Summary
Integrated incremental immunoreactive insulin and connecting peptide responses to an oral glucose load of 50 g and an “isoglycaemic” intravenous glucose infusion, respectively, were measured in 14 Type 2 (non-insulin-dependent) diabetic patients and 8 age- and weight-matched metabolically healthy control subjects. Differences between responses to oral and intravenous glucose administration are attributed to factors other than glucose itself (incretin effect). Despite higher glucose increases, immunoreactive insulin and connecting peptide responses after oral glucose were delayed in diabetic patients. Integrated responses were not significantly different between both groups. However, during “isoglycaemic” intravenous infusion, insulin and connecting peptide responses were greater in diabetic patients than in control subjects as a consequence of the higher glycaemic stimulus. The contribution of incretin factors to total insulin responses was 72.8 ± 6.9% (100% = response to oral load) in control subjects and 36.0 ± 8.8% in diabetic patients (p ≦ 0.05). The contribution to connecting peptide responses was 58.4 ± 7.6% in control subjects and 7.6 ± 14.5% (p ≦ 5 0.05) in diabetic patients. Ratios of integrated insulin to connecting peptide responses suggest a reduced (hepatic) insulin extraction in control subjects after oral as compared to intravenous glucose. This was not the case in diabetic patients. Immunoreactive gastric inhibitory polypeptide responses were not different between control subjects and diabetic patients. A reduced or lost incretin effect in the face of normal gastric inhibitory polypeptide response in Type 2 diabetic patients may be explained by decreased sensitivity of the B cells towards the insulinotropic effect of gastric inhibitory polypeptide or to hyposecretion or reduced effectiveness of as yet unidentified humoral or nervous gut factors with incretin activity.
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References
Creutzfeldt W (1979) The incretin concept today. Diabetologia 16: 75–85
Unger RH, Eisentraut AM (1969) Entero-insular axis. Arch Int Med 123: 261–266
Seltzer HS, Allen EW, Herron AL Jr, Brennan MT (1967) Insulin secretion in response to glycemic stimulus: Relation of delayed initial response to carbohydrate intolerance in mild diabetes. J Clin Invest 45: 323–335
Cerasi E, Luft R (1967) the plasma insulin response to glucose infusion in healthy subjects and in diabetes mellitus. Acta Endocrinol 55: 278–304
Reaven GM, Farquhar JW (1969) Steady state plasma insulin response to continuous glucose infusion in normal and diabetic subjects. Diabetes 18: 273–279
Nauck M, Homberger E, Siegel EG, Ebert R, Creutzfeldt W (1985) Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. Diabetes Res Clin Pract 9 (Suppl 1): S403 (Abstract)
Faber OK, Madsbad S, Kehlet H, Binder C (1979) Pancreatic beta cell secretion during oral and intravenous glucose administration. Acta Med Scand (Suppl) 624: 61–64
Gibby OM, Hales CN (1983) Oral glucose decreases hepatic extraction of insulin. Br Med J 286: 921–923
Madsbad S, Kehlet H, Hilsted J, Tronnier B (1983) Discrepancy between plasma C-peptide and insulin response to oral and intravenous glucose. Diabetes 32: 436–438
Perley MJ, Kipnis D (1967) Plasma insulin responses to oral and intravenous glucose: Studies in normal and diabetic subjects. J Clin Invest 46: 1954–1962
Crockett SE, Mazzaferri EC, Cataland S (1976) Gastric Inhibitory Polypeptide (GIP) in maturity-onset diabetes mellitus. Diabetes 25: 931–935
Ebert R, Frerichs H, Creutzfeldt W (1976) Serum Gastric Inhibitory Polypeptide (GIP) responses in patients with maturity onset diabetes and in juvenile diabetes. Diabetologia 12: 388 (Abstract)
Ross SA, Brown JC, Dupre J (1977) Hypersecretion of Gastric Inhibitory Polypeptide following oral glucose in diabetes mellitus. Diabetes 26: 525–529
Salera M, Giacomoni P, Pironi L, Cornia G, Capulli M, Marini A, Benfenati F, Miglioli M and Barbara C (1982) Gastric Inhibitory Polypeptide release after oral glucose: Relationship to glucose intolerance, diabetes mellitus and obesity. J Clin Endocrinol Metab 55: 329–336
Ebert R, Creutzfeldt W (1980) Hypo- and hypersecretion of GIP in maturity-onset diabetics. Diabetologia 19: 271–272 (Abstract)
Bloom SR (1975) GIP in diabetes (abstract). Diabetologia 11: 334
May JM, Williams RH (1978) The effect of endogenous Gastric Inhibitory Polypeptide on glucose-induced insulin secretion in mild diabetes. Diabetes 27: 849–855
Creutzfeldt W, Ebert R, Nauck M, Stöckmann F (1983) Disturbances of the entero-insular axis. Scand J Gastroenterol 18 (Suppl 82): 111–119
WHO Expert Committee on Diabetes Mellitus, Second Report, Technical Report Series 646, WHO, Geneva, 1980
Ito C, Mito K, Hara H (1983) Review of criteria for diagnosis of diabetes mellitus based on results of follow-up study. Diabetes 28: 1039–1057
National Diabetes Data Group (1979) Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 28: 1039–1057
Helderman JH, Elahi D, Andersen DK, Raizes GS, Tobin JD, Shocken D, Andres R (1983) Prevention of the glucose intolerance of thiazide diuretics by maintenance of body potassium. Diabetes 32: 106–111
Melani F, Ditschuneit H, Bartelt HM, Friedrich H, Pfeiffer EF (1965) Über die radioimmunologische Bestimmung von Insulin im Blut. Klin Wochenschr 43: 1000–1006
Heding LG (1975) Radioimmunological determination of human C-peptide. Diabetologia 11: 541–548
Kuzio M, Dryburgh JR, Malloy KM, Brown JC (1974) Radioimmunoassay for gastric inhibitory polypeptide. Gastroenterol 66: 357–364
Ebert R, Illmer K, Creutzfeldt W (1979) Release of gastric inhibitory polypeptide (GIP) by intraduodenal acidification in rats and humans and abolishment of the incretin effect of acid by GIP-antiserum in rats. Gastroenterol 76: 515–523
Waldhaeusl W, Bratusch-Marrain P, Gasic B, Korn A, Nowotny P (1979) Insulin production rate following glucose ingestion estimated by splanchnic C-peptide output in normal man. Diabetologia 17: 221–227
Honey RN, Price S (1979) The determinants of insulin extraction in the isolated perdused rat liver. Horm Metab Res 11: 111–117
Tranberg KG (1979) Hepatic uptake of insulin in man. Am J Physiol 237: E509–518
Madison LL, Kaplan N (1958) The hepatic binding of I-131 labeled insulin in human subjects during a single transhepatic circulation. J Lab Clin Med 52: 927–932
Kuzuya T, Matsuda A (1976) Disappearance rate of endogenous human C-peptide from blood. Diabetologia 12: 519–521
Polonsky K, Jaspan J, Pugh W, Cohen D, Schneider T, Schwartz T, Moossa AR, Tager H, Rubenstein AH (1983) Metabolism of C-peptide in the dog. In vivo demonstration of the absence of hepatic extraction. J Clin Invest 72: 1114–1123
Polonsky K, Rubenstein AH (1984) C-peptide as a measure of the secretion and hepatic extraction of insulin. Pitfalls and limitations. Diabetes 33: 486–493
Rubenstein AH, Clark JL, Melani F, Steiner DF (1969) Secretion of proinsulin C-peptide by pancreaticβ-cells and its circulation in blood. Nature 224: 697–699
Faber OK, Hagen C, Binder C, Markussen J, Naithani VK, Blix PM, Kuzuya H, Horwitz DL, Rubenstein AH, Rossing N (1978) Kinetics of human connecting peptide in normal and diabetic subjects. J Clin Invest 62: 197–203
Halter JB, Graf RJ, Porte D Jr. (1979) Potentiation of insulin secretory responses by plasma glucose levels in man: Evidence that hyperglycaemia in diabetes compensates for impaired glucose potentiation. J Clin Endocrinol Metab 48: 946–954
Garvey WT, Olefsky JM, Griffin J, Hamman RF, Kolterman OG (1985) The effect of insulin treatment on insulin secretion and insulin action in type 2 diabetes mellitus. Diabetes 34: 222–234
Kimmerling G, Javorski WC, Olefsky JM, Reaven GM (1976) Locating the site(s) of insulin resistance in patients with nonketotic diabetes mellitus. Diabetes 25: 673–678
Jaspan J, Polonsky K (1982) Glucose ingestion in dogs alters the hepatic extraction of insulin: In vivo evidence for a relation between biologic action and extraction of insulin. J Clin Invest 69: 516–525
Ross SA, Brown JC, Dupre J (1974) Effects of Gastric Inhibitory Polypeptide on endocrine pancreas in normal and diabetic subjects. Diabetologia 10: 384 (Abstract)
Krarup T, Moody AJ, Saurbrey N, Kühl C, Madsbad S (1984) Effect of porcine gastric inhibitory polypeptide onβ-cell-function in type 1 (insulin dependent) and type 2 (non-insulin-dependent) diabetes. Diabetologia 27: 299 (Abstract)
Ebert R, Creutzfeldt W (1982) Influence of Gastric Inhibitory Polypeptide antiserum on glucose-induced insulin secretion in rats. Endocrinol 111: 1601–1606
Ebert R, Unger H, Creutzfeldt W (1983) Preservation of incretin activity after removal of gastric inhibitory polypeptide (GIP) from rat gut extracts by immunoadsorption. Diabetologia 24: 449–454
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Nauck, M., Stöckmann, F., Ebert, R. et al. Reduced incretin effect in Type 2 (non-insulin-dependent) diabetes. Diabetologia 29, 46–52 (1986). https://doi.org/10.1007/BF02427280
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DOI: https://doi.org/10.1007/BF02427280