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Abstract

Impaired insulin action is a characteristic metabolic defect of obesity, type 2 diabetes and nonalcoholic fatty liver disease. Reducing obesity through non-pharmacological or pharmacological interventions improves whole-body insulin sensitivity. Drugs that directly enhance insulin sensitivity, the biguanide metformin and the thiazolidinediones, have been widely used in the treatment of type 2 diabetes. Other glucose-lowering medications may improve cellular insulin action via indirect mechanisms. The development of new insulin-sensitizing drugs requires robust and reproducible measurement of insulin action in humans. The hyperinsulinemic euglycemic clamp technique is widely regarded as the reference method for determining whole-body insulin sensitivity. Complementary techniques permit insulin action to be (a) partitioned between major organs and (b) broadened beyond glucose metabolism, e.g. to insulin lipid metabolism, vascular function.

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References

  1. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988;37(12):1595–607.

    Article  CAS  PubMed  Google Scholar 

  2. DeFronzo RA, Ferrannini E. Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care. 1991;14(3):173–94.

    Article  CAS  PubMed  Google Scholar 

  3. Krentz AJ. Insulin resistance. Br Med J. 1996;313(7069):1385–9.

    Article  CAS  Google Scholar 

  4. Krentz AJ. Insulin resistance: a clinical handbook. Oxford: Blackwell Science; 2002.

    Book  Google Scholar 

  5. Semple RK, Savage DB, Cochran EK, Gorden P, O’Rahilly S. Genetic syndromes of severe insulin resistance. Endocr Rev. 2011;32(4):498–514.

    Article  CAS  PubMed  Google Scholar 

  6. Friedman J. The long road to leptin. J Clin Invest. 2016;126(12):4727–34.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005;365(9468):1415–28.

    Article  CAS  PubMed  Google Scholar 

  8. White MF. Insulin signaling in health and disease. Science. 2003;302(5651):1710–1.

    Article  CAS  PubMed  Google Scholar 

  9. Konrad D, Rudich A, Klip A. Insulin-mediated regulation of glucose metabolism. In: Kumar S, O’Rahilly S, editors. Insulin resistance: insulin action and its disturbances in disease. Oxford: Wiley; 2005.

    Google Scholar 

  10. Rajala MW, Scherer PE. Minireview: the adipocyte--at the crossroads of energy homeostasis, inflammation, and atherosclerosis. Endocrinology. 2003;144(9):3765–73.

    Article  CAS  PubMed  Google Scholar 

  11. Schwartz MW, Porte D Jr. Diabetes, obesity, and the brain. Science. 2005;307(5708):375–9.

    Article  CAS  PubMed  Google Scholar 

  12. Kleinridders A, Ferris HA, Cai W, Kahn CR. Insulin action in brain regulates systemic metabolism and brain function. Diabetes. 2014;63(7):2232–43.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Bertrand L, Horman S, Beauloye C, Vanoverschelde JL. Insulin signalling in the heart. Cardiovasc Res. 2008;79(2):238–48.

    Article  CAS  PubMed  Google Scholar 

  14. Klein GL. Insulin and bone: recent developments. World J Diabetes. 2014;5(1):14–6.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Orava J, Nuutila P, Lidell ME, et al. Different metabolic responses of human brown adipose tissue to activation by cold and insulin. Cell Metab. 2011;14(2):272–9.

    Article  CAS  PubMed  Google Scholar 

  16. Diamanti-Kandarakis E, Dunaif A. Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocr Rev. 2012;33(6):981–1030.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Rask-Madsen C, Kahn CR. Tissue-specific insulin signaling, metabolic syndrome, and cardiovascular disease. Arterioscler Thromb Vasc Biol. 2012;32(9):2052–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Braun M, Ramracheya R, Rorsman P. Autocrine regulation of insulin secretion. Diabetes Obes Metab. 2012;14(Suppl 3):143–51.

    Article  CAS  PubMed  Google Scholar 

  19. Rhodes CJ, White MF, Leahy JL, Kahn SE. Direct autocrine action of insulin on beta-cells: does it make physiological sense? Diabetes. 2013;62(7):2157–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ahmadian M, Suh JM, Hah N, et al. PPARgamma signaling and metabolism: the good, the bad and the future. Nat Med. 2013;19(5):557–66.

    Article  CAS  PubMed  Google Scholar 

  21. Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med. 2016;374(14):1321–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Yki-Jarvinen H, Westerbacka J. Vascular actions of insulin in obesity. Int J Obes Relat Metab Disord. 2000;24(Suppl 2):S25–8.

    Article  CAS  PubMed  Google Scholar 

  23. Dandona P, Aljada A, Chaudhuri A, Mohanty P, Garg R. Metabolic syndrome: a comprehensive perspective based on interactions between obesity, diabetes, and inflammation. Circulation. 2005;111(11):1448–54.

    Article  PubMed  Google Scholar 

  24. Aroor AR, McKarns S, Demarco VG, Jia G, Sowers JR. Maladaptive immune and inflammatory pathways lead to cardiovascular insulin resistance. Metabolism. 2013;62(11):1543–52.

    Article  CAS  PubMed  Google Scholar 

  25. Bergman RN, Lilly Lecture. Toward physiological understanding of glucose tolerance. Minimal-model approach. Diabetes. 1989;38(12):1512–27.

    Article  CAS  PubMed  Google Scholar 

  26. Czech MP, Corvera S. Signaling mechanisms that regulate glucose transport. J Biol Chem. 1999;274(4):1865–8.

    Article  CAS  PubMed  Google Scholar 

  27. Chang L, Chiang SH, Saltiel AR. Insulin signaling and the regulation of glucose transport. Mol Med. 2004;10(7–12):65–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Huang S, Czech MP. The GLUT4 glucose transporter. Cell Metab. 2007;5(4):237–52.

    Article  CAS  PubMed  Google Scholar 

  29. Abdul-Ghani MA, DeFronzo RA. Pathogenesis of insulin resistance in skeletal muscle. J Biomed Biotechnol. 2010;2010:476279.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Straus DS. Effects of insulin on cellular growth and proliferation. Life Sci. 1981;29(21):2131–9.

    Article  CAS  PubMed  Google Scholar 

  31. Wang CC, Goalstone ML, Draznin B. Molecular mechanisms of insulin resistance that impact cardiovascular biology. Diabetes. 2004;53(11):2735–40.

    Article  CAS  PubMed  Google Scholar 

  32. Fujita S, Rasmussen BB, Cadenas JG, Grady JJ, Volpi E. Effect of insulin on human skeletal muscle protein synthesis is modulated by insulin-induced changes in muscle blood flow and amino acid availability. Am J Physiol Endocrinol Metab. 2006;291(4):E745–54.

    Article  CAS  PubMed  Google Scholar 

  33. Andres R, Baltzan MA, Cader G, Zierler KL. Effect of insulin on carbohydrate metabolism and on potassium in the forearm of man. J Clin Invest. 1962;41:108–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Reaven GM. The insulin resistance syndrome: definition and dietary approaches to treatment. Annu Rev Nutr. 2005;25:391–406.

    Article  CAS  PubMed  Google Scholar 

  35. Kahn CR. Insulin resistance, insulin insensitivity, and insulin unresponsiveness: a necessary distinction. Metabolism. 1978;27(12 Suppl 2):1893–902.

    Article  CAS  PubMed  Google Scholar 

  36. Roberts LD, Koulman A, Griffine JL. Towards metabolic biomarkers of insulin resistance and type 2 diabetes: progress from the metabolome. Lancet Diabetes Endocrinol. 2013;2:65–75.

    Article  PubMed  CAS  Google Scholar 

  37. Czech MP. Insulin action and resistance in obesity and type 2 diabetes. Nat Med. 2017;23(7):804–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature. 2006;444(7121):840–6.

    Article  CAS  PubMed  Google Scholar 

  39. Szendroedi J, Roden M. Ectopic lipids and organ function. Curr Opin Lipidol. 2009;20(1):50–6.

    Article  CAS  PubMed  Google Scholar 

  40. Ye J. Mechanisms of insulin resistance in obesity. Front Med. 2013;7(1):14–24.

    Article  PubMed  PubMed Central  Google Scholar 

  41. McLaughlin T, Allison G, Abbasi F, Lamendola C, Reaven G. Prevalence of insulin resistance and associated cardiovascular disease risk factors among normal weight, overweight, and obese individuals. Metabolism. 2004;53(4):495–9.

    Article  CAS  PubMed  Google Scholar 

  42. Reaven G, Abbasi F, McLaughlin T. Obesity, insulin resistance, and cardiovascular disease. Recent Prog Horm Res. 2004;59:207–23.

    Article  CAS  PubMed  Google Scholar 

  43. Alexopoulos N, Katritsis D, Raggi P. Visceral adipose tissue as a source of inflammation and promoter of atherosclerosis. Atherosclerosis. 2014;233(1):104–12.

    Article  CAS  PubMed  Google Scholar 

  44. Samuel VT, Shulman GI. Mechanisms for insulin resistance: common threads and missing links. Cell. 2012;148(5):852–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Sattar N, Gill JM. Type 2 diabetes as a disease of ectopic fat. BMC Med. 2014;12:123.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Lotta LA, Gulati P, Day FR, et al. Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance. Nat Genet. 2017;49(1):17–26.

    Article  CAS  PubMed  Google Scholar 

  47. Plutzky J. The vascular biology of atherosclerosis. Am J Med. 2003;115(Suppl 8A):55S–61S.

    Article  CAS  PubMed  Google Scholar 

  48. Reaven G. Insulin resistance and coronary heart disease in nondiabetic individuals. Arterioscler Thromb Vasc Biol. 2012;32(8):1754–9.

    Article  CAS  PubMed  Google Scholar 

  49. Ryden L, Mellbin L. Glucose perturbations and cardiovascular risk: challenges and opportunities. Diab Vasc Dis Res. 2012;9(3):170–6.

    Article  PubMed  Google Scholar 

  50. Grundy SM. Metabolic syndrome: connecting and reconciling cardiovascular and diabetes worlds. J Am Coll Cardiol. 2006;47(6):1093–100.

    Article  CAS  PubMed  Google Scholar 

  51. Reaven G. The metabolic syndrome or the insulin resistance syndrome? Different names, different concepts, and different goals. Endocrinol Metab Clin N Am. 2004;33(2):283–303.

    Article  Google Scholar 

  52. Alberti KG, Zimmet P, Shaw J. Metabolic syndrome--a new world-wide definition. A consensus statement from the international diabetes federation. Diabet Med. 2006;23(5):469–80.

    Article  CAS  PubMed  Google Scholar 

  53. Cusi K, Maezono K, Osman A, et al. Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle. J Clin Invest. 2000;105(3):311–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Reaven GM. Role of insulin resistance in the pathophysiology of non-insulin dependent diabetes mellitus. Diabetes Metab Rev. 1993;9(Suppl 1):5S–12S.

    Article  PubMed  Google Scholar 

  55. Kahn SE, Cooper ME, Prato SD. Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future. Lancet. 2014;383(9922):1068–83.

    Article  CAS  PubMed  Google Scholar 

  56. Kahn SE. The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes. Diabetologia. 2003;46(1):3–19.

    Article  CAS  PubMed  Google Scholar 

  57. Kolterman OG, Insel J, Saekow M, Olefsky JM. Mechanisms of insulin resistance in human obesity: evidence for receptor and postreceptor defects. J Clin Invest. 1980;65(6):1272–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kolterman OG, Gray RS, Griffin J, et al. Receptor and postreceptor defects contribute to the insulin resistance in noninsulin-dependent diabetes mellitus. J Clin Invest. 1981;68(4):957–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Mitrakou A, Kelley D, Mokan M, et al. Role of reduced suppression of glucose production and diminished early insulin release in impaired glucose tolerance. N Engl J Med. 1992;326(1):22–9.

    Article  CAS  PubMed  Google Scholar 

  60. Meyer C, Woerle HJ, Dostou JM, Welle SL, Gerich JE. Abnormal renal, hepatic, and muscle glucose metabolism following glucose ingestion in type 2 diabetes. Am J Physiol Endocrinol Metab. 2004;287(6):E1049–56.

    Article  CAS  PubMed  Google Scholar 

  61. Bril F, Barb D, Portillo-Sanchez P, et al. Metabolic and histological implications of intrahepatic triglyceride content in nonalcoholic fatty liver disease. Hepatology. 2017;65(4):1132–44.

    Article  CAS  PubMed  Google Scholar 

  62. DeFronzo RA. Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009. Diabetologia. 2010;53(7):1270–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Taylor R. Type 2 diabetes: etiology and reversibility. Diabetes Care. 2013;36(4):1047–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Lim EL, Hollingsworth KG, Aribisala BS, et al. Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia. 2011;54(10):2506–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Stumvoll M, Goldstein BJ, van Haeften TW. Type 2 diabetes: principles of pathogenesis and therapy. Lancet. 2005;365(9467):1333–46.

    Article  CAS  PubMed  Google Scholar 

  66. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35(6):1364–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Krentz AJ, Bailey CJ. Oral antidiabetic agents: current role in type 2 diabetes mellitus. Drugs. 2005;65(3):385–411.

    Article  CAS  PubMed  Google Scholar 

  68. Bailey CJ, Turner RC. Metformin. N Engl J Med. 1996;334(9):574–9.

    Article  CAS  PubMed  Google Scholar 

  69. Bailey CJ. Metformin: historical overview. Diabetologia. 2017;60(9):1566–76.

    Article  CAS  PubMed  Google Scholar 

  70. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393–403.

    Article  CAS  PubMed  Google Scholar 

  71. Krentz A. Thiazolidinediones: effects on the development and progression of type 2 diabetes and associated vascular complications. Diabetes Metab Res Rev. 2009;25(2):112–26.

    Article  CAS  PubMed  Google Scholar 

  72. Kahn CR, Chen L, Cohen SE. Unraveling the mechanism of action of thiazolidinediones. J Clin Invest. 2000;106(11):1305–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Yip J, Facchini FS, Reaven GM. Resistance to insulin-mediated glucose disposal as a predictor of cardiovascular disease. J Clin Endocrinol Metab. 1998;83(8):2773–6.

    Article  CAS  PubMed  Google Scholar 

  74. Kozakova M, Natali A, Dekker J, et al. Insulin sensitivity and carotid intima-media thickness: relationship between insulin sensitivity and cardiovascular risk study. Arterioscler Thromb Vasc Biol. 2013;33(6):1409–17.

    Article  CAS  PubMed  Google Scholar 

  75. Muniyappa R, Sowers JR. Role of insulin resistance in endothelial dysfunction. Rev Endocr Metab Disord. 2013;14(1):5–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352(9131):854–65.

    Article  Google Scholar 

  77. Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366(9493):1279–89.

    Article  CAS  PubMed  Google Scholar 

  78. Lamanna C, Monami M, Marchionni N, Mannucci E. Effect of metformin on cardiovascular events and mortality: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2011;13(3):221–8.

    Article  CAS  PubMed  Google Scholar 

  79. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356(24):2457–71.

    Article  CAS  PubMed  Google Scholar 

  80. Krentz AJ. Rosiglitazone: trials, tribulations and termination. Drugs. 2011;71(2):123–30.

    Article  CAS  PubMed  Google Scholar 

  81. Bailey CJ. Learning from tesaglitazar. Diab Vasc Dis Res. 2007;4(3):161–2.

    Article  PubMed  Google Scholar 

  82. Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA. 2005;294(20):2581–6.

    Article  CAS  PubMed  Google Scholar 

  83. Younk LM, Uhl L, Davis SN. Pharmacokinetics, efficacy and safety of aleglitazar for the treatment of type 2 diabetes with high cardiovascular risk. Expert Opin Drug Metab Toxicol. 2011;7(6):753–63.

    Article  CAS  PubMed  Google Scholar 

  84. Colca JR, Tanis SP, McDonald WG, Kletzien RF. Insulin sensitizers in 2013: new insights for the development of novel therapeutic agents to treat metabolic diseases. Expert Opin Investig Drugs. 2014;23(1):1–7.

    Article  CAS  PubMed  Google Scholar 

  85. Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol. 2010;72:219–46.

    Article  CAS  PubMed  Google Scholar 

  86. Esser N, Legrand-Poels S, Piette J, Scheen AJ, Paquot N. Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes Res Clin Pract. 2014;105(2):141–50.

    Article  CAS  PubMed  Google Scholar 

  87. Kim SH, Liu A, Ariel D, et al. Effect of salsalate on insulin action, secretion, and clearance in nondiabetic, insulin-resistant individuals: a randomized, placebo-controlled study. Diabetes Care. 2014;37(7):1944–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Everett BM, Donath MY, Pradhan AD, et al. Anti-inflammatory therapy with canakinumab for the prevention and management of diabetes. J Am Coll Cardiol. 2018;71(21):2392–401.

    Article  CAS  PubMed  Google Scholar 

  89. Lonardo A, Nascimbeni F, Mantovani A, Targher G. Hypertension, diabetes, atherosclerosis and NASH: cause or consequence? J Hepatol. 2018;68(2):335–52.

    Article  PubMed  Google Scholar 

  90. Bugianesi E, Gastaldelli A, Vanni E, et al. Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms. Diabetologia. 2005;48(4):634–42.

    Article  CAS  PubMed  Google Scholar 

  91. Cusi K. Role of insulin resistance and lipotoxicity in non-alcoholic steatohepatitis. Clin Liver Dis. 2009;13(4):545–63.

    Article  PubMed  Google Scholar 

  92. Yki-Jarvinen H. Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome. Lancet Diabetes Endocrinol. 2014;2(11):901–10.

    Article  CAS  PubMed  Google Scholar 

  93. Belfort R, Harrison SA, Brown K, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006;355(22):2297–307.

    Article  CAS  PubMed  Google Scholar 

  94. Caldwell S. NASH Therapy: omega 3 supplementation, vitamin E, insulin sensitizers and statin drugs. Clin Mol Hepatol. 2017;23(2):103–8.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Ratziu V, Harrison SA, Francque S, et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-alpha and -delta, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology. 2016;150(5):1147–1159 e5.

    Article  CAS  PubMed  Google Scholar 

  96. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 2015;385(9972):956–65.

    Article  CAS  PubMed  Google Scholar 

  97. Yarchoan M, Arnold SE. Repurposing diabetes drugs for brain insulin resistance in Alzheimer disease. Diabetes. 2014;63(7):2253–61.

    Article  PubMed  PubMed Central  Google Scholar 

  98. de la Monte SM. Insulin resistance and neurodegeneration: progress towards the development of new therapeutics for Alzheimer’s disease. Drugs. 2017;77(1):47–65.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Krentz AJ, Hitman GA. Sir Harold Himsworth and insulin insensitivity 75 years on. Diabet Med. 2011;28(12):1435.

    Article  CAS  PubMed  Google Scholar 

  100. Himsworth HP. Diabetes mellitus: a differentiation into insulin-sensitive and insulin-insenstive subtypes. Lancet. 1936;1:127–30.

    Article  Google Scholar 

  101. Kahn CR, Roth J. Berson, Yalow, and the JCI: the agony and the ecstasy. J Clin Invest. 2004;114(8):1051–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Karam JH, Grodsky GM, Forsham PH. Insulin secretion in obesity: pseudodiabetes? Am J Clin Nutr. 1968;21(12):1445–54.

    Article  CAS  PubMed  Google Scholar 

  103. Randle PJ, Garland PB, Hales CN, Newsholme EA. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet. 1963;1(7285):785–9.

    Article  CAS  PubMed  Google Scholar 

  104. Zierler KL, Rabinowitz D. Effect of very small concentrations of insulin on forearm metabolism. Persistence of its action on potassium and free fatty acids without its effect on glucose. J Clin Invest. 1964;43:950–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Phys. 1979;237(3):E214–23.

    CAS  Google Scholar 

  106. Kahn CR, White MF. The insulin receptor and the molecular mechanism of insulin action. J Clin Invest. 1988;82(4):1151–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Czech MP, Klarlund JK, Yagaloff KA, Bradford AP, Lewis RE. Insulin receptor signaling. Activation of multiple serine kinases. J Biol Chem. 1988;263(23):11017–20.

    CAS  PubMed  Google Scholar 

  108. Heinemann L, Anderson JH Jr. Measurement of insulin absorption and insulin action. Diabetes Technol Ther. 2004;6(5):698–718.

    Article  CAS  PubMed  Google Scholar 

  109. Krentz AJ, Bailey CJ, Melander A. Thiazolidinediones for type 2 diabetes. New agents reduce insulin resistance but need long term clinical trials. BMJ. 2000;321(7256):252–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Hiatt WR, Kaul S, Smith RJ. The cardiovascular safety of diabetes drugs--insights from the rosiglitazone experience. N Engl J Med. 2013;369(14):1285–7.

    Article  CAS  PubMed  Google Scholar 

  111. Alberti KG. Blood metabolites in the diagnosis and treatment of diabetes mellitus. Postgrad Med J. 1973;49(Suppl 7):955–63.

    CAS  Google Scholar 

  112. Krentz AJ, Nattrass M. Insulin resistance: a multifaceted metabolic syndrome. Insights gained using a low-dose insulin infusion technique. Diabet Med. 1996;13(1):30–9.

    Article  CAS  PubMed  Google Scholar 

  113. Sekiguchi H, Kasubuchi M, Hasegawa S, et al. A novel antidiabetic therapy: free fatty acid receptors as potential drug target. Curr Diabetes Rev. 2015;11(2):107–15.

    Article  CAS  PubMed  Google Scholar 

  114. Guerre-Millo M, Gervois P, Raspe E, et al. Peroxisome proliferator-activated receptor alpha activators improve insulin sensitivity and reduce adiposity. J Biol Chem. 2000;275(22):16638–42.

    Article  CAS  PubMed  Google Scholar 

  115. Knickelbein JE, Abbott AB, Chew EY. Fenofibrate and diabetic retinopathy. Curr Diab Rep. 2016;16(10):90.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  116. Zema MJ. Colesevelam hydrochloride: evidence for its use in the treatment of hypercholesterolemia and type 2 diabetes mellitus with insights into mechanism of action. Core Evid. 2012;7:61–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Scheen AJ, Paquot N. Use of cannabinoid CB1 receptor antagonists for the treatment of metabolic disorders. Best Pract Res Clin Endocrinol Metab. 2009;23(1):103–16.

    Article  CAS  PubMed  Google Scholar 

  118. Silvestri C, Di Marzo V. Second generation CB1 receptor blockers and other inhibitors of peripheral endocannabinoid overactivity and the rationale of their use against metabolic disorders. Expert Opin Investig Drugs. 2012;21(9):1309–22.

    Article  CAS  PubMed  Google Scholar 

  119. Koffarnus RL, Wargo KA, Phillippe HM. Rivoglitazone: a new thiazolidinedione for the treatment of type 2 diabetes mellitus. Ann Pharmacother. 2013;47(6):877–85.

    Article  PubMed  CAS  Google Scholar 

  120. Van Cauter E, Polonsky KS, Scheen AJ. Roles of circadian rhythmicity and sleep in human glucose regulation. Endocr Rev. 1997;18(5):716–38.

    PubMed  Google Scholar 

  121. Yki-Jarvinen H. Thiazolidinediones. N Engl J Med. 2004;351(11):1106–18.

    Article  PubMed  Google Scholar 

  122. Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol. 2012;8(12):728–42.

    Article  CAS  PubMed  Google Scholar 

  123. Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28(7):412–9.

    Article  CAS  PubMed  Google Scholar 

  124. Levy JC, Matthews DR, Hermans MP. Correct homeostasis model assessment (HOMA) evaluation uses the computer program. Diabetes Care. 1998;21(12):2191–2.

    Article  CAS  PubMed  Google Scholar 

  125. Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modeling. Diabetes Care. 2004;27(6):1487–95.

    Article  PubMed  Google Scholar 

  126. Katz A, Nambi SS, Mather K, et al. Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab. 2000;85(7):2402–10.

    Article  CAS  PubMed  Google Scholar 

  127. Pacini G, Mari A. Methods for clinical assessment of insulin sensitivity and beta-cell function. Best Pract Res Clin Endocrinol Metab. 2003;17(3):305–22.

    Article  CAS  PubMed  Google Scholar 

  128. Manley SE, Luzio SD, Stratton IM, Wallace TM, Clark PM. Preanalytical, analytical, and computational factors affect homeostasis model assessment estimates. Diabetes Care. 2008;31(9):1877–83.

    Article  PubMed  PubMed Central  Google Scholar 

  129. Reaven G. Wanted!: a standardized measurement of plasma insulin concentration. Arterioscler Thromb Vasc Biol. 2011;31(5):954–5.

    Article  CAS  PubMed  Google Scholar 

  130. Kim SH, Abbasi F, Reaven GM. Impact of degree of obesity on surrogate estimates of insulin resistance. Diabetes Care. 2004;27(8):1998–2002.

    Article  PubMed  Google Scholar 

  131. Wallace TM, Matthews DR. The assessment of insulin resistance in man. Diabet Med. 2002;19(7):527–34.

    Article  CAS  PubMed  Google Scholar 

  132. Jayagopal V, Kilpatrick ES, Jennings PE, Hepburn DA, Atkin SL. Biological variation of homeostasis model assessment-derived insulin resistance in type 2 diabetes. Diabetes Care. 2002;25(11):2022–5.

    Article  PubMed  Google Scholar 

  133. Aye MM, Kilpatrick ES, Afolabi P, et al. Postprandial effects of long-term niacin/laropiprant use on glucose and lipid metabolism and on cardiovascular risk in patients with polycystic ovary syndrome. Diabetes Obes Metab. 2014;16(6):545–52.

    Article  CAS  PubMed  Google Scholar 

  134. Yang Y, Wei RB, Xing Y, et al. A meta-analysis of the effect of angiotensin receptor blockers and calcium channel blockers on blood pressure, glycemia and the HOMA-IR index in non-diabetic patients. Metabolism. 2013;62(12):1858–66.

    Article  CAS  PubMed  Google Scholar 

  135. Elliott WJ, Meyer PM. Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis. Lancet. 2007;369(9557):201–7.

    Article  CAS  PubMed  Google Scholar 

  136. Hill NR, Levy JC, Matthews DR. Expansion of the homeostasis model assessment of beta-cell function and insulin resistance to enable clinical trial outcome modeling through the interactive adjustment of physiology and treatment effects: iHOMA2. Diabetes Care. 2013;36(8):2324–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Asmar M, Holst JJ. Glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide: new advances. Curr Opin Endocrinol Diabetes Obes. 2010;17(1):57–62.

    Article  CAS  PubMed  Google Scholar 

  138. Schernthaner G, Grimaldi A, Di Mario U, et al. GUIDE study: double-blind comparison of once-daily gliclazide MR and glimepiride in type 2 diabetic patients. Eur J Clin Investig. 2004;34(8):535–42.

    Article  CAS  Google Scholar 

  139. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368(9548):1696–705.

    Article  CAS  PubMed  Google Scholar 

  140. Bergman RN, Phillips LS, Cobelli C. Physiologic evaluation of factors controlling glucose tolerance in man: measurement of insulin sensitivity and beta-cell glucose sensitivity from the response to intravenous glucose. J Clin Invest. 1981;68(6):1456–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Beard JC, Bergman RN, Ward WK, Porte D Jr. The insulin sensitivity index in nondiabetic man. Correlation between clamp-derived and IVGTT-derived values. Diabetes. 1986;35(3):362–9.

    Article  CAS  PubMed  Google Scholar 

  142. Bergman RN, Ider YZ, Bowden CR, Cobelli C. Quantitative estimation of insulin sensitivity. Am J Phys. 1979;236(6):E667–77.

    CAS  Google Scholar 

  143. Bergman RN, Finegood DT, Ader M. Assessment of insulin sensitivity in vivo. Endocr Rev. 1985;6(1):45–86.

    Article  CAS  PubMed  Google Scholar 

  144. Saad MF, Anderson RL, Laws A, et al. A comparison between the minimal model and the glucose clamp in the assessment of insulin sensitivity across the spectrum of glucose tolerance. Insulin Resistance Atherosclerosis Study. Diabetes. 1994;43(9):1114–21.

    Article  CAS  PubMed  Google Scholar 

  145. Best JD, Kahn SE, Ader M, et al. Role of glucose effectiveness in the determination of glucose tolerance. Diabetes Care. 1996;19(9):1018–30.

    Article  CAS  PubMed  Google Scholar 

  146. Rayner CK, Horowitz M. Gastrointestinal motility and glycemic control in diabetes: the chicken and the egg revisited? J Clin Invest. 2006;116(2):299–302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Holst JJ, Vilsboll T, Deacon CF. The incretin system and its role in type 2 diabetes mellitus. Mol Cell Endocrinol. 2009;297(1–2):127–36.

    Article  CAS  PubMed  Google Scholar 

  148. Ferrannini E, Mari A. How to measure insulin sensitivity. J Hypertens. 1998;16(7):895–906.

    Google Scholar 

  149. 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(1):E15–26.

    Article  CAS  PubMed  Google Scholar 

  150. Kim SH. Measurement of insulin action: a tribute to Sir Harold Himsworth. Diabet Med. 2011;28(12):1487–93.

    Article  CAS  PubMed  Google Scholar 

  151. Schwartz MW, Seeley RJ, Tschop MH, et al. Cooperation between brain and islet in glucose homeostasis and diabetes. Nature. 2013;503(7474):59–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Ko GT, Chan JC, Woo J, et al. The reproducibility and usefulness of the oral glucose tolerance test in screening for diabetes and other cardiovascular risk factors. Ann Clin Biochem. 1998;35(Pt 1):62–7.

    Article  PubMed  Google Scholar 

  153. Vinik AI, Maser RE, Mitchell BD, Freeman R. Diabetic autonomic neuropathy. Diabetes Care. 2003;26(5):1553–79.

    Article  PubMed  Google Scholar 

  154. Due A, Larsen TM, Hermansen K, et al. Comparison of the effects on insulin resistance and glucose tolerance of 6-mo high-monounsaturated-fat, low-fat, and control diets. Am J Clin Nutr. 2008;87(4):855–62.

    Article  CAS  PubMed  Google Scholar 

  155. Heer M, Egert S. Nutrients other than carbohydrates: their effects on glucose homeostasis in humans. Diabetes Metab Res Rev. 2014;31(1):14–35.

    Article  CAS  Google Scholar 

  156. Karlsson F, Tremaroli V, Nielsen J, Backhed F. Assessing the human gut microbiota in metabolic diseases. Diabetes. 2013;62(10):3341–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med. 1998;15(7):539–53.

    Article  CAS  PubMed  Google Scholar 

  158. Bilku DK, Dennison AR, Hall TC, Metcalfe MS, Garcea G. Role of preoperative carbohydrate loading: a systematic review. Ann R Coll Surg Engl. 2014;96(1):15–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care. 1999;22(9):1462–70.

    Article  CAS  PubMed  Google Scholar 

  160. Stumvoll M, Mitrakou A, Pimenta W, et al. Use of the oral glucose tolerance test to assess insulin release and insulin sensitivity. Diabetes Care. 2000;23(3):295–301.

    Article  CAS  PubMed  Google Scholar 

  161. Mari A, Pacini G, Murphy E, Ludvik B, Nolan JJ. A model-based method for assessing insulin sensitivity from the oral glucose tolerance test. Diabetes Care. 2001;24(3):539–48.

    Article  CAS  PubMed  Google Scholar 

  162. Dalla Man C, Campioni M, Polonsky KS, et al. Two-hour seven-sample oral glucose tolerance test and meal protocol: minimal model assessment of beta-cell responsivity and insulin sensitivity in nondiabetic individuals. Diabetes. 2005;54(11):3265–73.

    Article  CAS  PubMed  Google Scholar 

  163. Beysen C, Murphy EJ, McLaughlin T, et al. Whole-body glycolysis measured by the deuterated-glucose disposal test correlates highly with insulin resistance in vivo. Diabetes Care. 2007;30(5):1143–9.

    Article  CAS  PubMed  Google Scholar 

  164. Meyer C, Dostou JM, Welle SL, Gerich JE. Role of human liver, kidney, and skeletal muscle in postprandial glucose homeostasis. Am J Physiol Endocrinol Metab. 2002;282(2):E419–27.

    Article  CAS  PubMed  Google Scholar 

  165. Dube S, Errazuriz I, Cobelli C, Basu R, Basu A. Assessment of insulin action on carbohydrate metabolism: physiological and non-physiological methods. Diabet Med. 2013;30(6):664–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Polidori D, Sha S, Mudaliar S, et al. Canagliflozin lowers postprandial glucose and insulin by delaying intestinal glucose absorption in addition to increasing urinary glucose excretion: results of a randomized, placebo-controlled study. Diabetes Care. 2013;36(8):2154–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Hucking K, Watanabe RM, Stefanovski D, Bergman RN. OGTT-derived measures of insulin sensitivity are confounded by factors other than insulin sensitivity itself. Obesity (Silver Spring). 2008;16(8):1938–45.

    Google Scholar 

  168. Chen CC, Wang TY, Hsu SY, et al. Is the short insulin tolerance test safe and reproducible? Diabet Med. 1998;15(11):924–7.

    Article  CAS  PubMed  Google Scholar 

  169. Gelding SV, Robinson S, Lowe S, Niththyananthan R, Johnston DG. Validation of the low dose short insulin tolerance test for evaluation of insulin sensitivity. Clin Endocrinol. 1994;40(5):611–5.

    Article  CAS  Google Scholar 

  170. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Harano Y, Hidaka H, Takatsuki K, et al. Glucose, insulin, and somatostatin infusion for the determination of insulin sensitivity in vivo. Metabolism. 1978;27(9 Suppl 1):1449–52.

    Article  CAS  PubMed  Google Scholar 

  172. Pei D, Jones CN, Bhargava R, Chen YD, Reaven GM. Evaluation of octreotide to assess insulin-mediated glucose disposal by the insulin suppression test. Diabetologia. 1994;37(8):843–5.

    Article  CAS  PubMed  Google Scholar 

  173. McLaughlin T, Yee G, Glassford A, Lamendola C, Reaven G. Use of a two-stage insulin infusion study to assess the relationship between insulin suppression of lipolysis and insulin-mediated glucose uptake in overweight/obese, nondiabetic women. Metabolism. 2011;60(12):1741–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Elahi D, Meneilly GS, Minaker KL, Andersen DK, Rowe JW. Escape of hepatic glucose production during hyperglycemic clamp. Am J Phys. 1989;257(5 Pt 1):E704–11.

    CAS  Google Scholar 

  175. Kruzynska Y. In: Pickup JC, Williams G, editors. Textbook of diabetes. Oxford: Blackwell Science; 1997.

    Google Scholar 

  176. Rizza RA, Mandarino LJ, Gerich JE. Dose-response characteristics for effects of insulin on production and utilization of glucose in man. Am J Phys. 1981;240(6):E630–9.

    CAS  Google Scholar 

  177. Stumvoll M, Meyer C, Mitrakou A, Gerich JE. Important role of the kidney in human carbohydrate metabolism. Med Hypotheses. 1999;52(5):363–6.

    Article  CAS  PubMed  Google Scholar 

  178. Gerich JE, Meyer C, Woerle HJ, Stumvoll M. Renal gluconeogenesis: its importance in human glucose homeostasis. Diabetes Care. 2001;24(2):382–91.

    Article  CAS  PubMed  Google Scholar 

  179. Conte C, Fabbrini E, Kars M, et al. Multiorgan insulin sensitivity in lean and obese subjects. Diabetes Care. 2012;35(6):1316–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Pratipanawatr T, Pratipanawatr W, Rosen C, et al. Effect of IGF-I on FFA and glucose metabolism in control and type 2 diabetic subjects. Am J Physiol Endocrinol Metab. 2002;282(6):E1360–8.

    Article  CAS  PubMed  Google Scholar 

  181. Van Pelt RE, Gozansky WS, Kohrt WM. A novel index of whole body antilipolytic insulin action. Obesity (Silver Spring). 2013;21(1):E162–5.

    Article  CAS  Google Scholar 

  182. Bavenholm PN, Pigon J, Ostenson CG, Efendic S. Insulin sensitivity of suppression of endogenous glucose production is the single most important determinant of glucose tolerance. Diabetes. 2001;50(6):1449–54.

    Article  CAS  PubMed  Google Scholar 

  183. Armstrong MJ, Hazlehurst JM, Hull D, et al. Abdominal subcutaneous adipose tissue insulin resistance and lipolysis in patients with non-alcoholic steatohepatitis. Diabetes Obes Metab. 2014;16(7):651–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Gastaldelli A, Cusi K, Pettiti M, et al. Relationship between hepatic/visceral fat and hepatic insulin resistance in nondiabetic and type 2 diabetic subjects. Gastroenterology. 2007;133(2):496–506.

    Article  CAS  PubMed  Google Scholar 

  185. Glintborg D, Frystyk J, Hojlund K, et al. Total and high molecular weight (HMW) adiponectin levels and measures of glucose and lipid metabolism following pioglitazone treatment in a randomized placebo-controlled study in polycystic ovary syndrome. Clin Endocrinol. 2008;68(2):165–74.

    Google Scholar 

  186. Morrow L, Hompesch M, Tideman AM, et al. Evaluation of a novel continuous glucose measurement device in patients with diabetes mellitus across the glycemic range. J Diabetes Sci Technol. 2011;5(4):853–9.

    Article  PubMed  PubMed Central  Google Scholar 

  187. Johansson E, Lubberink M, Heurling K, et al. Whole-body imaging of tissue-specific insulin sensitivity and body composition by using an integrated PET/MR system: a feasibility study. Radiology. 2018;286(1):271–8.

    Article  PubMed  Google Scholar 

  188. Morris AD, Ueda S, Petrie JR, et al. The euglycaemic hyperinsulinaemic clamp: an evaluation of current methodology. Clin Exp Pharmacol Physiol. 1997;24(7):513–8.

    Article  CAS  PubMed  Google Scholar 

  189. Sherwin RS, Kramer KJ, Tobin JD, et al. A model of the kinetics of insulin in man. J Clin Invest. 1974;53(5):1481–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Kampmann U, Hoeyem P, Mengel A, et al. Insulin dose-response studies in severely insulin-resistant type 2 diabetes--evidence for effectiveness of very high insulin doses. Diabetes Obes Metab. 2011;13(6):511–6.

    Article  CAS  PubMed  Google Scholar 

  191. Heinemann L, Ampudia-Blasco FJ. Glucose clamps with the Biostator: a critical reappraisal. Horm Metab Res. 1994;26(12):579–83.

    Article  CAS  PubMed  Google Scholar 

  192. Picchini U, De Gaetano A, Panunzi S, Ditlevsen S, Mingrone G. A mathematical model of the euglycemic hyperinsulinemic clamp. Theor Biol Med Model. 2005;2:44.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  193. Doberne L, Greenfield MS, Schulz B, Reaven GM. Enhanced glucose utilization during prolonged glucose clamp studies. Diabetes. 1981;30(10):829–35.

    Article  CAS  PubMed  Google Scholar 

  194. Roden M, Price TB, Perseghin G, et al. Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest. 1996;97(12):2859–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Revers RR, Kolterman OG, Olefsky JM. Relationship between serum glucose level and the metabolic clearance rate of glucose in non-insulin-dependent diabetes mellitus. Diabetes. 1983;32(7):627–32.

    Article  CAS  PubMed  Google Scholar 

  196. Heise T, Rave K, Weyer C, Heinemann L. Measurement of insulin sensitivity with the euglycaemic clamp technique: methodological pitfalls. Int J Diabetes. 1998;6:70–5.

    Google Scholar 

  197. Inzucchi SE, Maggs DG, Spollett GR, et al. Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. N Engl J Med. 1998;338(13):867–72.

    Article  CAS  PubMed  Google Scholar 

  198. Mancia G, Grassi G, Zanchetti A. New-onset diabetes and antihypertensive drugs. J Hypertens. 2006;24(1):3–10.

    Article  CAS  PubMed  Google Scholar 

  199. Kauh EA, Mixson LA, Shankar S, et al. Short-term metabolic effects of prednisone administration in healthy subjects. Diabetes Obes Metab. 2011;13(11):1001–7.

    Article  CAS  PubMed  Google Scholar 

  200. Merovci A, Solis-Herrera C, Daniele G, et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest. 2014;124(2):509–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Rossetti L, Giaccari A, DeFronzo RA. Glucose toxicity. Diabetes Care. 1990;13(6):610–30.

    Article  CAS  PubMed  Google Scholar 

  202. Ferrannini E, Muscelli E, Frascerra S, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014;124(2):499–508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Norjavaara E, Ericsson H, Sjoberg F, et al. Glucokinase activators AZD6370 and AZD1656 do not affect the central counterregulatory response to hypoglycemia in healthy males. J Clin Endocrinol Metab. 2012;97(9):3319–25.

    Article  CAS  PubMed  Google Scholar 

  204. Krentz AJ, Boyle PJ, Macdonald LM, Schade DS. Octreotide: a long-acting inhibitor of endogenous hormone secretion for human metabolic investigations. Metabolism. 1994;43(1):24–31.

    Article  CAS  PubMed  Google Scholar 

  205. DeFronzo RA, Hompesch M, Kasichayanula S, et al. Characterization of renal glucose reabsorption in response to dapagliflozin in healthy subjects and subjects with type 2 diabetes. Diabetes Care. 2013;36(10):3169–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Del Prato S, Matsuda M, Simonson DC, et al. Studies on the mass action effect of glucose in NIDDM and IDDM: evidence for glucose resistance. Diabetologia. 1997;40(6):687–97.

    Article  PubMed  Google Scholar 

  207. Soop M, Nygren J, Brismar K, Thorell A, Ljungqvist O. The hyperinsulinaemic-euglycaemic glucose clamp: reproducibility and metabolic effects of prolonged insulin infusion in healthy subjects. Clin Sci (Lond). 2000;98(4):367–74.

    CAS  Google Scholar 

  208. Bokemark L, Froden A, Attvall S, Wikstrand J, Fagerberg B. The euglycemic hyperinsulinemic clamp examination: variability and reproducibility. Scand J Clin Lab Invest. 2000;60(1):27–36.

    Article  CAS  PubMed  Google Scholar 

  209. Mak RH, DeFronzo RA. Glucose and insulin metabolism in uremia. Nephron. 1992;61(4):377–82.

    Article  CAS  PubMed  Google Scholar 

  210. Jung SH, Jung CH, Reaven GM, Kim SH. Adapting to insulin resistance in obesity: role of insulin secretion and clearance. Diabetologia. 2018;61(3):681–7.

    Article  CAS  PubMed  Google Scholar 

  211. Schade DS, Eaton RP. Dose response to insulin in man: differential effects on glucose and ketone body regulation. J Clin Endocrinol Metab. 1977;44(6):1038–53.

    Article  CAS  PubMed  Google Scholar 

  212. Rave K, Heise T, Weyer C, Sawicki P, Heinemann L. Measurement of insulin sensitivity: influence of potassium supply during euglycaemic glucose clamps in healthy volunteers. Exp Clin Endocrinol Diabetes. 1999;107(5):313–7.

    Article  CAS  PubMed  Google Scholar 

  213. Jones TA, Sautter M, Van Gaal LF, Jones NP. Addition of rosiglitazone to metformin is most effective in obese, insulin-resistant patients with type 2 diabetes. Diabetes Obes Metab. 2003;5(3):163–70.

    Article  CAS  PubMed  Google Scholar 

  214. Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia. 2009;52(1):17–30.

    Article  CAS  PubMed  Google Scholar 

  215. Mayerson AB, Hundal RS, Dufour S, et al. The effects of rosiglitazone on insulin sensitivity, lipolysis, and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes. Diabetes. 2002;51(3):797–802.

    Article  CAS  PubMed  Google Scholar 

  216. Miyazaki Y, Matsuda M, DeFronzo RA. Dose-response effect of pioglitazone on insulin sensitivity and insulin secretion in type 2 diabetes. Diabetes Care. 2002;25(3):517–23.

    Article  CAS  PubMed  Google Scholar 

  217. Natali A, Ferrannini E. Effects of metformin and thiazolidinediones on suppression of hepatic glucose production and stimulation of glucose uptake in type 2 diabetes: a systematic review. Diabetologia. 2006;49(3):434–41.

    Article  CAS  PubMed  Google Scholar 

  218. Stern SE, Williams K, Ferrannini E, et al. Identification of individuals with insulin resistance using routine clinical measurements. Diabetes. 2005;54(2):333–9.

    Article  CAS  PubMed  Google Scholar 

  219. Balkau B, Charles MA. Comment on the provisional report from the WHO consultation. European Group for the Study of Insulin Resistance (EGIR). Diabet Med. 1999;16(5):442–3.

    Article  CAS  PubMed  Google Scholar 

  220. Ascaso JF, Pardo S, Real JT, et al. Diagnosing insulin resistance by simple quantitative methods in subjects with normal glucose metabolism. Diabetes Care. 2003;26(12):3320–5.

    Article  CAS  PubMed  Google Scholar 

  221. Cobb J, Gall W, Adam KP, et al. A novel fasting blood test for insulin resistance and prediabetes. J Diabetes Sci Technol. 2013;7(1):100–10.

    Article  PubMed  PubMed Central  Google Scholar 

  222. Krentz AJ, Morrow L, Hompesch M. Developing new drugs for diabetes and cardiometabolic disorders: a changing paradigm. Drugs. 2012;72(13):1709–11.

    Article  PubMed  Google Scholar 

  223. Deanfield JE, Halcox JP, Rabelink TJ. Endothelial function and dysfunction: testing and clinical relevance. Circulation. 2007;115(10):1285–95.

    Article  PubMed  Google Scholar 

  224. Sidhu JS, Kaposzta Z, Markus HS, Kaski JC. Effect of rosiglitazone on common carotid intima-media thickness progression in coronary artery disease patients without diabetes mellitus. Arterioscler Thromb Vasc Biol. 2004;24(5):930–4.

    Article  CAS  PubMed  Google Scholar 

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Krentz, A.J., Weyer, C., Hompesch, M. (2019). Quantification of Insulin Action in Human Subjects. 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_1

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