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Quantification of Insulin Action in Human Subjects

  • Andrew J. KrentzEmail author
  • Christian Weyer
  • Marcus Hompesch
Chapter

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.

Keywords

Insulin resistance Hyperinsulinemic euglycemic clamp Oral glucose tolerance test Intravenous glucose tolerance test 

References

  1. 1.
    Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988;37(12):1595–607.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Krentz AJ. Insulin resistance. Br Med J. 1996;313(7069):1385–9.CrossRefGoogle Scholar
  4. 4.
    Krentz AJ. Insulin resistance: a clinical handbook. Oxford: Blackwell Science; 2002.CrossRefGoogle Scholar
  5. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Friedman J. The long road to leptin. J Clin Invest. 2016;126(12):4727–34.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005;365(9468):1415–28.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    White MF. Insulin signaling in health and disease. Science. 2003;302(5651):1710–1.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 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. 10.
    Rajala MW, Scherer PE. Minireview: the adipocyte--at the crossroads of energy homeostasis, inflammation, and atherosclerosis. Endocrinology. 2003;144(9):3765–73.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Schwartz MW, Porte D Jr. Diabetes, obesity, and the brain. Science. 2005;307(5708):375–9.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Bertrand L, Horman S, Beauloye C, Vanoverschelde JL. Insulin signalling in the heart. Cardiovasc Res. 2008;79(2):238–48.PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Klein GL. Insulin and bone: recent developments. World J Diabetes. 2014;5(1):14–6.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 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.PubMedCrossRefGoogle Scholar
  16. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Rask-Madsen C, Kahn CR. Tissue-specific insulin signaling, metabolic syndrome, and cardiovascular disease. Arterioscler Thromb Vasc Biol. 2012;32(9):2052–9.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Braun M, Ramracheya R, Rorsman P. Autocrine regulation of insulin secretion. Diabetes Obes Metab. 2012;14(Suppl 3):143–51.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Yki-Jarvinen H, Westerbacka J. Vascular actions of insulin in obesity. Int J Obes Relat Metab Disord. 2000;24(Suppl 2):S25–8.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Bergman RN, Lilly Lecture. Toward physiological understanding of glucose tolerance. Minimal-model approach. Diabetes. 1989;38(12):1512–27.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Czech MP, Corvera S. Signaling mechanisms that regulate glucose transport. J Biol Chem. 1999;274(4):1865–8.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Chang L, Chiang SH, Saltiel AR. Insulin signaling and the regulation of glucose transport. Mol Med. 2004;10(7–12):65–71.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Huang S, Czech MP. The GLUT4 glucose transporter. Cell Metab. 2007;5(4):237–52.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Abdul-Ghani MA, DeFronzo RA. Pathogenesis of insulin resistance in skeletal muscle. J Biomed Biotechnol. 2010;2010:476279.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Straus DS. Effects of insulin on cellular growth and proliferation. Life Sci. 1981;29(21):2131–9.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Wang CC, Goalstone ML, Draznin B. Molecular mechanisms of insulin resistance that impact cardiovascular biology. Diabetes. 2004;53(11):2735–40.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Reaven GM. The insulin resistance syndrome: definition and dietary approaches to treatment. Annu Rev Nutr. 2005;25:391–406.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Kahn CR. Insulin resistance, insulin insensitivity, and insulin unresponsiveness: a necessary distinction. Metabolism. 1978;27(12 Suppl 2):1893–902.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Czech MP. Insulin action and resistance in obesity and type 2 diabetes. Nat Med. 2017;23(7):804–14.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature. 2006;444(7121):840–6.PubMedCrossRefGoogle Scholar
  39. 39.
    Szendroedi J, Roden M. Ectopic lipids and organ function. Curr Opin Lipidol. 2009;20(1):50–6.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Ye J. Mechanisms of insulin resistance in obesity. Front Med. 2013;7(1):14–24.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Reaven G, Abbasi F, McLaughlin T. Obesity, insulin resistance, and cardiovascular disease. Recent Prog Horm Res. 2004;59:207–23.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Samuel VT, Shulman GI. Mechanisms for insulin resistance: common threads and missing links. Cell. 2012;148(5):852–71.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Sattar N, Gill JM. Type 2 diabetes as a disease of ectopic fat. BMC Med. 2014;12:123.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Plutzky J. The vascular biology of atherosclerosis. Am J Med. 2003;115(Suppl 8A):55S–61S.PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Reaven G. Insulin resistance and coronary heart disease in nondiabetic individuals. Arterioscler Thromb Vasc Biol. 2012;32(8):1754–9.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Ryden L, Mellbin L. Glucose perturbations and cardiovascular risk: challenges and opportunities. Diab Vasc Dis Res. 2012;9(3):170–6.PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Grundy SM. Metabolic syndrome: connecting and reconciling cardiovascular and diabetes worlds. J Am Coll Cardiol. 2006;47(6):1093–100.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 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.CrossRefGoogle Scholar
  52. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 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.PubMedCrossRefGoogle Scholar
  56. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  60. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  62. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Taylor R. Type 2 diabetes: etiology and reversibility. Diabetes Care. 2013;36(4):1047–55.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Stumvoll M, Goldstein BJ, van Haeften TW. Type 2 diabetes: principles of pathogenesis and therapy. Lancet. 2005;365(9467):1333–46.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Krentz AJ, Bailey CJ. Oral antidiabetic agents: current role in type 2 diabetes mellitus. Drugs. 2005;65(3):385–411.PubMedCrossRefGoogle Scholar
  68. 68.
    Bailey CJ, Turner RC. Metformin. N Engl J Med. 1996;334(9):574–9.PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Bailey CJ. Metformin: historical overview. Diabetologia. 2017;60(9):1566–76.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Kahn CR, Chen L, Cohen SE. Unraveling the mechanism of action of thiazolidinediones. J Clin Invest. 2000;106(11):1305–7.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 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.PubMedCrossRefGoogle Scholar
  75. 75.
    Muniyappa R, Sowers JR. Role of insulin resistance in endothelial dysfunction. Rev Endocr Metab Disord. 2013;14(1):5–12.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 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.CrossRefGoogle Scholar
  77. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  78. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  79. 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.CrossRefGoogle Scholar
  80. 80.
    Krentz AJ. Rosiglitazone: trials, tribulations and termination. Drugs. 2011;71(2):123–30.PubMedCrossRefGoogle Scholar
  81. 81.
    Bailey CJ. Learning from tesaglitazar. Diab Vasc Dis Res. 2007;4(3):161–2.PubMedCrossRefPubMedCentralGoogle Scholar
  82. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  83. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  84. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol. 2010;72:219–46.PubMedCrossRefPubMedCentralGoogle Scholar
  86. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Lonardo A, Nascimbeni F, Mantovani A, Targher G. Hypertension, diabetes, atherosclerosis and NASH: cause or consequence? J Hepatol. 2018;68(2):335–52.PubMedCrossRefPubMedCentralGoogle Scholar
  90. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Cusi K. Role of insulin resistance and lipotoxicity in non-alcoholic steatohepatitis. Clin Liver Dis. 2009;13(4):545–63.PubMedCrossRefPubMedCentralGoogle Scholar
  92. 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.PubMedCrossRefGoogle Scholar
  93. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  94. 94.
    Caldwell S. NASH Therapy: omega 3 supplementation, vitamin E, insulin sensitizers and statin drugs. Clin Mol Hepatol. 2017;23(2):103–8.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 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.PubMedCrossRefGoogle Scholar
  96. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Yarchoan M, Arnold SE. Repurposing diabetes drugs for brain insulin resistance in Alzheimer disease. Diabetes. 2014;63(7):2253–61.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Krentz AJ, Hitman GA. Sir Harold Himsworth and insulin insensitivity 75 years on. Diabet Med. 2011;28(12):1435.PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Himsworth HP. Diabetes mellitus: a differentiation into insulin-sensitive and insulin-insenstive subtypes. Lancet. 1936;1:127–30.CrossRefGoogle Scholar
  101. 101.
    Kahn CR, Roth J. Berson, Yalow, and the JCI: the agony and the ecstasy. J Clin Invest. 2004;114(8):1051–4.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Karam JH, Grodsky GM, Forsham PH. Insulin secretion in obesity: pseudodiabetes? Am J Clin Nutr. 1968;21(12):1445–54.PubMedCrossRefPubMedCentralGoogle Scholar
  103. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  104. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 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.Google Scholar
  106. 106.
    Kahn CR, White MF. The insulin receptor and the molecular mechanism of insulin action. J Clin Invest. 1988;82(4):1151–6.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 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.PubMedPubMedCentralGoogle Scholar
  108. 108.
    Heinemann L, Anderson JH Jr. Measurement of insulin absorption and insulin action. Diabetes Technol Ther. 2004;6(5):698–718.PubMedCrossRefPubMedCentralGoogle Scholar
  109. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 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.PubMedCrossRefGoogle Scholar
  111. 111.
    Alberti KG. Blood metabolites in the diagnosis and treatment of diabetes mellitus. Postgrad Med J. 1973;49(Suppl 7):955–63.Google Scholar
  112. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  113. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  114. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Knickelbein JE, Abbott AB, Chew EY. Fenofibrate and diabetic retinopathy. Curr Diab Rep. 2016;16(10):90.PubMedCrossRefPubMedCentralGoogle Scholar
  116. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  118. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  119. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  120. 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.PubMedPubMedCentralGoogle Scholar
  121. 121.
    Yki-Jarvinen H. Thiazolidinediones. N Engl J Med. 2004;351(11):1106–18.PubMedCrossRefGoogle Scholar
  122. 122.
    Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol. 2012;8(12):728–42.PubMedCrossRefPubMedCentralGoogle Scholar
  123. 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.PubMedCrossRefGoogle Scholar
  124. 124.
    Levy JC, Matthews DR, Hermans MP. Correct homeostasis model assessment (HOMA) evaluation uses the computer program. Diabetes Care. 1998;21(12):2191–2.PubMedCrossRefPubMedCentralGoogle Scholar
  125. 125.
    Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modeling. Diabetes Care. 2004;27(6):1487–95.PubMedCrossRefPubMedCentralGoogle Scholar
  126. 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.PubMedCrossRefGoogle Scholar
  127. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  128. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Reaven G. Wanted!: a standardized measurement of plasma insulin concentration. Arterioscler Thromb Vasc Biol. 2011;31(5):954–5.PubMedCrossRefPubMedCentralGoogle Scholar
  130. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  131. 131.
    Wallace TM, Matthews DR. The assessment of insulin resistance in man. Diabet Med. 2002;19(7):527–34.PubMedCrossRefGoogle Scholar
  132. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  133. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  134. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  135. 135.
    Elliott WJ, Meyer PM. Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis. Lancet. 2007;369(9557):201–7.PubMedCrossRefGoogle Scholar
  136. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  138. 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.CrossRefGoogle Scholar
  139. 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.PubMedCrossRefGoogle Scholar
  140. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  141. 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.PubMedCrossRefGoogle Scholar
  142. 142.
    Bergman RN, Ider YZ, Bowden CR, Cobelli C. Quantitative estimation of insulin sensitivity. Am J Phys. 1979;236(6):E667–77.Google Scholar
  143. 143.
    Bergman RN, Finegood DT, Ader M. Assessment of insulin sensitivity in vivo. Endocr Rev. 1985;6(1):45–86.PubMedCrossRefPubMedCentralGoogle Scholar
  144. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  145. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  146. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  147. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  148. 148.
    Ferrannini E, Mari A. How to measure insulin sensitivity. J Hypertens. 1998;16(7):895–906.Google Scholar
  149. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  150. 150.
    Kim SH. Measurement of insulin action: a tribute to Sir Harold Himsworth. Diabet Med. 2011;28(12):1487–93.PubMedCrossRefPubMedCentralGoogle Scholar
  151. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  152. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  153. 153.
    Vinik AI, Maser RE, Mitchell BD, Freeman R. Diabetic autonomic neuropathy. Diabetes Care. 2003;26(5):1553–79.PubMedCrossRefGoogle Scholar
  154. 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.PubMedCrossRefGoogle Scholar
  155. 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.CrossRefGoogle Scholar
  156. 156.
    Karlsson F, Tremaroli V, Nielsen J, Backhed F. Assessing the human gut microbiota in metabolic diseases. Diabetes. 2013;62(10):3341–9.PubMedPubMedCentralCrossRefGoogle Scholar
  157. 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.PubMedCrossRefGoogle Scholar
  158. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  159. 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.PubMedCrossRefGoogle Scholar
  160. 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.PubMedCrossRefGoogle Scholar
  161. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  162. 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.PubMedCrossRefGoogle Scholar
  163. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  164. 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.PubMedCrossRefGoogle Scholar
  165. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  166. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  167. 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. 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.PubMedCrossRefGoogle Scholar
  169. 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.CrossRefGoogle Scholar
  170. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  171. 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.PubMedCrossRefGoogle Scholar
  172. 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.PubMedCrossRefGoogle Scholar
  173. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  174. 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.Google Scholar
  175. 175.
    Kruzynska Y. In: Pickup JC, Williams G, editors. Textbook of diabetes. Oxford: Blackwell Science; 1997.Google Scholar
  176. 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.Google Scholar
  177. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  178. 178.
    Gerich JE, Meyer C, Woerle HJ, Stumvoll M. Renal gluconeogenesis: its importance in human glucose homeostasis. Diabetes Care. 2001;24(2):382–91.PubMedCrossRefGoogle Scholar
  179. 179.
    Conte C, Fabbrini E, Kars M, et al. Multiorgan insulin sensitivity in lean and obese subjects. Diabetes Care. 2012;35(6):1316–21.PubMedPubMedCentralCrossRefGoogle Scholar
  180. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  181. 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.CrossRefGoogle Scholar
  182. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  183. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  184. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  185. 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. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  187. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  188. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  189. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  190. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  191. 191.
    Heinemann L, Ampudia-Blasco FJ. Glucose clamps with the Biostator: a critical reappraisal. Horm Metab Res. 1994;26(12):579–83.PubMedCrossRefPubMedCentralGoogle Scholar
  192. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  193. 193.
    Doberne L, Greenfield MS, Schulz B, Reaven GM. Enhanced glucose utilization during prolonged glucose clamp studies. Diabetes. 1981;30(10):829–35.PubMedCrossRefPubMedCentralGoogle Scholar
  194. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  195. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  196. 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. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  198. 198.
    Mancia G, Grassi G, Zanchetti A. New-onset diabetes and antihypertensive drugs. J Hypertens. 2006;24(1):3–10.PubMedCrossRefPubMedCentralGoogle Scholar
  199. 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.PubMedCrossRefGoogle Scholar
  200. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  201. 201.
    Rossetti L, Giaccari A, DeFronzo RA. Glucose toxicity. Diabetes Care. 1990;13(6):610–30.PubMedCrossRefPubMedCentralGoogle Scholar
  202. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  203. 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.PubMedCrossRefGoogle Scholar
  204. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  205. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  206. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  207. 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.Google Scholar
  208. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  209. 209.
    Mak RH, DeFronzo RA. Glucose and insulin metabolism in uremia. Nephron. 1992;61(4):377–82.PubMedCrossRefPubMedCentralGoogle Scholar
  210. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  211. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  212. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  213. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  214. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  215. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  216. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  217. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  218. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  219. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  220. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  221. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  222. 222.
    Krentz AJ, Morrow L, Hompesch M. Developing new drugs for diabetes and cardiometabolic disorders: a changing paradigm. Drugs. 2012;72(13):1709–11.PubMedCrossRefGoogle Scholar
  223. 223.
    Deanfield JE, Halcox JP, Rabelink TJ. Endothelial function and dysfunction: testing and clinical relevance. Circulation. 2007;115(10):1285–95.PubMedCrossRefPubMedCentralGoogle Scholar
  224. 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.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Andrew J. Krentz
    • 1
    Email author
  • Christian Weyer
    • 1
  • Marcus Hompesch
    • 1
  1. 1.ProSciento, IncChula VistaUSA

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