A Brief Atlas of Insulin

Esra      Ayan; Hasan      DeMirci
doi:10.2174/1573399819666220610150342
Abstract

Insulin is an essential factor for mammalian organisms: a regulator of glucose metabolism and other key signaling pathways. Insulin is also a multifunctional hormone whose absence can cause many diseases. Recombinant insulin is widely used in the treatment of diabetes. Understanding insulin, biosimilars, and biobetters from a holistic perspective will help pharmacologically user-friendly molecules design and develop personalized medicine-oriented therapeutic strategies for diabetes. Additionally, it helps to understand the underlying mechanism of other insulindependent metabolic disorders. The purpose of this atlas is to review insulin from a biotechnological, basic science, and clinical perspective, explain nearly all insulin-related disorders and their underlying molecular mechanisms, explore exogenous/recombinant production strategies of patented and research-level insulin/analogs, and highlight their mechanism of action from a structural perspective. Combined with computational analysis, comparisons of insulin and analogs also provide novel information about the structural dynamics of insulin.
Keywords: Insulin, Diabetes, Insulin analogs, Insulin structures, Recombinant insulin, Insulin dynamics.
[1]
Warram J, Krolewski A. Joslin’s Diabetes Mellitus Epidemiology of diabetes mellitus  Philadelphia. Lippincott Williams & Wilkins 2005.

[2]
Goeddel DV, Kleid DG, Bolivar F, et al. Expression in Escherichia coli of chemically synthesized genes for human insulin. Proc Natl Acad Sci USA  1979; 76(1): 106-10.
 [http://dx.doi.org/10.1073/pnas.76.1.106] [PMID:  85300]

[3]
Johnson IS. Human insulin from recombinant DNA technology. Science  1983; 219(4585): 632-7.
 [http://dx.doi.org/10.1126/science.6337396]

[4]
Lipska KJ, Ross JS, Van Houten HK, Beran D, Yudkin JS, Shah ND. Use and out-of-pocket costs of insulin for type 2 diabetes mellitus from 2000 through 2010. JAMA  2014; 311(22): 2331-3.
 [http://dx.doi.org/10.1001/jama.2014.6316] [PMID:  24915266]

[5]
Zaykov AN, Mayer JP, DiMarchi RD. Pursuit of a perfect insulin. Nat Rev Drug Discov  2016; 15(6): 425-39.
 [http://dx.doi.org/10.1038/nrd.2015.36] [PMID:  26988411]

[6]
Glendorf T, Stidsen CE, Norrman M, Nishimura E, Sørensen AR, Kjeldsen T. Engineering of insulin receptor isoform-selective insulin analogues. PLoS One  2011; 6(5): e20288.
 [http://dx.doi.org/10.1371/journal.pone.0020288] [PMID:  21625452]

[7]
Edgerton DS, Moore MC, Winnick JJ, et al. Changes in glucose and fat metabolism in response to the administration of a hepato-preferential insulin analog. Diabetes  2014; 63(11): 3946-54.
 [http://dx.doi.org/10.2337/db14-0266] [PMID:  24947349]

[8]
Gough SCL, Bode BW, Woo VC, et al. One-year efficacy and safety of a fixed combination of insulin degludec and liraglutide in patients with type 2 diabetes: Results of a 26-week extension to a 26-week main trial. Diabetes Obes Metab  2015; 17(10): 965-73.
 [http://dx.doi.org/10.1111/dom.12498] [PMID:  25980900]

[9]
Mo R, Jiang T, Di J, Tai W, Gu Z. Emerging micro- and nanotechnology based synthetic approaches for insulin delivery. Chem Soc Rev  2014; 43(10): 3595-629.
 [http://dx.doi.org/10.1039/c3cs60436e] [PMID:  24626293]

[10]
Hovorka R. Closed-loop insulin delivery: From bench to clinical practice. Nat Rev Endocrinol  2011; 7(7): 385-95.
 [http://dx.doi.org/10.1038/nrendo.2011.32] [PMID:  21343892]

[11]
Banting FG, Best CH, Collip JB, Macleod JJR, Noble EC. The effect of pancreatic extract (insulin) on normal rabbits. Am J Physiol Content  1922; 62(1): 162-76.

[12]
Macleod JJR. Insulin and diabetes: A general statement of the physiological and therapeutic effects of insulin. BMJ  1922; 2(3227): 833-5.
 [http://dx.doi.org/10.1136/bmj.2.3227.833] [PMID:  20770902]

[13]
Lefever E, Vliebergh J, Mathieu C. Improving the treatment of patients with diabetes using insulin analogues: Current findings and future directions. Expert Opin Drug Saf  2021; 20(2): 155-69.
 [http://dx.doi.org/10.1080/14740338.2021.1856813] [PMID:  33249944]

[14]
Fralick M, Zinman B. The discovery of insulin in Toronto: Beginning a 100 year journey of research and clinical achievement. Diabetologia 2021.
 [http://dx.doi.org/10.1007/s00125-020-05371-6]

[15]
Bliss M. Banting’s, Best’s, and Collip’s accounts of the discovery of insulin. Bull Hist Med  1982; 56(4): 554-68.
 [PMID:  6760943]

[16]
Shah SN, Joshi SR, Parmar DV. History of insulin. J Assoc Physicians India  1997;  (Suppl. 1)4-9.
 [PMID:  11235634]

[17]
Vecchio I, Tornali C, Bragazzi NL, Martini M. The discovery of insulin: An important milestone in the history of medicine. Front Endocrinol (Lausanne)  2018; 9: 613.
 [http://dx.doi.org/10.3389/fendo.2018.00613] [PMID:  30405529]

[18]
Joshi SR, Parikh RM, Das AK. Insulin-history, biochemistry, physiology and pharmacology. J Assoc Physicians India  2007; 55 (Suppl.): 19-25.
 [PMID:  17927007]

[19]
Tokarz VL, MacDonald PE, Klip A. The cell biology of systemic insulin function. J Cell Biol  2018; 217(7): 2273-89.
 [http://dx.doi.org/10.1083/jcb.201802095] [PMID:  29622564]

[20]
Bogardus C, Lillioja S, Howard BV, Reaven G, Mott D. Relationships between insulin secretion, insulin action, and fasting plasma glucose concentration in nondiabetic and noninsulin-dependent diabetic subjects. J Clin Invest  1984; 74(4): 1238-46.
 [http://dx.doi.org/10.1172/JCI111533] [PMID:  6384267]

[21]
Howell SL, Taylor KW. Potassium ions and the secretion of insulin by islets of Langerhans incubated in vitro. Biochem J  1968; 108(1): 17-24.
 [http://dx.doi.org/10.1042/bj1080017] [PMID:  4297939]

[22]
Brissova M, Shiota M, Nicholson WE, et al. Reduction in pancreatic transcription factor PDX-1 impairs glucose-stimulated insulin secretion. J Biol Chem  2002; 277(13): 11225-32.
 [http://dx.doi.org/10.1074/jbc.M111272200] [PMID:  11781323]

[23]
Xia CQ, Zhang P, Li S, et al. C-Abl inhibitor imatinib enhances insulin production by β cells: c-Abl negatively regulates insulin production via interfering with the expression of NKx2.2 and GLUT-2. PLoS One  2014; 9(5): e97694.
 [http://dx.doi.org/10.1371/journal.pone.0097694] [PMID:  24835010]

[24]
Koranyi L, James DE, Kraegen EW, Permutt MA. Feedback inhibition of insulin gene expression by insulin. J Clin Invest  1992; 89(2): 432-6.
 [http://dx.doi.org/10.1172/JCI115602] [PMID:  1737834]

[25]
Harper ME, Ullrich A, Saunders GF. Localization of the human insulin gene to the distal end of the short arm of chromosome 11. Proc Natl Acad Sci USA  1981; 78(7): 4458-60.
 [http://dx.doi.org/10.1073/pnas.78.7.4458] [PMID:  7027261]

[26]
Lemaire K, Ravier MA, Schraenen A, et al. Insulin crystallization depends on zinc transporter ZnT8 expression, but is not required for normal glucose homeostasis in mice. Proc Natl Acad Sci USA  2009; 106(35): 14872-7.
 [http://dx.doi.org/10.1073/pnas.0906587106] [PMID:  19706465]

[27]
Fu Z, Gilbert ER, Liu D. Regulation of insulin synthesis and secretion and pancreatic Beta-cell dysfunction in diabetes. Curr Diabetes Rev  2013; 9(1): 25-53.
 [http://dx.doi.org/10.2174/157339913804143225] [PMID:  22974359]

[28]
Frederickson CJ, Koh JY, Bush AI. The neurobiology of zinc in health and disease. Nat Rev Neurosci  2005; 6(6): 449-62.
 [http://dx.doi.org/10.1038/nrn1671] [PMID:  15891778]

[29]
Carroll RJ, Hammer RE, Chan SJ, Swift HH, Rubenstein AH, Steiner DF. A mutant human proinsulin is secreted from islets of Langerhans in increased amounts via an unregulated pathway. Proc Natl Acad Sci USA  1988; 85(23): 8943-7.
 [http://dx.doi.org/10.1073/pnas.85.23.8943] [PMID:  3057496]

[30]
Emdin SO, Dodson GG, Cutfield JM, Cutfield SM. Role of zinc in insulin biosynthesis. Some possible zinc-insulin interactions in the pancreatic B-cell. Diabetologia  1980; 19(3): 174-82.
 [http://dx.doi.org/10.1007/BF00275265] [PMID:  6997118]

[31]
Smith LF. Species variation in the amino acid sequence of insulin. Am J Med  1966; 40(5): 662-6.
 [http://dx.doi.org/10.1016/0002-9343(66)90145-8] [PMID:  5949593]

[32]
Tiran J, Avruch LI, Albisser AM. A circulation and organs model for insulin dynamics. Am J Physiol Endocrinol Metab Gastrointest Physiol  1979; 237(4): E331-9.
 [http://dx.doi.org/10.1152/ajpendo.1979.237.4.E331]

[33]
Meier JJ, Veldhuis JD, Butler PC. Pulsatile insulin secretion dictates systemic insulin delivery by regulating hepatic insulin extraction in humans. Diabetes  2005; 54(6): 1649-56.
 [http://dx.doi.org/10.2337/diabetes.54.6.1649] [PMID:  15919785]

[34]
Li YV. Zinc and insulin in pancreatic beta-cells. Endocrine  2014; 45(2): 178-89.
 [http://dx.doi.org/10.1007/s12020-013-0032-x] [PMID:  23979673]

[35]
Lizcano JM, Alessi DR. The insulin signalling pathway. Curr Biol  2002; 12(7): R236-8.
 [http://dx.doi.org/10.1016/S0960-9822(02)00777-7] [PMID:  11937037]

[36]
Boura-Halfon S, Zick Y. Phosphorylation of IRS proteins, insulin action, and insulin resistance. Am J Physiol Endocrinol Metab  2009; 296(4): E581-91.
 [http://dx.doi.org/10.1152/ajpendo.90437.2008] [PMID:  18728222]

[37]
Shisheva A. Phosphoinositides in insulin action on GLUT4 dynamics: Not just PtdIns(3,4,5)P3. Am J Physiol Endocrinol Metab  2008; 295(3): E536-44.
 [http://dx.doi.org/10.1152/ajpendo.90353.2008] [PMID:  18492765]

[38]
Mackenzie RWA, Elliott BT. Akt/PKB activation and insulin signaling: A novel insulin signaling pathway in the treatment of type 2 diabetes. Diabetes Metab Syndr Obes  2014; 7: 55-64.
 [http://dx.doi.org/10.2147/DMSO.S48260] [PMID:  24611020]

[39]
Feng J, Park J, Cron P, Hess D, Hemmings BA. Identification of a PKB/Akt hydrophobic motif Ser-473 kinase as DNA-dependent protein kinase. J Biol Chem  2004; 279(39): 41189-96.
 [http://dx.doi.org/10.1074/jbc.M406731200] [PMID:  15262962]

[40]
Biondi RM, Kieloch A, Currie RA, Deak M, Alessi DR. The PIF-binding pocket in PDK1 is essential for activation of S6K and SGK, but not PKB. EMBO J  2001; 20(16): 4380-90.
 [http://dx.doi.org/10.1093/emboj/20.16.4380] [PMID:  11500365]

[41]
Chiang SH, Baumann CA, Kanzaki M, et al. Insulin-stimulated GLUT4 translocation requires the CAP-dependent activation of TC10. Nature  2001; 410(6831): 944-8.
 [http://dx.doi.org/10.1038/35073608] [PMID:  11309621]

[42]
Cohen P, Nimmo HG, Proud CG. How does insulin stimulate glycogen synthesis? Biochem Soc Symp  1978; (43): 69-95.
 [PMID:  219866]

[43]
Shen SW, Reaven GM, Farquhar JW. Comparison of impedance to insulin-mediated glucose uptake in normal subjects and in subjects with latent diabetes. J Clin Invest  1970; 49(12): 2151-60.
 [http://dx.doi.org/10.1172/JCI106433] [PMID:  5480843]

[44]
Gathercole LL, Morgan SA, Bujalska IJ, Hauton D, Stewart PM, Tomlinson JW. Regulation of lipogenesis by glucocorticoids and insulin in human adipose tissue. PLoS One  2011; 6(10): e26223.
 [http://dx.doi.org/10.1371/journal.pone.0026223] [PMID:  22022575]

[45]
Beitner R, Kalant N. Stimulation of glycolysis by insulin. J Biol Chem  1971; 246(2): 500-3.
 [http://dx.doi.org/10.1016/S0021-9258(18)62516-5] [PMID:  5542017]

[46]
Keku TO, Lund PK, Galanko J, Simmons JG, Woosley JT, Sandler RS. Insulin resistance, apoptosis, and colorectal adenoma risk. Cancer Epidemiol Biomarkers Prev  2005; 14(9): 2076-81.
 [http://dx.doi.org/10.1158/1055-9965.EPI-05-0239] [PMID:  16172212]

[47]
Proud CG. Regulation of protein synthesis by insulin. Biochem Soc Trans  2006; 34(Pt 2): 213-6.
 [http://dx.doi.org/10.1042/BST0340213] [PMID:  16545079]

[48]
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]

[49]
Goldstein BJ, Ahmad F, Ding W, Li PM, Zhang WR. Regulation of the insulin signalling pathway by cellular protein-tyrosine phosphatases. Mol Cell Biochem  1998; 182(1-2): 91-9.
 [http://dx.doi.org/10.1023/A:1006812218502] [PMID:  9609118]

[50]
Khan AH, Pessin JE. Insulin regulation of glucose uptake: A complex interplay of intracellular signalling pathways. Diabetologia  2002; 45(11): 1475-83.
 [http://dx.doi.org/10.1007/s00125-002-0974-7] [PMID:  12436329]

[51]
Di Camillo B, Carlon A, Eduati F, Toffolo GM. A rule-based model of insulin signalling pathway. BMC Syst Biol  2016; 10(1): 38.
 [http://dx.doi.org/10.1186/s12918-016-0281-4] [PMID:  27245161]

[52]
Diseases associated with INS | Open Targets Platform.  Available from: https://platform.opentargets.org/target/ENSG00000254647/associations?view=t:bubbles

[53]
EMBL-EBI.  Available from: https://www.ebi.ac.uk/ols/ontologies/efo/terms/graph?iri=https://www.ebi.ac.uk/efo/EFO_0009605

[54]
Hanna SJ, Powell WE, Long AE, et al. Slow progressors to type 1 diabetes lose islet autoantibodies over time, have few islet antigen-specific CD8+ T cells and exhibit a distinct CD95hi B cell phenotype. Diabetologia  2020; 63(6): 1174-85.
 [http://dx.doi.org/10.1007/s00125-020-05114-7] [PMID:  32157332]

[55]
Ramirez DG, Abenojar E, Hernandez C, et al. Contrast-enhanced ultrasound with sub-micron sized contrast agents detects insulitis in mouse models of type1 diabetes. Nat Commun  2020; 11(1): 2238.
 [http://dx.doi.org/10.1038/s41467-020-15957-8] [PMID:  32382089]

[56]
Bao S, Wu YL, Wang X, et al. Agriophyllum oligosaccharides ameliorate hepatic injury in type 2 diabetic db/db mice targeting INS-R/IRS-2/PI3K/AKT/PPAR-γ/Glut4 signal pathway. J Ethnopharmacol  2020; 257: 112863.
 [http://dx.doi.org/10.1016/j.jep.2020.112863] [PMID:  32302715]

[57]
Wei W, Tian H, Fu X, Yao R, Su D. Participates in vertical sleeve gastrectomy for type II diabetes mellitus by regulating TGR5. Med Sci Monit  2020; 26: e920628.
 [http://dx.doi.org/10.12659/MSM.920628] [PMID:  32242546]

[58]
De Franco E, Saint-Martin C, Brusgaard K, et al. Update of variants identified in the pancreatic β-cell KATP channel genes KCNJ11 and ABCC8 in individuals with congenital hyperinsulinism and diabetes. Hum Mutat  2020; 41(5): 884-905.
 [http://dx.doi.org/10.1002/humu.23995] [PMID:  32027066]

[59]
Alshaikh OM, Yoon JY, Chan BA, et al. Pancreatic neuroendocrine tumor producing insulin and vasopressin. Endocr Pathol  2018; 29(1): 15-20.
 [http://dx.doi.org/10.1007/s12022-017-9492-5] [PMID:  28718084]

[60]
Zheng Y, Wu C, Yang J, et al. Insulin-like growth factor 1-induced enolase 2 deacetylation by HDAC3 promotes metastasis of pancreatic cancer. Signal Transduct Target Ther  2020; 5(1): 53.
 [http://dx.doi.org/10.1038/s41392-020-0146-6] [PMID:  32398667]

[61]
Evidence for INS and cardiovascular disease. Open Targets Platform  Available from: https://platform.opentargets.org/evidence/ENSG00000254647/
EFO_0000319

[62]
Fontbonne AM, Eschwege EM. Insulin and cardiovascular disease: Paris prospective study. Diabetes Care  1991; 14(6): 461-9.

[63]
Nabel EG. Cardiovascular disease. N Engl J Med  2003; 349(1): 60-72.

[64]
Steinberger J, Moorehead C, Katch V, Rocchini AP. Relationship between insulin resistance and abnormal lipid profile in obese adolescents. J Pediatr  1995; 126(5 Pt 1): 690-5.
 [http://dx.doi.org/10.1016/S0022-3476(95)70394-2] [PMID:  7751990]

[65]
Ferreira AP, Oliveira CER, França NM. Metabolic syndrome and risk factors for cardiovascular disease in obese children: The relationship with insulin resistance (HOMA-IR). J Pediatr (Rio J)  2007; 83(1): 21-6.
 [http://dx.doi.org/10.2223/JPED.1562] [PMID:  17183416]

[66]
Ormazabal V, Nair S, Elfeky O, Aguayo C, Salomon C, Zuñiga FA. Association between insulin resistance and the development of cardiovascular disease. Cardiovasc Diabetol  2018; 17(1): 122.
 [http://dx.doi.org/10.1186/s12933-018-0762-4] [PMID:  30170598]

[67]
Reaven G. Insulin resistance and coronary heart disease in nondiabetic individuals. Arterioscler Thromb Vasc Biol  2012; 32(8): 1754-9.
 [http://dx.doi.org/10.1161/ATVBAHA.111.241885] [PMID:  22815340]

[68]
Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res  2010; 107(9): 1058-70.
 [http://dx.doi.org/10.1161/CIRCRESAHA.110.223545] [PMID:  21030723]

[69]
Bornfeldt KE, Tabas I. Insulin resistance, hyperglycemia, and atherosclerosis. Cell Metab  2011; 14(5): 575-85.
 [http://dx.doi.org/10.1016/j.cmet.2011.07.015] [PMID:  22055501]

[70]
Gast KB, Tjeerdema N, Stijnen T, Smit JWA, Dekkers OM. Insulin resistance and risk of incident cardiovascular events in adults without diabetes: Meta-analysis. PLoS One  2012; 7(12): e52036.
 [http://dx.doi.org/10.1371/journal.pone.0052036] [PMID:  23300589]

[71]
Sarwar N, Gao P, Seshasai SR, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: A collaborative meta-analysis of 102 prospective studies. Lancet  2010; 375(9733): 2215-22.
 [http://dx.doi.org/10.1016/S0140-6736(10)60484-9] [PMID:  20609967]

[72]
Sarwar N, Sattar N, Gudnason V, Danesh J. Circulating concentrations of insulin markers and coronary heart disease: A quantitative review of 19 Western prospective studies. Eur Heart J  2007; 28(20): 2491-7.
 [http://dx.doi.org/10.1093/eurheartj/ehm115] [PMID:  17513304]

[73]
Drinkwater JJ, Davis TME, Davis WA. The relationship between carotid disease and retinopathy in diabetes: A systematic review. Cardiovasc Diabetol  2020; 19(1): 54.
 [http://dx.doi.org/10.1186/s12933-020-01023-6] [PMID:  32375803]

[74]
Mujaj B, Bos D, Kavousi M, et al. Serum insulin levels are associated with vulnerable plaque components in the carotid artery: The Rotterdam Study. Eur J Endocrinol  2020; 182(3): 343-50.
 [http://dx.doi.org/10.1530/EJE-19-0620] [PMID:  31958313]

[75]
van Hoek I, Hodgkiss-Geere H, Bode EF, et al. Associations among echocardiography, cardiac biomarkers, insulin metabolism, morphology, and inflammation in cats with asymptomatic hypertrophic cardiomyopathy. J Vet Intern Med  2020; 34(2): 591-9.
 [http://dx.doi.org/10.1111/jvim.15730] [PMID:  32045061]

[76]
Chaudhuri A, Janicke D, Wilson MF, et al. Anti-inflammatory and profibrinolytic effect of insulin in acute ST-segment-elevation myocardial infarction. Circulation  2004; 109(7): 849-54.
 [http://dx.doi.org/10.1161/01.CIR.0000116762.77804.FC] [PMID:  14757687]

[77]
Kwon TG, Jang AY, Kim SW, et al. Design and rationale of a randomized control trial testing the effectiveness of combined therapy with STAtin plus FENOfibrate and statin alone in non-diabetic, combined dyslipidemia patients with non-intervened intermediate coronary artery disease - STAFENO study. Trials  2020; 21(1): 353.
 [http://dx.doi.org/10.1186/s13063-020-04291-5] [PMID:  32321551]

[78]
Larsen AH, Jessen N, Nørrelund H, et al. A randomised, double-blind, placebo-controlled trial of metformin on myocardial efficiency in insulin-resistant chronic heart failure patients without diabetes. Eur J Heart Fail  2020; 22(9): 1628-37.
 [http://dx.doi.org/10.1002/ejhf.1656] [PMID:  31863557]

[79]
Ohkuma T, Van Gaal L, Shaw W, et al. Clinical outcomes with canagliflozin according to baseline body mass index: results from post hoc analyses of the CANVAS Program. Diabetes Obes Metab  2020; 22(4): 530-9.
 [http://dx.doi.org/10.1111/dom.13920] [PMID:  31729107]

[80]
Immune system disease profile page. Open Targets Platform.  Available from:https://platform.opentargets.org/disease/EFO_0000540

[81]
Medzhitov R, Janeway CA Jr. Innate immunity: Impact on the adaptive immune response. Curr Opin Immunol  1997; 9(1): 4-9.
 [http://dx.doi.org/10.1016/S0952-7915(97)80152-5] [PMID:  9039775]

[82]
Eheim A, Medrikova D, Herzig S. Immune cells and metabolic dysfunction. Semin Immunopathol  2014; 36(1): 13-25.
 [http://dx.doi.org/10.1007/s00281-013-0403-7] [PMID:  24212254]

[83]
Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest  2003; 112(12): 1796-808.
 [http://dx.doi.org/10.1172/JCI200319246] [PMID:  14679176]

[84]
Morrison MC, Kleemann R. Role of macrophage migration inhibitory factor in obesity, insulin resistance, type 2 diabetes, and associated hepatic comorbidities: A comprehensive review of human and rodent studies. Front Immunol  2015; 6: 308.
 [http://dx.doi.org/10.3389/fimmu.2015.00308] [PMID:  26124760]

[85]
Patel PS, Buras ED, Balasubramanyam A. The role of the immune system in obesity and insulin resistance. J Obes  2013; 2013: 616193.
 [http://dx.doi.org/10.1155/2013/616193] [PMID:  23577240]

[86]
Lumeng CN, DelProposto JB, Westcott DJ, Saltiel AR. Phenotypic switching of adipose tissue macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes. Diabetes  2008; 57(12): 3239-46.
 [http://dx.doi.org/10.2337/db08-0872] [PMID:  18829989]

[87]
Miyachi Y, Tsuchiya K, Shiba K, et al. A reduced M1-like/M2-like ratio of macrophages in healthy adipose tissue expansion during SGLT2 inhibition. Sci Rep  2018; 8(1): 16113.
 [http://dx.doi.org/10.1038/s41598-018-34305-x] [PMID:  30382157]

[88]
Shimokawa C, Kato T, Takeuchi T, et al. CD8+ regulatory T cells are critical in prevention of autoimmune-mediated diabetes. Nat Commun  2020; 11(1): 1922.
 [http://dx.doi.org/10.1038/s41467-020-15857-x] [PMID:  32321922]

[89]
Yeo L, Pujol-Autonell I, Baptista R, et al. Circulating β cell-specific CD8+ T cells restricted by high-risk HLA class I molecules show antigen experience in children with and at risk of type 1 diabetes. Clin Exp Immunol  2020; 199(3): 263-77.
 [http://dx.doi.org/10.1111/cei.13391] [PMID:  31660582]

[90]
Kamoda T, Saito T, Kinugasa H, et al. A case of Shwachman-Diamond syndrome presenting with diabetes from early infancy. Diabetes Care  2005; 28(6): 1508-9.
 [http://dx.doi.org/10.2337/diacare.28.6.1508] [PMID:  15920082]

[91]
Murray BR, Jewell JR, Jackson KJ, Agboola O, Alexander BR, Sharma P. Type III hypersensitivity reaction to subcutaneous insulin preparations in a type 1 diabetic. J Gen Intern Med  2017; 32(7): 841-5.
 [http://dx.doi.org/10.1007/s11606-017-4037-7] [PMID:  28337685]

[92]
Li J, Sipple J, Maynard S, et al. Fanconi anemia links reactive oxygen species to insulin resistance and obesity. Antioxid Redox Signal  2012; 17(8): 1083-98.
 [http://dx.doi.org/10.1089/ars.2011.4417] [PMID:  22482891]

[93]
Cronin CC, Shanahan F. Insulin-dependent diabetes mellitus and coeliac disease. Lancet  1997; 349(9058): 1096-7.
 [http://dx.doi.org/10.1016/S0140-6736(96)09153-2] [PMID:  9107261]

[94]
Vigneri R, Sciacca L, Vigneri P. Rethinking the relationship between insulin and cancer. Trends Endocrinol Metab  2020; 31(8): 551-60.
 [http://dx.doi.org/10.1016/j.tem.2020.05.004] [PMID:  32600959]

[95]
Aaronson SA. Growth factors and cancer. Science  1991; 254(5035): 1146-53.
 [http://dx.doi.org/10.1126/science.1659742]

[96]
Cai W, Sakaguchi M, Kleinridders A, et al. Domain-dependent effects of insulin and IGF-1 receptors on signalling and gene expression. Nat Commun  2017; 8: 14892.
 [http://dx.doi.org/10.1038/ncomms14892] [PMID:  28345670]

[97]
Malaguarnera R, Belfiore A. The insulin receptor: A new target for cancer therapy. Front Endocrinol (Lausanne)  2011; 2: 93.
 [http://dx.doi.org/10.3389/fendo.2011.00093] [PMID:  22654833]

[98]
LeRoith D, Roberts CT Jr. The insulin-like growth factor system and cancer. Cancer Lett  2003; 195(2): 127-37.
 [http://dx.doi.org/10.1016/S0304-3835(03)00159-9] [PMID:  12767520]

[99]
Nervous system disease profile page. Open Targets Platform.  Available from:https://platform.opentargets.org/disease/EFO_0000618

[100]
Belfiore A, Frasca F, Pandini G, Sciacca L, Vigneri R. Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease. Endocr Rev  2009; 30(6): 586-623.
 [http://dx.doi.org/10.1210/er.2008-0047] [PMID:  19752219]

[101]
Ye P, Xing Y, Dai Z, D’Ercole AJ. In vivo actions of insulin-like growth factor-I (IGF-I) on cerebellum development in transgenic mice: Evidence that IGF-I increases proliferation of granule cell progenitors. Brain Res Dev Brain Res  1996; 95(1): 44-54.
 [http://dx.doi.org/10.1016/0165-3806(96)00492-0] [PMID:  8873975]

[102]
Park CR. Cognitive effects of insulin in the central nervous system. Neurosci Biobehav Rev  2001; 25(4): 311-23.
 [http://dx.doi.org/10.1016/S0149-7634(01)00016-1] [PMID:  11445137]

[103]
Kim B, Feldman EL. Insulin resistance in the nervous system. Trends Endocrinol Metab  2012; 23(3): 133-41.
 [http://dx.doi.org/10.1016/j.tem.2011.12.004] [PMID:  22245457]

[104]
O’Kusky JR, Ye P, D’Ercole AJ. Insulin-like growth factor-I promotes neurogenesis and synaptogenesis in the hippocampal dentate gyrus during postnatal development. J Neurosci  2000; 20(22): 8435-42.
 [http://dx.doi.org/10.1523/JNEUROSCI.20-22-08435.2000] [PMID:  11069951]

[105]
Poduslo JF, Curran GL, Wengenack TM, Malester B, Duff K. Permeability of proteins at the blood-brain barrier in the normal adult mouse and double transgenic mouse model of Alzheimer’s disease. Neurobiol Dis  2001; 8(4): 555-67.
 [http://dx.doi.org/10.1006/nbdi.2001.0402] [PMID:  11493021]

[106]
de la Monte SM, Wands JR. Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: Relevance to Alzheimer’s disease. J Alzheimers Dis  2005; 7(1): 45-61.
 [http://dx.doi.org/10.3233/JAD-2005-7106] [PMID:  15750214]

[107]
de la Monte SM. Insulin resistance and Alzheimer’s disease. BMB Rep  2009; 42: 475-81.

[108]
Batista AF, Forny-Germano L, Clarke JR, et al. The diabetes drug liraglutide reverses cognitive impairment in mice and attenuates insulin receptor and synaptic pathology in a non-human primate model of Alzheimer’s disease. J Pathol  2018; 245(1): 85-100.
 [http://dx.doi.org/10.1002/path.5056] [PMID:  29435980]

[109]
Ferreira LSS, Fernandes CS, Vieira MNN, De Felice FG. Insulin resistance in Alzheimer’s disease. Front Neurosci  2018; 12: 830.
 [http://dx.doi.org/10.3389/fnins.2018.00830] [PMID:  30542257]

[110]
De Felice FG, Vieira MN, Bomfim TR, et al. Protection of synapses against Alzheimer’s-linked toxins: Insulin signaling prevents the pathogenic binding of Abeta oligomers. Proc Natl Acad Sci USA  2009; 106(6): 1971-6.
 [http://dx.doi.org/10.1073/pnas.0809158106] [PMID:  19188609]

[111]
Townsend M, Mehta T, Selkoe DJ. Soluble Abeta inhibits specific signal transduction cascades common to the insulin receptor pathway. J Biol Chem  2007; 282(46): 33305-12.
 [http://dx.doi.org/10.1074/jbc.M610390200] [PMID:  17855343]

[112]
Bomfim TR, Forny-Germano L, Sathler LB, et al. An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease- associated Aβ oligomers. J Clin Invest  2012; 122(4): 1339-53.
 [http://dx.doi.org/10.1172/JCI57256] [PMID:  22476196]

[113]
Sebastião I, Candeias E, Santos MS, de Oliveira CR, Moreira PI, Duarte AI. Insulin as a bridge between type 2 diabetes and Alzheimer disease - how anti-diabetics could be a solution for dementia. Front Endocrinol (Lausanne)  2014; 5: 110.
 [http://dx.doi.org/10.3389/fendo.2014.00110] [PMID:  25071725]

[114]
Lourenco MV, Clarke JR, Frozza RL, et al. TNF-α mediates PKR-dependent memory impairment and brain IRS-1 inhibition induced by Alzheimer’s β-amyloid oligomers in mice and monkeys. Cell Metab  2013; 18(6): 831-43.
 [http://dx.doi.org/10.1016/j.cmet.2013.11.002] [PMID:  24315369]

[115]
Tai J, Liu W, Li Y, Li L, Hölscher C. Neuroprotective effects of a triple GLP-1/GIP/glucagon receptor agonist in the APP/PS1 transgenic mouse model of Alzheimer’s disease. Brain Res  2018; 1678: 64-74.
 [http://dx.doi.org/10.1016/j.brainres.2017.10.012] [PMID:  29050859]

[116]
Faheem A, Rehman K, Jabeen K, Akash MSH. Nicotine-mediated upregulation of microRNA-141 expression determines adipokine-intervened insulin resistance. Environ Toxicol Pharmacol  2020; 80: 103506.
 [http://dx.doi.org/10.1016/j.etap.2020.103506] [PMID:  33002592]

[117]
Cerecedo-Lopez CD, Cantu-Aldana A, Patel NJ, Aziz-Sultan MA, Frerichs KU, Du R. Insulin in the management of acute ischemic stroke: A systematic review and meta-analysis. World Neurosurg  2020; 136: e514-34.
 [http://dx.doi.org/10.1016/j.wneu.2020.01.056] [PMID:  31954893]

[118]
Ryan AS, Hafer-Macko C, Ortmeyer HK. Insulin resistance in skeletal muscle of chronic stroke. Brain Sci  2021; 11(1): 20.
 [PMID:  33375333]

[119]
Koslow SH, Stokes PE, Mendels J, Ramsey A, Casper R. Insulin tolerance test: human growth hormone response and insulin resistance in primary unipolar depressed, bipolar depressed and control subjects. Psychol Med  1982; 12(1): 45-55.
 [http://dx.doi.org/10.1017/S0033291700043270] [PMID:  7043520]

[120]
Corica G, Ceraudo M, Campana C, et al. Octreotide-resistant acromegaly: Challenges and solutions. Ther Clin Risk Manag  2020; 16: 379-91.
 [http://dx.doi.org/10.2147/TCRM.S183360] [PMID:  32440136]

[121]
Guerreiro V, Bernardes I, Pereira J, et al. Acromegaly with congenital generalized lipodystrophy - Two rare insulin resistance conditions in one patient: A case report. J Med Case Reports  2020; 14: 34.
 [http://dx.doi.org/10.1186/s13256-020-2352-9]

[122]
Peng S, Yang J, Wang Y, et al. Low-dose intranasal insulin improves cognitive function and suppresses the development of epilepsy. Brain Res  2020; 1726: 146474.
 [http://dx.doi.org/10.1016/j.brainres.2019.146474] [PMID:  31557476]

[123]
Ellis B, Arsiwalla D. The moderating role of anxiety in the associations
between sleep and insulin resistance. CSBS INSPIRE Student
Res Engagem Conf 2020.  Available from: https://scholarworks.uni.edu/csbsresearchconf/2020/all/73

[124]
Rodríguez-Rabassa M, López P, Sánchez R, et al. Inflammatory biomarkers, microbiome, depression, and executive dysfunction in alcohol users. Int J Environ Res Public Health  2020; 17(3): E689.
 [http://dx.doi.org/10.3390/ijerph17030689] [PMID:  31973090]

[125]
McDonald TS, Kumar V, Fung JN, Woodruff TM, Lee JD. Glucose clearance and uptake is increased in the SOD1G93A mouse model of amyotrophic lateral sclerosis through an insulin-independent mechanism. FASEB J  2021; 35(7): e21707.
 [http://dx.doi.org/10.1096/fj.202002450R] [PMID:  34118098]

[126]
Toth C, Brussee V, Martinez JA, McDonald D, Cunningham FA, Zochodne DW. Rescue and regeneration of injured peripheral nerve axons by intrathecal insulin. Neuroscience  2006; 139(2): 429-49.
 [http://dx.doi.org/10.1016/j.neuroscience.2005.11.065] [PMID:  16529870]

[127]
Brener A, Sagi L, Shtamler A, Levy S, Fattal-Valevski A, Lebenthal Y. Insulin-like growth factor-1 status is associated with insulin resistance in young patients with spinal muscular atrophy. Neuromuscul Disord  2020; 30(11): 888-96.
 [http://dx.doi.org/10.1016/j.nmd.2020.09.025] [PMID:  33071067]

[128]
 Genetic, familial or congenital disease profile page.  Open Targets
Platform Available from: https://platform.opentargets.org/disease/OTAR_0000018

[129]
Zambon AA, Muntoni F. Congenital muscular dystrophies: What is new? Neuromuscul Disord  2021; 31(10): 931-42.
 [http://dx.doi.org/10.1016/j.nmd.2021.07.009] [PMID:  34470717]

[130]
Lindhurst MJ, Parker VER, Payne F, et al. Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA. Nat Genet  2012; 44(8): 928-33.
 [http://dx.doi.org/10.1038/ng.2332] [PMID:  22729222]

[131]
Mori M, Kumada T, Inoue K, et al. Ketogenic diet for refractory epilepsy with MEHMO syndrome: Caution for acute necrotizing pancreatitis. Brain Dev  2021; 43(6): 724-8.
 [http://dx.doi.org/10.1016/j.braindev.2021.02.002] [PMID:  33714664]

[132]
Auer MK, Birnbaum W, Hartmann MF, et al. Metabolic effects of estradiol versus testosterone in complete androgen insensitivity syndrome. Endocrine 2022.
 [http://dx.doi.org/10.1007/s12020-022-03017-8]

[133]
Baker LA, Nef S, Nguyen MT, et al. The insulin-3 gene: Lack of a genetic basis for human cryptorchidism. J Urol  2002; 167(6): 2534-7.
 [http://dx.doi.org/10.1016/S0022-5347(05)65029-X] [PMID:  11992081]

[134]
Kanaka-Gantenbein C, Kitsiou S, Mavrou A, et al. Tall stature, insulin resistance, and disturbed behavior in a girl with the triple X syndrome harboring three SHOX genes: Offspring of a father with mosaic Klinefelter syndrome but with two maternal X chromosomes. Horm Res  2004; 61(5): 205-10.
 [PMID:  14752208]

[135]
Rasio E, Antaki A, Van Campenhout J. Diabetes mellitus in gonadal dysgenesis: studies of insulin and growth hormone secretion. Eur J Clin Invest  1976; 6(1): 59-66.
 [http://dx.doi.org/10.1111/j.1365-2362.1976.tb00494.x] [PMID:  1253808]

[136]
Musculoskeletal or connective tissue disease profile page. Open Targets Platform  Available from: https://platform.opentargets.org/disease/OTAR_0000006

[137]
DeFronzo RA, Tripathy D. Skeletal muscle insulin resistance is the primary defect in type 2 diabetes. Diabetes Care  2009; 32 (Suppl. 2): S157-63.
 [http://dx.doi.org/10.2337/dc09-S302] [PMID:  19875544]

[138]
Garneau L, Aguer C. Role of myokines in the development of skeletal muscle insulin resistance and related metabolic defects in type 2 diabetes. Diabetes Metab  2019; 45(6): 505-16.
 [http://dx.doi.org/10.1016/j.diabet.2019.02.006] [PMID:  30844447]

[139]
Jabłońska K, Molęda P, Safranow K, Majkowska L. Rapid-acting and regular insulin are equal for high fat-protein meal in individuals with type 1 diabetes treated with multiple daily injections. Diabetes Ther  2018; 9(1): 339-48.
 [http://dx.doi.org/10.1007/s13300-017-0364-2] [PMID:  29344829]

[140]
Avery H. Insulin fat atrophy a traumatic atrophic panniculitis. BMJ  1929; 1(3560): 597-9.
 [http://dx.doi.org/10.1136/bmj.1.3560.597-a] [PMID:  20774578]

[141]
Shigematsu Y, Hamada M, Nagai T, et al. Risk for atrial fibrillation in patients with hypertrophic cardiomyopathy: Association with insulin resistance. J Cardiol  2011; 58(1): 18-25.
 [http://dx.doi.org/10.1016/j.jjcc.2011.03.001] [PMID:  21515029]

[142]
Cannarella R, Barbagallo F, Condorelli RA, Aversa A, La Vignera S, Calogero AE. Osteoporosis from an endocrine perspective: The role of hormonal changes in the elderly. J Clin Med  2019; 8(10): E1564.
 [http://dx.doi.org/10.3390/jcm8101564] [PMID:  31581477]

[143]
Xia J, Zhong Y, Huang G, Chen Y, Shi H, Zhang Z. The relationship between insulin resistance and osteoporosis in elderly male type 2 diabetes mellitus and diabetic nephropathy. Ann Endocrinol (Paris)  2012; 73(6): 546-51.
 [http://dx.doi.org/10.1016/j.ando.2012.09.009]

[144]
Prill H, Luu A, Yip B, et al. Differential uptake of NAGLU-IGF2 and unmodified NAGLU in cellular models of Sanfilippo syndrome type B. Mol Ther Methods Clin Dev  2019; 14: 56-63.
 [http://dx.doi.org/10.1016/j.omtm.2019.05.008] [PMID:  31309128]

[145]
Muniyappa R, Warren MA, Zhao X, et al. Reduced insulin sensitivity in adults with pseudohypoparathyroidism type 1a. J Clin Endocrinol Metab  2013; 98(11): E1796-801.
 [http://dx.doi.org/10.1210/jc.2013-1594] [PMID:  24030943]

[146]
Liu J, Liu W, Li H, et al. Identification of key genes and pathways associated with cholangiocarcinoma development based on weighted gene correlation network analysis. PeerJ  2019; 7: e7968.
 [http://dx.doi.org/10.7717/peerj.7968] [PMID:  31687280]

[147]
Liu G, Liu S, Xing G, Wang F. lncRNA PVT1/MicroRNA-17-5p/PTEN axis regulates secretion of E2 and P4, proliferation, and apoptosis of ovarian granulosa cells in PCOS. Mol Ther Nucleic Acids  2020; 20: 205-16.
 [http://dx.doi.org/10.1016/j.omtn.2020.02.007] [PMID:  32179451]

[148]
Devis-Jauregui L, Eritja N, Davis ML, Matias-Guiu X, Llobet-Navàs D. Autophagy in the physiological endometrium and cancer. Autophagy  2021; 17(5): 1077-95.
 [http://dx.doi.org/10.1080/15548627.2020.1752548] [PMID:  32401642]

[149]
Pugliese G, Penno G, Natali A, et al. Diabetic kidney disease: new clinical and therapeutic issues. Joint position statement of the Italian Diabetes Society and the Italian Society of Nephrology on “The natural history of diabetic kidney disease and treatment of hyperglycemia in patients with type 2 diabetes and impaired renal function”. J Nephrol  2020; 33(1): 9-35.
 [http://dx.doi.org/10.1007/s40620-019-00650-x] [PMID:  31576500]

[150]
Kukla A, Hill J, Merzkani M, et al. The use of GLP1R agonists for the treatment of type 2 diabetes in kidney transplant recipients. Transplant Direct  2020; 6(2): e524.
 [http://dx.doi.org/10.1097/TXD.0000000000000971] [PMID:  32095510]

[151]
Ratnakumar A, Weinhold N, Mar JC, Riaz N. Protein-Protein interactions uncover candidate ‘core genes’ within omnigenic disease networks. PLoS Genet  2020; 16(7): e1008903.
 [http://dx.doi.org/10.1371/journal.pgen.1008903] [PMID:  32678846]

[152]
Gao W, Guo N, Zhao S, et al. Carboxypeptidase A4 promotes cardiomyocyte hypertrophy through activating PI3K-AKT-mTOR signaling. Biosci Rep  2020; 40(5): BSR20200669.
 [http://dx.doi.org/10.1042/BSR20200669] [PMID:  32347291]

[153]
Meerson A. Leptin-responsive MiR-4443 is a small regulatory RNA independent of the canonic microRNA biogenesis pathway. Biomolecules  2020; 10(2): E293.
 [http://dx.doi.org/10.3390/biom10020293] [PMID:  32069948]

[154]
Kern W, Stange EF, Fehm HL, Klein HH. Glucocorticoid-induced diabetes mellitus in gastrointestinal diseases TT - Glucocorticoid-induzierter Diabetes mellitus bei gastroenterologischen Erkrankungen. Z Gastroenterol 1999.

[155]
Kaaks R. Nutrition, hormones, and breast cancer: Is insulin the missing link? Cancer Causes Control  1996; 7(6): 605-25.
 [http://dx.doi.org/10.1007/BF00051703] [PMID:  8932921]

[156]
Pellegrino M, Traversi G, Arena A, et al. Effect of p53 activation through targeting MDM2/MDM4 heterodimer on T regulatory and effector cells in the peripheral blood of Type 1 diabetes patients. PLoS One  2020; 15(1): e0228296.
 [http://dx.doi.org/10.1371/journal.pone.0228296] [PMID:  31995625]

[157]
Rose DP, Komninou D, Stephenson GD. Obesity, adipocytokines, and insulin resistance in breast cancer. Obes Rev  2004; 5(3): 153-65.
 [http://dx.doi.org/10.1111/j.1467-789X.2004.00142.x] [PMID:  15245384]

[158]
Bruning PF, Bonfrèr JMG, van Noord PAH, Hart AAM, de Jong-Bakker M, Nooijen WJ. Insulin resistance and breast-cancer risk. Int J Cancer  1992; 52(4): 511-6.
 [http://dx.doi.org/10.1002/ijc.2910520402] [PMID:  1399128]

[159]
Papa V, Pezzino V, Costantino A, et al. Elevated insulin receptor content in human breast cancer. J Clin Invest  1990; 86(5): 1503-10.
 [http://dx.doi.org/10.1172/JCI114868] [PMID:  2243127]

[160]
Lee J, Chang Y, Kim Y, Park B, Ryu S. Insulin resistance and the development of breast cancer in premenopausal women: The Kangbuk Samsung Health Study. Breast Cancer Res Treat  2022; 192(2): 401-9.
 [http://dx.doi.org/10.1007/s10549-022-06513-7] [PMID:  34997879]

[161]
Barbieri M, Ragno E, Benvenuti E, et al. New aspects of the insulin resistance syndrome: Impact on haematological parameters. Diabetologia  2001; 44(10): 1232-7.
 [http://dx.doi.org/10.1007/s001250100634] [PMID:  11692171]

[162]
Niklasson B, Hörnfeldt B, Lundman B. Could myocarditis, insulin-dependent diabetes mellitus, and Guillain-Barré syndrome be caused by one or more infectious agents carried by rodents? Emerg Infect Dis  1998; 4(2): 187-93.
 [http://dx.doi.org/10.3201/eid0402.980206] [PMID:  9621189]

[163]
Maeno T, Okumura A, Ishikawa T, et al. Mechanisms of increased insulin resistance in non-cirrhotic patients with chronic hepatitis C virus infection. J Gastroenterol Hepatol  2003; 18(12): 1358-63.
 [http://dx.doi.org/10.1046/j.1440-1746.2003.03179.x] [PMID:  14675263]

[164]
Bisschop PH, de Rooij SE, Zwinderman AH, van Oosten HE, van Munster BC. Cortisol, insulin, and glucose and the risk of delirium in older adults with hip fracture. J Am Geriatr Soc  2011; 59(9): 1692-6.
 [http://dx.doi.org/10.1111/j.1532-5415.2011.03575.x] [PMID:  21883119]

[165]
Amgarth-Duff I, Hosie A, Caplan G, Agar M. A systematic review of the overlap of fluid biomarkers in delirium and advanced cancer-related syndromes. BMC Psychiatry  2020; 20(1): 182.
 [http://dx.doi.org/10.1186/s12888-020-02584-2] [PMID:  32321448]

[166]
Association AD. Diagnosis and classification of diabetes mellitus. Diabetes Care  2010; 33: S62-9.

[167]
Inzucchi SE. Clinical practice. Diagnosis of diabetes. N Engl J Med  2012; 367(6): 542-50.
 [http://dx.doi.org/10.1056/NEJMcp1103643] [PMID:  22873534]

[168]
Mantzoros C.  Insulin resistance: Definition and clinical spectrum UpToDate 2018.

[169]
Banting FG, Best CH, Collip JB, Campbell WR, Fletcher AA. Pancreatic extracts in the treatment of diabetes mellitus. 1922. Indian J Med Res  2007; 125(3): 141-6.
 [PMID:  17580419]

[170]
Haeusler RA, McGraw TE, Accili D. Metabolic Signalling: Biochemical and cellular properties of insulin receptor signalling. Nat Rev Mol Cell Biol  2018; 19: 31-44.

[171]
Himsworth HP. Diabetes mellitus. Its differentiation into insolin-sensitive and insulin-insensitive types. Lancet  1936; 230: 127-30.
 [http://dx.doi.org/10.1016/S0140-6736(01)36134-2]

[172]
Hagedorn HC. Protamine Insulinate. Proc R Soc Med  1937; 30(6): 805-14.
 [http://dx.doi.org/10.1177/003591573703000643] [PMID:  19991109]

[173]
Siddiqui H, Scupola A. User involvement in R&D at novo nordisk
diabetes treatment development.  Available from: https://rucforsk.ruc.dk/ws/portalfiles/portal/64978123/Master_Thes
is_2019_Helmand__Turu.pdf

[174]
Odegard PS, Capoccia KL. Inhaled insulin: Exubera. Ann Pharmacother  2005; 39(5): 843-53.

[175]
White S, Bennett DB, Cheu S, et al. EXUBERA: Pharmaceutical development of a novel product for pulmonary delivery of insulin. Diabetes Technol Ther  2005; 7(6): 896-906.
 [http://dx.doi.org/10.1089/dia.2005.7.896] [PMID:  16386095]

[176]
Bailey CJ, Barnett AH. Why is Exubera being withdrawn? BMJ  2007; 335: 1156.
 [http://dx.doi.org/10.1136/bmj.39409.507662.94]

[177]
Monami M, Mannucci E. Efficacy and safety of degludec insulin: A meta-analysis of randomised trials. Curr Med Res Opin  2013; 29(4): 339-42.
 [http://dx.doi.org/10.1185/03007995.2013.772507] [PMID:  23368895]

[178]
De Jesus DF, Kulkarni RN. “Omics” and “epi-omics” underlying the β-cell adaptation to insulin resistance. Mol Metab  2019; 27S: S42-8.
 [http://dx.doi.org/10.1016/j.molmet.2019.06.003] [PMID:  31500830]

[179]
Grant SFA, Thorleifsson G, Reynisdottir I, et al. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet  2006; 38(3): 320-3.
 [http://dx.doi.org/10.1038/ng1732] [PMID:  16415884]

[180]
Altshuler D, Hirschhorn JN, Klannemark M, et al. The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet  2000; 26(1): 76-80.
 [http://dx.doi.org/10.1038/79216] [PMID:  10973253]

[181]
Mitchell RK, Mondragon A, Chen L, et al. Selective disruption of Tcf7l2 in the pancreatic β cell impairs secretory function and lowers β cell mass. Hum Mol Genet  2015; 24(5): 1390-9.
 [http://dx.doi.org/10.1093/hmg/ddu553] [PMID:  25355422]

[182]
Scott LJ, Mohlke KL, Bonnycastle LL, et al. A genome-wide association study of type 2 diabetes in finns detects multiple susceptibility variants. Science  2007; 316(5829): 1341-5.
 [http://dx.doi.org/10.1126/science.1142382]

[183]
Consortium WTCC, Burton PR, Donnelly P, et al. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature  2007; 447(7145): 661-78.
 [http://dx.doi.org/10.1038/nature05911] [PMID:  17554300]

[184]
Saxena R, Voight BF, Lyssenko V, et al. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science  2007; 316(5829): 1331-6.
 [http://dx.doi.org/10.1126/science.1142358]

[185]
Davidson HW, Wenzlau JM, O’Brien RM. Zinc transporter 8 (ZnT8) and β cell function. Trends Endocrinol Metab  2014; 25(8): 415-24.
 [http://dx.doi.org/10.1016/j.tem.2014.03.008] [PMID:  24751356]

[186]
Syring KE, Boortz KA, Oeser JK, et al. Combined deletion of Slc30a7 and Slc30a8 unmasks a critical role for ZnT8 in glucose-stimulated insulin secretion. Endocrinology  2016; 157(12): 4534-41.
 [http://dx.doi.org/10.1210/en.2016-1573] [PMID:  27754787]

[187]
Ayers K, Kumar R, Robevska G, et al. Familial bilateral cryptorchidism is caused by recessive variants in RXFP2. J Med Genet  2019; 56(11): 727-33.
 [http://dx.doi.org/10.1136/jmedgenet-2019-106203] [PMID:  31167797]

[188]
Cannon ME, Currin KW, Young KL, et al. Open chromatin profiling in adipose tissue marks genomic regions with functional roles in cardiometabolic traits. G3 (Bethesda)  2019; 9(8): 2521-33.

[189]
Tekola-Ayele F, Lee A, Workalemahu T, et al. Genetic overlap between birthweight and adult cardiometabolic diseases has implications for genomic medicine. Sci Rep  2019; 9(1): 4076.
 [http://dx.doi.org/10.1038/s41598-019-40834-w] [PMID:  30858448]

[190]
Harrison sm, Bush nc,  Wang y, et al. Insulin-like peptide 3 (insl3) serum concentration during human male fetal life. Front Endocrinol (Lausanne) 2019; 10: 596.
 [http://dx.doi.org/10.3389/fendo.2019.00596] [PMID:  31611843]

[191]
Zhu Z, Zhang F, Hu H, et al. Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets. Nat Genet  2016; 48(5): 481-7.
 [http://dx.doi.org/10.1038/ng.3538] [PMID:  27019110]

[192]
Wu Y, Zeng J, Zhang F, et al. Integrative analysis of omics summary data reveals putative mechanisms underlying complex traits. Nat Commun  2018; 9(1): 918.
 [http://dx.doi.org/10.1038/s41467-018-03371-0] [PMID:  29500431]

[193]
Xue A, Wu Y, Zhu Z, et al. Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes. Nat Commun  2018; 9(1): 2941.
 [http://dx.doi.org/10.1038/s41467-018-04951-w] [PMID:  30054458]

[194]
Jaspers S, Lok S, Lofton-Day CE, et al. The genomics of Insulin 5. In: Tregear GW, Ivell R, Bathgate RA, Wade JD, Eds. Relaxin 2000.  Dordrecht: Springer 2001; pp. 363-9.
 [http://dx.doi.org/10.1007/978-94-017-2877-5_61]

[195]
Bhandare R, Schug J, Le Lay J, et al. Genome-wide analysis of histone modifications in human pancreatic islets. Genome Res  2010; 20(4): 428-33.
 [http://dx.doi.org/10.1101/gr.102038.109] [PMID:  20181961]

[196]
Khetan S, Kursawe R, Youn A, et al. Type 2 diabetes-associated genetic variants regulate chromatin accessibility in human islets. Diabetes  2018; 67(11): 2466-77.
 [http://dx.doi.org/10.2337/db18-0393]

[197]
Raurell-Vila H, Ramos-Rodríguez M, Pasquali L. Assay for transposase accessible chromatin (ATAC-Seq) to chart the open chromatin landscape of human Pancreatic Islets. Methods Mol Biol  2018; 1766: 197-208.

[198]
Gao T, McKenna B, Li C, et al. Pdx1 maintains β cell identity and function by repressing an α cell program. Cell Metab  2014; 19(2): 259-71.
 [http://dx.doi.org/10.1016/j.cmet.2013.12.002] [PMID:  24506867]

[199]
Parveen N, Dhawan S. DNA methylation patterning and the regulation of beta cell homeostasis. Front Endocrinol (Lausanne)  2021; 12: 651258.
 [http://dx.doi.org/10.3389/fendo.2021.651258] [PMID:  34025578]

[200]
LaPierre MP, Stoffel M. MicroRNAs as stress regulators in pancreatic beta cells and diabetes. Mol Metab  2017; 6(9): 1010-23.
 [http://dx.doi.org/10.1016/j.molmet.2017.06.020] [PMID:  28951825]

[201]
Frost RJA, Olson EN. Control of glucose homeostasis and insulin sensitivity by the Let-7 family of microRNAs. Proc Natl Acad Sci USA  2011; 108(52): 21075-80.
 [http://dx.doi.org/10.1073/pnas.1118922109] [PMID:  22160727]

[202]
Motterle A, Gattesco S, Peyot ML, et al. Identification of islet-enriched long non-coding RNAs contributing to β-cell failure in type 2 diabetes. Mol Metab  2017; 6(11): 1407-18.
 [http://dx.doi.org/10.1016/j.molmet.2017.08.005] [PMID:  29107288]

[203]
Singer RA, Sussel L. Islet long noncoding RNAs: A playbook for discovery and characterization. Diabetes  2018; 67(8): 1461-70.
 [http://dx.doi.org/10.2337/dbi18-0001] [PMID:  29937433]

[204]
Poy MN, Hausser J, Trajkovski M, et al. miR-375 maintains normal pancreatic alpha- and beta-cell mass. Proc Natl Acad Sci USA  2009; 106(14): 5813-8.
 [http://dx.doi.org/10.1073/pnas.0810550106] [PMID:  19289822]

[205]
De Jesus DF, Kulkarni RN. Epigenetic modifiers of islet function and mass. Trends Endocrinol Metab  2014; 25(12): 628-36.
 [http://dx.doi.org/10.1016/j.tem.2014.08.006] [PMID:  25246382]

[206]
Ling C, Del Guerra S, Lupi R, et al. Epigenetic regulation of PPARGC1A in human type 2 diabetic islets and effect on insulin secretion. Diabetologia  2008; 51(4): 615-22.
 [http://dx.doi.org/10.1007/s00125-007-0916-5] [PMID:  18270681]

[207]
Sachdeva MM, Claiborn KC, Khoo C, et al. Pdx1 (MODY4) regulates pancreatic beta cell susceptibility to ER stress. Proc Natl Acad Sci USA  2009; 106(45): 19090-5.
 [http://dx.doi.org/10.1073/pnas.0904849106] [PMID:  19855005]

[208]
Stoffers DA, Zinkin NT, Stanojevic V, Clarke WL, Habener JF. Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Genet  1997; 15(1): 106-10.
 [http://dx.doi.org/10.1038/ng0197-106] [PMID:  8988180]

[209]
Volkmar M, Dedeurwaerder S, Cunha DA, et al. DNA methylation profiling identifies epigenetic dysregulation in pancreatic islets from type 2 diabetic patients. EMBO J  2012; 31(6): 1405-26.
 [http://dx.doi.org/10.1038/emboj.2011.503] [PMID:  22293752]

[210]
Yang BT, Dayeh TA, Kirkpatrick CL, et al. Insulin promoter DNA methylation correlates negatively with insulin gene expression and positively with HbA1c levels in human pancreatic islets. Diabetologia  2011; 54: 360-7.
 [http://dx.doi.org/10.1007/s00125-010-1967-6]

[211]
Volkov P, Bacos K, Ofori JK, et al. Whole-Genome bisulfite sequencing of human pancreatic islets reveals novel differentially methylated regions in type 2 diabetes pathogenesis. Diabetes  2017; 66(4): 1074-85.
 [http://dx.doi.org/10.2337/db16-0996] [PMID:  28052964]

[212]
Willmer T, Johnson R, Louw J, Pheiffer C. Blood-based DNA methylation biomarkers for type 2 diabetes: Potential for clinical applications. Front Endocrinol (Lausanne)  2018; 9: 744.
 [http://dx.doi.org/10.3389/fendo.2018.00744] [PMID:  30564199]

[213]
Gunton JE, Kulkarni RN, Yim S, et al. Loss of ARNT/HIF1beta mediates altered gene expression and pancreatic-islet dysfunction in hu-man type 2 diabetes. Cell  2005; 122(3): 337-49.
 [http://dx.doi.org/10.1016/j.cell.2005.05.027] [PMID:  16096055]

[214]
Marselli L, Thorne J, Dahiya S, et al. Gene expression profiles of Beta-cell enriched tissue obtained by laser capture microdissection from subjects with type 2 diabetes. PLoS One  2010; 5(7): e11499.
 [http://dx.doi.org/10.1371/journal.pone.0011499] [PMID:  20644627]

[215]
Fadista J, Vikman P, Laakso EO, et al. Global genomic and transcriptomic analysis of human pancreatic islets reveals novel genes influencing glucose metabolism. Proc Natl Acad Sci USA  2014; 111(38): 13924-9.
 [http://dx.doi.org/10.1073/pnas.1402665111] [PMID:  25201977]

[216]
Bader E, Migliorini A, Gegg M, et al. Identification of proliferative and mature β-cells in the islets of Langerhans. Nature  2016; 535(7612): 430-4.
 [http://dx.doi.org/10.1038/nature18624] [PMID:  27398620]

[217]
Dorrell C, Schug J, Canaday PS, et al. Human islets contain four distinct subtypes of β cells. Nat Commun  2016; 7: 11756.
 [http://dx.doi.org/10.1038/ncomms11756] [PMID:  27399229]

[218]
Williams MD, Joglekar MV, Satoor SN, et al. Epigenetic and transcriptome profiling identifies a population of visceral adipose-derived progenitor cells with the potential to differentiate into an endocrine pancreatic lineage. Cell Transplant  2019; 28(1): 89-104.
 [http://dx.doi.org/10.1177/0963689718808472] [PMID:  30376726]

[219]
Xin Y, Kim J, Okamoto H, et al. RNA sequencing of single human islet cells reveals type 2 diabetes genes. Cell Metab  2016; 24(4): 608-15.
 [http://dx.doi.org/10.1016/j.cmet.2016.08.018] [PMID:  27667665]

[220]
Segerstolpe Å, Palasantza A, Eliasson P, et al. Single-cell transcriptome profiling of human pancreatic islets in health and type 2 diabetes. Cell Metab  2016; 24(4): 593-607.
 [http://dx.doi.org/10.1016/j.cmet.2016.08.020] [PMID:  27667667]

[221]
Lawlor N, George J, Bolisetty M, et al. Single-cell transcriptomes identify human islet cell signatures and reveal cell-type-specific expression changes in type 2 diabetes. Genome Res  2017; 27(2): 208-22.
 [http://dx.doi.org/10.1101/gr.212720.116] [PMID:  27864352]

[222]
Arystarkhova E, Liu YB, Salazar C, et al. Hyperplasia of pancreatic beta cells and improved glucose tolerance in mice deficient in the FXYD2 subunit of Na,K-ATPase. J Biol Chem  2013; 288(10): 7077-85.
 [http://dx.doi.org/10.1074/jbc.M112.401190] [PMID:  23344951]

[223]
Nachtergaele S, He C. Chemical modifications in the life of an mRNA transcript. Annu Rev Genet  2018; 52: 349-72.
 [http://dx.doi.org/10.1146/annurev-genet-120417-031522] [PMID:  30230927]

[224]
Desrosiers R, Friderici K, Rottman F. Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells. Proc Natl Acad Sci USA  1974; 71(10): 3971-5.
 [http://dx.doi.org/10.1073/pnas.71.10.3971] [PMID:  4372599]

[225]
Lavi S, Shatkin AJ. Methylated simian virus 40-specific RNA from nuclei and cytoplasm of infected BSC-1 cells. Proc Natl Acad Sci USA  1975; 72(6): 2012-6.
 [http://dx.doi.org/10.1073/pnas.72.6.2012] [PMID:  166375]

[226]
Zheng G, Dahl JA, Niu Y, et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol Cell  2013; 49(1): 18-29.
 [http://dx.doi.org/10.1016/j.molcel.2012.10.015] [PMID:  23177736]

[227]
Jia G, Fu Y, Zhao X, et al. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol  2011; 7(12): 885-7.
 [http://dx.doi.org/10.1038/nchembio.687] [PMID:  22002720]

[228]
Roignant JY, Soller M. m6A in mRNA: An ancient mechanism for fine-tuning gene expression. Trends Genet  2017; 33(6): 380-90.
 [http://dx.doi.org/10.1016/j.tig.2017.04.003] [PMID:  28499622]

[229]
Nedelkov D, Niederkofler EE, Oran PE, Peterman S, Nelson RW. Top-down mass spectrometric immunoassay for human insulin and its therapeutic analogs. J Proteomics  2018; 175: 27-33.
 [http://dx.doi.org/10.1016/j.jprot.2017.08.001] [PMID:  28780057]

[230]
Marks V, Teale JD. Investigation of hypoglycaemia. Clin Endocrinol (Oxf)  1996; 44(2): 133-6.
 [http://dx.doi.org/10.1046/j.1365-2265.1996.659478.x] [PMID:  8849564]

[231]
Brackenridge A, Wallbank H, Lawrenson RA, Russell-Jones D. Emergency management of diabetes and hypoglycaemia. Emerg Med J  2006; 23(3): 183-5.
 [http://dx.doi.org/10.1136/emj.2005.026252] [PMID:  16498153]

[232]
Kristensen PL, Hansen LS, Jespersen MJ, et al. Insulin analogues and severe hypoglycaemia in type 1 diabetes. Diabetes Res Clin Pract  2012; 96(1): 17-23.
 [http://dx.doi.org/10.1016/j.diabres.2011.10.046] [PMID:  22136722]

[233]
Sonksen PH. Insulin, growth hormone and sport. J Endocrinol  2001; 170(1): 13-25.
 [http://dx.doi.org/10.1677/joe.0.1700013] [PMID:  11431133]

[234]
Marks V, Wark G. Forensic aspects of insulin. Diabetes Res Clin Pract  2013; 101(3): 248-54.
 [http://dx.doi.org/10.1016/j.diabres.2013.05.002] [PMID:  23751444]

[235]
Parfitt C, Church D, Armston A, et al. Commercial insulin immunoassays fail to detect commonly prescribed insulin analogues. Clin Biochem  2015; 48(18): 1354-7.
 [http://dx.doi.org/10.1016/j.clinbiochem.2015.07.017] [PMID:  26171976]

[236]
Blackburn M. Advances in the quantitation of therapeutic insulin analogues by LC-MS/MS. Bioanalysis  2013; 5(23): 2933-46.
 [http://dx.doi.org/10.4155/bio.13.257] [PMID:  24295119]

[237]
Sundsten T, Ortsäter H. Proteomics in diabetes research. Mol Cell Endocrinol  2009; 297(1-2): 93-103.
 [http://dx.doi.org/10.1016/j.mce.2008.06.018] [PMID:  18657591]

[238]
Mitok KA, Freiberger EC, Schueler KL, et al. Islet proteomics reveals genetic variation in dopamine production resulting in altered insulin secretion. J Biol Chem  2018; 293(16): 5860-77.
 [http://dx.doi.org/10.1074/jbc.RA117.001102] [PMID:  29496998]

[239]
Larsson S, Resjö S, Gomez MF, James P, Holm C. Characterization of the lipid droplet proteome of a clonal insulin-producing β-cell line (INS-1 832/13). J Proteome Res  2012; 11(2): 1264-73.
 [http://dx.doi.org/10.1021/pr200957p] [PMID:  22268682]

[240]
Elhadad MA, Jonasson C, Huth C, et al. Deciphering the plasma proteome of type 2 diabetes. Diabetes  2020; 69(12): 2766-78.
 [http://dx.doi.org/10.2337/db20-0296] [PMID:  32928870]

[241]
Carlsson AC, Nowak C, Lind L, et al. Growth differentiation factor 15 (GDF-15) is a potential biomarker of both diabetic kidney disease and future cardiovascular events in cohorts of individuals with type 2 diabetes: A proteomics approach. Ups J Med Sci  2020; 125(1): 37-43.
 [http://dx.doi.org/10.1080/03009734.2019.1696430] [PMID:  31805809]

[242]
Jedrychowski MP, Gartner CA, Gygi SP, et al. Proteomic analysis of GLUT4 storage vesicles reveals LRP1 to be an important vesicle component and target of insulin signaling. J Biol Chem  2010; 285(1): 104-14.
 [http://dx.doi.org/10.1074/jbc.M109.040428] [PMID:  19864425]

[243]
Gibney MJ, Walsh M, Brennan L, Roche HM, German B, van Ommen B. Metabolomics in human nutrition: opportunities and challenges. Am J Clin Nutr  2005; 82(3): 497-503.
 [http://dx.doi.org/10.1093/ajcn/82.3.497] [PMID:  16155259]

[244]
Lu J, Xie G, Jia W, Jia W. Metabolomics in human type 2 diabetes research. Front Med  2013; 7(1): 4-13.
 [http://dx.doi.org/10.1007/s11684-013-0248-4] [PMID:  23377891]

[245]
Gu X, Al Dubayee M, Alshahrani A, et al. Distinctive metabolomics patterns associated with insulin resistance and type 2 diabetes mellitus. Front Mol Biosci  2020; 7: 609806.
 [http://dx.doi.org/10.3389/fmolb.2020.609806] [PMID:  33381523]

[246]
Bos MM, Noordam R, Bennett K, et al. Metabolomics analyses in non-diabetic middle-aged individuals reveal metabolites impacting early glucose disturbances and insulin sensitivity. Metabolomics  2020; 16(3): 35.
 [http://dx.doi.org/10.1007/s11306-020-01653-7] [PMID:  32124065]

[247]
Salihovic S, Broeckling CD, Ganna A, et al. Non-targeted urine metabolomics and associations with prevalent and incident type 2 diabetes. Sci Rep  2020; 10(1): 16474.
 [http://dx.doi.org/10.1038/s41598-020-72456-y] [PMID:  33020500]

[248]
Yan Z, Wu H, Zhou H, et al. Integrated metabolomics and gut microbiome to the effects and mechanisms of naoxintong capsule on type 2 diabetes in rats. Sci Rep  2020; 10(1): 10829.
 [http://dx.doi.org/10.1038/s41598-020-67362-2] [PMID:  32616735]

[249]
Li L, Krznar P, Erban A, et al. Metabolomics identifies a biomarker revealing in vivo loss of functional β-cell mass before diabetes onset. Diabetes  2019; 68(12): 2272-86.
 [http://dx.doi.org/10.2337/db19-0131] [PMID:  31537525]

[250]
Zhang Y, Zhang S, Wang G. Metabolomic biomarkers in diabetic kidney diseases-A systematic review. J Diabetes Complications  2015; 29(8): 1345-51.
 [http://dx.doi.org/10.1016/j.jdiacomp.2015.06.016] [PMID:  26253264]

[251]
Kim OY, Lee JH, Sweeney G. Metabolomic profiling as a useful tool for diagnosis and treatment of chronic disease: Focus on obesity, diabetes and cardiovascular diseases. Expert Rev Cardiovasc Ther  2013; 11(1): 61-8.
 [http://dx.doi.org/10.1586/erc.12.121] [PMID:  23259446]

[252]
Lynch CJ, Adams SH. Branched-chain amino acids in metabolic signalling and insulin resistance. Nat Rev Endocrinol  2014; 10(12): 723-36.
 [http://dx.doi.org/10.1038/nrendo.2014.171] [PMID:  25287287]

[253]
Zhao X, Gang X, Liu Y, Sun C, Han Q, Wang G. Using metabolomic profiles as biomarkers for insulin resistance in childhood obesity: A systematic review. J Diabetes Res  2016; 2016: 8160545.
 [http://dx.doi.org/10.1155/2016/8160545] [PMID:  27517054]

[254]
Huang M, Joseph JW. Metabolomic analysis of pancreatic β-cell insulin release in response to glucose. Islets  2012; 4(3): 210-22.
 [http://dx.doi.org/10.4161/isl.20141] [PMID:  22847496]

[255]
Han J, Tan H, Duan Y, et al. The cardioprotective properties and the involved mechanisms of NaoXinTong capsule. Pharmacol Res  2019; 141: 409-17.
 [http://dx.doi.org/10.1016/j.phrs.2019.01.024] [PMID:  30660824]

[256]
Parry S, Hadaschik D, Blancher C, et al. Glycomics investigation into insulin action. Biochim Biophys Acta  2006; 1760(4): 652-68.
 [http://dx.doi.org/10.1016/j.bbagen.2005.12.013] [PMID:  16473469]

[257]
Apweiler R, Hermjakob H, Sharon N. On the frequency of protein glycosylation, as deduced from analysis of the SWISS-PROT database. Biochim Biophys Acta  1999; 1473(1): 4-8.
 [http://dx.doi.org/10.1016/S0304-4165(99)00165-8] [PMID:  10580125]

[258]
Wormald MR, Petrescu AJ, Pao YL, Glithero A, Elliott T, Dwek RA. Conformational studies of oligosaccharides and glycopeptides: Complementarity of NMR, X-ray crystallography, and molecular modelling. Chem Rev  2002; 102(2): 371-86.
 [http://dx.doi.org/10.1021/cr990368i] [PMID:  11841247]

[259]
Crocker PR. Siglecs: sialic-acid-binding immunoglobulin-like lectins in cell-cell interactions and signalling. Curr Opin Struct Biol  2002; 12(5): 609-15.
 [http://dx.doi.org/10.1016/S0959-440X(02)00375-5] [PMID:  12464312]

[260]
Esko JD, Selleck SB. Order out of chaos: Assembly of ligand binding sites in heparan sulfate. Annu Rev Biochem  2002; 71: 435-71.
 [http://dx.doi.org/10.1146/annurev.biochem.71.110601.135458] [PMID:  12045103]

[261]
Rabinovich GA, Baum LG, Tinari N, et al. Galectins and their ligands: Amplifiers, silencers or tuners of the inflammatory response? Trends Immunol  2002; 23(6): 313-20.
 [http://dx.doi.org/10.1016/S1471-4906(02)02232-9] [PMID:  12072371]

[262]
Dwek RA. Towards understanding the function of sugars. Biochem Soc Trans  1995; 23(1): 1-25.

[263]
Helenius A, Aebi M. Roles of N-linked glycans in the endoplasmic reticulum. Annu Rev Biochem  2004; 73: 1019-49.
 [http://dx.doi.org/10.1146/annurev.biochem.73.011303.073752] [PMID:  15189166]

[264]
Wang C, Eufemi M, Turano C, Giartosio A. Influence of the carbohydrate moiety on the stability of glycoproteins. Biochemistry  1996; 35(23): 7299-307.
 [http://dx.doi.org/10.1021/bi9517704] [PMID:  8652506]

[265]
Dennis JW, Granovsky M, Warren CE. Protein glycosylation in development and disease. BioEssays  1999; 21(5): 412-21.
 [http://dx.doi.org/10.1002/(SICI)1521-1878(199905)21:5<412:AID-BIES8>3.0.CO;2-5] [PMID:  10376012]

[266]
Eckel RH, Alberti KGMM, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet  2010; 375(9710): 181-3.
 [http://dx.doi.org/10.1016/S0140-6736(09)61794-3] [PMID:  20109902]

[267]
Lim J-M, Wollaston-Hayden EE, Teo CF, Hausman D, Wells L. Quantitative secretome and glycome of primary human adipocytes during insulin resistance. Clin Proteomics  2014; 11(1): 20.
 [http://dx.doi.org/10.1186/1559-0275-11-20] [PMID:  24948903]

[268]
Marshall S, Bacote V, Traxinger RR. Discovery of a metabolic pathway mediating glucose-induced desensitization of the glucose transport system. Role of hexosamine biosynthesis in the induction of insulin resistance. J Biol Chem  1991; 266(8): 4706-12.
 [http://dx.doi.org/10.1016/S0021-9258(19)67706-9] [PMID:  2002019]

[269]
Patti ME, Virkamäki A, Landaker EJ, Kahn CR, Yki-Järvinen H. Activation of the hexosamine pathway by glucosamine in vivo induces insulin resistance of early postreceptor insulin signaling events in skeletal muscle. Diabetes  1999; 48(8): 1562-71.
 [http://dx.doi.org/10.2337/diabetes.48.8.1562] [PMID:  10426374]

[270]
Bosch RR, Pouwels MJJM, Span PN, et al. Hexosamines are unlikely to function as a nutrient-sensor in 3T3-L1 adipocytes: A comparison of UDP-hexosamine levels after increased glucose flux and glucosamine treatment. Endocrine  2004; 23(1): 17-24.
 [http://dx.doi.org/10.1385/ENDO:23:1:17] [PMID:  15034192]

[271]
Cohen-Forterre L, Andre J, Mozere G, Peyroux J, Sternberg M. Kidney sialidase and sialyltransferase activities in spontaneously and experimentally diabetic rats. Influence of insulin and sorbinil treatments. Biochem Pharmacol  1990; 40(3): 507-13.
 [http://dx.doi.org/10.1016/0006-2952(90)90549-Z] [PMID:  2200408]

[272]
Rellier N, Ruggiero-Lopez D, Lecomte M, Lagarde M, Wiernsperger N. In vitro and in vivo alterations of enzymatic glycosylation in diabetes. Life Sci  1999; 64(17): 1571-83.
 [http://dx.doi.org/10.1016/S0024-3205(99)00094-6] [PMID:  10353622]

[273]
Wiese TJ, Dunlap JA, Yorek MA. Effect of L-fucose and D-glucose concentration on L-fucoprotein metabolism in human Hep G2 cells and changes in fucosyltransferase and α-L-fucosidase activity in liver of diabetic rats. Biochim Biophys Acta  1997; 1335(1-2): 61-72.
 [http://dx.doi.org/10.1016/S0304-4165(96)00123-7] [PMID:  9133643]

[274]
Pickup JC, Day C, Bailey CJ, et al. Plasma sialic acid in animal models of diabetes mellitus: evidence for modulation of sialic acid concentrations by insulin deficiency. Life Sci  1995; 57(14): 1383-91.
 [http://dx.doi.org/10.1016/0024-3205(95)02096-2] [PMID:  7564886]

[275]
Biol MC, Lenoir D, Greco S, Galvain D, Hugueny I, Louisot P. Role of insulin and nutritional factors in intestinal glycoprotein fucosylation during postnatal development. Am J Physiol  1998; 275(5): G936-42.
 [PMID:  9815021]

[276]
Lenoir D, Gréco S, Louisot P, Biol MC. Implication of insulin and nutritional factors in the regulation of intestinal galactosyltransferase activity during postnatal development. Metabolism  2000; 49(4): 526-31.
 [http://dx.doi.org/10.1016/S0026-0495(00)80020-7] [PMID:  10778880]

[277]
Pak K, Kim K, Seo S, Lee MJ, Kim IJ. Serotonin transporter is negatively associated with body mass index after glucose loading in humans. Brain Imaging Behav  2022; 16(3): 1246-51.

[278]
Jia W, He Y-F, Qian X-J, Chen J. TPMT mRNA expression: A novel prognostic biomarker for patients with colon cancer by bioinformatics analysis. Int J Gen Med  2022; 15: 151-60.
 [http://dx.doi.org/10.2147/IJGM.S338575] [PMID:  35023953]

[279]
Mooranian A, Ionescu CM, Walker D, et al. Single-cellular biological effects of cholesterol-catabolic bile acid-based nano/micro capsules as anti-inflammatory cell protective systems. Biomolecules  2022; 12(1): 73.
 [http://dx.doi.org/10.3390/biom12010073] [PMID:  35053221]

[280]
Chan SJ, Cao QP, Steiner DF. Evolution of the insulin superfamily: Cloning of a hybrid insulin/insulin-like growth factor cDNA from amphioxus. Proc Natl Acad Sci USA  1990; 87(23): 9319-23.
 [http://dx.doi.org/10.1073/pnas.87.23.9319] [PMID:  1701257]

[281]
Wang S, Wei W, Zheng Y, et al. The role of insulin C-peptide in the coevolution analyses of the insulin signaling pathway: A hint for its functions. PLoS One  2012; 7(12): e52847.
 [http://dx.doi.org/10.1371/journal.pone.0052847] [PMID:  23300796]

[282]
Wahren J, Ekberg K, Johansson J, et al. Role of C-peptide in human physiology. Am J Physiol Endocrinol Metab  2000; 278(5): E759-68.
 [http://dx.doi.org/10.1152/ajpendo.2000.278.5.E759] [PMID:  10780930]

[283]
Hills CE, Brunskill NJ. Intracellular signalling by C-peptide. Exp Diabetes Res  2008; 2008: 635158.
 [http://dx.doi.org/10.1155/2008/635158] [PMID:  18382618]

[284]
Wahren J, Kallas A, Sima AAF. The clinical potential of C-peptide replacement in type 1 diabetes. Diabetes  2012; 61(4): 761-72.
 [http://dx.doi.org/10.2337/db11-1423] [PMID:  22442295]

[285]
Nordquist L, Brown R, Fasching A, Persson P, Palm F. Proinsulin C-peptide reduces diabetes-induced glomerular hyperfiltration via efferent arteriole dilation and inhibition of tubular sodium reabsorption. Am J Physiol -. Ren Physiol  2009; 297(5): F1265.

[286]
Johansson BL, Borg K, Fernqvist-Forbes E, Kernell A, Odergren T, Wahren J. Beneficial effects of C-peptide on incipient nephropathy and neuropathy in patients with type 1 diabetes mellitus. Diabet Med  2000; 17(3): 181-9.
 [http://dx.doi.org/10.1046/j.1464-5491.2000.00274.x] [PMID:  10784221]

[287]
Samnegård B, Jacobson SH, Jaremko G, et al. C-peptide prevents glomerular hypertrophy and mesangial matrix expansion in diabetic rats. Nephrol Dial Transplant  2005; 20(3): 532-8.
 [http://dx.doi.org/10.1093/ndt/gfh683] [PMID:  15665028]

[288]
Johansson J, Ekberg K, Shafqat J, et al. Molecular effects of proinsulin C-peptide. Biochem Biophys Res Commun  2002; 295(5): 1035-40.
 [http://dx.doi.org/10.1016/S0006-291X(02)00721-0] [PMID:  12135597]

[289]
Munte CE, Vilela L, Kalbitzer HR, Garratt RC. Solution structure of human proinsulin C-peptide. FEBS J  2005; 272(16): 4284-93.
 [http://dx.doi.org/10.1111/j.1742-4658.2005.04843.x] [PMID:  16098208]

[290]
Shafqat J, Juntti-Berggren L, Zhong Z, et al. Proinsulin C-peptide and its analogues induce intracellular Ca2+ increases in human renal tubular cells. Cell Mol Life Sci  2002; 59(7): 1185-9.
 [http://dx.doi.org/10.1007/s00018-002-8496-5] [PMID:  12222964]

[291]
Rhodes CJ. Processing of the insulin molecule. In: LeRoith D, Taylor SI, Olefsky JM, Eds.  Diabetes Mellitus: A Fundamental and Clinical Text. Philadelphia: Lippincott Williams & Wilkin 2004.

[292]
Liu M, Wright J, Guo H, Xiong Y, Arvan P. Proinsulin entry and transit through the endoplasmic reticulum in pancreatic beta cells. Vitam Horm  2014; 95: 35-62.
 [http://dx.doi.org/10.1016/B978-0-12-800174-5.00002-8]

[293]
Sun J, Cui J, He Q, Chen Z, Arvan P, Liu M. Proinsulin misfolding and endoplasmic reticulum stress during the development and progression of diabetes. Mol Aspects Med  2015; 42: 105-18.
 [http://dx.doi.org/10.1016/j.mam.2015.01.001] [PMID:  25579745]

[294]
Hills CE, Brunskill NJ. Cellular and physiological effects of C-peptide. Clin Sci (Lond)  2009; 116(7): 565-74.
 [http://dx.doi.org/10.1042/CS20080441] [PMID:  19243312]

[295]
Wahren J, Shafqat J, Johansson J, Chibalin A, Ekberg K, Jörnvall H. Molecular and cellular effects of C-peptide--new perspectives on an old peptide. Exp Diabesity Res  2004; 5(1): 15-23.
 [http://dx.doi.org/10.1080/15438600490424479] [PMID:  15198368]

[296]
Wahren J, Ekberg K, Jörnvall H. C-peptide is a bioactive peptide. Diabetologia  2007; 50(3): 503-9.
 [http://dx.doi.org/10.1007/s00125-006-0559-y] [PMID:  17235526]

[297]
Chevenne D, Trivin F, Porquet D. Insulin assays and reference values. Diabetes Metab  1999; 25(6): 459-76.
 [PMID:  10633871]

[298]
Steiner DF, Seino S. The biosynthesis of insulin. In: Bell GI, Ed.  Pancreatic Beta Cell in Health and Disease.  Tokyo: Springer 2008; pp. 31-49.
 [http://dx.doi.org/10.1007/978-4-431-75452-7_3]

[299]
Docherty K, Hutton JC. Carboxypeptidase activity in the insulin secretory granule. FEBS Lett  1983; 162(1): 137-41.
 [http://dx.doi.org/10.1016/0014-5793(83)81065-5] [PMID:  6311629]

[300]
Orci L, Ravazzola M, Amherdt M, et al. Conversion of proinsulin to insulin occurs coordinately with acidification of maturing secretory vesicles. J Cell Biol  1986; 103(6 Pt 1): 2273-81.
 [http://dx.doi.org/10.1083/jcb.103.6.2273] [PMID:  3536964]

[301]
Smith GD, Swenson DC, Dodson EJ, Dodson GG, Reynolds CD. Structural stability in the 4-zinc human insulin hexamer. Proc Natl Acad Sci USA  1984; 81(22): 7093-7.
 [http://dx.doi.org/10.1073/pnas.81.22.7093] [PMID:  6390430]

[302]
Mayer JP, Zhang F, DiMarchi RD. Insulin structure and function. Peptide Sci  2007; 88(5): 687-713.

[303]
Smith GD, Ciszak E, Magrum LA, Pangborn WA, Blessing RH. R6 hexameric insulin complexed with m-cresol or resorcinol. Acta
Crystallogr Sect D Biol Crystallogr  2000; 56(Pt 12): 1541-8.

[304]
Ciszak E, Smith GD. Crystallographic evidence for dual coordination around zinc in the T3R3 human insulin hexamer. Biochemistry  1994; 33(6): 1512-7.
 [http://dx.doi.org/10.1021/bi00172a030] [PMID:  8312271]

[305]
Schlitter J, Engels M, Krüger P, Jacoby E, Wollmer A. Targeted molecular dynamics simulation of conformational change-application to the T↔ R transition in insulin. Mol Simul  1993; 10(2–6): 291-308.
 [http://dx.doi.org/10.1080/08927029308022170]

[306]
Hodgkin DC. X rays and the structures of insulin. BMJ  1971; 4(5785): 447-51.
 [http://dx.doi.org/10.1136/bmj.4.5785.447] [PMID:  5166450]

[307]
Weiss MA. The structure and function of insulin: Decoding the TR transition. Vitam Horm  2009; 80: 33-49.

[308]
Rahuel-Clermont S, French CA, Kaarsholm NC, Dunn MF, Chou CI. Mechanisms of stabilization of the insulin hexamer through allosteric ligand interactions. Biochemistry  1997; 36(19): 5837-45.
 [http://dx.doi.org/10.1021/bi963038q] [PMID:  9153424]

[309]
Setter SM, Corbett CF, Campbell RK, White JR. Insulin aspart: A new rapid-acting insulin analog. Ann Pharmacother  2000; 34(12): 1423-31.
 [http://dx.doi.org/10.1345/aph.19414] [PMID:  11144701]

[310]
Malaisse WJ, Hutton JC, Kawazu S, Herchuelz A, Valverde I, Sener A. The stimulus-secretion coupling of glucose-induced insulin release. XXXV. The links between metabolic and cationic events. Diabetologia  1979; 16(5): 331-41.
 [http://dx.doi.org/10.1007/BF01223623] [PMID:  37138]

[311]
Lacy PE. Structure and function of the endocrine cell types of the islets. Adv Metab Disord  1974; 7(0): 171-82.
 [http://dx.doi.org/10.1016/B978-0-12-027307-2.50013-X] [PMID:  4213400]

[312]
Smith GD, Ciszak E. The structure of a complex of hexameric insulin and 4′-hydroxyacetanilide. Proc Natl Acad Sci USA  1994; 91(19): 8851-5.
 [http://dx.doi.org/10.1073/pnas.91.19.8851] [PMID:  8090735]

[313]
Ciszak E, Beals JM, Frank BH, Baker JC, Carter ND, Smith GD. Role of C-terminal B-chain residues in insulin assembly: the structure of hexameric LysB28ProB29-human insulin. Structure  1995; 3(6): 615-22.
 [http://dx.doi.org/10.1016/S0969-2126(01)00195-2] [PMID:  8590022]

[314]
Smith GD, Ciszak E, Pangborn W. A novel complex of a phenolic derivative with insulin: structural features related to the T-->R transition. Protein Sci  1996; 5(8): 1502-11.
 [http://dx.doi.org/10.1002/pro.5560050806] [PMID:  8844841]

[315]
Whittingham JL, Havelund S, Jonassen I. Crystal structure of a prolonged-acting insulin with albumin-binding properties. Biochemistry  1997; 36(10): 2826-31.
 [http://dx.doi.org/10.1021/bi9625105] [PMID:  9062110]

[316]
Whittingham JL, Edwards DJ, Antson AA, Clarkson JM, Dodson GG. Interactions of phenol and m-cresol in the insulin hexamer, and their effect on the association properties of B28 pro --> Asp insulin analogues. Biochemistry  1998; 37(33): 11516-23.
 [http://dx.doi.org/10.1021/bi980807s] [PMID:  9708987]

[317]
Yao ZP, Zeng ZH, Li HM, Zhang Y, Feng YM, Wang DC. Structure of an insulin dimer in an orthorhombic crystal: The structure analysis of a human insulin mutant (B9 Ser→Glu). Acta Crystallogr
Sect D Biol Crystallogr  1999; 55(Pt 9): 1524-32.

[318]
Tang L, Whittingham JL, Verma CS, Caves LSD, Dodson GG. Structural consequences of the B5 histidine --> tyrosine mutation in human insulin characterized by X-ray crystallography and conformational analysis. Biochemistry  1999; 38(37): 12041-51.
 [http://dx.doi.org/10.1021/bi990700k] [PMID:  10508408]

[319]
Von Dreele RB, Stephens PW, Smith GD, Blessing RH. The first protein crystal structure determined from high-resolution X-ray powder diffraction data: A variant of T3R3 human insulin-zinc complex produced by grinding. Acta Crystallogr Sect D Biol Crystallogr  2000; 56(Pt 12): 1549-53.

[320]
Smith GD, Pangborn WA, Blessing RH. Phase changes in T(3)R(3)(f) human insulin: temperature or pressure induced? Acta Crystallogr D Biol Crystallogr  2001; 57(Pt 8): 1091-100.
 [http://dx.doi.org/10.1107/S0907444901007685] [PMID:  11468392]

[321]
Ye J, Chang W, Liang D. Crystal structure of destripeptide (B28-B30) insulin: Implications for insulin dissociation. Biochim Biophys Acta  2001; 1547(1): 18-25.
 [http://dx.doi.org/10.1016/S0167-4838(01)00160-1] [PMID:  11343787]

[322]
Lee KH, Wucherpfennig KW, Wiley DC. Correction: Structure of a human insulin peptide–HLA-DQ8 complex and susceptibility to type 1 diabetes. Nat Immunol  2001; 2(6): 501-7.

[323]
Weiss MA, Wan Z, Zhao M, et al. Non-standard insulin design: structure-activity relationships at the periphery of the insulin receptor. J Mol Biol  2002; 315(2): 103-11.
 [http://dx.doi.org/10.1006/jmbi.2001.5224] [PMID:  11779231]

[324]
Smith GD, Blessing RH. Lessons from an aged, dried crystal of T(6) human insulin. Acta Crystallogr D Biol Crystallogr  2003; 59(Pt 8): 1384-94.
 [http://dx.doi.org/10.1107/S090744490301165X] [PMID:  12876340]

[325]
Wan ZL, Xu B, Chu YC, Katsoyannis PG, Weiss MA. Crystal structure of allo-IleA2-insulin, an inactive chiral analogue: Implications for the mechanism of receptor binding. Biochemistry  2003; 42(44): 12770-83.

[326]
Smith GD, Pangborn WA, Blessing RH. The structure of T6 human
insulin at 1.0 Å resolution. Acta Crystallogr - Sect D Biol
Crystallogr  2003; 59(Pt 3): 474-82.

[327]
Wan Z, Xu B, Huang K, et al. Enhancing the activity of insulin at the receptor interface: Crystal structure and photo-cross-linking of A8 analogues. Biochemistry  2004; 43(51): 16119-33.
 [http://dx.doi.org/10.1021/bi048223f] [PMID:  15610006]

[328]
Whittingham JL, Jonassen I, Havelund S, et al. Crystallographic and solution studies of N-lithocholyl insulin: A new generation of prolonged-acting human insulins. Biochemistry  2004; 43(20): 5987-95.
 [http://dx.doi.org/10.1021/bi036163s] [PMID:  15147182]

[329]
Záková L, Brynda J, Au-Alvarez O, et al. Toward the insulin-IGF-I intermediate structures: Functional and structural properties of the [TyrB25NMePheB26] insulin mutant. Biochemistry  2004; 43(51): 16293-300.
 [http://dx.doi.org/10.1021/bi048856u] [PMID:  15610023]

[330]
Wan ZL, Huang K, Xu B, et al. Diabetes-associated mutations in human insulin: Crystal structure and photo-cross-linking studies of a-chain variant insulin Wakayama. Biochemistry  2005; 44(13): 5000-16.
 [http://dx.doi.org/10.1021/bi047585k] [PMID:  15794638]

[331]
Vernede X, Lavault B, Ohana J, et al. UV laser-excited fluorescence as a tool for the visualization of protein crystals mounted in loops. Acta Crystallogr Sect D Biol Crystallogr  2006; 62(Pt 3): 253-61.
 [http://dx.doi.org/10.1107/S0907444905041429]

[332]
Whittingham JL, Youshang Z, Žáková L, et al. I222 crystal form of despentapeptide (B26-B30) insulin provides new insights into the properties of monomeric insulin. Acta Crystallogr Sect D Biol Crystallogr  2006; 62(Pt 5): 505-11.

[333]
Shen Y, Joachimiak A, Rosner MR, Tang WJ. Structures of human insulin-degrading enzyme reveal a new substrate recognition mecha-nism. Nature  2006; 443(7113): 870-4.
 [http://dx.doi.org/10.1038/nature05143] [PMID:  17051221]

[334]
Norrman M, Schluckebier G. Crystallographic characterization of two novel crystal forms of human insulin induced by chaotropic agents and a shift in pH. BMC Struct Biol  2007; 7: 83.
 [http://dx.doi.org/10.1186/1472-6807-7-83] [PMID:  18093308]

[335]
Norrman M, Hubálek F, Schluckebier G. Structural characterization of insulin NPH formulations. Eur J Pharm Sci  2007; 30(5): 414-23.
 [http://dx.doi.org/10.1016/j.ejps.2007.01.003] [PMID:  17339105]

[336]
Sreekanth R, Pattabhi V, Rajan SS. Structural interpretation of reduced insulin activity as seen in the crystal structure of human Arg-insulin. Biochimie  2008; 90(3): 467-73.
 [http://dx.doi.org/10.1016/j.biochi.2007.09.012] [PMID:  18029081]

[337]
Sreekanth R, Pattabhi V, Rajan SS. Metal induced structural changes observed in hexameric insulin. Int J Biol Macromol  2009; 44(1): 29-36.
 [http://dx.doi.org/10.1016/j.ijbiomac.2008.09.019] [PMID:  18977386]

[338]
Hua QX, Nakagawa SH, Jia W, et al. Design of an active ultrastable single-chain insulin analog: synthesis, structure, and therapeutic implications. J Biol Chem  2008; 283(21): 14703-16.
 [http://dx.doi.org/10.1074/jbc.M800313200] [PMID:  18332129]

[339]
Wagner A, Diez J, Schulze-Briese C, Schluckebier G. Crystal structure of Ultralente - A microcrystalline insulin suspension. Proteins Struct Funct Bioinforma 2009.
 [http://dx.doi.org/10.1002/prot.22213]

[340]
Manolopoulou M, Guo Q, Malito E, Schilling AB, Tang WJ. Molecular basis of catalytic chamber-assisted unfolding and cleavage of human insulin by human insulin-degrading enzyme. J Biol Chem  2009; 284(21): 14177-88.
 [http://dx.doi.org/10.1074/jbc.M900068200] [PMID:  19321446]

[341]
Zhao M, Wan ZL, Whittaker L, et al. Design of an insulin analog with enhanced receptor binding selectivity: Rationale, structure, and therapeutic implications. J Biol Chem  2009; 284(46): 32178-87.
 [http://dx.doi.org/10.1074/jbc.M109.028399] [PMID:  19773552]

[342]
Thorsøe KS, Schlein M, Steensgaard DB, Brandt J, Schluckebier G, Naver H. Kinetic evidence for the sequential association of insulin binding sites 1 and 2 to the insulin receptor and the influence of receptor isoform. Biochemistry  2010; 49(29): 6234-46.
 [http://dx.doi.org/10.1021/bi1000118] [PMID:  20568733]

[343]
Jirácek J, Záková L, Antolíková E, et al. Implications for the active form of human insulin based on the structural convergence of highly active hormone analogues. Proc Natl Acad Sci USA  2010; 107(5): 1966-70.
 [http://dx.doi.org/10.1073/pnas.0911785107] [PMID:  20133841]

[344]
Timofeev VI, Chuprov-Netochin RN, Samigina VR, Bezuglov VV, Miroshnikov KA, Kuranova IP. X-ray investigation of gene-engineered human insulin crystallized from a solution containing polysialic acid. Acta Crystallogr Sect F Struct Biol Cryst Commun  2010; 66(Pt 3): 259-63.

[345]
Phillips NB, Wan ZL, Whittaker L, et al. Supramolecular protein engineering: design of zinc-stapled insulin hexamers as a long acting depot. J Biol Chem  2010; 285(16): 11755-9.
 [http://dx.doi.org/10.1074/jbc.C110.105825] [PMID:  20181952]

[346]
Chinai JM, Taylor AB, Ryno LM, et al. Molecular recognition of insulin by a synthetic receptor. J Am Chem Soc  2011; 133(23): 8810-3.
 [http://dx.doi.org/10.1021/ja201581x] [PMID:  21473587]

[347]
Antolíková E, Žáková L, Turkenburg JP, et al. Non-equivalent role of inter- and intramolecular hydrogen bonds in the insulin dimer inter-face. J Biol Chem  2011; 286(42): 36968-77.
 [http://dx.doi.org/10.1074/jbc.M111.265249] [PMID:  21880708]

[348]
Vinther TN, Norrman M, Strauss HM, et al. Novel covalently linked insulin dimer engineered to investigate the function of insulin dimeri-zation. PLoS One  2012; 7(2): e30882.
 [http://dx.doi.org/10.1371/journal.pone.0030882] [PMID:  22363506]

[349]
Bulek AM, Cole DK, Skowera A, et al. Structural basis for the killing of human beta cells by CD8(+) T cells in type 1 diabetes. Nat Immunol  2012; 13(3): 283-9.
 [http://dx.doi.org/10.1038/ni.2206] [PMID:  22245737]

[350]
Prugovečki B, Pulić I, Toth M, Matković-Čalogović D. High resolution structure of the manganese derivative of insulin. Croat Chem Acta  2012; 85(4): 435-9.
 [http://dx.doi.org/10.5562/cca2108]

[351]
Menting JG, Whittaker J, Margetts MB, et al. How insulin engages its primary binding site on the insulin receptor. Nature  2013; 493(7431): 241-5.
 [http://dx.doi.org/10.1038/nature11781] [PMID:  23302862]

[352]
Žáková L, Kletvíková E, Veverka V, et al. Structural integrity of the B24 site in human insulin is important for hormone functionality. J Biol Chem  2013; 288(15): 10230-40.
 [http://dx.doi.org/10.1074/jbc.M112.448050] [PMID:  23447530]

[353]
Steensgaard DB, Schluckebier G, Strauss HM, et al. Ligand-controlled assembly of hexamers, dihexamers, and linear multihexamer struc-tures by the engineered acylated insulin degludec. Biochemistry  2013; 52(2): 295-309.
 [http://dx.doi.org/10.1021/bi3008609] [PMID:  23256685]

[354]
Vinther TN, Norrman M, Ribel U, et al. Insulin analog with additional disulfide bond has increased stability and preserved activity. Protein Sci  2013; 22(3): 296-305.
 [http://dx.doi.org/10.1002/pro.2211] [PMID:  23281053]

[355]
Fávero-Retto MP, Palmieri LC, Souza TACB, Almeida FCL, Lima LMTR. Structural meta-analysis of regular human insulin in pharmaceutical formulations. Eur J Pharm Biopharm  2013; 85 (3 Pt B): 1112-21.
 [http://dx.doi.org/10.1016/j.ejpb.2013.05.005] [PMID:  23692694]

[356]
Avital-Shmilovici M, Mandal K, Gates ZP, Phillips NB, Weiss MA, Kent SBH. Fully convergent chemical synthesis of ester insulin: determination of the high resolution X-ray structure by racemic protein crystallography. J Am Chem Soc  2013; 135(8): 3173-85.
 [http://dx.doi.org/10.1021/ja311408y] [PMID:  23343390]

[357]
Palmieri LC, Fávero-Retto MP, Lourenço D, Lima LMTR. A T3R3 hexamer of the human insulin variant B28Asp. Biophys Chem  2013; 173-174: 1-7.
 [http://dx.doi.org/10.1016/j.bpc.2013.01.003] [PMID:  23428413]

[358]
Kosinová L, Veverka V, Novotná P, et al. Insight into the structural and biological relevance of the T/R transition of the N-terminus of the B-chain in human insulin. Biochemistry  2014; 53(21): 3392-402.
 [http://dx.doi.org/10.1021/bi500073z] [PMID:  24819248]

[359]
Menting JG, Yang Y, Chan SJ, et al. Protective hinge in insulin opens to enable its receptor engagement. Proc Natl Acad Sci USA  2014; 111(33): E3395-404.
 [http://dx.doi.org/10.1073/pnas.1412897111] [PMID:  25092300]

[360]
Pandyarajan V, Smith BJ, Phillips NB, et al. Aromatic anchor at an invariant hormone-receptor interface: function of insulin residue B24 with application to protein design. J Biol Chem  2014; 289(50): 34709-27.
 [http://dx.doi.org/10.1074/jbc.M114.608562] [PMID:  25305014]

[361]
Žáková L, Kletvíková E, Lepšík M, et al. Human insulin analogues modified at the B26 site reveal a hormone conformation that is undetected in the receptor complex Acta Crystallogr Sect D Biol 	Crystallogr, 2014.

[362]
Beringer DX, Kleijwegt FS, Wiede F, et al. T cell receptor reversed polarity recognition of a self-antigen major histocompatibility complex. Nat Immunol  2015; 16(11): 1153-61.
 [http://dx.doi.org/10.1038/ni.3271] [PMID:  26437244]

[363]
Motozono C, Pearson JA, De Leenheer E, et al. Distortion of the major histocompatibility complex class I binding groove to accommodate an insulin-derived 10-mer peptide. J Biol Chem  2015; 290(31): 18924-33.
 [http://dx.doi.org/10.1074/jbc.M114.622522] [PMID:  26085090]

[364]
Mandal K, Dhayalan B, Avital-Shmilovici M, Tokmakoff A, Kent SBH. Crystallization of enantiomerically pure proteins from quasi-racemic mixtures: Structure determination by x-ray diffraction of isotope-labeled ester insulin and human insulin. ChemBioChem  2016; 17(5): 421-5.
 [http://dx.doi.org/10.1002/cbic.201500600] [PMID:  26707939]

[365]
Viková J, Collinsová M, Kletvíková E, et al. Rational steering of insulin binding specificity by intra-chain chemical crosslinking. Sci Rep  2016; 6: 19431.
 [http://dx.doi.org/10.1038/srep19431] [PMID:  26792393]

[366]
Hjorth CF, Norrman M, Wahlund PO, et al. Structure, Aggregation, and Activity of a Covalent Insulin Dimer Formed During Storage of Neutral Formulation of Human Insulin. J Pharm Sci  2016; 105(4): 1376-86.
 [http://dx.doi.org/10.1016/j.xphs.2016.01.003] [PMID:  26921119]

[367]
Cole DK, Bulek AM, Dolton G, et al. Hotspot autoimmune T cell receptor binding underlies pathogen and insulin peptide cross-reactivity. J Clin Invest 2016.
 [http://dx.doi.org/10.1172/JCI85679]

[368]
El Hage K, Pandyarajan V, Phillips NB, et al. Extending halogen-based medicinal chemistry to proteins: Iodo-insulin as a case study. J Biol Chem  2016; 291(53): 27023-41.
 [http://dx.doi.org/10.1074/jbc.M116.761015] [PMID:  27875310]

[369]
Stadinski BD, Obst R, Huseby ESAA. “hotspot” for autoimmune T cells in type 1 diabetes. J Clin Invest  2016; 126(6): 2040-2.
 [http://dx.doi.org/10.1172/JCI88165] [PMID:  27183386]

[370]
Dhayalan B, Mandal K, Rege N, et al. Scope and limitations of fmoc chemistry spps-based approaches to the total synthesis of insulin lispro via ester insulin. Chemistry  2017; 23(7): 1709-16.
 [http://dx.doi.org/10.1002/chem.201605578] [PMID:  27905149]

[371]
Lisgarten DR, Palmer RA, Lobley CMC, et al. Ultra-high resolution X-ray structures of two forms of human recombinant insulin at 100 K. Chem Cent J  2017; 11(1): 73.
 [http://dx.doi.org/10.1186/s13065-017-0296-y] [PMID:  29086855]

[372]
Lieblich SA, Fang KY, Cahn JKB, et al. 4S-hydroxylation of insulin at ProB28 accelerates hexamer dissociation and delays fibrillation. J Am Chem Soc  2017; 139(25): 8384-7.
 [http://dx.doi.org/10.1021/jacs.7b00794] [PMID:  28598606]

[373]
Palivec V, Viola CM, Kozak M, et al. Computational and structural evidence for neurotransmitter-mediated modulation of the oligomeric states of human insulin in storage granules. J Biol Chem  2017; 292(20): 8342-55.
 [http://dx.doi.org/10.1074/jbc.M117.775924] [PMID:  28348075]

[374]
van Lierop B, Ong SC, Belgi A, et al. Insulin in motion: The A6-A11 disulfide bond allosterically modulates structural transitions required for insulin activity. Sci Rep  2017; 7(1): 17239.
 [http://dx.doi.org/10.1038/s41598-017-16876-3] [PMID:  29222417]

[375]
Glidden MD, Aldabbagh K, Phillips NB, et al. An ultra-stable single-chain insulin analog resists thermal inactivation and exhibits biological signaling duration equivalent to the native protein. J Biol Chem  2018; 293(1): 47-68.
 [http://dx.doi.org/10.1074/jbc.M117.808626] [PMID:  29114035]

[376]
Zhang Z, Liang WG, Bailey LJ, et al. Ensemble cryoEM elucidates the mechanism of insulin capture and degradation by human insulin degrading enzyme. eLife  2018; 7: e33572.
 [http://dx.doi.org/10.7554/eLife.33572] [PMID:  29596046]

[377]
Rege NK, Wickramasinghe NP, Tustan AN, et al. Structure-based stabilization of insulin as a therapeutic protein assembly via enhanced aromatic-aromatic interactions. J Biol Chem  2018; 293(28): 10895-910.
 [http://dx.doi.org/10.1074/jbc.RA118.003650] [PMID:  29880646]

[378]
Taylor SK, Tran TH, Liu MZ, et al. Insulin hexamer-caged gadolinium ion as MRI contrast-o-phore. Chemistry  2018; 24(42): 10646-52.
 [http://dx.doi.org/10.1002/chem.201801388] [PMID:  29873848]

[379]
Weil-Ktorza O, Rege N, Lansky S, et al. Substitution of an internal disulfide bridge with a diselenide enhances both foldability and stabil-ity of human insulin. Chemistry  2019; 25(36): 8513-21.
 [http://dx.doi.org/10.1002/chem.201900892] [PMID:  31012517]

[380]
Hubálek F, Refsgaard HHF, Gram-Nielsen S, Madsen P, Nishimura E, Münzel M, et al. Molecular engineering of safe and efficacious oral basal insulin. Nat Commun  2020; 11: 3746.
 [http://dx.doi.org/10.1038/s41467-020-17487-9]

[381]
Xiong X, Blakely A, Karra P, et al. Novel four-disulfide insulin analog with high aggregation stability and potency. Chem Sci (Camb)  2019; 11(1): 195-200.
 [http://dx.doi.org/10.1039/C9SC04555D] [PMID:  32110371]

[382]
Xiong X, Menting JG, Disotuar MM, et al. A structurally minimized yet fully active insulin based on cone-snail venom insulin principles. Nat Struct Mol Biol  2020; 27(7): 683.

[383]
Gillis RB, Solomon HV, Govada L, et al. Analysis of insulin glulisine at the molecular level by X-ray crystallography and biophysical techniques. Sci Rep  2021; 11(1): 1737.
 [http://dx.doi.org/10.1038/s41598-021-81251-2] [PMID:  33462295]

[384]
Freeman JS. Insulin analog therapy: Improving the match with physiologic insulin secretion. J Am Osteopath Assoc  2009; 109(1): 26-36.
 [PMID:  19193822]

[385]
Donner T, Sarkar S. Insulin-pharmacology, therapeutic regimens, and principles of intensive insulin therapy. 2019 Feb 23. In: Feingold KR, Anawalt B, Boyce A, Eds. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc. 2000.

[386]
Fullerton B, Siebenhofer A, Jeitler K, et al. Short-acting insulin analogues versus regular human insulin for adult, non-pregnant persons with type 2 diabetes mellitus. Cochrane Database Syst Rev  2018; 12: CD013228.
 [http://dx.doi.org/10.1002/14651858.CD013228] [PMID:  30556900]

[387]
Atkin S, Javed Z, Fulcher G. Insulin degludec and insulin aspart: Novel insulins for the management of diabetes mellitus. Ther Adv Chronic Dis  2015; 6(6): 375-88.
 [http://dx.doi.org/10.1177/2040622315608646] [PMID:  26568812]

[388]
Hirsch IB, Juneja R, Beals JM, Antalis CJ, Wright EE. The evolution of insulin and how it informs therapy and treatment choices. Endocr Rev  2020; 41(5): 733-55.
 [PMID:  32396624]

[389]
Mannucci E, Monami M, Marchionni N. Short-acting insulin analogues vs. regular human insulin in type 2 diabetes: A meta-analysis. Diabetes Obes Metab  2009; 11(1): 53-9.
 [http://dx.doi.org/10.1111/j.1463-1326.2008.00934.x] [PMID:  18671795]

[390]
Fullerton B, Siebenhofer A, Jeitler K, et al. Short-acting insulin analogues versus regular human insulin for adults with type 1 diabetes mellitus. Cochrane Database Syst Rev  2016; (6): CD012161.
 [http://dx.doi.org/10.1002/14651858.CD012161] [PMID:  27362975]

[391]
Daugherty KK. Review of insulin therapy. J Pharm Pract  2004; 17(1): 10-9.
 [http://dx.doi.org/10.1177/0897190003261304]

[392]
Goldman J, Kapitza C, Pettus J, Heise T. Understanding how pharmacokinetic and pharmacodynamic differences of basal analog insulins influence clinical practice. Curr Med Res Opin  2017; 33(10): 1821-31.
 [http://dx.doi.org/10.1080/03007995.2017.1335192] [PMID:  28537449]

[393]
Liebl A, Davidson J, Mersebach H, Dykiel P, Tack CJ, Heise T. A novel insulin combination of insulin degludec and insulin aspart achieves a more stable overnight glucose profile than insulin glargine: Results from continuous glucose monitoring in a proof-of-concept trial. J Diabetes Sci Technol  2013; 7(5): 1328-36.
 [http://dx.doi.org/10.1177/193229681300700524] [PMID:  24124961]

[394]
Oleck J, Kassam S, Goldman JD. Commentary: Why was inhaled insulin a failure in the market? Diabetes Spectr  2016; 29(3): 180-4.
 [http://dx.doi.org/10.2337/diaspect.29.3.180] [PMID:  27574374]

[395]
Gast K, Schüler A, Wolff M, et al. Rapid-acting and human insulins: Hexamer dissociation kinetics upon dilution of the pharmaceutical formulation. Pharm Res  2017; 34(11): 2270-86.
 [http://dx.doi.org/10.1007/s11095-017-2233-0] [PMID:  28762200]

[396]
Nettleton EJ, Tito P, Sunde M, Bouchard M, Dobson CM, Robinson CV. Characterization of the oligomeric states of insulin in self-assembly and amyloid fibril formation by mass spectrometry. Biophys J  2000; 79(2): 1053-65.
 [http://dx.doi.org/10.1016/S0006-3495(00)76359-4] [PMID:  10920035]

[397]
Maikawa CL, Smith AAA, Zou L, et al. Stable Monomeric Insulin Formulations Enabled by Supramolecular PEGylation of Insulin Analogues. Adv Ther (Weinh)  2020; 3(1): 1900094.
 [http://dx.doi.org/10.1002/adtp.201900094] [PMID:  32190729]

[398]
Birnbaum DT, Kilcomons MA, DeFelippis MR, Beals JM. Assembly and dissociation of human insulin and LysB28ProB29-insulin hexamers: A comparison study. Pharm Res  1997; 14(1): 25-36.
 [http://dx.doi.org/10.1023/A:1012095115151] [PMID:  9034217]

[399]
Yang LW, Rader AJ, Liu X, et al. oGNM: online computation of structural dynamics using the Gaussian Network Model. Nucleic Acids Res  2006; 34: W24-31.
 [PMID:  16845002]

[400]
Bahar I, Rader AJ. Coarse-grained normal mode analysis in structural biology. Curr Opin Struct Biol  2005; 15(5): 586-92.
 [http://dx.doi.org/10.1016/j.sbi.2005.08.007] [PMID:  16143512]

[401]
Mirmira RG, Nakagawa SH, Tager HS. Importance of the character and configuration of residues B24, B25, and B26 in insulin-receptor interactions. J Biol Chem  1991; 266(3): 1428-36.
 [http://dx.doi.org/10.1016/S0021-9258(18)52312-7] [PMID:  1988428]

[402]
Derewenda U, Derewenda Z, Dodson EJ, Dodson GG, Bing X, Markussen J. X-ray analysis of the single chain B29-A1 peptide-linked insulin molecule. A completely inactive analogue. J Mol Biol  1991; 220(2): 425-33.
 [http://dx.doi.org/10.1016/0022-2836(91)90022-X] [PMID:  1856866]

[403]
Leyer S, Gattner H-G, Leithäuser M, Brandenburg D, Wollmer A, Höcker H. The role of the C‐terminus of the insulin B‐chain in modulating structural and functional properties of the hormone. Int J Pept Protein Res  1995; 46(5): 397-407.

[404]
Hartman I. Insulin analogs: impact on treatment success, satisfaction, quality of life, and adherence. Clin Med Res  2008; 6(2): 54-67.
 [http://dx.doi.org/10.3121/cmr.2008.793] [PMID:  18801953]

[405]
Holleman F. Insulin lispro (revision number 20). Diapedia 2015.
 [http://dx.doi.org/10.14496/dia.8104096170.20]

[406]
Garnock-Jones KP, Plosker GL. Insulin glulisine: A review of its use in the management of diabetes mellitus. Drugs  2009; 69(8): 1035-57.
 [http://dx.doi.org/10.2165/00003495-200969080-00006] [PMID:  19496630]

[407]
Haahr H, Heise T. Fast-acting insulin aspart: A review of its pharmacokinetic and pharmacodynamic properties and the clinical consequences. Clin Pharmacokinet  2020; 59(2): 155-72.
 [http://dx.doi.org/10.1007/s40262-019-00834-5] [PMID:  31667789]

[408]
Simpson KL, Spencer CM. Insulin aspart. Drugs  1999; 57(5): 759-65.
 [http://dx.doi.org/10.2165/00003495-199957050-00013] [PMID:  10353301]

[409]
Becker RHA, Frick AD. Clinical pharmacokinetics and pharmacodynamics of insulin glulisine. Clin Pharmacokinet  2008; 47(1): 7-20.
 [http://dx.doi.org/10.2165/00003088-200847010-00002] [PMID:  18076215]

[410]
Bolli GB, Owens DR. Insulin glargine. Lancet  2000; 356(9228): 443-5.
 [http://dx.doi.org/10.1016/S0140-6736(00)02546-0] [PMID:  10981882]

[411]
Dunn CJ, Plosker GL, Keating GM, McKeage K, Scott LJ. Insulin glargine: An updated review of its use in the management of diabetes mellitus. Drugs  2003; 63(16): 1743-78.
 [http://dx.doi.org/10.2165/00003495-200363160-00007] [PMID:  12904090]

[412]
McKeage K, Goa KL. Insulin glargine: A review of its therapeutic use as a long-acting agent for the management of type 1 and 2 diabetes mellitus. Drugs  2001; 61(11): 1599-624.
 [http://dx.doi.org/10.2165/00003495-200161110-00007] [PMID:  11577797]

[413]
Chapman TM, Perry CM. Insulin detemir: A review of its use in the management of type 1 and 2 diabetes mellitus. Drugs  2004; 64(22): 2577-95.
 [http://dx.doi.org/10.2165/00003495-200464220-00008] [PMID:  15516157]

[414]
Jonassen I, Havelund S, Hoeg-Jensen T, Steensgaard DB, Wahlund PO, Ribel U. Design of the novel protraction mechanism of insulin degludec, an ultra-long-acting basal insulin. Pharm Res  2012; 29(8): 2104-14.
 [http://dx.doi.org/10.1007/s11095-012-0739-z] [PMID:  22485010]

[415]
Vora J, Cariou B, Evans M, et al. Clinical use of insulin degludec. Diabetes Res Clin Pract  2015; 109(1): 19-31.
 [http://dx.doi.org/10.1016/j.diabres.2015.04.002] [PMID:  25963320]

[416]
Wu T, Betty B, Downie M, et al. Practical guidance on the use of premix insulin analogs in initiating, intensifying, or switching insulin regimens in type 2 diabetes. Diabetes Ther  2015; 6(3): 273-87.
 [http://dx.doi.org/10.1007/s13300-015-0116-0] [PMID:  26104878]

[417]
Chance RE, Kroeff EP, Hoffmann JA, Frank BH. Chemical, physical, and biologic properties of biosynthetic human insulin. Diabetes Care  1981; 4(2): 147-54.
 [http://dx.doi.org/10.2337/diacare.4.2.147] [PMID:  7011716]

[418]
Zimmerman RE, Stokell DJ. Insulin production methods and proinsulin	constructs.  US Patent 7790677B2,, 2010.

[419]
Thim L, Hansen MT, Norris K, et al. Secretion and processing of insulin precursors in yeast. Proc Natl Acad Sci USA  1986; 83(18): 6766-70.
 [http://dx.doi.org/10.1073/pnas.83.18.6766] [PMID:  3529091]

[420]
Chan SJ, Weiss J, Konrad M, et al. Biosynthesis and periplasmic segregation of human proinsulin in Escherichia coli. Proc Natl Acad Sci USA  1981; 78(9): 5401-5.
 [http://dx.doi.org/10.1073/pnas.78.9.5401] [PMID:  7029534]

[421]
Chance RE, Dimarci RD, Fank BH, Shields JE.  Insulin analogs. AU Patent 630912B2, 1992.

[422]
Brange JJV, Havelund S. Insulin analogues.  WO Patent 1989010937A1, 1989.

[423]
Chance RE, DiMarchi RD, Frank BH, Shields JE. Process for preparing insulin analogs. US Patent 5700662A, 1997.

[424]
Ertl J, Haberman P, Geisen K, Seipke G.  Insulin derivatives having a rapid onset of action.  US Patent 6221633B1, 2001.

[425]
Berchtold H.  Crystals of insulin analogs and processes for their	preparation.  US Patent 7193035B2, 2007.

[426]
Zimmerman RE, Stokell DJ, Akers MP. Compositions de proinsuline aspart et procédés de production d’analogues de l’insuline aspart. WO Patent 2012115637A1, 2012.

[427]
Zimmerman RE, Stokell DJ, Akers MP. Glargine proinsulin and methods of producing glargine insulin analogs there from  US Patent 20120214965A1, 2012.

[428]
Chan Y-P, Vialas C, Blas M. Long-acting insulin glargine analogue. WO Patent 2015071368A1, 2015.

[429]
Li Y, Du J, Si J, Chu Y, Sun M. Purification method of insulin
detemir. CN Patent 103145829B, 2015.

[430]
Zimmerman RE, Stokell DJ, Akers MP. Lis-pro proinsulin compositions and methods of producing lis-pro insulin analogs therefrom. US Patent 20120214199A1, 2012.

[431]
Loos P, Gehrmann T, Berchtold H, Werner U, Ganz M. Stable
formulation of insulin glulisine. WO Patent 2015059302A1, 2015.

[432]
Ortigosa AD, Coleman MP, George ST, Rauscher MA, Sleevi MC, Chow K. Purifying insulin using cation exchange and reverse phase
chromatography in the presence of an organic modifier and elevated
temperature. WO Patent 2015138548A1, 2015.

[433]
Grant SS, Iammarino MJ, Kerchner K, et al. Process for preparing	recombinant insulin using microfiltration. WO Patent
2016144658A1, 2016.

[434]
Ortigosa AD, Chimielowski RA, Sleevi MC. A process for obtaining
insulin with correctly formed disulfide bonds. WO Patent
2017040363A1, 2017.

[435]
Borowicz P, Płucienniczak A, Płucienniczak G, et al. A method for
producing insulin and insulin derivatives, and hybrid peptide used
in this method. WO Patent 2017126984A1, 2017.

[436]
Qian X, Kraft J, Ni Y, Zhao FQ. Production of recombinant human proinsulin in the milk of transgenic mice. Sci Rep  2014; 4: 6465.
 [http://dx.doi.org/10.1038/srep06465] [PMID:  25267062]

[437]
Kim CK, Lee SB, Son YJ. Large-scale refolding and enzyme reaction of human preproinsulin for production of human insulin. J Microbiol Biotechnol  2015; 25(10): 1742-50.
 [http://dx.doi.org/10.4014/jmb.1504.04062] [PMID:  26139616]

[438]
Ling Z, Qi-Qing J, Yu W, et al. Transgenic expression and identification of recombinant human proinsulin in peanut. Braz Arch Biol Technol  2016; 59: e16150131.
 [http://dx.doi.org/10.1590/1678-4324-2016150131]

[439]
Akbarian M, Yousefi R. Human αB-crystallin as fusion protein and molecular chaperone increases the expression and folding efficiency of recombinant insulin. PLoS One  2018; 13(10): e0206169.
 [http://dx.doi.org/10.1371/journal.pone.0206169] [PMID:  30339677]

[440]
Zieliński M, Romanik-Chruścielewska A, Mikiewicz D, et al. Expression and purification of recombinant human insulin from E. coli 20 strain. Protein Expr Purif  2019; 157: 63-9.
 [http://dx.doi.org/10.1016/j.pep.2019.02.002] [PMID:  30735706]

[441]
Govender K, Naicker T, Lin J, et al. A novel and more efficient biosynthesis approach for human insulin production in Escherichia coli (E. coli). AMB Express  2020; 10(1): 43.
 [http://dx.doi.org/10.1186/s13568-020-00969-w] [PMID:  32152803]
Rights & Permissions Print Cite
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/1573399819666220610150342	Print ISSN 1573-3998
Publisher Name Bentham Science Publisher	Online ISSN 1875-6417
Current Diabetes Reviews

A Brief Atlas of Insulin

Abstract Play Pause

Related Journals

Related Books

Abstract
