Journal of Clinical Endocrinology & Metabolism, Vol 63, 492-498, Copyright © 1986 by Endocrine Society

ARTICLES

Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses

MA Nauck, E Homberger, EG Siegel, RC Allen, RP Eaton, R Ebert and W Creutzfeldt

Integrated insulin secretion rates calculated from peripheral venous C- peptide measurements by two-compartment kinetic analysis were measured in six young normal subjects after increasing oral glucose loads of 25, 50, and 100 g and respective isoglycemic glucose infusions. The differences in B-cell secretory responses between oral and iv glucose challenges were attributed to factors other than glycemia itself (incretin effect). Both insulin and C-peptide concentrations as well as calculated integrated insulin secretion rates increased with increasing oral glucose loads. Due to the similarity in the glucose profiles after all oral loads, almost identical amounts of iv glucose (approximately 20 g) were infused in all "isoglycemic" infusion experiments, with resulting similar hormone profiles and insulin secretion rates. The percent contribution of incretin factors to total immunoreactive insulin responses after 25, 50, and 100 g glucose (85.6%, 74.9%, and 93.0%; response to oral load, 100%) was significantly higher than their contribution to integrated C-peptide responses (27.6-62.9%) or calculated integrated insulin secretion rates (19.2-61.0%). These findings indicate that the degree of incretin stimulation of insulin secretion depends on the amount of glucose ingested. A discrepancy between the estimates of the incretin effect derived from peripheral venous insulin responses, on the one hand, and C-peptide responses or calculated insulin secretion rates, on the other hand, exists. Inasmuch as peripheral insulin values reflect both insulin secretion and hepatic insulin removal, this discrepancy suggests that elimination kinetics of insulin differ between oral and iv glucose administration. This difference can be related to a significantly reduced fractional hepatic insulin extraction after oral (46.9-54.6%) compared to iv (63.4-76.5%) glucose administration when calculated by a three-compartment kinetic model. This reduction in fractional hepatic insulin extraction could be caused by gastrointestinal factors (hormones or nerves) stimulated in the course of glucose ingestion.

This article has been cited by other articles:

				B. Laferrere, J. Teixeira, J. McGinty, H. Tran, J. R. Egger, A. Colarusso, B. Kovack, B. Bawa, N. Koshy, H. Lee, et al. Effect of Weight Loss by Gastric Bypass Surgery Versus Hypocaloric Diet on Glucose and Incretin Levels in Patients with Type 2 Diabetes J. Clin. Endocrinol. Metab., July 1, 2008; 93(7): 2479 - 2485. [Abstract] [Full Text] [PDF]

				E. Muscelli, A. Mari, A. Casolaro, S. Camastra, G. Seghieri, A. Gastaldelli, J. J. Holst, and E. Ferrannini Separate Impact of Obesity and Glucose Tolerance on the Incretin Effect in Normal Subjects and Type 2 Diabetic Patients Diabetes, May 1, 2008; 57(5): 1340 - 1348. [Abstract] [Full Text] [PDF]

				B. Ahren, M. S. Winzell, and G. Pacini The augmenting effect on insulin secretion by oral versus intravenous glucose is exaggerated by high-fat diet in mice J. Endocrinol., April 1, 2008; 197(1): 181 - 187. [Abstract] [Full Text] [PDF]

				K. Vollmer, J. J. Holst, B. Baller, M. Ellrichmann, M. A. Nauck, W. E. Schmidt, and J. J. Meier Predictors of Incretin Concentrations in Subjects With Normal, Impaired, and Diabetic Glucose Tolerance Diabetes, March 1, 2008; 57(3): 678 - 687. [Abstract] [Full Text] [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]

				H. Chahal and T.A. Chowdhury Gliptins: a new class of oral hypoglycaemic agent QJM, November 1, 2007; 100(11): 671 - 677. [Abstract] [Full Text] [PDF]

				J. J. Holst The Physiology of Glucagon-like Peptide 1 Physiol Rev, October 1, 2007; 87(4): 1409 - 1439. [Abstract] [Full Text] [PDF]

				J. J. Meier, J. J. Holst, W. E. Schmidt, and M. A. Nauck Reduction of hepatic insulin clearance after oral glucose ingestion is not mediated by glucagon-like peptide 1 or gastric inhibitory polypeptide in humans Am J Physiol Endocrinol Metab, September 1, 2007; 293(3): E849 - E856. [Abstract] [Full Text] [PDF]

				Y.-L. He, R. Sabo, G. Sunkara, M.-N. Bizot, G.-J. Riviere, S. Leon, M. Ligueros-Saylan, W. P. Dole, and D. Howard Evaluation of Pharmacokinetic Interactions Between Vildagliptin and Digoxin in Healthy Volunteers J. Clin. Pharmacol., August 1, 2007; 47(8): 998 - 1004. [Abstract] [Full Text] [PDF]

				J. S. Freeman The Pathophysiologic Role of Incretins J Am Osteopath Assoc, May 1, 2007; 107(suppl_3): S6 - S9. [Abstract] [Full Text] [PDF]

				P. J. Boyle and J. S. Freeman Application of Incretin Mimetics and Dipeptidyl Peptidase IV Inhibitors in Managing Type 2 Diabetes Mellitus J Am Osteopath Assoc, May 1, 2007; 107(suppl_3): S10 - S16. [Abstract] [Full Text] [PDF]

				M. Campioni, G. Toffolo, L. T. Shuster, F. J. Service, R. A. Rizza, and C. Cobelli Incretin effect potentiates beta-cell responsivity to glucose as well as to its rate of change: OGTT and matched intravenous study Am J Physiol Endocrinol Metab, January 1, 2007; 292(1): E54 - E60. [Abstract] [Full Text] [PDF]

				R K. Campbell Rationale for Dipeptidyl Peptidase 4 Inhibitors: A New Class of Oral Agents for the Treatment of Type 2 Diabetes Mellitus Ann. Pharmacother., January 1, 2007; 41(1): 51 - 60. [Abstract] [Full Text] [PDF]

				F. K. Knop, T. Vilsboll, S. Larsen, P. V. Hojberg, A. Volund, S. Madsbad, J. J. Holst, and T. Krarup Increased postprandial responses of GLP-1 and GIP in patients with chronic pancreatitis and steatorrhea following pancreatic enzyme substitution Am J Physiol Endocrinol Metab, January 1, 2007; 292(1): E324 - E330. [Abstract] [Full Text] [PDF]

				E. Muscelli, A. Mari, A. Natali, B. D. Astiarraga, S. Camastra, S. Frascerra, J. J. Holst, and E. Ferrannini Impact of incretin hormones on beta-cell function in subjects with normal or impaired glucose tolerance Am J Physiol Endocrinol Metab, December 1, 2006; 291(6): E1144 - E1150. [Abstract] [Full Text] [PDF]

				A. Weissman, L. Lowenstein, A. Peleg, I. Thaler, and E. Z. Zimmer Power Spectral Analysis of Heart Rate Variability During the 100-g Oral Glucose Tolerance Test in Pregnant Women. Diabetes Care, March 1, 2006; 29(3): 571 - 574. [Abstract] [Full Text] [PDF]

				M. J. Theodorakis, O. Carlson, S. Michopoulos, M. E. Doyle, M. Juhaszova, K. Petraki, and J. M. Egan Human duodenal enteroendocrine cells: source of both incretin peptides, GLP-1 and GIP Am J Physiol Endocrinol Metab, March 1, 2006; 290(3): E550 - E559. [Abstract] [Full Text] [PDF]

				M. C. Riddle and D. J. Drucker Emerging Therapies Mimicking the Effects of Amylin and Glucagon-Like Peptide 1 Diabetes Care, February 1, 2006; 29(2): 435 - 449. [Full Text] [PDF]

				J Schirra, M Nicolaus, R Roggel, M Katschinski, M Storr, H J Woerle, and B Goke Endogenous glucagon-like peptide 1 controls endocrine pancreatic secretion and antro-pyloro-duodenal motility in humans Gut, February 1, 2006; 55(2): 243 - 251. [Abstract] [Full Text] [PDF]

				J. H. Schou, K. Pilgaard, T. Vilsboll, C. B. Jensen, C. F. Deacon, J. J. Holst, A. Volund, S. Madsbad, and A. A. Vaag Normal Secretion and Action of the Gut Incretin Hormones Glucagon-Like Peptide-1 and Glucose-Dependent Insulinotropic Polypeptide in Young Men with Low Birth Weight J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4912 - 4919. [Abstract] [Full Text] [PDF]

				T. Miki, K. Minami, H. Shinozaki, K. Matsumura, A. Saraya, H. Ikeda, Y. Yamada, J. J. Holst, and S. Seino Distinct Effects of Glucose-Dependent Insulinotropic Polypeptide and Glucagon-Like Peptide-1 on Insulin Secretion and Gut Motility Diabetes, April 1, 2005; 54(4): 1056 - 1063. [Abstract] [Full Text] [PDF]

				M. A. Nauck, B. Baller, and J. J. Meier Gastric Inhibitory Polypeptide and Glucagon-Like Peptide-1 in the Pathogenesis of Type 2 Diabetes Diabetes, December 1, 2004; 53(suppl_3): S190 - S196. [Abstract] [Full Text] [PDF]

				J. J. Holst and J. Gromada Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans Am J Physiol Endocrinol Metab, August 1, 2004; 287(2): E199 - E206. [Abstract] [Full Text] [PDF]

				M. J. Theodorakis, O. Carlson, D. C. Muller, and J. M. Egan Elevated Plasma Glucose-Dependent Insulinotropic Polypeptide Associates With Hyperinsulinemia in Impaired Glucose Tolerance Diabetes Care, July 1, 2004; 27(7): 1692 - 1698. [Abstract] [Full Text] [PDF]

				T. Vilsboll, F. K. Knop, T. Krarup, A. Johansen, S. Madsbad, S. Larsen, T. Hansen, O. Pedersen, and J. J. Holst 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., October 1, 2003; 88(10): 4897 - 4903. [Abstract] [Full Text] [PDF]

				N. Pamir, F. C. Lynn, A. M. J. Buchan, J. Ehses, S. A. Hinke, J. A. Pospisilik, K. Miyawaki, Y. Yamada, Y. Seino, C. H. S. McIntosh, et al. Glucose-dependent insulinotropic polypeptide receptor null mice exhibit compensatory changes in the enteroinsular axis Am J Physiol Endocrinol Metab, May 1, 2003; 284(5): E931 - E939. [Abstract] [Full Text] [PDF]

				R. A. Ritzel, J. D. Veldhuis, and P. C. Butler Glucose Stimulates Pulsatile Insulin Secretion from Human Pancreatic Islets by Increasing Secretory Burst Mass: Dose-Response Relationships J. Clin. Endocrinol. Metab., February 1, 2003; 88(2): 742 - 747. [Abstract] [Full Text] [PDF]

				G. W. Van Citters, M. Kabir, S. P. Kim, S. D. Mittelman, M. K. Dea, P. L. Brubaker, and R. N. Bergman Elevated Glucagon-Like Peptide-1-(7-36)-Amide, but Not Glucose, Associated with Hyperinsulinemic Compensation for Fat Feeding J. Clin. Endocrinol. Metab., November 1, 2002; 87(11): 5191 - 5198. [Abstract] [Full Text] [PDF]

				C. J. Greenbaum, R. L. Prigeon, and D. A. D'Alessio Impaired {beta}-Cell Function, Incretin Effect, and Glucagon Suppression in Patients With Type 1 Diabetes Who Have Normal Fasting Glucose Diabetes, April 1, 2002; 51(4): 951 - 957. [Abstract] [Full Text] [PDF]

				J. J. Meier, K. Hucking, J. J. Holst, C. F. Deacon, W. H. Schmiegel, and M. A. Nauck Reduced Insulinotropic Effect of Gastric Inhibitory Polypeptide in First-Degree Relatives of Patients With Type 2 Diabetes Diabetes, November 1, 2001; 50(11): 2497 - 2504. [Abstract] [Full Text] [PDF]

				H. Kindmark, J. Pigon, and S. Efendic Glucose-Dependent Insulinotropic Hormone Potentiates the Hypoglycemic Effect of Glibenclamide in Healthy Volunteers: Evidence for an Effect on Insulin Extraction J. Clin. Endocrinol. Metab., May 1, 2001; 86(5): 2015 - 2019. [Abstract] [Full Text]

				D. A. D’Alessio, T. J. Kieffer, G. J. Taborsky Jr., and P. J. Havel Activation of the Parasympathetic Nervous System Is Necessary for Normal Meal-Induced Insulin Secretion in Rhesus Macaques J. Clin. Endocrinol. Metab., March 1, 2001; 86(3): 1253 - 1259. [Abstract] [Full Text]

				M. C. Moore, P.-S. Hsieh, D. W. Neal, and A. D. Cherrington Nonhepatic response to portal glucose delivery in conscious dogs Am J Physiol Endocrinol Metab, December 1, 2000; 279(6): E1271 - E1277. [Abstract] [Full Text] [PDF]

				J. T. Lewis, B. Dayanandan, J. F. Habener, and T. J. Kieffer Glucose-Dependent Insulinotropic Polypeptide Confers Early Phase Insulin Release to Oral Glucose in Rats: Demonstration by a Receptor Antagonist Endocrinology, October 1, 2000; 141(10): 3710 - 3716. [Abstract] [Full Text] [PDF]

				T. J. Kieffer and J. Francis Habener The Glucagon-Like Peptides Endocr. Rev., December 1, 1999; 20(6): 876 - 913. [Abstract] [Full Text]

				R. Hovorka, L. Chassin, S. D. Luzio, R. Playle, and D. R. Owens 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., March 1, 1998; 83(3): 744 - 750. [Abstract] [Full Text]