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Drug Development for Diabetes Mellitus: Beyond Hemoglobin A1c

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Translational Research Methods in Diabetes, Obesity, and Nonalcoholic Fatty Liver Disease

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Abstract

Improved understanding of the complex pathophysiology of type 2 diabetes provides a logical basis for target identification and the development of novel glucose-lowering agents. While the major driver of type 2 diabetes is obesity, if β-cells of the pancreatic islets are able to compensate for the obesity-associated insulin resistance by increasing insulin secretion, plasma glucose levels are initially preserved. Once β-cells are unable to maintain this high rate of insulin secretion, hyperglycemia develops. Despite being a relatively late manifestation in the course of insulin resistance, hyperglycemia remains the most important measurements used for the diagnosis and follow-up of patients with type 2 diabetes and to assess treatment response. Ideal biomarkers should be able to detect the early stages of the disease, when insulin resistance is present, but before the development of clinically significant hyperglycemia. We describe biomarkers related to hyperglycemia and their utility in drug development, as well as biomarkers of insulin resistance, which have the potential to identify early abnormalities in patients with type 2 diabetes and to detect nondiabetic subjects at risk of developing type 2 diabetes. Type 1 diabetes is characterized by severe insulin deficiency that necessitates life-long insulin replacement therapy. We consider the expanding role of continuous glucose monitoring in patients with diabetes. This technology is providing new insights into glucose variability, and it is being increasingly used to inform daily treatment decisions. Moreover, continuous glucose monitoring is also being used to inform the development of novel insulins and other classes of glucose-lowering medications.

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References

  1. DeFronzo RA, Ferrannini E, Groop L, Henry RR, Herman WH, Holst JJ, et al. Type 2 diabetes mellitus. Nat Rev Dis Primers. 2015;1:15019.

    Article  PubMed  Google Scholar 

  2. Caprio S, Perry R, Kursawe R. Adolescent obesity and insulin resistance: roles of ectopic fat accumulation and adipose inflammation. Gastroenterology. 2017;152:1638–46.

    Article  CAS  PubMed  Google Scholar 

  3. Cusi K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology. 2012;142:711–725.e6.

    Article  CAS  PubMed  Google Scholar 

  4. Parker VE, Semple RK. Genetics in endocrinology: genetic forms of severe insulin resistance: what endocrinologists should know. Eur J Endocrinol. 2013;169:R71–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Sun K, Kusminski CM, Scherer PE. Adipose tissue remodeling and obesity. J Clin Invest. 2011;121:2094–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Schenk S, Saberi M, Olefsky JM. Insulin sensitivity: modulation by nutrients and inflammation. J Clin Invest. 2008;118:2992–3002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Cusi K. The epidemic of type 2 diabetes mellitus: Its links to obesity, insulin resistance, and lipotoxicity. In: Regensteiner JG, Reusch JEB, Stewart KJ, Veves A, editors. Diabetes and exercise. 1st ed. New York: Humana Press; 2009. p. 3–54.

    Chapter  Google Scholar 

  8. Bril F, Cusi K. Nonalcoholic fatty liver disease: the new complication of type 2 diabetes mellitus. Endocrinol Metab Clin N Am. 2016;45:765–81.

    Article  Google Scholar 

  9. Cusi K. The role of adipose tissue and lipotoxicity in the pathogenesis of type 2 diabetes. Curr Diab Rep. 2010;10:306–15.

    Article  CAS  PubMed  Google Scholar 

  10. American Diabetes Association. Classification and diagnosis of diabetes: standards of medical care in diabetes-2018. Diabetes Care. 2018;41:S13–27.

    Article  Google Scholar 

  11. Edwards CM, Cusi K. Prediabetes: a worldwide epidemic. Endocrinol Metab Clin N Am. 2016;45:751–64.

    Article  Google Scholar 

  12. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977–86.

    Article  Google Scholar 

  13. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837–53.

    Article  Google Scholar 

  14. Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545–59.

    Article  Google Scholar 

  15. Bril F, Barb D, Portillo-Sanchez P, Biernacki D, Lomonaco R, Suman A, et al. Metabolic and histological implications of intrahepatic triglyceride content in nonalcoholic fatty liver disease. Hepatology. 2017;65:1132–44.

    Article  CAS  PubMed  Google Scholar 

  16. Hazlehurst JM, Woods C, Marjot T, Cobbold JF, Tomlinson JW. Non-alcoholic fatty liver disease and diabetes. Metabolism. 2016;65:1096–108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modeling. Diabetes Care. 2004;27:1487–95.

    Article  PubMed  Google Scholar 

  18. Radziuk J. Homeostastic model assessment and insulin sensitivity/resistance. Diabetes. 2014;63:1850–4.

    Article  CAS  PubMed  Google Scholar 

  19. Bril F, Lomonaco R, Orsak B, Ortiz-Lopez C, Webb A, Tio F, et al. Relationship between disease severity, hyperinsulinemia, and impaired insulin clearance in patients with nonalcoholic steatohepatitis. Hepatology. 2014;59:2178–87.

    Article  CAS  PubMed  Google Scholar 

  20. Chen H, Sullivan G, Quon MJ. Assessing the predictive accuracy of QUICKI as a surrogate index for insulin sensitivity using a calibration model. Diabetes. 2005;54:1914–25.

    Article  CAS  PubMed  Google Scholar 

  21. Abdul-Ghani MA, Matsuda M, Balas B, DeFronzo RA. Muscle and liver insulin resistance indexes derived from the oral glucose tolerance test. Diabetes Care. 2007;30:89–94.

    Article  CAS  PubMed  Google Scholar 

  22. Stumvoll M, Van Haeften T, Fritsche A, Gerich J. Oral glucose tolerance test indexes for insulin sensitivity and secretion based on various availabilities of sampling times. Diabetes Care. 2001;24:796–7.

    Article  CAS  PubMed  Google Scholar 

  23. Soonthornpun S, Setasuban W, Thamprasit A, Chayanunnukul W, Rattarasarn C, Geater A. Novel insulin sensitivity index derived from oral glucose tolerance test. J Clin Endocrinol Metab. 2003;88:1019–23.

    Article  CAS  PubMed  Google Scholar 

  24. Radziuk J. Insulin sensitivity and its measurement: structural commonalities among the methods. J Clin Endocrinol Metab. 2000;85:4426–33.

    CAS  PubMed  Google Scholar 

  25. Muniyappa R, Lee S, Chen H, Quon MJ. Current approaches for assessing insulin sensitivity and resistance in vivo: advantages, limitations, and appropriate usage. Am J Physiol Endocrinol Metab. 2008;294:E15–26.

    Article  CAS  PubMed  Google Scholar 

  26. McKillop AM, Flatt PR. Emerging applications of metabolomic and genomic profiling in diabetic clinical medicine. Diabetes Care. 2011;34:2624–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Newgard CB, An J, Bain JR, Muehlbauer MJ, Stevens RD, Lien LF, et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab. 2009;9:311–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Huffman KM, Shah SH, Stevens RD, Bain JR, Muehlbauer M, Slentz CA, et al. Relationships between circulating metabolic intermediates and insulin action in overweight to obese, inactive men and women. Diabetes Care. 2009;32:1678–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Tai ES, Tan ML, Stevens RD, Low YL, Muehlbauer MJ, Goh DL, et al. Insulin resistance is associated with a metabolic profile of altered protein metabolism in Chinese and Asian-Indian men. Diabetologia. 2010;53:757–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Palmer ND, Stevens RD, Antinozzi PA, Anderson A, Bergman RN, Wagenknecht LE, et al. Metabolomic profile associated with insulin resistance and conversion to diabetes in the Insulin Resistance Atherosclerosis Study. J Clin Endocrinol Metab. 2015;100:E463–8.

    Article  CAS  PubMed  Google Scholar 

  31. Wurtz P, Makinen VP, Soininen P, Kangas AJ, Tukiainen T, Kettunen J, et al. Metabolic signatures of insulin resistance in 7,098 young adults. Diabetes. 2012;61:1372–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Menni C, Fauman E, Erte I, Perry JR, Kastenmuller G, Shin SY, et al. Biomarkers for type 2 diabetes and impaired fasting glucose using a nontargeted metabolomics approach. Diabetes. 2013;62:4270–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang TJ, Larson MG, Vasan RS, Cheng S, Rhee EP, McCabe E, et al. Metabolite profiles and the risk of developing diabetes. Nat Med. 2011;17:448–53.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Laferrere B, Reilly D, Arias S, Swerdlow N, Gorroochurn P, Bawa B, et al. Differential metabolic impact of gastric bypass surgery versus dietary intervention in obese diabetic subjects despite identical weight loss. Sci Transl Med. 2011;3:80re82.

    Article  CAS  Google Scholar 

  35. Magkos F, Bradley D, Schweitzer GG, Finck BN, Eagon JC, Ilkayeva O, et al. Effect of Roux-en-Y gastric bypass and laparoscopic adjustable gastric banding on branched-chain amino acid metabolism. Diabetes. 2013;62:2757–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Sunny NE, Kalavalapalli S, Bril F, Garrett TJ, Nautiyal M, Mathew JT, et al. Cross-talk between branched-chain amino acids and hepatic mitochondria is compromised in nonalcoholic fatty liver disease. Am J Physiol Endocrinol Metab. 2015;309:E311–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kalavalapalli S, Bril F, Koelmel JP, Abdo K, Guingab J, Andrews P, et al. Pioglitazone improves hepatic mitochondrial function in a mouse model of nonalcoholic steatohepatitis. Am J Physiol Endocrinol Metab. 2018;315:E163–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Newgard CB. Metabolomics and metabolic diseases: where do we stand? Cell Metab. 2017;25:43–56.

    Article  CAS  PubMed  Google Scholar 

  39. Glynn EL, Piner LW, Huffman KM, Slentz CA, Elliot-Penry L, AbouAssi H, et al. Impact of combined resistance and aerobic exercise training on branched-chain amino acid turnover, glycine metabolism and insulin sensitivity in overweight humans. Diabetologia. 2015;58:2324–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ferrannini E, Natali A, Camastra S, Nannipieri M, Mari A, Adam KP, et al. Early metabolic markers of the development of dysglycemia and type 2 diabetes and their physiological significance. Diabetes. 2013;62:1730–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Thalacker-Mercer AE, Ingram KH, Guo F, Ilkayeva O, Newgard CB, Garvey WT. BMI, RQ, diabetes, and sex affect the relationships between amino acids and clamp measures of insulin action in humans. Diabetes. 2014;63:791–800.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Gall WE, Beebe K, Lawton KA, Adam KP, Mitchell MW, Nakhle PJ, et al. alpha-hydroxybutyrate is an early biomarker of insulin resistance and glucose intolerance in a nondiabetic population. PLoS One. 2010;5:e10883.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Wang TJ, Ngo D, Psychogios N, Dejam A, Larson MG, Vasan RS, et al. 2-Aminoadipic acid is a biomarker for diabetes risk. J Clin Invest. 2013;123:4309–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Roberts LD, Koulman A, Griffin JL. Towards metabolic biomarkers of insulin resistance and type 2 diabetes: progress from the metabolome. Lancet Diabetes Endocrinol. 2014;2:65–75.

    Article  CAS  PubMed  Google Scholar 

  45. Mozaffarian D, Cao H, King IB, Lemaitre RN, Song X, Siscovick DS, et al. Circulating palmitoleic acid and risk of metabolic abnormalities and new-onset diabetes. Am J Clin Nutr. 2010;92:1350–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Mozaffarian D, Lemaitre RN, King IB, Song X, Spiegelman D, Sacks FM, et al. Circulating long-chain omega-3 fatty acids and incidence of congestive heart failure in older adults: the cardiovascular health study: a cohort study. Ann Intern Med. 2011;155:160–70.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Kotronen A, Velagapudi VR, Yetukuri L, Westerbacka J, Bergholm R, Ekroos K, et al. Serum saturated fatty acids containing triacylglycerols are better markers of insulin resistance than total serum triacylglycerol concentrations. Diabetologia. 2009;52:684–90.

    Article  CAS  PubMed  Google Scholar 

  48. Rhee EP, Cheng S, Larson MG, Walford GA, Lewis GD, McCabe E, et al. Lipid profiling identifies a triacylglycerol signature of insulin resistance and improves diabetes prediction in humans. J Clin Invest. 2011;121:1402–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Chavez JA, Summers SA. A ceramide-centric view of insulin resistance. Cell Metab. 2012;15:585–94.

    Article  CAS  PubMed  Google Scholar 

  50. Erion DM, Shulman GI. Diacylglycerol-mediated insulin resistance. Nat Med. 2010;16:400–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Xie X, Yi Z, Sinha S, Madan M, Bowen BP, Langlais P, et al. Proteomics analyses of subcutaneous adipocytes reveal novel abnormalities in human insulin resistance. Obesity (Silver Spring). 2016;24:1506–14.

    Article  CAS  Google Scholar 

  52. Hwang H, Bowen BP, Lefort N, Flynn CR, De Filippis EA, Roberts C, et al. Proteomics analysis of human skeletal muscle reveals novel abnormalities in obesity and type 2 diabetes. Diabetes. 2010;59:33–42.

    Article  CAS  PubMed  Google Scholar 

  53. Pedersen BA, Wang W, Taylor JF, Khattab OS, Chen YH, Edwards RA, et al. Hepatic proteomic analysis revealed altered metabolic pathways in insulin resistant Akt1(+/−)/Akt2(−/−) mice. Metabolism. 2015;64:1694–703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Park SE, Park CY, Sweeney G. Biomarkers of insulin sensitivity and insulin resistance: past, present and future. Crit Rev Clin Lab Sci. 2015;52:180–90.

    Article  CAS  PubMed  Google Scholar 

  55. American Diabetes Association. Glycemic targets: standards of medical care in diabetes-2018. Diabetes Care. 2018;41:S55–64.

    Article  Google Scholar 

  56. Goldstein DE, Little RR, Lorenz RA, Malone JI, Nathan DM, Peterson CM, et al. Tests of glycemia in diabetes. Diabetes Care. 2004;27(Suppl 1):S91–3.

    PubMed  Google Scholar 

  57. Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria, The DECODE Study Group, European Diabetes Epidemiology Group. Diabetes epidemiology: collaborative analysis of diagnostic criteria in Europe. Lancet. 1999;354:617–21.

    Article  Google Scholar 

  58. McMillin JM. Blood glucose. In: Walker HK, Hall WD, Hurst JW, editors. Clinical methods: the history, physical, and laboratory examinations. 3rd ed. Boston: Butterworths; 1990.

    Google Scholar 

  59. U.S. Department of Health and Human Services, Food and Drug Administration, (CDER). CfDEaR. Guidance for Industry. Diabetes Mellitus — Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. 2008. Available at: https://www.fda.gov/downloads/Drugs/.../Guidances/ucm071624.pdf. Last accessed 15 Jan 2018.

  60. Ziegler R, Heidtmann B, Hilgard D, Hofer S, Rosenbauer J, Holl R, et al. Frequency of SMBG correlates with HbA1c and acute complications in children and adolescents with type 1 diabetes. Pediatr Diabetes. 2011;12:11–7.

    Article  PubMed  Google Scholar 

  61. Garber AJ. Treat-to-target trials: uses, interpretation and review of concepts. Diabetes Obes Metab. 2014;16:193–205.

    Article  CAS  PubMed  Google Scholar 

  62. Young LA, Buse JB, Weaver MA, Vu MB, Mitchell CM, Blakeney T, et al. Glucose self-monitoring in non-insulin-treated patients with type 2 diabetes in primary care settings: a randomized trial. JAMA Intern Med. 2017;177:920–9.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Simon J, Gray A, Clarke P, Wade A, Neil A, Farmer A, et al. Cost effectiveness of self monitoring of blood glucose in patients with non-insulin treated type 2 diabetes: economic evaluation of data from the DiGEM trial. BMJ. 2008;336:1177–80.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Elgart JF, Gonzalez L, Prestes M, Rucci E, Gagliardino JJ. Frequency of self-monitoring blood glucose and attainment of HbA1c target values. Acta Diabetol. 2016;53:57–62.

    Article  CAS  PubMed  Google Scholar 

  65. Bril F, Portillo-Sanchez P, Liu IC, Kalavalapalli S, Dayton K, Cusi K. Clinical and histologic characterization of nonalcoholic steatohepatitis in African American patients. Diabetes Care. 2017;41:187–92.

    Article  PubMed  CAS  Google Scholar 

  66. Bril F, Sninsky JJ, Baca AM, Superko HR, Portillo Sanchez P, Biernacki D, et al. Hepatic steatosis and insulin resistance, but not steatohepatitis, promote atherogenic dyslipidemia in NAFLD. J Clin Endocrinol Metab. 2016;101:644–52.

    Article  CAS  PubMed  Google Scholar 

  67. Kingwell K. FDA eyes new diabetes end points. Nat Rev Drug Discov. 2016;15:666–7.

    Article  CAS  PubMed  Google Scholar 

  68. Danne T, Nimri R, Battelino T, Bergenstal RM, Close KL, DeVries JH, et al. International consensus on use of continuous glucose monitoring. Diabetes Care. 2017;40:1631–40.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Bergenstal RM, Bailey TS, Rodbard D, Ziemen M, Guo H, Muehlen-Bartmer I, et al. Comparison of insulin glargine 300 units/mL and 100 units/mL in adults with type 1 diabetes: continuous glucose monitoring profiles and variability using morning or evening injections. Diabetes Care. 2017;40:554–60.

    Article  CAS  PubMed  Google Scholar 

  70. Wright LA, Hirsch IB. Metrics beyond hemoglobin A1C in diabetes management: time in range, hypoglycemia, and other parameters. Diabetes Technol Ther. 2017;19:S16–26.

    Article  PubMed  CAS  Google Scholar 

  71. Jendle J, Testa MA, Martin S, Jiang H, Milicevic Z. Continuous glucose monitoring in patients with type 2 diabetes treated with glucagon-like peptide-1 receptor agonist dulaglutide in combination with prandial insulin lispro: an AWARD-4 substudy. Diabetes Obes Metab. 2016;18:999–1005.

    Article  CAS  PubMed  Google Scholar 

  72. Heise T, Stender-Petersen K, Hovelmann U, Jacobsen JB, Nosek L, Zijlstra E, et al. Pharmacokinetic and pharmacodynamic properties of faster-acting insulin aspart versus insulin aspart across a clinically relevant dose range in subjects with type 1 diabetes mellitus. Clin Pharmacokinet. 2017;56:649–60.

    Article  CAS  PubMed  Google Scholar 

  73. Rodbard HW, Peters AL, Slee A, Cao A, Traina SB, Alba M. The effect of canagliflozin, a sodium glucose cotransporter 2 inhibitor, on glycemic end points assessed by continuous glucose monitoring and patient-reported outcomes among people with type 1 diabetes. Diabetes Care. 2017;40:171–80.

    Article  CAS  PubMed  Google Scholar 

  74. Investigators F-ST. Glucose variability in a 26-week randomized comparison of mealtime treatment with rapid-acting insulin versus GLP-1 agonist in participants with type 2 diabetes at high cardiovascular risk. Diabetes Care. 2016;39:973–81.

    Article  CAS  Google Scholar 

  75. Welsh KJ, Kirkman MS, Sacks DB. Role of glycated proteins in the diagnosis and nanagement of diabetes: research gaps and future directions. Diabetes Care. 2016;39:1299–306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Shapiro R, McManus MJ, Zalut C, Bunn HF. Sites of nonenzymatic glycosylation of human hemoglobin A. J Biol Chem. 1980;255:3120–7.

    CAS  PubMed  Google Scholar 

  77. Little RR, Rohlfing CL, Sacks DB, National Glycohemoglobin Standardization Program Steering C. Status of hemoglobin A1c measurement and goals for improvement: from chaos to order for improving diabetes care. Clin Chem. 2011;57:205–14.

    Article  CAS  PubMed  Google Scholar 

  78. Bonora E, Tuomilehto J. The pros and cons of diagnosing diabetes with A1C. Diabetes Care. 2011;34(Suppl 2):S184–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Zhou X, Pang Z, Gao W, Wang S, Zhang L, Ning F, et al. Performance of an A1C and fasting capillary blood glucose test for screening newly diagnosed diabetes and pre-diabetes defined by an oral glucose tolerance test in Qingdao, China. Diabetes Care. 2010;33:545–50.

    Article  CAS  PubMed  Google Scholar 

  80. Little RR, Roberts WL. A review of variant hemoglobins interfering with hemoglobin A1c measurement. J Diabetes Sci Technol. 2009;3:446–51.

    Article  PubMed  PubMed Central  Google Scholar 

  81. National Glycohemoglobin Standardization Program. Factors that Interfere with HbA1c Test Results. 2017. Available at: http://www.ngsp.org/factors.asp. Last accessed 15 Jan 2018.

  82. Lipska KJ, Krumholz HM. Is hemoglobin A1c the right outcome for studies of diabetes? JAMA. 2017;317:1017–8.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Agiostratidou G, Anhalt H, Ball D, Blonde L, Gourgari E, Harriman KN, et al. Standardizing clinically meaningful outcome measures beyond HbA1c for type 1 diabetes: a Consensus Report of the American Association of Clinical Endocrinologists, the American Association of Diabetes Educators, the American Diabetes Association, the Endocrine Society, JDRF International, The Leona M. and Harry B. Helmsley Charitable Trust, the Pediatric Endocrine Society, and the T1D Exchange. Diabetes Care. 2017;40:1622–30.

    Article  PubMed  PubMed Central  Google Scholar 

  84. European Medicines Agency. Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus. 2012. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129256.pdf. Last accessed 10 Mar 2018.

  85. Cohen RM, Holmes YR, Chenier TC, Joiner CH. Discordance between HbA1c and fructosamine: evidence for a glycosylation gap and its relation to diabetic nephropathy. Diabetes Care. 2003;26:163–7.

    Article  CAS  PubMed  Google Scholar 

  86. Wu WC, Ma WY, Wei JN, Yu TY, Lin MS, Shih SR, et al. Serum glycated albumin to guide the diagnosis of diabetes mellitus. PLoS One. 2016;11:e0146780.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Nathan DM, McGee P, Steffes MW, Lachin JM, Group DER. Relationship of glycated albumin to blood glucose and HbA1c values and to retinopathy, nephropathy, and cardiovascular outcomes in the DCCT/EDIC study. Diabetes. 2014;63:282–90.

    Article  CAS  PubMed  Google Scholar 

  88. Inoue Y, Inoue M, Saito M, Yoshikawa H, Tamiya E. Sensitive detection of glycated albumin in human serum albumin using electrochemiluminescence. Anal Chem. 2017;89:5909–15.

    Article  CAS  PubMed  Google Scholar 

  89. Goldin A, Beckman JA, Schmidt AM, Creager MA. Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation. 2006;114:597–605.

    Article  CAS  PubMed  Google Scholar 

  90. Uribarri J, Woodruff S, Goodman S, Cai W, Chen X, Pyzik R, et al. Advanced glycation end products in foods and a practical guide to their reduction in the diet. J Am Diet Assoc. 2010;110:911–16.e12.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Uribarri J, del Castillo MD, de la Maza MP, Filip R, Gugliucci A, Luevano-Contreras C, et al. Dietary advanced glycation end products and their role in health and disease. Adv Nutr. 2015;6:461–73.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Koska J, Saremi A, Howell S, Bahn G, De Courten B, Ginsberg H, et al. Advanced glycation end products, oxidation products, and incident cardiovascular events in patients with type 2 diabetes. Diabetes Care. 2018;41(3):570–6.

    Article  CAS  PubMed  Google Scholar 

  93. Kilhovd BK, Juutilainen A, Lehto S, Ronnemaa T, Torjesen PA, Hanssen KF, et al. Increased serum levels of advanced glycation endproducts predict total, cardiovascular and coronary mortality in women with type 2 diabetes: a population-based 18 year follow-up study. Diabetologia. 2007;50:1409–17.

    Article  CAS  PubMed  Google Scholar 

  94. Saremi A, Howell S, Schwenke DC, Bahn G, Beisswenger PJ, Reaven PD, et al. Advanced glycation end products, oxidation products, and the extent of atherosclerosis during the VA diabetes trial and follow-up study. Diabetes Care. 2017;40:591–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Hanssen NM, Beulens JW, van Dieren S, Scheijen JL, van der AD, Spijkerman AM, et al. Plasma advanced glycation end products are associated with incident cardiovascular events in individuals with type 2 diabetes: a case-cohort study with a median follow-up of 10 years (EPIC-NL). Diabetes. 2015;64:257–65.

    Article  CAS  PubMed  Google Scholar 

  96. Nin JW, Jorsal A, Ferreira I, Schalkwijk CG, Prins MH, Parving HH, et al. Higher plasma levels of advanced glycation end products are associated with incident cardiovascular disease and all-cause mortality in type 1 diabetes: a 12-year follow-up study. Diabetes Care. 2011;34:442–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Hanssen NM, Engelen L, Ferreira I, Scheijen JL, Huijberts MS, van Greevenbroek MM, et al. Plasma levels of advanced glycation endproducts Nepsilon-(carboxymethyl)lysine, Nepsilon-(carboxyethyl)lysine, and pentosidine are not independently associated with cardiovascular disease in individuals with or without type 2 diabetes: the Hoorn and CODAM studies. J Clin Endocrinol Metab. 2013;98:E1369–73.

    Article  CAS  PubMed  Google Scholar 

  98. Nagai R, Murray DB, Metz TO, Baynes JW. Chelation: a fundamental mechanism of action of AGE inhibitors, AGE breakers, and other inhibitors of diabetes complications. Diabetes. 2012;61:549–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Sourris KC, Harcourt BE, Forbes JM. A new perspective on therapeutic inhibition of advanced glycation in diabetic microvascular complications: common downstream endpoints achieved through disparate therapeutic approaches? Am J Nephrol. 2009;30:323–35.

    Article  CAS  PubMed  Google Scholar 

  100. Manigrasso MB, Juranek J, Ramasamy R, Schmidt AM. Unlocking the biology of RAGE in diabetic microvascular complications. Trends Endocrinol Metab. 2014;25:15–22.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, USA

    Fernando Bril

  2. Malcom Randall Veterans Affairs Medical Center, Gainesville, FL, USA

    Fernando Bril

  3. OWL Metabolomics, Parque Tecnológico de Bizkaia, Derio, Spain

    Marta Iruarrizaga-Lejarreta & Cristina Alonso

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  1. Fernando Bril
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  3. Cristina Alonso
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Correspondence to Fernando Bril .

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  1. ProSciento, Chula Vista, CA, USA

    Andrew J. Krentz

  2. ProSciento, Chula Vista, CA, USA

    Christian Weyer

  3. ProSciento, Chula Vista, CA, USA

    Marcus Hompesch

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Bril, F., Iruarrizaga-Lejarreta, M., Alonso, C. (2019). Drug Development for Diabetes Mellitus: Beyond Hemoglobin A1c. In: Krentz, A., Weyer, C., Hompesch, M. (eds) Translational Research Methods in Diabetes, Obesity, and Nonalcoholic Fatty Liver Disease. Springer, Cham. https://doi.org/10.1007/978-3-030-11748-1_15

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