Methods of determining insulin sensitivity that use an oral challenge of glucose are preferred to those using intravenous administration since the measurement is made in conditions more akin to normal physiology. One previously reported protocol (ODILE) studies glucose uptake in isolation from absorption and endogenous production by the intravenous administration of tracer approximately forty-five minutes after the oral dose is given. However, this methodology has not been validated against other accredited procedures. This study utilizes the euglycemic hyperinsulinemic clamp in order to validate the ODILE method. 1. Introduction The determination of the parameters of glucose metabolism, and in particular peripheral insulin sensitivity, is of great interest to clinicians and researchers interested in the aetiology of type 2 diabetes and the metabolic syndrome. Currently, there are two procedures accredited with providing estimates of peripheral insulin sensitivity on a cardinal scale [1]: the euglycaemic clamp [2] and the intravenous glucose tolerance test (IVGTT) interpreted via the minimal model [3]. The clamp methodology is clinically intensive and usually applicable only to studies with relatively few subjects ( ). The IVGTT is more widely employed and has been used in intervention studies with many hundreds of participants [4, 5]. The IVGTT, however, fails to conform to Groop’s [6] list of desirable properties of a methodology to measure insulin sensitivity, inasmuch as it creates unphysiological conditions. Intravenous administration of a glucose bolus gives an almost instantaneous increase in plasma glucose from basal (fasting) levels to a condition where the renal threshold is frequently exceeded, and because of the transitory nature of the glucose input, the period of hyperglycemia is generally less than one hour in normal subjects. During this time, the concentration of glucose in the peripheral circulation exceeds that in the portal vein, in contrast to normal post-prandial conditions. As a consequence, only first phase insulin secretion can be reliably determined, yet such a response never occurs in isolation in the normal state. Secondly, in the absence of incretin effects, the endogenous insulin response is too small (~200？pM) and too transitory to be a satisfactory stimulus for peripheral glucose uptake. Although the latter can be ameliorated to some extent by exogenous insulin administration [7], this removes the physiological conditions of the test even further from reality. These objections could be overcome if oral administration of
References
[1]
L. U. Monzillo and O. Hamdy, “Evaluation of insulin sensitivity in clinical practice and in research settings,” Nutrition Reviews, vol. 61, no. 12, pp. 397–412, 2003.
[2]
R. A. de Fronzo, J. D. Tobin, and R. Andres, “Glucose clamp technique: a method for quantifying insulin secretion and resistance,” The American Journal of Physiology-Endocrinology Metabolism and Gastrointestinal Physiology, vol. 237, no. 3, pp. E214–E223, 1979.
[3]
R. N. Bergman, Y. Z. Ider, C. R. Bowden, and C. Cobelli, “Quantitative estimation of insulin sensitivity,” The American Journal of Physiology-Endocrinology Metabolism and Gastrointestinal Physiology, vol. 236, no. 6, pp. E667–E677, 1979.
[4]
L. E. Wagenknecht, E. J. Mayer, M. Rewers et al., “The insulin resistance atherosclerosis study (iris): objectives, design, and recruitment results,” Annals of Epidemiology, vol. 5, no. 6, pp. 464–472, 1995.
[5]
S. A. Jebb, G. Frost, B. Griffin et al., “The RISCK study: testing the impact of the amount and type of dietary fat and carbohydrate on metabolic risk,” Nutrition Bulletin, vol. 32, no. 2, pp. 154–156, 2007.
[6]
L. C. Groop, E. Widen, and E. Ferrannini, “Insulin resistance and insulin deficiency in the pathogenesis of type 2 (non-insulin-dependent) diabetes mellitus: errors of metabolism or of methods?” Diabetologia, vol. 36, no. 12, pp. 1326–1331, 1993.
[7]
M. F. Saad, R. L. Anderson, A. Laws et al., “A comparison between the minimal model and the glucose clamp in the assessment of insulin sensitivity across the spectrum of glucose tolerance,” Diabetes, vol. 43, no. 9, pp. 1114–1121, 1994.
[8]
L. J. C. Bluck, A. T. Clapperton, and W. A. Coward, “A stable isotope minimal model protocol with oral glucose administration,” Rapid Communications in Mass Spectrometry, vol. 20, no. 3, pp. 493–498, 2006.
[9]
S. J. Jackson, J. S. Waterhouse, and L. J. C. Bluck, “A single glucose derivative suitable for gas chromatography/mass spectrometry and gas chromatography/combustion/isotope ratio mass spectrometry,” Rapid Communications in Mass Spectrometry, vol. 21, no. 18, pp. 3123–3128, 2007.
[10]
L. J. C. Bluck and W. A. Coward, “Peak measurement in gas chromatographic mass spectrometric isotope studies,” Journal of Mass Spectrometry, vol. 32, no. 11, pp. 1212–1218, 1997.
[11]
L. J. C. Bluck and W. A. Coward, “The application of a simple algorithm to isotope ratio measurements by gas chromatography/combustion/isotope ratio mass spectrometry,” Measurement Science and Technology, vol. 15, no. 2, pp. N21–N24, 2004.
[12]
A. T. Clapperton and L. J. Bluck, “Measuring insulin sensitivity using 13C glucose and gas chromatography/combustion/isotope ratio mass spectrometry,” Proceedings of the Nutrition Society, vol. 60, p. 217A, 2001.
[13]
A. T. Clapperton, W. A. Coward, and L. J. C. Bluck, “Measurement of insulin sensitivity indices using 13C-labelled glucose and gas chromatography/combustion/isotope ratio mass spectrometry,” Rapid Communications in Mass Spectrometry, vol. 16, pp. 2009–2014, 2002.
[14]
A. Caumo and C. Cobelli, “Hepatic glucose production during the labeled IVGTT: estimation by deconvolution with a new minimal model,” The American Journal of Physiology-Endocrinology and Metabolism, vol. 264, no. 5, part 1, pp. E829–E841, 1993.
[15]
G. Toffolo and C. Cobelli, “The hot IVGTT two-compartment minimal model: an improved version,” The American Journal of Physiology-Endocrinology and Metabolism, vol. 284, no. 2, pp. E317–E321, 2003.
[16]
P. Vicini, A. Caumo, and C. Cobelli, “The hot IVGTT two-compartment minimal model: indexes of glucose effectiveness and insulin sensitivity,” The American Journal of Physiology-Endocrinology and Metabolism, vol. 273, no. 5, part 1, pp. E1024–E1032, 1997.
[17]
A. Mari, “Assessment of insulin sensitivity with minimal model: role of model assumptions,” The American Journal of Physiology-Endocrinology and Metabolism, vol. 272, no. 5, part 1, pp. E925–E934, 1997.
[18]
M. Matsuda and R. A. de Fronzo, “Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp,” Diabetes Care, vol. 22, no. 9, pp. 1462–1470, 1999.
[19]
G. I. Shulman, D. L. Rothman, T. Jue, P. Stein, R. A. de Fronzo, and R. G. Shulman, “Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13C nuclear magnetic resonance spectroscopy,” The New England Journal of Medicine, vol. 322, no. 4, pp. 223–228, 1990.
[20]
P. N. B？venholm, J. Pigon, C.-G. ？stenson, and S. Efendic, “Insulin sensitivity of suppression of endogenous glucose production is the single most important determinant of glucose tolerance,” Diabetes, vol. 50, no. 6, pp. 1449–1454, 2001.
[21]
R. A. de Fronzo, E. Ferrannini, and D. C. Simonson, “Fasting hyperglycemia in non-insulin-dependent diabetes mellitus: contributions of excessive hepatic glucose production and impaired tissue glucose uptake,” Metabolism, vol. 38, no. 4, pp. 387–395, 1989.
[22]
A. Avogaro, J. D. Bristow, D. M. Bier, C. Cobelli, and G. Toffolo, “Stable-label intravenous glucose tolerance test minimal model,” Diabetes, vol. 38, no. 8, pp. 1048–1055, 1989.
[23]
C. Cobelli, G. Pacini, G. Toffolo, and L. Sacca, “Estimation of insulin sensitivity and glucose clearance from minimal model: new insights from labeled IVGTT,” The American Journal of Physiology-Endocrinology and Metabolism, vol. 250, no. 5, part 1, pp. E591–E598, 1986.
[24]
L. J. C. Bluck, A. T. Clapperton, and W. A. Coward, “13C and 2H-labelled glucose compared for minimal model estimates of glucose metabolism in man,” Clinical Science, vol. 109, no. 6, pp. 513–521, 2005.
[25]
C. B. Douthitt, “Hyphenation of gas chromatographic techniques with isotope ratio mass spectrometry: present status and future,” Analusis, vol. 27, no. 3, pp. 197–199, 1999.
[26]
W. Meier-Augenstein, “Applied gas chromatography coupled to isotope ratio mass spectrometry,” Journal of Chromatography A, vol. 842, no. 1-2, pp. 351–371, 1999.
[27]
A. J. Midwood and B. A. McGaw, “Recent developments in the analysis of light isotopes by continuous flow isotope ratio mass spectrometry,” Analytical Communications, vol. 36, no. 8, pp. 291–294, 1999.
[28]
J. C. Beard, R. N. Bergman, W. K. Ward, and D. Porte Jr., “The insulin sensitivity index in nondiabetic man: correlation between clamp-derived and IVGTT-derived values,” Diabetes, vol. 35, no. 3, pp. 362–369, 1986.
[29]
C. C. Donner, E. Fraze, and Y.-D. I. Chen, “Presentation of a new method for specific measurement of in vivo insulin-stimulated glucose disposal in humans: comparison of this approach with the insulin clamp and minimal model techniques,” Journal of Clinical Endocrinology & Metabolism, vol. 60, no. 4, pp. 723–726, 1985.
[30]
J. E. Foley, Y. D. I. Chen, and C. K. Lardinois, “Estimates of in vivo insulin action in humans: comparison of the insulin clamp and the minimal model techniques,” Hormone and Metabolic Research, vol. 17, no. 8, pp. 406–409, 1985.
[31]
J. W. Swan, C. Walton, and I. F. Godsland, “Assessment of insulin sensitivity in man-a comparison of minimal model-derived and euglycemic clamp-derived measures in health and heart-failure,” Clinical Science, vol. 86, no. 3, pp. 317–322, 1994.
[32]
R. Basu, A. Basu, C. M. Johnson, W. F. Schwenk, and R. A. Rizza, “Insulin dose-response curves for stimulation of splanchnic glucose uptake and suppression of endogenous glucose production differ in nondiabetic humans and are abnormal in people with type 2 diabetes,” Diabetes, vol. 53, no. 8, pp. 2042–2050, 2004.
[33]
S. Satake, M. C. Moore, K. Igawa et al., “Direct and indirect effects of insulin on glucose uptake and storage by the liver,” Diabetes, vol. 51, no. 6, pp. 1663–1671, 2002.
[34]
K. M. Kiser, R. L. Prigeon, and S. E. Kahn, “Insulin sensitivity quantified with the minimal model is lower with the insulin-modified than the tolbutamide-modified frequently sampled intravenous glucose tolerance test,” Journal of Investigative Medicine, vol. 51, p. 15, 2003.
[35]
R. A. de Fronzo, E. Ferrannini, and R. Hendler, “Influence of hyperinsulinemia, hyperglycemia, and the route of glucose administration on splanchnic glucose exchange,” Proceedings of the National Academy of Sciences of the United States of America, vol. 75, no. 10, pp. 5173–5177, 1978.
[36]
M. J. Pagliassotti, L. C. Holste, M. C. Moore, D. W. Neal, and A. D. Cherrington, “Comparison of the time courses of insulin and the portal signal on hepatic glucose and glycogen metabolism in the conscious dog,” Journal of Clinical Investigation, vol. 97, no. 1, pp. 81–91, 1996.
