Summary
A combined biochemical and morpho-cytochemical investigation was carried out in order to assess insulin absorption by the duodenal and colon epithelium. Insulin was introduced in the lumen of the rat duodenum or colon in combination with sodium cholate and aprotinin. Blood analysis made at several time points has demonstrated a rapid increase in circulating levels of insulin followed by significant and consistent decreases in blood glucose. This indicates that biologically active insulin is absorbed by the intestinal mucosa and transferred to the circulation. Because of the initial high blood glucose levels, the lowering of the glycaemic values was more significant in diabetic animals. Also, levels of circulating insulin remained higher for longer time when the administration was performed in the colon. The integrity of the intestinal wall after insulin administration, evaluated morphologically, was retained. Application of protein A-gold immunocytochemistry has established the pathway for insulin absorption. In both duodenal and colon epithelial cells the labelling for insulin was detected in the endosomal compartment, in the Golgi apparatus and in association with the baso-lateral plasma membrane interdigitations. Some labelling was also present in the interstitial space and in capillary endothelial plasmalemmal vesicles. Insulin introduced in the lumen of the rat duodenum and colon appears thus to be rapidly internalized by the epithelial cells and transferred through a transcytotic pathway to the interstitial space from which it reaches the blood circulation. This exogenous insulin then induces significant decreases in plasma glucose levels which lasts for several hours. The results obtained support the possibility for the clinical development of an oral preparation of insulin.
Article PDF
Similar content being viewed by others
References
Hirai S, Ikenaga T, Matasuzawa T (1978) Nasal absorption of insulin in dogs. Diabetes 27: 296–299
Salzman R, Manson JE, Griffing GT et al. (1985) Intranasal aerosolized insulin mixed meal studies and long-term use in type I diabetes. N Engl J Med 312: 1078–1084
Gordon GS, Moses AC, Silver RD, Flier JS, Carey MC (1985) Nasal absorption of insulin: enhancement by hydrophobic bile salts. Proc Natl Acad Sci USA 82: 7419–7423
Ichikawa K, Ohata I, Mitomi M, Kawamura S, Maeno H, Kawata H (1980) Rectal absorption of insulin suppositories in rabbits. J Pharm Pharmacol 32: 314–318
Ziv E, Kidron M, Berry EM, Bar-On H (1981) Bile salts promote the absorption of insulin from the rat colon. Life Sci 29: 803–809
Ziv E, Kleinman Y, Bar-On H, Kidron M (1984) Treatment of diabetic rats with enterai insulin. In: Shafrir E, Renold AE (eds) Lessons from animal diabetes. John Libbey, London, pp 642–647
Ritschel WA, Ritschel GE (1984) Rectal administration of insulin. Methods Find Exp Clin Pharmacol 6: 513–529
Raz I, Bar-On H, Kidron M, Ziv E (1984) Rectal administration of insulin. Isr J Med Sci 20: 173–175
Nishihata T, Rytting JH, Kamada A, Higuchi T (1981) Enhanced intestinal absorption of insulin in rats in the presence of sodium 5-methoxy-salicylate. Diabetes 30: 1065–1067
Bar-On H, Berry EM, Eldor A, Kidron M, Lichtenberg D, Ziv E (1981) Enterai administration of insulin in the rat. Br J Pharmacol 73: 21–24
Kidron M, Bar-On H, Berry EM, Ziv E (1982) The absorption of insulin from various regions of the rat intestine. Life Sci 31: 2837–2841
Ziv E, Lior O, Kidron M (1987) Absorption of protein via the intestinal wall: a quantitative model. Biochem Pharmacol 36: 1035–1039
Damge C, Michel C, Aprahamian M, Couvreur P (1988) New approach for oral administration of insulin with polyal-kylcyahoacrylate manocapsules as drug carrier. Diabetes 37: 246–251
Kidron M, Krausz MM, Raz I, Bar-On H, Ziv E (1989) The absorption of insulin from the intestine in dogs. Tenside Surf Det 26: 352–354
Bendayan M, Ziv E, Ben-Sasson R, Bar-On H, Kidron M (1990) Morpho-cytochemical and biochemical evidence for insulin absorption by the rat ileal epithelium. Diabetologia 33: 197–204
Cho YW, Flynn M (1989) Oral delivery of insulin. Lancet II: 1518–1519
Murlin JR, Sutter CC, Allen RS, Piper HA (1924) Some favorable effects from the alimentary administration of insulin. Endocrinology 8: 331–339
Salen E (1924) Einige Versuche mit peroraler Darreichung von Insulin. Acta Med Scand 60: 74–87
Murlin JR, Young LE, Phillips WA (1937) New results on the absorption of insulin from the alimentary tract. Science 86: 412
Murlin JR, Gibbs CBF, Romansky MJ, Steinhausen TB, Truax FL (1940) Effectiveness or per-oral insulin in human diabetes. J Clin Invest 19: 709–722
Hanzlik PJ, Cutting WC (1941) Agents promoting gastrointestinal absorption of insulin. Endocrinology 28: 368–374
Bendayan M (1984) Protein A-gold electron microscopic immuno-cytochemistry: methods, applications and limitations. J Electron Microsc Tech 1: 243–270
Bendayan M (1989) Protein A-gold and protein G-gold postembedding immunoelectron microscopy. In: Hayat MA (ed) Colloidal gold cytochemistry techniques and applications. Academic Press, New York, pp 33–94
Willison JHM, Rowe AJ (1980) Replica, shadowing and freeze-etching techniques. In: Glauert AM (ed) Practical methods in electron microscopy Vol 8. North-Holland Pub Co, New York, pp 171–276
Ghitescu L, Bendayan M (1990) Immunolabelling efficiency of protein A-gold complexes. J Histochem Cytochem 38: 1523–1530
Rodier-Bruant C, Vaxman F, Lambert A et al. (1991) Etude de l’absorption intestinal de l’insuline chez le chien grâce â une nouvelle capsule de largage télémétrique. Gastroenterol Clin Biol 15: 187–193
Madara JL, Pappenheimer JR (1987) Structural basis for physiological regulation of paracellular pathways in intestinal epithelia. J Membrane Biol 100: 149–164
Bergeron JJM, Rachubinski R, Searle N, Borts D, Sikstrom R, Posner BI (1980) Polypeptide hormone receptors, in vivo: demonstration of insulin binding to adrenal gland and gastrointestinal epithelium by quantitative radioautography. J Histochem Cytochem 28: 824–835
Pillion DF, Ganapathy V, Leibach FH (1985) Identification of insulin receptors on the mucosal surface of colon epithelial cells. J Biol Chem 260: 5244–5247
Fernandez-Moreno MD, Serrano-Rios M, Prieto JC (1987) Identification of insulin receptors in epithelial cells from duodenum, jejunum, ileum, caecum, colon and rectum in the rat. Diabete Metab 13: 135–139
Bendayan M (1993) Pathway of insulin in pancreatic tissue on its release by the B-cell. Am J Physiol 264: G187-G194
Ziv E, Kidron M, Raz I et al. (1991) The treatment of diabetes by oral delivery of insulin. Diabetes 40: 341A (Abstract)
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Bendayan, M., Ziv, E., Gingras, D. et al. Biochemical and morpho-cytochemical evidence for the intestinal absorption of insulin in control and diabetic rats. Comparison between the effectiveness of duodenal and colon mucosa. Diabetologia 37, 119–126 (1994). https://doi.org/10.1007/s001250050081
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/s001250050081