This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jones, C. N. O. Articles by Reaven, G. M. Search for Related Content PubMed PubMed Citation Articles by Jones, C. N. O. Articles by Reaven, G. M.

Alterations in the Glucose-Stimulated Insulin Secretory Dose-Response Curve and in Insulin Clearance in Nondiabetic Insulin-Resistant Individuals

Departments of Medicine, Stanford University School of Medicine, Stanford, California 94305; University of Chicago, Pritzker School of Medicine, Chicago, Illinois 60637; and Shaman Pharmaceuticals, Inc., South San Francisco, California 94080

Address all correspondence and requests for reprints to: G. M. Reaven, M.D., Shaman Pharmaceuticals, Inc., 213 East Grand Avenue, South San Francisco, California 94080-4812.

Plasma glucose and insulin responses to a graded iv infusion of glucose were compared in two groups of glucose-tolerant women divided on the basis of their insulin sensitivity. Resistance to insulin-mediated glucose disposal was measured using the insulin suppression test, and the women studied were chosen to represent the highest and lowest quartiles of insulin resistance seen in the normal population. The sensitivity of the pancreatic ß-cell to glucose was assessed by measuring the glucose, insulin, and C peptide concentrations in response to continuous graded iv infusions of glucose at rates of 1, 2, 3, 4, 6, and 8 mg/kg·min for 40 min each. In addition, insulin secretion rates in response to the graded glucose infusion, calculated over each sampling period, were derived from deconvolution of peripheral plasma C peptide concentrations, using a two-compartment model of C peptide kinetics and standard parameters for C peptide clearance. Although plasma glucose concentrations were only slightly higher throughout the glucose infusion, the insulin concentrations were approximately doubled in the insulin-resistant subjects. When expressed as a function of the molar increments in plasma glucose achieved during the glucose infusion studies, the insulin-resistant women had a 90% higher (684 ± 55 vs. 360 ± 36 pmol/L·mmol/L; P < 0.001) total integrated plasma insulin response as the glucose concentration was increased from 5 to 9 mmol/L. However, the total integrated insulin secretory rate was only increased by 37% (1494 ± 133 vs. 1093 ± 125 pmol/mmol/L·min; P < 0.05) in the insulin-resistant group. This discrepancy suggested that insulin clearance was lower in the insulin-resistant subjects, and the calculation of this value, as the ratio of the total secretion of insulin to the area under the plasma insulin curve, was significantly lower in the insulin-resistant group (1.25 ± 0.05 vs. 1.87 ± 0.16 L/min·m²; P < 0.005). These results show that the hyperinsulinemia of insulin resistance results from an increase in insulin secretion secondary to a shift to the left of the glucose-stimulated insulin response curve as well as a decrease in insulin clearance.

This article has been cited by other articles:

				G. M. Reaven HOMA-beta in the UKPDS and ADOPT. Is the natural history of type 2 diabetes characterised by a progressive and inexorable loss of insulin secretory function? Maybe? Maybe not? Diabetes and Vascular Disease Research, April 1, 2009; 6(2): 133 - 138. [PDF]

				J. Erdmann, B. Kallabis, U. Oppel, O. Sypchenko, S. Wagenpfeil, and V. Schusdziarra Development of hyperinsulinemia and insulin resistance during the early stage of weight gain Am J Physiol Endocrinol Metab, March 1, 2008; 294(3): E568 - E575. [Abstract] [Full Text] [PDF]

				E. M. Eggleston, L. A. Jahn, and E. J. Barrett Hyperinsulinemia Rapidly Increases Human Muscle Microvascular Perfusion but Fails to Increase Muscle Insulin Clearance: Evidence That a Saturable Process Mediates Muscle Insulin Uptake Diabetes, December 1, 2007; 56(12): 2958 - 2963. [Abstract] [Full Text] [PDF]

				A. Kotronen, S. Vehkavaara, A. Seppala-Lindroos, R. Bergholm, and H. Yki-Jarvinen Effect of liver fat on insulin clearance Am J Physiol Endocrinol Metab, December 1, 2007; 293(6): E1709 - E1715. [Abstract] [Full Text] [PDF]

				D. W. Dunstan, J. Salmon, G. N. Healy, J. E. Shaw, D. Jolley, P. Z. Zimmet, N. Owen, and on behalf of the AusDiab Steering Committee Association of Television Viewing With Fasting and 2-h Postchallenge Plasma Glucose Levels in Adults Without Diagnosed Diabetes Diabetes Care, March 1, 2007; 30(3): 516 - 522. [Abstract] [Full Text] [PDF]

				S. H. Kim, F. Abbasi, J. W. Chu, T. L. McLaughlin, C. Lamendola, K. S. Polonsky, and G. M. Reaven Rosiglitazone Reduces Glucose-Stimulated Insulin Secretion Rate and Increases Insulin Clearance in Nondiabetic, Insulin-Resistant Individuals Diabetes, August 1, 2005; 54(8): 2447 - 2452. [Abstract] [Full Text] [PDF]

				M.-E. Piche, J.-F. Arcand-Bosse, J.-P. Despres, L. Perusse, S. Lemieux, and S. J. Weisnagel What is a Normal Glucose Value?: Differences in indexes of plasma glucose homeostasis in subjects with normal fasting glucose Diabetes Care, October 1, 2004; 27(10): 2470 - 2477. [Abstract] [Full Text] [PDF]

				N. N. Rudovich, H. J. Rochlitz, and A. F.H. Pfeiffer Reduced Hepatic Insulin Extraction in Response to Gastric Inhibitory Polypeptide Compensates for Reduced Insulin Secretion in Normal-Weight and Normal Glucose Tolerant First-Degree Relatives of Type 2 Diabetic Patients Diabetes, September 1, 2004; 53(9): 2359 - 2365. [Abstract] [Full Text] [PDF]

				S. Kashyap, R. Belfort, A. Gastaldelli, T. Pratipanawatr, R. Berria, W. Pratipanawatr, M. Bajaj, L. Mandarino, R. DeFronzo, and K. Cusi A Sustained Increase in Plasma Free Fatty Acids Impairs Insulin Secretion in Nondiabetic Subjects Genetically Predisposed to Develop Type 2 Diabetes Diabetes, October 1, 2003; 52(10): 2461 - 2474. [Abstract] [Full Text] [PDF]

				C. J. Groves, S. Wiltshire, D. Smedley, K. R. Owen, T. M. Frayling, M. Walker, G. A. Hitman, J. C. Levy, S. O'Rahilly, S. Menzel, et al. Association and Haplotype Analysis of the Insulin-Degrading Enzyme (IDE) Gene, a Strong Positional and Biological Candidate for Type 2 Diabetes Susceptibility Diabetes, May 1, 2003; 52(5): 1300 - 1305. [Abstract] [Full Text] [PDF]

				S. A. Arslanian, R. Saad, V. Lewy, K. Danadian, and J. Janosky Hyperinsulinemia in African-American Children: Decreased Insulin Clearance and Increased Insulin Secretion and Its Relationship to Insulin Sensitivity Diabetes, October 1, 2002; 51(10): 3014 - 3019. [Abstract] [Full Text] [PDF]

				M. C. Moore, S. Satake, B. Baranowski, P.-S. Hsieh, D. W. Neal, and A. D. Cherrington Effect of hepatic denervation on peripheral insulin sensitivity in conscious dogs Am J Physiol Endocrinol Metab, February 1, 2002; 282(2): E286 - E296. [Abstract] [Full Text] [PDF]

				T. W. van Haeften, W. Pimenta, A. Mitrakou, M. Korytkowski, T. Jenssen, H. Yki-Jarvinen, and J. E. Gerich Disturbances in {beta}-Cell Function in Impaired Fasting Glycemia Diabetes, February 1, 2002; 51(90001): S265 - 270. [Abstract] [Full Text] [PDF]

				M. C.Y. Ng, S.-C. Lee, G. T.C. Ko, J. K.Y. Li, W.-Y. So, Y. Hashim, A. H. Barnett, I. R. Mackay, J. A.J.H. Critchley, C. S. Cockram, et al. Familial Early-Onset Type 2 Diabetes in Chinese Patients: Obesity and genetics have more significant roles than autoimmunity Diabetes Care, April 1, 2001; 24(4): 663 - 671. [Abstract] [Full Text]

				H. Fakhrai-Rad, A. Nikoshkov, A. Kamel, M. Fernstrom, J. R. Zierath, S. Norgren, H. Luthman, and J. Galli Insulin-degrading enzyme identified as a candidate diabetes susceptibility gene in GK rats Hum. Mol. Genet., September 1, 2000; 9(14): 2149 - 2158. [Abstract] [Full Text] [PDF]

				C. N. O. Jones, F. Abbasi, M. Carantoni, K. S. Polonsky, and G. M. Reaven Roles of insulin resistance and obesity in regulation of plasma insulin concentrations Am J Physiol Endocrinol Metab, March 1, 2000; 278(3): E501 - E508. [Abstract] [Full Text] [PDF]

				K. J. Kaiyala, R. L. Prigeon, S. E. Kahn, S. C. Woods, D. Porte Jr., and M. W. Schwartz Reduced beta -cell function contributes to impaired glucose tolerance in dogs made obese by high-fat feeding Am J Physiol Endocrinol Metab, October 1, 1999; 277(4): E659 - E667. [Abstract] [Full Text] [PDF]

				W. C. Duckworth, R. G. Bennett, and F. G. Hamel Insulin Degradation: Progress and Potential Endocr. Rev., October 1, 1998; 19(5): 608 - 624. [Abstract] [Full Text]