Summary
Experimental and clinical work over the last 6 years has confirmed and broadened, but also challenged, the incretin concept. The nervous component of the entero-insular axis is still poorly defined, especially the peptidergic nerves, of which several contain insulinotropic regulatory peptides. The incretin effect is preserved after complete denervation of the porcine pancreas. Type 2 (non insulin-dependent) diabetic patients have a significantly decreased incretin effect. GIP (gastric inhibitory polypeptide; glucose dependent insulin releasing peptide) remains the strongest incretin factor. Its secretion depends on the absorption of nutrients. However, the correlation between the GIP response and disturbances of the entero-insular axis in some gastrointestinal diseases and, in particular, Type 2 diabetes, is poor. Furthermore, physiological concentrations of exogenous GIP do not produce fully the incretin effect and injection of GIP antibodies does not abolish the incretin effect. This suggests the existence of additional humoral incretin factors. On the other hand, GIP seems to have direct metabolic effects independent of its insulinotropic activity. The incretin effect of oral glucose is smaller if plasma levels of C-peptide rather than insulin are measured. However, decreased hepatic extraction of insulin after glucose ingestion only accounts partially for the incretin effect. GIP is unlikely to be the gut factor which regulates hepatic insulin extraction.
Article PDF
Similar content being viewed by others
References
Creutzfeldt W (1979) The incretin concept today. Diabetologia 16: 75–85
Creutzfeldt W, Ebert R, Nauck M, Stöckmann F (1983) Disturbances of the entero-insular axis. Scand J Gastroenterol 18 (Suppl 83): 111–119
Zunz E, LaBarre J (1929) Contributions à l'étude des variations physiologiques de la sécrétion interne du pancreas: relations entre les sécrétions externe et interne du pancréas. Arch Int Physiol Biochim 31: 20–44
Unger RH, Eisentraut AH (1969) Entero-insular axis. Arch Intern Med 123: 261–266
Ähren B, Hedner P, Lundquist I (1983) Interaction of gastric inhibitory polypeptide (GIP) and cholecystokinin (CCK-8) with basal and stimulated insulin secretion in mice. Acta Endocrinol 102: 96–102
Woods SC, Porte D Jr (1974) Neural control of the endocrine pancreas. Physiol Rev 54: 596–619
Hommel H, Fischer U, Retzlaff K, Knöfler H (1972) The mechanism of insulin secretion after oral glucose administration. II. Reflex insulin secretion in conscious dogs bearing fistulas of the digestive tract by sham-feeding of glucose or tap water. Diabetologia 8: 111–116
Louis-Sylvestre J (1978) Relationship between two stages of prandial insulin release in rats. Am J Physiol 235: E103-E111
Siegel EG, Trimble ER, Renold AE, Berthoud HR (1980) The importance of preabsorptive insulin release on oral glucose tolerance: studies in pancreatic islets transplanted rats. Gut 21: 1002–1009
Goldfine JD, Abraira C, Gruenewald D, Goldstein MS (1970) Plasma insulin during imaginary food ingestion under hypnosis. Proc Soc Exp Med 133: 274–278
Parra-Covarrubias A, Rivera-Rodriguez J, Almarez-Ugalde A (1971) Cephalic phase of insulin release in obese adolescents. Diabetes 20: 800–806
Sjöström L, Garellick G, Krotkiewski M, Luyckx A (1980) Peripheral insulin in response to the sight and smell of food. Metabolism 29: 901–909
Taylor JL, Feldman M (1982) Effect of cephalic-vagal stimulation on insulin, gastric inhibitory polypeptide, and pancreatic polypeptide release in humans. J Clin Endocrinol Metab 55: 1114–1117
Gibby OM, Loke M, Sarson DL, Bloom SR, McMaster P, Colne RY (1980) Disruption of the entero-insular axis in pancreatic transplantation. Regul Pept 1 (Suppl 2): 42 A
Jakob A, Largiadér F, Froesch ER (1970) Glucose turnover and insulin secretion in dogs with orthotopic pancreatic allograft. Diabetologia 6: 441–444
Lindkaer Jensen S, Vagn Meisen O, Kühl C (1976) The enteral insulin-stimulation after pancreas transplantation in the pig. Diabetologia 12: 617–620
Nauck M, van Hoorn W, Gubernatis G, Ebert R, Siewert JR, Creutzfeldt W (1985) Preserved incretin effect after complete surgical denervation of the pancreas in young pigs. Res Exp Med 185: 291–298
Larsson LI, Rehfeld JF (1979) Peptidergic and adrenergic innervation of pancreatic ganglia. Scand J Gastroenterol 14: 433–437
Larsson LI (1979) Innervation of the pancreas by substance P, enkephalin, vasoactive intestinal polypeptide and gastrin/CCK nerves. J Histochem Cytochem 27: 1283–1284
Alumets J, Hakanson R, Sundler F, Chang KJ (1978) Leu-enkephalin-like material in nerves and enterochromaffin cells in the gut. An immunohistochemical study. Histochemistry 56: 187–196
Hart IC, Cowie AT (1978) Effect of morphine, naloxone and an enkephalin analogue on plasma prolactin, growth hormone, insulin and thyroxine in goats. J Endocrinol 77: 16–17P
Ipp E, Dobbs R, Unger RH (1978) Morphine and β-endorphine influence the secretion of the endocrine pancreas. Nature 276: 190–191
Larsson LI, Fahrenkrag J, Hoist JJ, Schaffalitzky de Muckadell OB (1978) Innervation of the pancreas by vasoactive intestinal polypeptide (VIP) immunoreactive nerves. Life Sci 22: 773–780
Schebalin M, Said SI, Makhlouf GM (1977) Stimulation of insulin and glucagon secretion by vasoactive intestinal peptide. Am J Physiol 232: E197-E200
Christofides ND, Adalaja AB, Tatemoto K, Ferri GL, Polak JM, Bloom SR (1982) Presence of PHI in the human intestine. Regul Pept 3: 69–72
Szecowka J, Lins PE, Tatemoto K, Efendic S (1983) Effects of porcine intestinal heptacosapeptide and vasoactive intestinal polypeptide on insulin and glucagon secretion in rats. Endocrinology 112: 1469–1473
Brown JC, Vale W (1976) Effects of neurotensin and substance P on plasma insulin, glucagon and glucose levels. Endocrinology 98: 819–823
Feurle GE, Reinecke M (1983) Neurotensin interacts with carbachol, secretin, and caerulein in the stimulation of the exocrine pancreas of the rat in vitro. Regul Pept 7: 137–143
Fletcher DR, Blackburn AM, Adrian TE, Chadwick VS, Bloom SR (1981) Effect of neurotensin on pancreatic function in man. Life Sci 29: 2157–1261
Hökfeldt T, Efendic S, Hellerström C, Johansson O, Luft R, Arimura A (1975) Cellular localization of somatostatin in endocrine-like cells and neurons of the rat with special references to the A1-cells of the pancreatic islets and to the hypothalamus. Acta Endocrinol 80 (Suppl 299): 1–41
Bertaccini G (1980) Peptides of the amphibian skin active on the gut. I. Tachykinins (substance P-like peptides) and ceruleins. Isolation structure and basic functions. In: GBJ Glass (ed) Gastrointestinal hormones. Raven Press, New York, pp 315–341
McDonald TJ, Dupré J, Tatemoto K, Greenberg GR, Radziuk J, Mutt V (1985) Galanin inhibits insulin secretion and induces hyperglycemia in dogs. Diabetes 34: 192–196
Larrimer JN, Mazzaferri EL, Cataland S, Mekhjian HS (1978) Effect of atropine on glucose-stimulated gastric inhibitory polypeptide. Diabetes 27: 638–642
Flaten O, Sand T, Myren J (1982) Beta-adrenergic stimulation and blockade of the release of gastric inhibitory polypeptide and insulin in man. Scand J Gastroenterol 17: 283–288
Brown JC, Dahl M, Kwauk S, McIntosh CHS, Müller M, Otte SC, Pederson RA (1981) Properties and actions of GIP. In: SR Bloom, JM Polak (eds) Gut hormones, 2nd edn. Churchill Livingstone, Edinburgh, pp 248–255
Moody AJ, Damm Jörgensen K, Thim L (1981) Structure-function relationships in porcine GIP. Diabetologia 21: 306 A
Moroder L, Hallett A, Thamm P, Wilschowitz L, Brown JC, Wünsch E (1978) Studies on gastric inhibitory polypeptide: synthesis of the octatriacentapeptide GIP1–38 with full insulinotropic activity. Scand J Gastroenterol 13 (Suppl 49): 129 A
Moody AJ, Thim L, Valverde I (1984) The isolation and sequencing of human gastric inhibitory polypeptide (GIP). FEBS Lett 172: 142–149
Carlquist M, Maletti M, Jörnvall H, Mutt V (1984) A novel form of gastric inhibitory polypeptide (GIP) isolated from bovine intestine using a radioreceptor assay. Eur J Biochem 145: 573–577
Usellini L, Capella C, Solcia E, Buchan AMJ, Brown JC (1984) Ultrastructural localization of gastric inhibitory polypeptide (GIP) in a well characterized endocrine cell of canine duodenal mucosa. Histochemistry 80: 85–89
Ebert R, Creutzfeldt W (1980) Decreased GIP secretion through impairment of absorption. Front Horm Res 7: 192–201
Sykes S, Morgan LM, English J, Marks V (1980) Evidence for preferential stimulation of gastric inhibitory polypeptide secretion in the rat by actively transported carbohydrates and their analogues. J Endocrinol 85: 201–207
Fölsch UR, Ebert R, Creutzfeldt W (1981) Response of serum levels of gastric inhibitory polypeptide and insulin to sucrose ingestion during long-term application of acarbose. Scand J Gastroenterol 16: 629–632
Martin EW, Sirinek KR, Crockett SE, O'Dorisio TM, Mazzaferri EL, Thomford NR, Cataland S (1975) Release of gastric inhibitory polypeptide: caomparison of hyperosmolar carbohydrate solutions as stimuli. Surg Forum 26: 381–382
O'Dorisio TM, Spaeth JT, Martin EW, Sirinek KR, Thomford NR, Mazzaferri EL, Cataland S (1978) Mannitol and glucose: effects on gastric acid secretion and endogenous gastric inhibitory polypeptide (GIP). Am J Dig Dis 23: 1079–1083
Brown JC, Dryburgh JR, Ross SA, Dupré J (1975) Identification and actions of gastric inhibitory polypeptide. Recent Progr Horm Res 31: 487–532
Cleator JGM, Gourlay RH (1975) Release of immunoreactive gastric inhibitory polypeptide (IR-GIP) by oral ingestion of food substances. Am J Surg 130: 128–135
Falko JM, Crockett SE, Cataland S, Mazzaferri EL (1975) Gastric inhibitory polypeptide (GIP) stimulated by fat ingestion in man. J Clin Endocrinol Metab 41: 260–265
Andersen DK, Elahi D, Brown JC, Tobin JD, Andres R (1978) Oral glucose augmentation of insulin secretion: Interactions of gastric inhibitory polypeptide with ambient glucose and insulin levels. J Clin Invest 62: 152–161
Ebert R, Creutzfeldt W (1984) Evidence that fat induced secretion of gastric inhibitory polypeptide is coupled to chylomicron formation. Eur J Clin Invest 14: 9A
O'Dorisio TM, Cataland S, Stevenson M, Mazzaferri EL (1976) Gastric inhibitory polypeptide (GIP). Intestinal distribution and stimulation by amino acids and medium-chain triglycerides. Am J Dig Dis 21: 761–765
Ross SA, Shaffer EH (1981) The importance of triglyceride hydrolysis for the release of gastric inhibitory polypeptide. Gastroenterology 80: 108–111
Tso P, Buch KL, Balint JA, Rodgers JB (1982) Maximal lymphatic triglyceride transport rate from the rat small intestine. Am J Physiol 242: G408-G415
Crockett SE, Cataland S, Falko JM, Mazzaferri EL (1976) The insulinotropic effect of endogenous gastric inhibitory polypeptide in normal subjects. J Clin Endocrinol Metab 42: 1098–1103
Ebert R, Frerichs H, Creutzfeldt W (1979) Impaired feedback control of fat induced gastric inhibitory polypeptide (GIP) secretion by insulin in obesity and glucose intolerance. Eur J Clin Invest 9: 129–135
Creutzfeldt W, Talaulicar M, Ebert R, Willms B (1980) Inhibition of gastric inhibitory polypeptide (GIP) release by insulin and glucose in juvenile diabetes. Diabetes 29: 140–145
Dryburgh JR, Hampton SM, Marks V (1980) Endocrine pancreatic control of the release of gastric inhibitory polypeptide. A possible physiological role for C-peptide. Diabetologia 19: 397–401
Verdonk CA, Rizza RA, Nelson RL, Go VLW, Gerich JE, and Service FJ (1980) Interaction of fat-stimulated gastric inhibitory polypeptide on pancreatic alpha and beta cell function. J Clin Invest 65: 1119–1125
Stöckmann F, Ebert R, Creutzfeldt W (1984) Preceding hyperinsulinemia prevents demonstration of insulin effect on fat-induced gastric inhibitory polypeptide (GIP). Diabetes 33: 580–585
Dupré J, Greenidge N, McDonald TJ, Ross SA, Rubinstein D (1976) Inhibition of actions of glucagon in adipocytes by gastric inhibitory polypeptide. Metabolism 25: 1197–1199
Ebert R, Brown JC (1976) Effect of gastric inhibitory polypeptide (GIP) on lipolysis and cyclic AMP levels in isolated fat cells. Eur J Clin Invest 6: 327A
Andersen DK, Putnam WS, Hanks JB, Wise JE, Lebovitz HE, Jones RS (1980) Gastric inhibitory polypeptide (GIP) suppression of hepatic glucose production. Regul Pept 1 (Suppl 2): 4A
Ebert R, Arends J, Creutzfeldt W (1980) Insulin-dependent suppression of hepatic glucose output by GIP in the perfused rat liver. Regul Pept 1 (Suppl 2): 162A
Eckel RH, Fujimoto WY, Brunzell JD (1979) Gastric inhibitory polypeptide enhanced lipoprotein lipase activity in cultured preadipocytes. Diabetes 28: 1141–1142
Wasada T, McCorkle K, Harris V, Kawai K, Howard B, Unger RH (1981) Effect of gastric inhibitory polypeptide on plasma levels of chylomicron triglycerides in dogs. J Clin Invest 68: 1106–1107
Ohneda A, Kobayashi T, Nihei J (1983) Effect of endogenous gastric inhibitory polypeptide (GIP) on the removal of triacylglycerol in dogs. Regul Pept 6: 25–32
Creutzfeldt W, Ebert R, Willms B, Frerichs H, Brown JC (1978) Gastric inhibitory polypeptide (GIP) and insulin in obesity: increased response to stimulation and defective feedback control of serum levels. Diabetologia 14: 15–24
Deschamps J, Heptner W, Desjeux JF, Baltaske V, Machinot S, Lestradet H (1980) Effects of diet on insulin and gastric inhibitory polypeptide levels in obese children. Pediatr Res 14: 300–309
Elahi D, Andersen DK, Müller DG, Tobin JD, Brown JC, Andres R (1984) The enteric enhancement of glucose-stimulated insulin release. The role of GIP in aging, obesity and non-insulin-dependent diabetes mellitus. Diabetes 33: 950–957
Salera M, Giacomoni P, Pironi L, Cornia G, Capella M, Marini A, Beufenate F, Miglioli M, Barbara L (1982) Gastric inhibitory polypeptide release after oral glucose: relationship to glucose intolerance, diabetes mellitus and obesity. J Clin Endocrinol Metab 55: 329–337
Jorde R, Amland PF, Burhol PG, Giercksky KE, Ebert R (1983) GIP and insulin responses to a test meal in healthy and obese subjects. Scand J Gastroenterol 18: 1115–1119
Lauritsen KB, Christensen KC, Stokholm KH (1980) Gastric inhibitory polypeptide (GIP) release and incretin effect after oral glucose in obesity and after jejunoileal bypass. Scand J Gastroenterol 15: 489–495
Sarson DL, Besterman HS, Bloom SR (1979) Radioimmunoassay of gastric inhibitory polypetide and its release in morbid obesity and after jejuno-ileal bypass. J Endocrinol 81: 155–164
Service FJ, Rizza RA, Westland RE, Hall LD, Gerich JE, Go VLW (1984) Gastric inhibitory polypeptide in obesity and diabetes mellitus. J Clin Endocrinol Metab 58: 1133–1140
Arnold R, Creutzfeldt W, Ebert R, Becker HD, Borger HW, Schafmayer A (1978) Serum gastric inhibitory polypeptide (GIP) in duodenal ulcer disease: relationship to glucose tolerance insulin, and gastrin release. Scand J Gastroenterol 13: 41–47
Lauritsen KB, Moody AJ (1978) The response of gastric inhibitory polypeptide (GIP) and insulin to glucose in duodenal ulcer patients. Diabetologia 14: 149–153
Thomford NR, Sirinek KR, Crockett SE, Mazzaferri EL, Cataland S (1974) Gastric inhibitory polypeptide. Response to oral glucose after vagotomy and pyloroplasty. Arch Surg 109: 177–182
Becker HD (1980) Hormonal changes after gastric surgery. Clin Gastroenterol 9: 755–771
Schattenmann G, Ebert R, Siewert R, Creutzfeldt W (1984) Different response of gastric inhibitory polypeptide to glucose and fat from duodenum and jejunum. Scand J Gastroenterol 19: 260–266
Creutzfeldt W, Ebert R (1977) Release of gastric inhibitory polypeptide (GIP) to a test meal under normal and pathological conditions in man. In: JS Bajaj (ed) Diabetes Excerpta Medica, Amsterdam, pp 63–75
Crockett SE, Mazzaferri EL, Cataland S (1976) Gastric inhibitory polypeptide in maturity-onset diabetes mellitus. Diabetes 25: 931–935
Ross SA, Brown JC, Dupré J (1977) Hypersecretion of gastric inhibitory polypeptide following oral glucose in diabetes mellitus. Diabetes 26: 525–529
Ross SA, Dupré J (1978) Effects of ingestion of triglyceride or galactose on secretion of gastric inhibitory polypeptide and on responses to intravenous glucose in normal and diabetic subjects. Diabetes 27: 327–333
Takemura J, Seino Y, Tsuda K, Seino S, Ikeda M, Sakurai H, Imura H (1981) Hypersecretion of gastric inhibitory polypeptide induced by glucose ingestion in diabetes mellitus. Endocrinology 28: 17–22
Cataland S, O'Dorisio TM (1980) Pathology of gastric inhibitory polypeptide. Front Horm Res 7: 145–154
Perley MJ, Kipnis DM (1967) Plasma insulin responses to oral and intravenous glucose: studies in normal and diabetic subjects. J Clin Invest 46: 1954–1962
Raptis S, Rau RM, Schröder KE, Hartmann W, Faulhaber JD, Clodi PH, Pfeiffer EF (1971) The role of the exocrine pancreas in the stimulation of insulin secretion by intestinal hormones. Diabetologia 7: 160–167
Ross SA, Brown JC, Dupré J (1974) Effects of gastric inhibitory polypeptide on endocrine pancreas in normal and diabetic subjects. Diabetologia 10: 384A
Krarup T, Moody AJ, Saurbrey N, Kühl C, Madsbad S (1984) Effect of porcine gastric inhibitory polypeptide and B-cell function in Type 1 (insulin-dependent) and Type 2 (non-insulin dependent) diabetes. Diabetologia 27: 299A
Lauritsen KB, Lauritzen JB, Christensen KC (1982): Gastric inhibitory polypeptide and insulin release in response to oral and intravenous glucose in coeliac disease. Scand J Gastroenterol 17: 241–245
Sarson DL, Wood SM, Holder D, and Bloom SR (1982) The effect of glucose-dependent insulinotropic polypeptide infused at physiological concentrations on the release of insulin in man. Diabetologia 22: 33–36
Sarson DL, Wood SM, Kansal PC, and Bloom SR (1984) Glucose-dependent insulinotropic polypeptide augmentation of insulin: physiology or pharmacology? Diabetes 33: 389–393
Ebert R, Creutzfeldt W (1982) Influence of gastric inhibitory polypeptide antiserum on glucose-induced insulin secretion in rats. Endocrinology 111: 1601–1606
Lauritsen KB, Holst JJ, Moody AJ (1981) Depression of insulin release by anti-GIP serum after oral glucose in rats. Scand J Gastroenterol 16: 417–421
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
Levin SR, Pehlevanian MZ, Lavee AE, Adachi RI (1979) Secretion of an insulinotropic factor from the isolated perfused rat intestine. Am J Physiol 236: E710-E720
Goldberg NJ, Wingert TD, Levin SR, Adachi RI (1980) Augmentation of insulin secretion in man by a non-nutrient drink. Gastroenterology 78: 1458–1462
Zermatten A, Felber JP (1974) Sensitivity to glucose of an intestinal factor stimulating insulin release. Horm Metab Res 6: 272–274
Moody AJ (1977) Insulin releasing polypeptides. In: JS Bajaj (ed) Diabetes, Excerpta Medica, Amsterdam, pp 76–82
Rojdmark S, Bloom G, Chou MCU, Field JB (1978) Hepatic extraction of exogenous insulin and glucagon in the dog. Endocrinology 102: 806–813
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
Polonsky KS, Rubenstein AH (1984) C-peptide as a measure of the secretion and hepatic extraction of insulin: pitfalls and limitations. Diabetes 33: 486–494
Gibby OM, Hales CN (1983) Oral glucose decreases hepatic extraction of insulin. Br Med J 286: 921–923
Madsbad S, Kehlet H, Hilsted J, Tronier B (1983) Discrepancy between plasma C-peptide and insulin response to oral and intravenous glucose. Diabetes 32: 436–438
DeFronzo RA, Ferranini E, Hendler R, Wahren J, Felig P (1978) Influence of hyperinsulinemia, hyperglycemia, and the route of glucose administration on splanchnic glucose exchange. Proc Natl Acad Sci USA 75: 5173–5177
Polonsky KS, Jaspan J, Pugh W, Cohen D, Schneider M, 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
Ishida T, Lewis RM, Hartley CJ, Entman ML, Field JB (1983) Comparison of hepatic extraction of insulin and glucagon in conscious and anaesthetized dogs. Endocrinology 112: 1098–1109
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Creutzfeldt, W., Ebert, R. New developments in the incretin concept. Diabetologia 28, 565–573 (1985). https://doi.org/10.1007/BF00281990
Published:
Issue Date:
DOI: https://doi.org/10.1007/BF00281990