Assessment of Islet Alpha- and Beta-Cell Function

  • Sten Madsbad
  • Jens J. HolstEmail author


Abnormal secretion of insulin and glucagon are key hormonal defects in the pathogenesis of diabetes. Type 1 diabetes is characterized by severely impaired β-cell function; glucagon secretion in response to hypoglycemia becomes impaired over time. In type 2 diabetes, hyperglycemia results from impaired insulin secretion allied to inappropriate glucagon secretion. Analysis of islet α- and β-cell function is required to understand the pathophysiology of diabetes and the mechanisms of action of pharmacotherapies. Assessing the integrity of the incretin axis and α- and β-cell function has come to prominence with the development of the dipeptidyl peptidase (DPP-4) inhibitors and glucagon-like peptide (GLP)-1 receptor agonists, as well as glucagon receptor antagonists. The range of techniques for the clinical assessment of insulin secretion and response to therapeutic interventions reflects the absence of a gold standard reference method. Since no single method adequately captures all potentially relevant aspects of α- and β-cell function several methods may be required to inform drug development decisions.


α-Cell function β-Cell function Fasting tests Proinsulin HOMA-B Intravenous glucose tolerance test Arginine test Glucagon test Hyperglycemic clamp Graded glucose infusion Incretin effect Oral glucose tolerance test Meal tests 


  1. 1.
    Atkinson MA, von Herrath M, Powers AC, Clare-Salzler M. Current concepts on the pathogenesis of type 1 diabetes–considerations for attempts to prevent and reverse the disease. Diabetes Care. 2015;38(6):979–88.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Madsbad S. Prevalence of residual B cell function and its metabolic consequences in Type 1 (insulin-dependent) diabetes. Diabetologia. 1983;24(3):141–7.PubMedCrossRefGoogle Scholar
  3. 3.
    Palmer JP, Fleming GA, Greenbaum CJ, Herold KC, Jansa LD, Kolb H, et al. C-peptide is the appropriate outcome measure for type 1 diabetes clinical trials to preserve beta-cell function: report of an ADA workshop, 21–22 October 2001. Diabetes. 2004;53(1):250–64.Google Scholar
  4. 4.
    Bresson D, von Herrath M. Immunotherapy for the prevention and treatment of type 1 diabetes: optimizing the path from bench to bedside. Diabetes Care. 2009;32(10):1753–68.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    DeFronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58(4):773–95.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Pratley RE, Weyer C. The role of impaired early insulin secretion in the pathogenesis of Type II diabetes mellitus. Diabetologia. 2001;44(8):929–45.PubMedCrossRefGoogle Scholar
  7. 7.
    Vilsboll T, Krarup T, Madsbad S, Holst JJ. Both GLP-1 and GIP are insulinotropic at basal and postprandial glucose levels and contribute nearly equally to the incretin effect of a meal in healthy subjects. Regul Pept. 2003;114(2–3):115–21.PubMedCrossRefGoogle Scholar
  8. 8.
    Nauck M, Stockmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia. 1986;29(1):46–52.PubMedCrossRefGoogle Scholar
  9. 9.
    Knop FK, Aaboe K, Vilsboll T, Volund A, Holst JJ, Krarup T, et al. Impaired incretin effect and fasting hyperglucagonaemia characterizing type 2 diabetic subjects are early signs of dysmetabolism in obesity. Diabetes Obes Metab. 2012;14(6):500–10.PubMedCrossRefGoogle Scholar
  10. 10.
    Baron AD, Schaeffer L, Shragg P, Kolterman OG. Role of hyperglucagonemia in maintenance of increased rates of hepatic glucose output in type II diabetics. Diabetes. 1987;36(3):274–83.PubMedCrossRefGoogle Scholar
  11. 11.
    Shah P, Basu A, Basu R, Rizza R. Impact of lack of suppression of glucagon on glucose tolerance in humans. Am J Phys. 1999;277(2 Pt 1):E283–90.Google Scholar
  12. 12.
    Shah P, Vella A, Basu A, Basu R, Schwenk WF, Rizza RA. Lack of suppression of glucagon contributes to postprandial hyperglycemia in subjects with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2000;85(11):4053–9.PubMedGoogle Scholar
  13. 13.
    Kahn SE, Carr DB, Faulenbach MV, Utzschneider KM. An examination of beta-cell function measures and their potential use for estimating beta-cell mass. Diabetes Obes Metab. 2008;10(Suppl 4):63–76.Google Scholar
  14. 14.
    Leahy JL. Natural history of beta-cell dysfunction in NIDDM. Diabetes Care. 1990;13(9):992–1010.PubMedCrossRefGoogle Scholar
  15. 15.
    Porte D Jr, Kahn SE. Beta-cell dysfunction and failure in type 2 diabetes: potential mechanisms. Diabetes. 2001;50(Suppl 1):S160–3.PubMedCrossRefGoogle Scholar
  16. 16.
    Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. Management of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia. 2015;58(3):429–42.PubMedCrossRefGoogle Scholar
  17. 17.
    Merovci A, Solis-Herrera C, Daniele G, Eldor R, Fiorentino TV, Tripathy D, et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest. 2014;124(2):509–14.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Hojberg PV, Vilsboll T, Rabol R, Knop FK, Bache M, Krarup T, et al. Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes. Diabetologia. 2009;52(2):199–207.PubMedCrossRefGoogle Scholar
  19. 19.
    Retnakaran R, Zinman B. Short-term intensified insulin treatment in type 2 diabetes: long-term effects on beta-cell function. Diabetes Obes Metab. 2012;14(Suppl 3):161–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Garvey WT, Olefsky JM, Griffin J, Hamman RF, Kolterman OG. The effect of insulin treatment on insulin secretion and insulin action in type II diabetes mellitus. Diabetes. 1985;34(3):222–34.PubMedCrossRefGoogle Scholar
  21. 21.
    Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group. JAMA. 1999;281(21):2005–12.PubMedCrossRefGoogle Scholar
  22. 22.
    Cersosimo E, Solis-Herrera C, Trautmann ME, Malloy J, Triplitt CL. Assessment of pancreatic beta-cell function: review of methods and clinical applications. Curr Diabetes Rev. 2014;10(1):2–42.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Turner RC, Harris E, Ounsted M, Ponsford C. Two abnormalities of glucose-induced insulin secretion: dose-response characteristics and insulin sensitivity. Acta Endocrinol. 1979;92(1):148–65.PubMedCrossRefGoogle Scholar
  24. 24.
    Aparicio NJ, Puchulu FE, Gagliardino JJ, Ruiz M, Llorens JM, Ruiz J, et al. Circadian variation of the blood glucose, plasma insulin and human growth hormone levels in response to an oral glucose load in normal subjects. Diabetes. 1974;23(2):132–7.PubMedCrossRefGoogle Scholar
  25. 25.
    Porksen N. The in vivo regulation of pulsatile insulin secretion. Diabetologia. 2002;45(1):3–20.PubMedCrossRefGoogle Scholar
  26. 26.
    Horwitz DL, Starr JI, Mako ME, Blackard WG, Rubenstein AH. Proinsulin, insulin, and C-peptide concentrations in human portal and peripheral blood. J Clin Invest. 1975;55(6):1278–83.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Grespan E, Giorgino T, Arslanian S, Natali A, Ferrannini E, Mari A. Defective amplifying pathway of beta-cell secretory response to glucose in type 2 diabetes: integrated modeling of in vitro and in vivo evidence. Diabetes. 2018;67(3):496–506.PubMedCrossRefGoogle Scholar
  28. 28.
    Henquin JC. Regulation of insulin secretion: a matter of phase control and amplitude modulation. Diabetologia. 2009;52(5):739–51.PubMedCrossRefGoogle Scholar
  29. 29.
    Rorsman P, Eliasson L, Renstrom E, Gromada J, Barg S, Gopel S. The cell physiology of biphasic insulin secretion. News Physiol Sci. 2000;15:72–7.PubMedGoogle Scholar
  30. 30.
    Ahren B, Larsson H. Quantification of insulin secretion in relation to insulin sensitivity in nondiabetic postmenopausal women. Diabetes. 2002;51(Suppl 1):S202–11.PubMedCrossRefGoogle Scholar
  31. 31.
    Bergman RN, Ader M, Huecking K, Van CG. Accurate assessment of beta-cell function: the hyperbolic correction. Diabetes. 2002;51(Suppl 1):S212–20.PubMedCrossRefGoogle Scholar
  32. 32.
    Kahn SE, Prigeon RL, McCulloch DK, Boyko EJ, Bergman RN, Schwartz MW, et al. Quantification of the relationship between insulin sensitivity and beta-cell function in human subjects. Evidence for a hyperbolic function. Diabetes. 1993;42(11):1663–72.PubMedCrossRefGoogle Scholar
  33. 33.
    Mari A, Ahren B, Pacini G. Assessment of insulin secretion in relation to insulin resistance. Curr Opin Clin Nutr Metab Care. 2005;8(5):529–33.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Gosmanov NR, Gosmanov AR, Gerich JE. In: De Groot LJ, Chrousos G, Dungan K, et al., editors. Glucagon physiology. South Dartmouth:, Inc; 2000.Google Scholar
  35. 35.
    Galsgaard KD, Winther-Sorensen M, Orskov C, Kissow H, Poulsen SS, Vilstrup H, et al. Disruption of glucagon receptor signaling causes hyperaminoacidemia exposing a possible liver-alpha-cell axis. Am J Physiol Endocrinol Metab. 2018;314(1):E93–E103.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Holst JJ, Wewer Albrechtsen NJ, Pedersen J, Knop FK. Glucagon and Amino Acids are linked in a mutual feedback cycle: the liver-alpha-cell axis. Diabetes. 2017;66(2):235–40.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Larger E, Wewer Albrechtsen NJ, Hansen LH, Gelling RW, Capeau J, Deacon CF, et al. Pancreatic alpha-cell hyperplasia and hyperglucagonemia due to a glucagon receptor splice mutation. Endocrinol Diabetes Metab Case Rep. 2016;2016:16-0081.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Bagger JI, Knop FK, Holst JJ, Vilsboll T. Glucagon antagonism as a potential therapeutic target in type 2 diabetes. Diabetes Obes Metab. 2011;13(11):965–71.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Holst JJ, Holland W, Gromada J, Lee Y, Unger RH, Yan H, et al. Insulin and glucagon: partners for life. Endocrinology. 2017;158(4):696–701.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Mari A, Ferrannini E. Beta-cell function assessment from modelling of oral tests: an effective approach. Diabetes Obes Metab. 2008;10(Suppl 4):77–87.PubMedCrossRefGoogle Scholar
  41. 41.
    Polonsky KS, Given BD, Van CE. Twenty-four-hour profiles and pulsatile patterns of insulin secretion in normal and obese subjects. J Clin Invest. 1988;81(2):442–8.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Ferrannini E, Mari A. Beta cell function and its relation to insulin action in humans: a critical appraisal. Diabetologia. 2004;47(5):943–56.PubMedCrossRefGoogle Scholar
  43. 43.
    Mari A, Tura A, Pacini G, Kautzky-Willer A, Ferrannini E. Relationships between insulin secretion after intravenous and oral glucose administration in subjects with glucose tolerance ranging from normal to overt diabetes. Diabet Med. 2008;25(6):671–7.PubMedCrossRefGoogle Scholar
  44. 44.
    Utzschneider KM, Prigeon RL, Faulenbach MV, Tong J, Carr DB, Boyko EJ, et al. Oral disposition index predicts the development of future diabetes above and beyond fasting and 2-h glucose levels. Diabetes Care. 2009;32(2):335–41.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Faerch K, Brons C, Alibegovic AC, Vaag A. The disposition index: adjustment for peripheral vs. hepatic insulin sensitivity? J Physiol. 2010;588(Pt 5):759–64.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    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
  47. 47.
    Bergman RN, Finegood DT, Ader M. Assessment of insulin sensitivity in vivo. Endocr Rev. 1985;6(1):45–86.PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Boston RC, Stefanovski D, Moate PJ, Sumner AE, Watanabe RM, Bergman RN. MINMOD Millennium: a computer program to calculate glucose effectiveness and insulin sensitivity from the frequently sampled intravenous glucose tolerance test. Diabetes Technol Ther. 2003;5(6):1003–15.PubMedCrossRefGoogle Scholar
  49. 49.
    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
  50. 50.
    Matsuda M. Measuring and estimating insulin resistance in clinical and research settings. Nutr Metab Cardiovasc Dis. 2010;20(2):79–86.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Wallace TM, Matthews DR. The assessment of insulin resistance in man. Diabet Med. 2002;19(7):527–34.PubMedCrossRefGoogle Scholar
  52. 52.
    Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modeling. Diabetes Care. 2004;27(6):1487–95.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Dimitriadis GD, Pehling GB, Gerich JE. Abnormal glucose modulation of islet A- and B-cell responses to arginine in non-insulin-dependent diabetes mellitus. Diabetes. 1985;34(6):541–7.PubMedCrossRefGoogle Scholar
  54. 54.
    Hosker JP, Rudenski AS, Burnett MA, Matthews DR, Turner RC. Similar reduction of first- and second-phase B-cell responses at three different glucose levels in type II diabetes and the effect of gliclazide therapy. Metabolism. 1989;38(8):767–72.PubMedCrossRefGoogle Scholar
  55. 55.
    Madsbad S, Sauerbrey N, Moller-Jensen B, Krarup T, Kuhl C. Outcome of the glucagon test depends upon the prevailing blood glucose concentration in type I (insulin-dependent) diabetic patients. Acta Med Scand. 1987;222(1):71–4.PubMedCrossRefGoogle Scholar
  56. 56.
    van Haeften TW, Boonstra E, Veneman TF, Gerich JE, van der Veen EA. Dose-response characteristics for glucose-stimulated insulin release in man and assessment of influence of glucose on arginine-stimulated insulin release. Metabolism. 1990;39(12):1292–9.PubMedCrossRefGoogle Scholar
  57. 57.
    Ward WK, Bolgiano DC, McKnight B, Halter JB, Porte D Jr. Diminished B cell secretory capacity in patients with noninsulin-dependent diabetes mellitus. J Clin Invest. 1984;74(4):1318–28.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Kjems LL, Holst JJ, Volund A, Madsbad S. The influence of GLP-1 on glucose-stimulated insulin secretion: effects on beta-cell sensitivity in type 2 and nondiabetic subjects. Diabetes. 2003;52(2):380–6.PubMedCrossRefGoogle Scholar
  59. 59.
    Bojsen-Moller KN, Dirksen C, Jorgensen NB, Jacobsen SH, Hansen DL, Worm D, et al. Increased hepatic insulin clearance after Roux-en-Y gastric bypass. J Clin Endocrinol Metab. 2013;98(6):E1066–71.PubMedCrossRefGoogle Scholar
  60. 60.
    Duckworth WC, Bennett RG, Hamel FG. Insulin degradation: progress and potential. Endocr Rev. 1998;19(5):608–24.PubMedGoogle Scholar
  61. 61.
    Polonsky KS, Rubenstein AH. C-peptide as a measure of the secretion and hepatic extraction of insulin. Pitfalls and limitations. Diabetes. 1984;33(5):486–94.Google Scholar
  62. 62.
    Polonsky KS, Given BD, Hirsch L, Shapiro ET, Tillil H, Beebe C, et al. Quantitative study of insulin secretion and clearance in normal and obese subjects. J Clin Invest. 1988;81(2):435–41.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Polonsky KS, Gumbiner B, Ostrega D, Griver K, Tager H, Henry RR. Alterations in immunoreactive proinsulin and insulin clearance induced by weight loss in NIDDM. Diabetes. 1994;43(7):871–7.PubMedCrossRefGoogle Scholar
  64. 64.
    Tillil H, Shapiro ET, Miller MA, Karrison T, Frank BH, Galloway JA, et al. Dose-dependent effects of oral and intravenous glucose on insulin secretion and clearance in normal humans. Am J Phys. 1988;254(3 Pt 1):E349–57.Google Scholar
  65. 65.
    Tillil H, Shapiro ET, Rubenstein AH, Galloway JA, Polonsky KS. Reduction of insulin clearance during hyperglycemic clamp. Dose-response study in normal humans. Diabetes. 1988;37(10):1351–7.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Shapiro ET, Tillil H, Rubenstein AH, Polonsky KS. Peripheral insulin parallels changes in insulin secretion more closely than C-peptide after bolus intravenous glucose administration. J Clin Endocrinol Metab. 1988;67(5):1094–9.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Kjems LL, Christiansen E, Volund A, Bergman RN, Madsbad S. Validation of methods for measurement of insulin secretion in humans in vivo. Diabetes. 2000;49(4):580–8.PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Polonsky KS, Given BD, Pugh W, Licinio-Paixao J, Thompson JE, Karrison T, et al. Calculation of the systemic delivery rate of insulin in normal man. J Clin Endocrinol Metab. 1986;63(1):113–8.PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Polonsky KS, Rubenstein AH. Current approaches to measurement of insulin secretion. Diabetes Metab Rev. 1986;2(3–4):315–29.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Polonsky KS, Licinio-Paixao J, Given BD, Pugh W, Rue P, Galloway J, et al. Use of biosynthetic human C-peptide in the measurement of insulin secretion rates in normal volunteers and type I diabetic patients. J Clin Invest. 1986;77(1):98–105.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Van CE, Mestrez F, Sturis J, Polonsky KS. Estimation of insulin secretion rates from C-peptide levels. Comparison of individual and standard kinetic parameters for C-peptide clearance. Diabetes. 1992;41(3):368–77.CrossRefGoogle Scholar
  72. 72.
    Licinio-Paixao J, Polonsky KS, Given BD, Pugh W, Ostrega D, Frank BF, et al. Ingestion of a mixed meal does not affect the metabolic clearance rate of biosynthetic human C-peptide. J Clin Endocrinol Metab. 1986;63(2):401–3.PubMedCrossRefGoogle Scholar
  73. 73.
    Polonsky KS, Pugh W, Jaspan JB, Cohen DM, Karrison T, Tager HS, et al. C-peptide and insulin secretion. Relationship between peripheral concentrations of C-peptide and insulin and their secretion rates in the dog. J Clin Invest. 1984;74(5):1821–9.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Ferner RE, Alberti KG. Why is there still disagreement over insulin secretion in non-insulin-dependent diabetes? Diabet Med. 1986;3(1):13–7.PubMedCrossRefGoogle Scholar
  75. 75.
    Eaton RP, Allen RC, Schade DS, Erickson KM, Standefer J. Prehepatic insulin production in man: kinetic analysis using peripheral connecting peptide behavior. J Clin Endocrinol Metab. 1980;51(3):520–8.PubMedCrossRefGoogle Scholar
  76. 76.
    Hovorka R, Soons PA, Young MA. ISEC: a program to calculate insulin secretion. Comput Methods Prog Biomed. 1996;50(3):253–64.CrossRefGoogle Scholar
  77. 77.
    Kjems LL, Volund A, Madsbad S. Quantification of beta-cell function during IVGTT in Type II and non-diabetic subjects: assessment of insulin secretion by mathematical methods. Diabetologia. 2001;44(10):1339–48.PubMedCrossRefGoogle Scholar
  78. 78.
    Volund A, Polonsky KS, Bergman RN. Calculated pattern of intraportal insulin appearance without independent assessment of C-peptide kinetics. Diabetes. 1987;36(10):1195–202.PubMedCrossRefGoogle Scholar
  79. 79.
    Christiansen E, Kjems LL, Volund A, Tibell A, Binder C, Madsbad S. Insulin secretion rates estimated by two mathematical methods in pancreas-kidney transplant recipients. Am J Phys. 1998;274(4 Pt 1):E716–25.Google Scholar
  80. 80.
    Cobelli C, Pacini G. Insulin secretion and hepatic extraction in humans by minimal modeling of C-peptide and insulin kinetics. Diabetes. 1988;37(2):223–31.PubMedCrossRefGoogle Scholar
  81. 81.
    Oram RA, Jones AG, Besser RE, Knight BA, Shields BM, Brown RJ, et al. The majority of patients with long-duration type 1 diabetes are insulin microsecretors and have functioning beta cells. Diabetologia. 2014;57(1):187–91.Google Scholar
  82. 82.
    Tillil H, Shapiro ET, Given BD, Rue P, Rubenstein AH, Galloway JA, et al. Reevaluation of urine C-peptide as measure of insulin secretion. Diabetes. 1988;37(9):1195–201.Google Scholar
  83. 83.
    Jones AG, McDonald TJ, Shields BM, Hill AV, Hyde CJ, Knight BA, et al. Markers of beta-cell failure predict poor glycemic response to GLP-1 receptor agonist therapy in type 2 diabetes. Diabetes Care. 2016;39(2):250–7.PubMedGoogle Scholar
  84. 84.
    Christiansen E, Roder M, Tibell A, Hales CN, Madsbad S. Effect of pancreas transplantation and immunosuppression on proinsulin secretion. Diabet Med. 1998;15(9):739–46.PubMedCrossRefGoogle Scholar
  85. 85.
    Kahn SE, Horber FF, Prigeon RL, Haymond MW, Porte D Jr. Effect of glucocorticoid and growth hormone treatment on proinsulin levels in humans. Diabetes. 1993;42(7):1082–5.PubMedCrossRefGoogle Scholar
  86. 86.
    Kahn SE, Leonetti DL, Prigeon RL, Boyko EJ, Bergstrom RW, Fujimoto WY. Relationship of proinsulin and insulin with noninsulin-dependent diabetes mellitus and coronary heart disease in Japanese-American men: impact of obesity–clinical research center study. J Clin Endocrinol Metab. 1995;80(4):1399–406.PubMedGoogle Scholar
  87. 87.
    Kahn SE, Leonetti DL, Prigeon RL, Boyko EJ, Bergstrom RW, Fujimoto WY. Proinsulin as a marker for the development of NIDDM in Japanese-American men. Diabetes. 1995;44(2):173–9.PubMedCrossRefGoogle Scholar
  88. 88.
    Eaton RP, Allen RC, Schade DS. Hepatic removal of insulin in normal man: dose response to endogenous insulin secretion. J Clin Endocrinol Metab. 1983;56(6):1294–300.PubMedCrossRefGoogle Scholar
  89. 89.
    Faber OK, Christensen K, Kehlet H, Madsbad S, Binder C. Decreased insulin removal contributes to hyperinsulinemia in obesity. J Clin Endocrinol Metab. 1981;53(3):618–21.PubMedCrossRefGoogle Scholar
  90. 90.
    Shapiro ET, Tillil H, Miller MA, Frank BH, Galloway JA, Rubenstein AH, et al. Insulin secretion and clearance. Comparison after oral and intravenous glucose. Diabetes. 1987;36(12):1365–71.PubMedCrossRefGoogle Scholar
  91. 91.
    Robertson RP. Estimation of beta-cell mass by metabolic tests: necessary, but how sufficient? Diabetes. 2007;56(10):2420–4.PubMedCrossRefGoogle Scholar
  92. 92.
    Hojberg PV, Zander M, Vilsboll T, Knop FK, Krarup T, Volund A, et al. Near normalisation of blood glucose improves the potentiating effect of GLP-1 on glucose-induced insulin secretion in patients with type 2 diabetes. Diabetologia. 2008;51(4):632–40.PubMedCrossRefGoogle Scholar
  93. 93.
    Madsbad S, Krarup T, Faber OK, Binder C, Regeur L. The transient effect of strict glycaemic control on B cell function in newly diagnosed type 1 (insulin-dependent) diabetic patients. Diabetologia. 1982;22(1):16–20.PubMedCrossRefGoogle Scholar
  94. 94.
    Vilsboll T, Brock B, Perrild H, Levin K, Lervang HH, Kolendorf K, et al. Liraglutide, a once-daily human GLP-1 analogue, improves pancreatic B-cell function and arginine-stimulated insulin secretion during hyperglycaemia in patients with Type 2 diabetes mellitus. Diabet Med. 2008;25(2):152–6.PubMedCrossRefGoogle Scholar
  95. 95.
    Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes. 2003;52(1):102–10.PubMedCrossRefGoogle Scholar
  96. 96.
    Kielgast U, Asmar M, Madsbad S, Holst JJ. Effect of glucagon-like peptide-1 on alpha- and beta-cell function in C-peptide-negative type 1 diabetic patients. J Clin Endocrinol Metab. 2010;95(5):2492–6.PubMedCrossRefGoogle Scholar
  97. 97.
    Faerch K, Vistisen D, Pacini G, Torekov SS, Johansen NB, Witte DR, et al. Insulin resistance is accompanied by increased fasting glucagon and delayed glucagon suppression in individuals with normal and impaired glucose regulation. Diabetes. 2016;65(11):3473–81.PubMedCrossRefGoogle Scholar
  98. 98.
    Aaboe K, Krarup T, Madsbad S, Holst JJ. GLP-1: physiological effects and potential therapeutic applications. Diabetes Obes Metab. 2008;10(11):994–1003.PubMedCrossRefGoogle Scholar
  99. 99.
    Hare KJ, Vilsboll T, Asmar M, Deacon CF, Knop FK, Holst JJ. The glucagonostatic and insulinotropic effects of glucagon-like peptide 1 contribute equally to its glucose-lowering action. Diabetes. 2010;59(7):1765–70.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Chang AM, Jakobsen G, Sturis J, Smith MJ, Bloem CJ, An B, et al. The GLP-1 derivative NN2211 restores beta-cell sensitivity to glucose in type 2 diabetic patients after a single dose. Diabetes. 2003;52(7):1786–91.PubMedCrossRefGoogle Scholar
  101. 101.
    Vilsboll T, Krarup T, Madsbad S, Holst JJ. Defective amplification of the late phase insulin response to glucose by GIP in obese Type II diabetic patients. Diabetologia. 2002;45(8):1111–9.PubMedCrossRefGoogle Scholar
  102. 102.
    Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, 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
  103. 103.
    Wewer Albrechtsen NJ, Hartmann B, Veedfald S, Windelov JA, Plamboeck A, Bojsen-Moller KN, et al. Hyperglucagonaemia analysed by glucagon sandwich ELISA: nonspecific interference or truly elevated levels? Diabetologia. 2014;57(9):1919–26.PubMedCrossRefGoogle Scholar
  104. 104.
    Wewer Albrechtsen NJ, Veedfald S, Plamboeck A, Deacon CF, Hartmann B, Knop FK, et al. Inability of some commercial assays to measure suppression of glucagon secretion. J Diabetes Res. 2016;2016:8352957.Google Scholar
  105. 105.
    Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. 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
  106. 106.
    Nauck M, Frid A, Hermansen K, Shah NS, Tankova T, Mitha IH, et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care. 2009;32(1):84–90.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Jaspan JB, Lever E, Polonsky KS, Van CE. In vivo pulsatility of pancreatic islet peptides. Am J Phys. 1986;251(2 Pt 1):E215–26.Google Scholar
  108. 108.
    Lang DA, Matthews DR, Peto J, Turner RC. Cyclic oscillations of basal plasma glucose and insulin concentrations in human beings. N Engl J Med. 1979;301(19):1023–7.PubMedCrossRefGoogle Scholar
  109. 109.
    Lang DA, Matthews DR, Burnett M, Turner RC. Brief, irregular oscillations of basal plasma insulin and glucose concentrations in diabetic man. Diabetes. 1981;30(5):435–9.PubMedCrossRefGoogle Scholar
  110. 110.
    Lang DA, Matthews DR, Burnett M, Ward GM, Turner RC. Pulsatile, synchronous basal insulin and glucagon secretion in man. Diabetes. 1982;31(1):22–6.PubMedCrossRefGoogle Scholar
  111. 111.
    Sturis J, Van CE, Blackman JD, Polonsky KS. Entrainment of pulsatile insulin secretion by oscillatory glucose infusion. J Clin Invest. 1991;87(2):439–45.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Sturis J, Polonsky KS, Shapiro ET, Blackman JD, O’Meara NM, Van CE. Abnormalities in the ultradian oscillations of insulin secretion and glucose levels in type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1992;35(7):681–9.PubMedCrossRefGoogle Scholar
  113. 113.
    Van CE, Blackman JD, Roland D, Spire JP, Refetoff S, Polonsky KS. Modulation of glucose regulation and insulin secretion by circadian rhythmicity and sleep. J Clin Invest. 1991;88(3):934–42.CrossRefGoogle Scholar
  114. 114.
    U.K. prospective diabetes study 16. Overview of 6 years’ therapy of type II diabetes: a progressive disease. U.K. Prospective Diabetes Study Group. Diabetes. 1995;44(11):1249–58.CrossRefGoogle Scholar
  115. 115.
    Ahren B, Pratley RE, Soubt M, Dunning BE, Foley JE. Clinical measures of islet function: usefulness to characterize defects in diabetes. Curr Diabetes Rev. 2008;4(2):129–45.Google Scholar
  116. 116.
    Fredheim S, Andersen ML, Porksen S, Nielsen LB, Pipper C, Hansen L, et al. The influence of glucagon on postprandial hyperglycaemia in children 5 years after onset of type 1 diabetes. Diabetologia. 2015;58(4):828–34.PubMedCrossRefGoogle Scholar
  117. 117.
    Wewer Albrechtsen NJ, Junker AE, Christensen M, Haedersdal S, Wibrand F, Lund AM, et al. Hyperglucagonemia correlates with plasma levels of non-branched chained amino acids in patients with liver disease independent of type 2 diabetes. Am J Physiol Gastrointest Liver Physiol. 2017;
  118. 118.
    Wewer Albrechtsen NJ, Faerch K, Jensen TM, Witte DR, Pedersen J, Mahendran Y, et al. Evidence of a liver-alpha cell axis in humans: hepatic insulin resistance attenuates relationship between fasting plasma glucagon and glucagonotropic amino acids. Diabetologia. 2018;61(3):671–80.PubMedCrossRefGoogle Scholar
  119. 119.
    Aronoff SL, Bennett PH, Unger RH. Immunoreactive glucagon (IRG) responses to intravenous glucose in prediabetes and diabetes among Pima Indians and normal Caucasians. J Clin Endocrinol Metab. 1977;44(5):968–72.PubMedCrossRefGoogle Scholar
  120. 120.
    Brunzell JD, Robertson RP, Lerner RL, Hazzard WR, Ensinck JW, Bierman EL, et al. Relationships between fasting plasma glucose levels and insulin secretion during intravenous glucose tolerance tests. J Clin Endocrinol Metab. 1976;42(2):222–9.PubMedCrossRefGoogle Scholar
  121. 121.
    Fehse F, Trautmann M, Holst JJ, Halseth AE, Nanayakkara N, Nielsen LL, et al. Exenatide augments first- and second-phase insulin secretion in response to intravenous glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab. 2005;90(11):5991–7.PubMedCrossRefGoogle Scholar
  122. 122.
    Martinussen C, Bojsen-Moller KN, Dirksen C, Jacobsen SH, Jorgensen NB, Kristiansen VB, et al. Immediate enhancement of first-phase insulin secretion and unchanged glucose effectiveness in patients with type 2 diabetes after Roux-en-Y gastric bypass. Am J Physiol Endocrinol Metab. 2015;308(6):E535–44.PubMedCrossRefGoogle Scholar
  123. 123.
    Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet. 2002;359(9309):824–30.PubMedCrossRefGoogle Scholar
  124. 124.
    Rayman G, Clark P, Schneider AE, Hales CN. The first phase insulin response to intravenous glucose is highly reproducible. Diabetologia. 1990;33(10):631–4.PubMedCrossRefGoogle Scholar
  125. 125.
    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
  126. 126.
    Toffolo G, Bergman RN, Finegood DT, Bowden CR, Cobelli C. Quantitative estimation of beta cell sensitivity to glucose in the intact organism: a minimal model of insulin kinetics in the dog. Diabetes. 1980;29(12):979–90.PubMedCrossRefGoogle Scholar
  127. 127.
    Gerich JE. Is reduced first-phase insulin release the earliest detectable abnormality in individuals destined to develop type 2 diabetes? Diabetes. 2002;51(Suppl 1):S117–21.PubMedCrossRefGoogle Scholar
  128. 128.
    Jensen CB, Storgaard H, Dela F, Holst JJ, Madsbad S, Vaag AA. Early differential defects of insulin secretion and action in 19-year-old caucasian men who had low birth weight. Diabetes. 2002;51(4):1271–80.PubMedCrossRefGoogle Scholar
  129. 129.
    Vaag A, Henriksen JE, Madsbad S, Holm N, Beck-Nielsen H. Insulin secretion, insulin action, and hepatic glucose production in identical twins discordant for non-insulin-dependent diabetes mellitus. J Clin Invest. 1995;95(2):690–8.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Aronoff SL, Bennett PH, Rushforth NB, Miller M, Unger RH. Normal glucagon response to arginine infusion in “prediabetic” Pima Indians. J Clin Endocrinol Metab. 1976;43(2):279–86.PubMedCrossRefGoogle Scholar
  131. 131.
    Knop FK, Vilsboll T, Madsbad S, Holst JJ, Krarup T. Inappropriate suppression of glucagon during OGTT but not during isoglycaemic i.v. glucose infusion contributes to the reduced incretin effect in type 2 diabetes mellitus. Diabetologia. 2007;50(4):797–805.PubMedCrossRefPubMedCentralGoogle Scholar
  132. 132.
    Meier JJ, Deacon CF, Schmidt WE, Holst JJ, Nauck MA. Suppression of glucagon secretion is lower after oral glucose administration than during intravenous glucose administration in human subjects. Diabetologia. 2007;50(4):806–13.PubMedCrossRefPubMedCentralGoogle Scholar
  133. 133.
    Larsson H, Ahren B. Glucose-dependent arginine stimulation test for characterization of islet function: studies on reproducibility and priming effect of arginine. Diabetologia. 1998;41(7):772–7.PubMedCrossRefPubMedCentralGoogle Scholar
  134. 134.
    Ahren B, Larsson H, Holst JJ. Effects of glucagon-like peptide-1 on islet function and insulin sensitivity in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1997;82(2):473–8.PubMedPubMedCentralGoogle Scholar
  135. 135.
    Faber OK, Binder C. C-peptide response to glucagon. A test for the residual beta-cell function in diabetes mellitus. Diabetes. 1977;26(7):605–10.PubMedCrossRefGoogle Scholar
  136. 136.
    Madsbad S, Krarup T, McNair P, Christiansen C, Faber OK, Transbol I, et al. Practical clinical value of the C-peptide response to glucagon stimulation in the choice of treatment in diabetes mellitus. Acta Med Scand. 1981;210(3):153–6.PubMedGoogle Scholar
  137. 137.
    Arnold-Larsen S, Madsbad S, Kuhl C. Reproducibility of the glucagon test. Diabet Med. 1987;4(4):299–303.PubMedCrossRefGoogle Scholar
  138. 138.
    Miki H, Matsuyama T, Fujii S, Komatsu R, Nishioeda Y, Omae T. Glucagon-glucose (GG) test for the estimation of the insulin reserve in diabetes. Diabetes Res Clin Pract. 1992;18(2):99–105.PubMedCrossRefGoogle Scholar
  139. 139.
    Christiansen E, Tibell A, Volund A, Rasmussen K, Groth CG, Holst JJ, et al. Pancreatic endocrine function in recipients of segmental and whole pancreas transplantation. J Clin Endocrinol Metab. 1996;81(11):3972–9.PubMedPubMedCentralGoogle Scholar
  140. 140.
    Ward WK, Wallum BJ, Beard JC, Taborsky GJ Jr, Porte D Jr. Reduction of glycemic potentiation. Sensitive indicator of beta-cell loss in partially pancreatectomized dogs. Diabetes. 1988;37(6):723–9.PubMedCrossRefGoogle Scholar
  141. 141.
    Vilsboll T, Toft-Nielsen MB, Krarup T, Madsbad S, Dinesen B, Holst JJ. Evaluation of beta-cell secretory capacity using glucagon-like peptide 1. Diabetes Care. 2000;23(6):807–12.PubMedCrossRefGoogle Scholar
  142. 142.
    Vilsboll T, Knop FK, Krarup T, Johansen A, Madsbad S, Larsen S, et al. The pathophysiology of diabetes involves a defective amplification of the late-phase insulin response to glucose by glucose-dependent insulinotropic polypeptide-regardless of etiology and phenotype. J Clin Endocrinol Metab. 2003;88(10):4897–903.PubMedCrossRefGoogle Scholar
  143. 143.
    Byrne MM, Sturis J, Polonsky KS. Insulin secretion and clearance during low-dose graded glucose infusion. Am J Phys. 1995;268(1 Pt 1):E21–7.Google Scholar
  144. 144.
    Ferrannini E, Gastaldelli A, Miyazaki Y, Matsuda M, Mari A, DeFronzo RA. Beta-Cell function in subjects spanning the range from normal glucose tolerance to overt diabetes: a new analysis. J Clin Endocrinol Metab. 2005;90(1):493–500.PubMedCrossRefGoogle Scholar
  145. 145.
    Ehrmann DA, Breda E, Cavaghan MK, Bajramovic S, Imperial J, Toffolo G, et al. Insulin secretory responses to rising and falling glucose concentrations are delayed in subjects with impaired glucose tolerance. Diabetologia. 2002;45(4):509–17.PubMedCrossRefGoogle Scholar
  146. 146.
    Toffolo G, Breda E, Cavaghan MK, Ehrmann DA, Polonsky KS, Cobelli C. Quantitative indexes of beta-cell function during graded up&down glucose infusion from C-peptide minimal models. Am J Physiol Endocrinol Metab. 2001;280(1):E2–10.PubMedCrossRefGoogle Scholar
  147. 147.
    Cryer PE, Tse TF, Clutter WE, Shah SD. Roles of glucagon and epinephrine in hypoglycemic and nonhypoglycemic glucose counterregulation in humans. Am J Phys. 1984;247(2 Pt 1):E198–205.Google Scholar
  148. 148.
    Degn KB, Brock B, Juhl CB, Djurhuus CB, Grubert J, Kim D, et al. Effect of intravenous infusion of exenatide (synthetic exendin-4) on glucose-dependent insulin secretion and counterregulation during hypoglycemia. Diabetes. 2004;53(9):2397–403.PubMedCrossRefPubMedCentralGoogle Scholar
  149. 149.
    Frandsen CS, Dejgaard TF, Andersen HU, Holst JJ, Hartmann B, Thorsteinsson B, et al. Liraglutide as adjunct to insulin treatment in type 1 diabetes does not interfere with glycaemic recovery or gastric emptying rate during hypoglycaemia: a randomized, placebo-controlled, double-blind, parallel-group study. Diabetes Obes Metab. 2017;19(6):773–82.PubMedCrossRefPubMedCentralGoogle Scholar
  150. 150.
    Nauck MA, Heimesaat MM, Behle K, Holst JJ, Nauck MS, Ritzel R, et al. Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. J Clin Endocrinol Metab. 2002;87(3):1239–46.PubMedCrossRefGoogle Scholar
  151. 151.
    Palmer JP, Ensinck JW. Stimulation of glucagon secretion by ethanol-induced hypoglycemia in man. Diabetes. 1975;24(3):295–300.PubMedCrossRefGoogle Scholar
  152. 152.
    Choudhury SM, Tan TM, Bloom SR. Gastrointestinal hormones and their role in obesity. Curr Opin Endocrinol Diabetes Obes. 2016;23(1):18–22.PubMedCrossRefGoogle Scholar
  153. 153.
    Fehmann HC, Goke R, Goke B. Cell and molecular biology of the incretin hormones glucagon-like peptide-I and glucose-dependent insulin releasing polypeptide. Endocr Rev. 1995;16(3):390–410.PubMedCrossRefGoogle Scholar
  154. 154.
    Unger RH, Eisentraut AM. Entero-insular axis. Arch Intern Med. 1969;123(3):261–6.PubMedCrossRefGoogle Scholar
  155. 155.
    Eriksen M, Jensen DH, Tribler S, Holst JJ, Madsbad S, Krarup T. Reduction of insulinotropic properties of GLP-1 and GIP after glucocorticoid-induced insulin resistance. Diabetologia. 2015;58(5):920–8.PubMedCrossRefGoogle Scholar
  156. 156.
    Jacobsen SH, Olesen SC, Dirksen C, Jorgensen NB, Bojsen-Moller KN, Kielgast U, et al. Changes in gastrointestinal hormone responses, insulin sensitivity, and beta-cell function within 2 weeks after gastric bypass in non-diabetic subjects. Obes Surg. 2012;22(7):1084–96.PubMedCrossRefGoogle Scholar
  157. 157.
    Jensen DH, Aaboe K, Henriksen JE, Volund A, Holst JJ, Madsbad S, et al. Steroid-induced insulin resistance and impaired glucose tolerance are both associated with a progressive decline of incretin effect in first-degree relatives of patients with type 2 diabetes. Diabetologia. 2012;55(5):1406–16.PubMedCrossRefGoogle Scholar
  158. 158.
    Polonsky KS, Given BD, Hirsch LJ, Tillil H, Shapiro ET, Beebe C, et al. Abnormal patterns of insulin secretion in non-insulin-dependent diabetes mellitus. N Engl J Med. 1988;318(19):1231–9.PubMedCrossRefGoogle Scholar
  159. 159.
    Bagger JI, Knop FK, Lund A, Holst JJ, Vilsboll T. Glucagon responses to increasing oral loads of glucose and corresponding isoglycaemic intravenous glucose infusions in patients with type 2 diabetes and healthy individuals. Diabetologia. 2014;57(8):1720–5.PubMedCrossRefPubMedCentralGoogle Scholar
  160. 160.
    Nauck MA, Homberger E, Siegel EG, Allen RC, Eaton RP, Ebert R, et al. Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab. 1986;63(2):492–8.PubMedCrossRefPubMedCentralGoogle Scholar
  161. 161.
    Dirksen C, Bojsen-Moller KN, Jorgensen NB, Jacobsen SH, Kristiansen VB, Naver LS, et al. Exaggerated release and preserved insulinotropic action of glucagon-like peptide-1 underlie insulin hypersecretion in glucose-tolerant individuals after Roux-en-Y gastric bypass. Diabetologia. 2013;56(12):2679–87.PubMedCrossRefPubMedCentralGoogle Scholar
  162. 162.
    Burns SF, Bacha F, Lee SJ, Tfayli H, Gungor N, Arslanian SA. Declining beta-cell function relative to insulin sensitivity with escalating OGTT 2-h glucose concentrations in the nondiabetic through the diabetic range in overweight youth. Diabetes Care. 2011;34(9):2033–40.PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Christiansen E, Tibell A, Volund AA, Holst JJ, Rasmussen K, Schaffer L, et al. Metabolism of oral glucose in pancreas transplant recipients with normal and impaired glucose tolerance. J Clin Endocrinol Metab. 1997;82(7):2299–307.PubMedPubMedCentralGoogle Scholar
  164. 164.
    Hovorka R, Chassin L, Luzio SD, Playle R, Owens DR. Pancreatic beta-cell responsiveness during meal tolerance test: model assessment in normal subjects and subjects with newly diagnosed noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1998;83(3):744–50.PubMedGoogle Scholar
  165. 165.
    Mari A, Pacini G, Brazzale AR, Ahren B. Comparative evaluation of simple insulin sensitivity methods based on the oral glucose tolerance test. Diabetologia. 2005;48(4):748–51.PubMedCrossRefGoogle Scholar
  166. 166.
    Phillips DI, Clark PM, Hales CN, Osmond C. Understanding oral glucose tolerance: comparison of glucose or insulin measurements during the oral glucose tolerance test with specific measurements of insulin resistance and insulin secretion. Diabet Med. 1994;11(3):286–92.PubMedCrossRefGoogle Scholar
  167. 167.
    Jensen CC, Cnop M, Hull RL, Fujimoto WY, Kahn SE. Beta-cell function is a major contributor to oral glucose tolerance in high-risk relatives of four ethnic groups in the U.S. Diabetes. 2002;51(7):2170–8.PubMedCrossRefGoogle Scholar
  168. 168.
    Sjaarda LG, Bacha F, Lee S, Tfayli H, Andreatta E, Arslanian S. Oral disposition index in obese youth from normal to prediabetes to diabetes: relationship to clamp disposition index. J Pediatr. 2012;161(1):51–7.PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Utzschneider KM, Prigeon RL, Tong J, Gerchman F, Carr DB, Zraika S, et al. Within-subject variability of measurements of beta cell function derived from a 2 h OGTT: implications for research studies. Diabetologia. 2007;50(12):2516–25.Google Scholar
  170. 170.
    Gastaldelli A, Ferrannini E, Miyazaki Y, Matsuda M, DeFronzo RA. Beta-cell dysfunction and glucose intolerance: results from the San Antonio metabolism (SAM) study. Diabetologia. 2004;47(1):31–9.PubMedCrossRefGoogle Scholar
  171. 171.
    Bojsen-Moller KN, Dirksen C, Svane MS, Jorgensen NB, Holst JJ, Richter EA, et al. Variable reliability of surrogate measurements of insulin sensitivity after Roux-en-Y gastric bypass. Am J Physiol Regul Integr Comp Physiol. 2017;312(5):R797–805.Google Scholar
  172. 172.
    Retnakaran R, Shen S, Hanley AJ, Vuksan V, Hamilton JK, Zinman B. Hyperbolic relationship between insulin secretion and sensitivity on oral glucose tolerance test. Obesity (Silver Spring). 2008;16(8):1901–7.CrossRefGoogle Scholar
  173. 173.
    Breda E, Cavaghan MK, Toffolo G, Polonsky KS, Cobelli C. Oral glucose tolerance test minimal model indexes of beta-cell function and insulin sensitivity. Diabetes. 2001;50(1):150–8.PubMedCrossRefGoogle Scholar
  174. 174.
    Cobelli C, Dalla MC, Toffolo G, Basu R, Vella A, Rizza R. The oral minimal model method. Diabetes. 2014;63(4):1203–13.PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Hare KJ, Vilsboll T, Holst JJ, Knop FK. Inappropriate glucagon response after oral compared with isoglycemic intravenous glucose administration in patients with type 1 diabetes. Am J Physiol Endocrinol Metab. 2010;298(4):E832–7.PubMedCrossRefGoogle Scholar
  176. 176.
    Holst JJ, Gribble F, Horowitz M, Rayner CK. Roles of the gut in glucose homeostasis. Diabetes Care. 2016;39(6):884–92.PubMedCrossRefGoogle Scholar
  177. 177.
    Nilsson M, Stenberg M, Frid AH, Holst JJ, Bjorck IM. Glycemia and insulinemia in healthy subjects after lactose-equivalent meals of milk and other food proteins: the role of plasma amino acids and incretins. Am J Clin Nutr. 2004;80(5):1246–53.PubMedCrossRefGoogle Scholar
  178. 178.
    Golay A, Chen N, Chen YD, Hollenbeck C, Reaven GM. Effect of central obesity on regulation of carbohydrate metabolism in obese patients with varying degrees of glucose tolerance. J Clin Endocrinol Metab. 1990;71(5):1299–304.PubMedCrossRefGoogle Scholar
  179. 179.
    Reaven GM, Chen YD, Hollenbeck CB, Sheu WH, Ostrega D, Polonsky KS. Plasma insulin, C-peptide, and proinsulin concentrations in obese and nonobese individuals with varying degrees of glucose tolerance. J Clin Endocrinol Metab. 1993;76(1):44–8.PubMedGoogle Scholar
  180. 180.
    O’Meara NM, Shapiro ET, Van CE, Polonsky KS. Effect of glyburide on beta cell responsiveness to glucose in non-insulin-dependent diabetes mellitus. Am J Med. 1990;89(2A):11S–6S.PubMedCrossRefGoogle Scholar
  181. 181.
    Madsbad S, Faber OK, Binder C, Alberti KG, Lloyd B. Diurnal profiles of intermediary metabolites in insulin-dependent diabetes and their relationship to different degrees of residual B-cell function. Acta Diabetol Lat. 1981;18(2):115–21.PubMedCrossRefGoogle Scholar
  182. 182.
    Kapitza C, Forst T, Coester HV, Poitiers F, Ruus P, Hincelin-Mery A. Pharmacodynamic characteristics of lixisenatide once daily versus liraglutide once daily in patients with type 2 diabetes insufficiently controlled on metformin. Diabetes Obes Metab. 2013;15(7):642–9.PubMedPubMedCentralCrossRefGoogle Scholar
  183. 183.
    Hope SV, Knight BA, Shields BM, Hattersley AT, McDonald TJ, Jones AG. Random non-fasting C-peptide: bringing robust assessment of endogenous insulin secretion to the clinic. Diabet Med. 2016;33(11):1554–8.PubMedPubMedCentralCrossRefGoogle Scholar
  184. 184.
    Bak MJ, Albrechtsen NW, Pedersen J, Hartmann B, Christensen M, Vilsboll T, et al. Specificity and sensitivity of commercially available assays for glucagon and oxyntomodulin measurement in humans. Eur J Endocrinol. 2014;170(4):529–38.PubMedCrossRefGoogle Scholar
  185. 185.
    Hannon TS, Kahn SE, Utzschneider KM, Buchanan TA, Nadeau KJ, Zeitler PS, et al. Review of methods for measuring beta-cell function: design considerations from the Restoring Insulin Secretion (RISE) consortium. Diabetes Obes Metab. 2018;20(1):14–24.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of EndocrinologyHvidovre Hospital, University of CopenhagenCopenhagenDenmark
  2. 2.Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
  3. 3.Department of Biomedical Sciences, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark

Personalised recommendations