Fujiyama, Katsumi

Hoshino, Tazue

Ikeda, Tadasu

Mashiba, Hiroto

Ohtani, Izumi

Takeuchi, Tatsuo

Tanaka, Yasushi

Tottori University Research Result Repository

Study Reports Tottori U niv Col Med Care Technol : 16， 1--8， 1991. Effects of atropine and propranolol on glucose-and arglnlne剛inducedinsulin release in ra ts Tadasu IKEDA， Izumi OHT ANI，* Katsumi FUJIY AMK， Tazue HOSHINO~ Yasushi TANAKA~ Tatsuo TAKEUCHI* and Hiroto MASHIBA家Tottori University College of Medical Care Technology， and *The First Department of Internal Medicine， Tottori University School of Medicine， Y onago 683， Japan Several observations lead to support the suggestion that the pancreatic beta-<cell responds in different ways to an oral ingestion and an intravenous infusion of nu-trients 1-3. It is well known fact that insulin concentration in plasma provoked by a certain amount of orally ingested glucose is several times higher than that pro-voked by intravenously infused glucose， which is injected by a corresponding 1-3i amount for blood concentration (incretin effect)'"'. The insulin response to a meal is of the result from composite neural and endocrine input to the islets. Both of the sympathetic and parasympathetic nervous systems are known to affect on the secre-tion of insulin 4-6， and blockades of sympathetic or parasympathetic nervous sys-tems (beta-adrenergic blockade or atropine) have been reported to reduce the in・sulin response after oral or intravenous glucose 7-111. However， the effect of the autonomic nervous system on insulin secretion after oral or intravenous ingestion of nu trients remains to be fully elucidated. In this study， the effect of an admin-istration of atropine or propranolol into rats on insulin secretion after intraduo咽denal or intravenous infusion of glucose or argmme was investigated to elucidate the possible role of the autonomic nervous system in insulin response. Materials and methods Animals Male Wistar albino rats weighing approximately 200g were provided through this study. After fasting overnight， the rats were anesthetized with intraperitoneal pento barbital sodi um (30mg/kg)， then being exposed to bilateral femoral veins. 1 2 Neura1 factors in insu1in re1ease lntrαvenous (lV) infusion of glucose 0γαrgzη{ηe G1ucose (0.5g/kg in a 20% solution) or L-arginine (0.5g/kg in a 20 % sol-ution) was infused into the femora1 vein， and b100d was drawn from the contra-1atera1 femora1 vein at given times. lηtγαduodeηal (lD) iη:fusion of glucose or argiη{ηe After anesthesia， the abdomen was opened. Then the equa1 amount (0.5g/kg in a 20 % solution) of glucose or L-arginine was infused into the duodenum through a po1yethy 1ene cannula， and blood was drawn from the femora1 vein at given times. Atγopine 0γργ01りγαnololpγetreatment In some groups of the experiments， atropine su1phate (lmg/kg， Tanabe Seiyaku， Osaka， Japan) or proprano1ol hydrochloride (0.5mgパcg，ICI Pharma， Osaka， Japan) was injected subcutaneous1y 30 min before the administration of the inducers. Me asurement s Blood glucose concentration was measured by a glucose oxidase method. Insu司lin and gl ucagon were ana1ysed by respective radioimmunoassays 12. 131， of which sensi ti vi ties were 白 timated to be 2μU/ml for insulin and 20pg/ml for glucagon. Intra-and interassay coefficients of variation were 5 and 10 % for insulin and 7 and 15 % for glucagon， r田pectively. Stαtistics of data The data were expressed as the mean士 SD.Analysis of variance and two-tailed Student's non-paired t test were applied. Results Basal levels of blood gl ucose and plasma insulin were not altered by the atro-pine or propranolol administration. While basal plasma glucagon level was not al-tered by atropine but raised slightly by propranolol (Figs. 1 and 2). Resρonses of blood glucose，ρlasmα 向suliη andplasma glucagon to the glucose tηgestzoη Figure 1 shows variations of three kinds of deduction from the glucose infusion. In a case of ID ingestion， blood gl ucose was increased in the similar pattern in spite of the presence of atropine or propranolol. While increase of plasma insulin was in somewhat different pattern from that in blood glucose， and at a 30min point after ID ingestion， insulin reached to the peak values of 80 士 13，67士 15，and 50 士 15，uU/ml in control， atropine and propranolol groups， respectively. In the middle left figure， at 30 and 60 min points， plasma insulin level was significantly red uced under the propranolol pretreatment. Plasma glucagon was suppressed in the similar 3 et al. Ikeda， T. I V 100 300 200 200 ぴ下回100 .晶刀O E 150 100 50 100 50 ??? ?。80 60 。80 E o 0. 60 <D Zピ60 30 。40 120 mln 60 。? ???Eピ町11n plasma and (IRI ) insulin plasma (BS)， glucose Blood l Fig. the glucose ingestion in rats. (IRG) responses to glucagon ingestion (left side)， SD， ID ， intraduodenal Bars represent control group O side) ， ( right lngestlOn IV ; intravenous A atropin ト(n=7) ， * pく0.02，group • propranolol-treated (n=7) ， pomts and different from control. * p<0.05 (n=7)， group treated signifi cantly of the blockades. manner regardless glucagon showed plasma and glucose blood lngestlon， IV of case another In lnsu“ plasma Besides， or less similar variations as in the case of ID ingestion. 立lorewere 75 after IV ingestion pomt ロllnand the peak values at a 30 lin was increased， atropine and propranolql plasma in・control， at 15 and 30 min points， ln the middle right figure， ロlln30 at 11μU/ml 土and 32 In 15， r es p ect i vel y. 47十groups， 士 16，N eural factors in insulin release 4 or even atroplne. under the propranolol extremely red uced was sulin level of blood glucose， plasma iη'-suliηαηd glucagon to the arglnzne ingestion Resρonses argmme infusion. variations of three kinds of deduction from the Figure 2 shows arginine but its level remained lower Blood glucose was slightly increased by the ID was slightly in司insulin Plasma blockades. the of regardless arglnlne， IV by the compared As were not available. the blockades ????or IV arginine lD by creased by IV more ind uci ble to plasma insulin slightly lngestlve routes， arglnlne was agaln IV though the extent of its release was stil1 weak. and ID through arglnlne by increased was glucagon regardless of the blockades， Plasma ro u te. ID routes， than V J JO 90 D 、i一120司3(JI E 的 100m . 50 25 . 50 25 ? ?? ?庄80 60 。E 100 0 a 60 60 mln 30 。. 120 η可In60 。，ー(!) Eピresponses plasma insulin and plasma glucagon Blood glucose， Fig. 2 1. to the argmme ingestion. See legends at the footnote of Fig. 1 keda， T. et al. Discussion F d In the intravenous glucose infusion test， insulin concentration in rat plasma was significantly reduced by an administration of propranolol. It has been reported that glucose-induced insulin release in men is reduced by the propranolol administra-tion 9. lQ¥， w hile Ro bertson and Porte l4l could detect no alteration in the insulin re-sponse in men to intravenous glucose during propranolol infusion. Acetylcholine has been known to enhance glucose-induced insulin release 4. 51 • The administration of a cholinergic blockade， atropine， was sure to significantly inhibit this time intraがven ous glucose-induced ins ulin release in rats. Henderson et al. 71 however， have reported that insulin release brought about by intravenous glucose is not altered by 15; atropine (lmg) in men. While， Daniel et al. >" have reported that atropine inhibits insulin release as stimulated by intravenous glucose in rhesus monkeys. These contra-dictions may be due to the difference of species. In rats so far， both cholinergic and beta-adrenergic blockades may inhibit the release of intravenous， glucose-induced insulin. Because atropine or propranolol might alter the gastric emptying rate and subse-quent glucose absorption， glucose was administered directly into the duodenum in-stead of oral infusion. Atropine hardly reduced insulin secretion in intraduodenal glucose ingestion. Because the quantity of insulin secreted after the oral glucose ad-ministration is affected by gastrointestinal factors 1-ペ insulinsecreted this time after an intraduodenal glucose may be almost due to influence by insulinotropic intestinal factors (incretin effect)， rather than due to the glucose stimulation. Atropine may have not affected the incretin effect and thus an inhibitory effect of atropine on glu-cose-induced insulin release may be overcome by the incretin effect in the intraduo-denal glucose infusion test. Henderson et al. 7) have reported that insulin release after oral glucose is significantly diminished by atropine in men. This discrepancy may be due to the difference of the route of administration， because atropine is a strong inhibitor of gastric emptying. On the other hand， insulin release by intraduodenal glucose was suppressed by propranolol administration. This result agreed with the report of Imura et al. 81， which the insulin response to oral glucose was impaired dur・ingconcomitant infu-sion with propranolol in men. Glucose absorption in rats was not altered by pro-pranolol， though Flaten et al.161 have reported that propranolol inhibits release of the gastric inhibitory polypeptide (GIP， most probable candidate of incretin) after intraduodenal glucose in men. These suggest that propranolol may in-hibit insulin release by intraduodenal glucose probably through the mechanism of 6 Neural factors in insulin release the decreased GIP secretion and/or inhibitory effect on some insulinotropic intes-tinal hormone( s). Further studies are needed to explain well this phenomenon. Plasma insulin level after intravenous argmme was slightly higher than that after intraduodenal arginine. Raptis et al. 17J and Moxley et al. 18: have indepen-dently reported that the insulin response to amino acids after oral or intraduodenal infusion is greater than that after intravenous infusion in men. While， N ogowski et al. 19J have reported that argmme is four times more effective when given in rabbits by the intravenous way than by the oral one. These differences may depend on species applied and/or methods examined. In this study， neither atropine nor pro-pranolol did affect insulin secretion by intraduodenal or intravenous arginine， sug-gesting that cholinergic and beta-adrenergic systems may have no important roles in arginine-induced insulin secretion. In conclusion， itmay be able to draw that both cholinergic and beta-abrenergic mechanisms may have important roles in insulin secretion induced by intravenous glucose not by intravenous arginine， and that the beta-adrenergic mechanism， but not the cholinergic one， may affect insulin release in rats by oral glucose. Summary Effects of atropine or propranolol on insulin or glucagon release in rats by secretagogues， glucose or L-arginine， were investigated. In highly sensitive measure-men t， the insulin release by the intravenous ingestion of glucose was sure to be ex-tremely blocked in the presence of either atropine or propranolol， while by the in-traduodenal ingestion it was blocked not by atropine but by propranolol. On the contrary， the insulin release in response to L-arginine by both of the ingestive routes was not blocked at all. Besides， the glucagon release by gl ucose or L-arginine was not altered at all. These findings postulate the possible role of the a utonomic nervous system to release of the pancreatic hormones; (1) cholinergic mechanism my be involved in insulin release by IV glucose， (2) beta-adrenergic mechanism may be involved in insulin release by IV and ID glucose， and (3) autonomic nervous system may not be involved in both of insulin and glucagon responses to L-arginine. References 1) McIntyre， N.， Holdworth， C. D. and Tnrner， D. S.， ].Clin. Endocrinol. Metab.， 25， 1317-1326， 1965. Ikeda， T. et al. 7 2) Creutzfeldt， W.， Diabetologia， 16， 75-85， 1979. 3) U nger， R. H. and Eisentraut， A. M.， Arch. Intern. Med.， 123， 261-266， 1969. 4) Iversen， J.， Diabetes， 22， 381-387， 1973. 5) Kaneto， A. and Kosaka， K.， Endocrinology， 95， 676-681， 1974 6) Day， J.L.， Metabolism， 24， 987-996， 1975. 7) Henderson， J.R.， Jefferys， D. B.， Jones， R. H. and Stanley， D.， Acta Endocrinol.， 83， 772-780， 1976. 8) 1 mura， H.， Kato， Y.， Ikeda， M.， Mor・imoto，M. and Yawata， M.， J.Clin. Invest.， 50， 1069-1079， 1971. 9) Cerasi， E.， Luft， R. and Efendic， S.， Acta Endocrinol.， 69， 335-346， 1972. 10) Raptis， S.， Dollinger， H.， Chrissiku， M.， Rothenbuchner， G司 and Pfeiffer， E. F.， Europ. J. Clin. Invest.， 3， 163-168， 1973. 11) Flaten，O.， Sand， T. and Myren， J.， Acta Physiol. Scand.， 113，415-416， 1981. 12) Yalow， R. S. and Berson， S.A.， J. Clin. Invest.， 39， 1157-1175， 1960. 13) Nishino， T.， Kodaira， T.， Shin， S.， Imagawa， K.， Shima， K.， Kumahara， Y.， Yanaトhara， C. and Yanaihara， N.， Clin. Chem.， 27， 1690-1697， 1981. 14) Robertson， R. P. and Porte， D.， J.Clin. Invest.， 52， 870-876， 1973. 15) Daniel， P. M. and Henderson， J.R.， Acta Endocrinol.， 78， 736-745， 1975. 16) Flaten， 0.， Scand. J. Gastroenterol.， 16， 641-645， 1981. 17) Raptis， S.， Dollinger， H. C.， Schroder， K. E.， Schleyer， J¥ι， Rothenbuchner， G. and Pfeiffer， E. F.， New Engl. J. Med.， 288， 1199-1202， 1973. 18) Moxley， R. T.， Lockwood， D. H.， Amatruda， J.M.， Tobin， J.D. and Pozefsky， T.， Diabetes， 27， 78-84， 1978. 19) Nogowski， L. and Nowak， K. W.， Horm. Metab. Res.， 18，730-733， 1986. (Received Fe bruary 20， 1991) 

Effects of atropine and propranolol on glucose- and arginine-induced insulin release in rats

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Effects of atropine and propranolol on glucose- and arginine-induced insulin release in rats

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