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Current Diabetes Reviews

Editor-in-Chief

ISSN (Print): 1573-3998
ISSN (Online): 1875-6417

Mini-Review Article

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

Author(s): Arshida Ashraf, Abdulrasheed Palakkott and Mohammed Akli Ayoub*

Volume 17, Issue 2, 2021

Published on: 04 June, 2020

Page: [198 - 206] Pages: 9

DOI: 10.2174/1573399816666200604122345

Price: $65

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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