膵内外分泌相関に関する研究-CaeruleinおよびCholecystokininの膵外分泌並びに各種濃度ブドウ糖刺激下における膵内分泌への作用-

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Since Meade et al. reported the insulinotropic effects of the extracts of intestinal mucosa, many investigators have shown that cholecystokinin (CCK) is one of the gastrointestinal hormones stimulating insulin secretion. Contrary to these observations, Rabinovitch et al. observed no effect of pure preparations of CCK on insulin secretion and also pointed out that only crude preparations of CCK had a stimulating action on the β cell of the pancreatic islet. Recently, the insulinotropic effect previously attributed to CCK has been suggested to be due to contaminating gastric inhibitory polypeptide (GIP) present in crude preparations of CCK, not to CCK itself. Moreover, GIP has been demonstrated to potentiate the glucose-stimulated insulin release and had been found to be released by the intraduodenal administration of glucose and protein. More recently, synthetic octapeptide of CCK and synthetic caerulein, of which C-terminal pentapeptide was identical to that of CCK, have also been shown to stimulate insulin and glucagon secretion. However, it was difficult to discuss whether the insulinotropic action of these peptides administered exogenously was physiological or not because the plasma levels of CCK to which effects of exogenous CCK should be compared are unknown. The present study was, therefore, undertaken to make clear whether physiological concentrations of highly purified natural porcine CCK or synthetic caerulein have an insulinotropic effect in the isolated perfused rat pancreas. Since the well-known physiological action of CCK is its activity to increase secretion of amylase by the pancreas, insulinotropic effects of these peptides were investigated by paying attention to pancreatic exocrine secretion.<BR>Wistar strain male rats weighing 250-300g were used in all experiments. The pancreases were isolated according to the technique of Kanno and perfused with a Krebs Ringer bicarbonate buffer containing 4.6% Dextran T-70 and 0.25% bovine serum albumin. The effects of caerulein of the doses ranging from 0.01 to 100 ng/ml and CCK from 0.1 to 250 mU/ml were studied in the presence of 50,100,150 and 200 mg/dl glucose in the perfusion medium. Insulin (IRI) and glucagon (IRG) levels in the portal effluent were determined by radioimmunoassay using polyethylene glycol and charcoaled dextran with antiserum 30 K, respectively. Amylase activity in the pancreatic juice was assayed by a chromogenic method with blue-dyed starch polymer.<BR>In the presence of 50 mg/dl glucose, IRI and IRG releases were stimulated only with high doses of CCK or caerulein, i.e., more than 50mU/ml or 1 ng/ml. Moreover, the IRI and IRG responses to any doses were over in 5 min despite the prolonged infusion of the peptides. On the other hand, IRI and IRG releasing doses of CCK or caerulein resulted in lower rates of release of fluid and amylase when compared with those stimulated by the maximally effective dose of CCK or caerulein.<BR>The possibility that IRI stimulation by pure natural porcine CCK might depend, at least in part, on the contaminating GIP can be excluded under this experimental system where a glucose concentration of 50 mg/dl was used, because an infusion of GIP at a concentration of 5 ng/ml known to be effective at 100 mg/dl glucose, has been revealed to be ineffective at 80 mg/di glucose. Moreover, the concentration of GIP may be less than the threshold dose to stimulate IRI release at 50 mg/di glucose, even if highly purified preparations of CCK from G.I.H. Laboratory may have contained 10% (actually 1 to 2%) by weight of GIP. The concentration of GIP in the 50 mU/ml CCK could be calculated as 1.43 ng/ml (CCK; 3500 Units = 1 mg). Similarities between the effects of synthetic caerulein, certainly free of GIP and other contaminated peptides,
一般社団法人日本内分泌学会の論文

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坂本長逸
神戸大学医学部第2内科学教室

膵内外分泌相関に関する研究-CaeruleinおよびCholecystokininの膵外分泌並びに各種濃度ブドウ糖刺激下における膵内分泌への作用-

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