.M704599200] [PMID:  17925406] 
[32] 
Bailey CJ. Glucose-lowering therapies in type 2 diabetes: Opportunities and challenges for peptides. Peptides  2018; 100: 9-17.
[http://dx.doi.org/10.1016/j.peptides.2017.11.012] [PMID:  29412837] 
[33] 
Ussar S, Vienberg SG, Kahn CR. Receptor antibodies as novel therapeutics for diabetes. Sci Transl Med  2011; 3(113)113ps47
[http://dx.doi.org/10.1126/scitranslmed.3003447] [PMID:  22174312] 
[34] 
Corbin JA, Bhaskar V, Goldfine ID, et al. Inhibition of insulin receptor function by a human, allosteric monoclonal antibody: a potential new approach for the treatment of hyperinsulinemic hypoglycemia. MAbs  2014; 6(1): 262-72.
[http://dx.doi.org/10.4161/mabs.26871] [PMID:  24423625] 
[35] 
Corbin JA, Bhaskar V, Goldfine ID, et al. Improved glucose metabolism in vitro and in vivo by an allosteric monoclonal antibody that increases insulin receptor binding affinity. PLoS One  2014; 9(2)e88684
[http://dx.doi.org/10.1371/journal.pone.0088684] [PMID:  24533136] 
[36] 
Bezwada P, Zhao J, Der K, et al. A Novel Allosteric Insulin Receptor-Activating Antibody Reduces Hyperglycemia without Hypoglycemia in Diabetic Cynomolgus Monkeys. J Pharmacol Exp Ther  2016; 356(2): 466-73.
[http://dx.doi.org/10.1124/jpet.115.229690] [PMID:  26578267] 
[37] 
Hinke SA, Cieniewicz AM, Kirchner T, et al. Unique pharmacology of a novel allosteric agonist/sensitizer insulin receptor monoclonal antibody. Mol Metab  2018; 10: 87-99.
[http://dx.doi.org/10.1016/j.molmet.2018.01.014] [PMID:  29453154] 
[38] 
Bhaskar V, Goldfine ID, Bedinger DH, et al. A fully human, allosteric monoclonal antibody that activates the insulin receptor and improves glycemic control. Diabetes  2012; 61(5): 1263-71.
[http://dx.doi.org/10.2337/db11-1578] [PMID:  22403294] 
[39] 
Patel P, Charles L, Corbin J, et al. A unique allosteric insulin receptor monoclonal antibody that prevents hypoglycemia in the SUR-1-/- mouse model of KATP hyperinsulinism. MAbs  2018; 10(5): 796-802.
[http://dx.doi.org/10.1080/19420862.2018.1457599] [PMID:  29589989] 
[40] 
Issafras H, Bedinger DH, Corbin JA, et al. Selective allosteric antibodies to the insulin receptor for the treatment of hyperglycemic and hypoglycemic disorders. J Diabetes Sci Technol  2014; 8(4): 865-73.
[http://dx.doi.org/10.1177/1932296814529886] [PMID:  24876415] 
[41] 
Iaboni M, Fontanella R, Rienzo A, et al. Targeting Insulin Receptor with a Novel Internalizing Aptamer. Mol Ther Nucleic Acids  2016; 5(9)e365
[http://dx.doi.org/10.1038/mtna.2016.73] [PMID:  27648925] 
[42] 
Yunn N-O, Koh A, Han S, et al. Agonistic aptamer to the insulin receptor leads to biased signaling and functional selectivity through allosteric modulation. Nucleic Acids Res  2015; 43(16): 7688-701.
[http://dx.doi.org/10.1093/nar/gkv767] [PMID:  26245346] 
[43] 
Flier JS, Kahn CR, Roth J, Bar RS. Antibodies that impair insulin receptor binding in an unusual diabetic syndrome with severe insulin resistance. Science  1975; 190(4209): 63-5.
[http://dx.doi.org/10.1126/science.170678] [PMID:  170678] 
[44] 
Maron R, Elias D, de Jongh BM, et al. Autoantibodies to the insulin receptor in juvenile onset insulin-dependent diabetes. Nature  1983; 303(5920): 817-8.
[http://dx.doi.org/10.1038/303817a0] [PMID:  6346102] 
[45] 
Batarseh H, Thompson RA, Odugbesan O, Barnett AH. Insulin receptor antibodies in diabetes mellitus. Clin Exp Immunol  1988; 71(1): 85-90.
[PMID:  3280181] 
[46] 
Elias D, Cohen IR, Schechter Y, Spirer Z, Golander A. Antibodies to insulin receptor followed by anti-idiotype. Antibodies to insulin in child with hypoglycemia. Diabetes  1987; 36(3): 348-54.
[http://dx.doi.org/10.2337/diab.36.3.348] [PMID:  3803741] 
[47] 
Shimoyama R, Fujita-Yamaguchi Y, Boden G. Anti-insulin receptor antibodies in human diabetes. Diabetes Res Clin Pract  1989; 7(Suppl. 1): S59-66.
[http://dx.doi.org/10.1016/0168-8227(89)90089-2] [PMID:  2806057] 
[48] 
Shimoyama R, Shelmet JJ, Savage CR Jr, Boden G. Effects of anti-insulin receptor antibodies (AIRA) on downregulation and turnover of insulin receptors on cultured hepatocytes. Diabetes  1986; 35(1): 28-32.
[http://dx.doi.org/10.2337/diab.35.1.28] [PMID:  3510136] 
[49] 
Brierley GV, Siddle K, Semple RK. Evaluation of anti-insulin receptor antibodies as potential novel therapies for human insulin receptoropathy using cell culture models. Diabetologia  2018; 61(7): 1662-75.
[http://dx.doi.org/10.1007/s00125-018-4606-2] [PMID:  29700562] 
[50] 
Kim HN, Fesseha B, Anzaldi L, Tsao A, Galiatsatos P, Sidhaye A. Antibody-Mediated Extreme Insulin Resistance: A Report of Three Cases. Am J Med  2018; 131(1): 102-6.
[http://dx.doi.org/10.1016/j.amjmed.2017.08.004] [PMID:  28822702] 
[51] 
Maiza J-C, Caron-Debarle M, Vigouroux C, Schneebeli S. Anti-insulin receptor antibodies related to hypoglycemia in a previously diabetic patient. Diabetes Care  2013; 36(6)e77
[http://dx.doi.org/10.2337/dc12-2664] [PMID:  23704685] 
[52] 
Toshihiro M, Katagiri H, Kataoka K, et al. Recurrent hypoglycemia during pregnancies in a woman with multiple autoantibodies including anti-insulin receptor antibody and anti-platelet antibody, whose serum lowered murine blood glucose levels and phosphorylated insulin receptor of CHO-IR cells. Endocr J  2011; 58(12): 1037-43.
[http://dx.doi.org/10.1507/endocrj.EJ11-0145] [PMID:  21931226] 
[53] 
Bortolotti D, Mothe-Satney I, Ferrari P, et al. Spontaneous hypoglycaemia in the presence of both anti-insulin antibody and anti-insulin receptor antibody. Diabetes Metab  2006; 32(6): 598-603.
[http://dx.doi.org/10.1016/S1262-3636(07)70314-2] [PMID:  17296513] 
[54] 
Castaño L, Ziegler AG, Ziegler R, Shoelson S, Eisenbarth GS. Characterization of insulin autoantibodies in relatives of patients with type I diabetes. Diabetes  1993; 42(8): 1202-9.
[http://dx.doi.org/10.2337/diab.42.8.1202] [PMID:  8325453] 
[55] 
Rochet N, Sadoul JL, Ferrua B, et al. Autoantibodies to the insulin receptor are infrequent findings in type 1 (insulin-dependent) diabetes mellitus of recent onset. Diabetologia  1990; 33(7): 411-6.
[http://dx.doi.org/10.1007/BF00404090] [PMID:  2205528] 
[56] 
Di Paolo S, Lattanzi V, Guastamacchia E, et al. Extreme insulin resistance due to anti-insulin receptor antibodies: a direct demonstration of autoantibody secretion by peripheral lymphocytes. Diabetes Res Clin Pract  1990; 9(1): 65-73.
[http://dx.doi.org/10.1016/0168-8227(90)90011-H] [PMID:  2190781] 
[57] 
Kim CH, Park JH, Park TS, Baek HS. Autoimmune hypoglycemia in a type 2 diabetic patient with anti-insulin and insulin receptor antibodies. Diabetes Care  2004; 27(1): 288-9.
[http://dx.doi.org/10.2337/diacare.27.1.288] [PMID:  14694017] 
[58] 
El-Reshaid K, Al-Mofti S, Stepic NR. Induction of insulin resistance by autoantibodies to insulin receptors following on an acute Coxsackie B4 infection. Diabetes Res Clin Pract  1994; 25(3): 207-10.
[http://dx.doi.org/10.1016/0168-8227(94)90010-8] [PMID:  7851276] 
[59] 
Segal T, Webb E, Viner R, Pusey C, Wild G, Allgrove J. Severe insulin resistance secondary to insulin antibodies: successful treatment with the immunosuppressant MMF. Pediatr Diabetes  2008; 9(3 Pt 1): 250-4.
[http://dx.doi.org/10.1111/j.1399-5448.2008.00408.x] [PMID:  18547238] 
[60] 
Magsino CH Jr, Spencer J. Insulin receptor antibodies and insulin resistance. South Med J  1999; 92(7): 717-9.
[http://dx.doi.org/10.1097/00007611-199907000-00013] [PMID:  10414483] 
[61] 
Greenfield JR, Tuthill A, Soos MA, et al. Severe insulin resistance due to anti-insulin antibodies: response to plasma exchange and immunosuppressive therapy. Diabet Med  2009; 26(1): 79-82.
[http://dx.doi.org/10.1111/j.1464-5491.2008.02621.x] [PMID:  19125765] 
[62] 
De Pirro R, Roth RA, Rossetti L, Goldfine ID. Characterization of the serum from a patient with insulin resistance and hypoglycemia. Evidence for multiple populations of insulin receptor antibodies with different receptor binding and insulin-mimicking activities. Diabetes  1984; 33(3): 301-4.
[http://dx.doi.org/10.2337/diab.33.3.301] [PMID:  6365664] 
[63] 
Jarrett DB, Roth J, Kahn CR, Flier JS. Direct method for detection and characterization of cell surface receptors for insulin by means of 125I-labeled autoantibodies against the insulin receptor. Proc Natl Acad Sci USA  1976; 73(11): 4115-9.
[http://dx.doi.org/10.1073/pnas.73.11.4115] [PMID:  1069300] 
[64] 
Kahn CR, Baird K, Filier JS, Jarrett DB. Effects of autoantibodies to the insulin receptor on isolated adipocytes. Studies of insulin binding and insulin action. J Clin Invest  1977; 60(5): 1094-106.
[http://dx.doi.org/10.1172/JCI108861] [PMID:  908753] 
[65] 
Flier JS, Kahn CR, Jarrett DB, Roth J. Autoantibodies to the insulin receptor. Effect on the insulin-receptor interaction in IM-9 lymphocytes. J Clin Invest  1977; 60(4): 784-94.
[http://dx.doi.org/10.1172/JCI108832] [PMID:  893677] 
[66] 
Taylor SI, Schroer JA, Marcus-Samuels B, McElduff A, Bender TP. Binding of insulin to its receptor impairs recognition by monoclonal anti-insulin antibodies. Diabetes  1984; 33(8): 778-84.
[http://dx.doi.org/10.2337/diab.33.8.778] [PMID:  6378700] 
[67] 
Auclair M, Vigouroux C, Desbois-Mouthon C, et al. Antiinsulin receptor autoantibodies induce insulin receptors to constitutively associate with insulin receptor substrate-1 and -2 and cause severe cell resistance to both insulin and insulin-like growth factor I. J Clin Endocrinol Metab  1999; 84(9): 3197-206.
[PMID:  10487687] 
[68] 
Fujita N, Yamasaki H, Yamakawa K, et al. Decrease in the insulin receptor protein level by anti-insulin receptor antibodies: roles of tyrosine kinase activity and receptor internalization. Acta Diabetol  2002; 39(4): 221-7.
[http://dx.doi.org/10.1007/s005920200038] [PMID:  12486497] 
[69] 
Lu R-M, Hwang Y-C, Liu I-J, et al. Development of therapeutic antibodies for the treatment of diseases. J Biomed Sci  2020; 27(1): 1.
[http://dx.doi.org/10.1186/s12929-019-0592-z] [PMID:  31894001] 
[70] 
Leavy O. Therapeutic antibodies: past, present and future. Nat Rev Immunol  2010; 10(5): 297.
[http://dx.doi.org/10.1038/nri2763] [PMID:  20422787] 
[71] 
Bedinger DH, Goldfine ID, Corbin JA, Roell MK, Adams SH. Differential pathway coupling of the activated insulin receptor drives signaling selectivity by XMetA, an allosteric partial agonist antibody. J Pharmacol Exp Ther  2015; 353(1): 35-43.
[http://dx.doi.org/10.1124/jpet.114.221309] [PMID:  25613982] 
[72] 
Bhaskar V, Lau A, Goldfine ID, et al. XMetA, an allosteric monoclonal antibody to the insulin receptor, improves glycaemic control in mice with diet-induced obesity. Diabetes Obes Metab  2013; 15(3): 272-5.
[http://dx.doi.org/10.1111/dom.12019] [PMID:  23039274] 
[73] 
Samuel VT, Shulman GI. Mechanisms for insulin resistance: common threads and missing links. Cell  2012; 148(5): 852-71.
[http://dx.doi.org/10.1016/j.cell.2012.02.017] [PMID:  22385956] 
[74] 
Erion K, Corkey BE. β-Cell Failure or β-Cell Abuse? Front Endocrinol (Lausanne)  2018; 9: 532.
[http://dx.doi.org/10.3389/fendo.2018.00532] [PMID:  30271382] 
[75] 
Heller SR. Minimizing hypoglycemia while maintaining glycemic control in diabetes. Diabetes  2008; 57(12): 3177-83.
[http://dx.doi.org/10.2337/db08-1195] [PMID:  19033404] 
[76] 
Heller S, Amiel SA, Khunti K. International Hypoglycaemia Study Group. Hypoglycaemia, a global cause for concern. Diabetes Res Clin Pract  2015; 110(2): 229-32.
[http://dx.doi.org/10.1016/j.diabres.2015.11.004] [PMID:  26669588] 
[77] 
Cryer PE. The barrier of hypoglycemia in diabetes. Diabetes  2008; 57(12): 3169-76.
[http://dx.doi.org/10.2337/db08-1084] [PMID:  19033403] 
[78] 
Thrasher J. Pharmacologic Management of Type 2 Diabetes Mellitus: Available Therapies. Am J Cardiol  2017; 120(1S): S4-S16.
[http://dx.doi.org/10.1016/j.amjcard.2017.05.009] [PMID:  28606343] 
[79] 
Raptis SA, Dimitriadis GD. Oral hypoglycemic agents: insulin secretagogues, alpha-glucosidase inhibitors and insulin sensitizers. Exp Clin Endocrinol Diabetes  2001; 109(Suppl. 2): S265-87.
[http://dx.doi.org/10.1055/s-2001-18588] [PMID:  11460577] 
[80] 
Johnson KW, Neale A, Gordon A, et al. Attenuation of Insulin Action by an Allosteric Insulin Receptor Antibody in Healthy Volunteers J. Clin Endocrinol Metab  2017; 102(8): 3021-8.
[81] 
Cieniewicz AM, Kirchner T, Hinke SA, et al. Novel Monoclonal Antibody Is an Allosteric Insulin Receptor Antagonist That Induces Insulin Resistance. Diabetes  2017; 66(1): 206-17.
[http://dx.doi.org/10.2337/db16-0633] [PMID:  27797911] 
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DOI https://dx.doi.org/10.2174/1573399816666200604122345	Print ISSN 1573-3998
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