Takaaki Takebe

Insulin and glucagon response of the diabetic Chinese hamster in the Asahikawa colony

The relationship between pancreatic hormone content and pattern of hormone release has not been completely elucidated because of heterogeneity in diabetes. Accordingly, this study was performed to establish the relationship, using spontaneously diabetic Chinese hamsters in the Asahikawa colony, a newly discovered experimental model resembling insulin-deficient diabetes in humans. As a result of investigations of insulin and glucagon responses to glucose or arginine in vivo and in vitro using isolated islets obtained by the collagenase procedure, a decreased insulin response and paradoxical glucagon response to glucose, and an excessive glucagon response to arginine were found in the diabetic animals. While the yield of isolated islets tended to decrease, a decreased pancreatic insulin content and increased pancreatic glucagon content were found as the diabetic state advanced. It may be suggested, therefore, that the relationship between pancreatic hormone content and pattern of hormone release in diabetic animals in the Asahikawa colony is based on the disruption of islets, disruption or dysfunction of B-cells and hyperplasia or hypertrophy of A-cells by some cause genetically determined.

Paradoxical glucagon response in perifused islets of the diabetic Chinese hamster

Dynamic insulin and glucagon response to glucose was examined in the perifusion system to investigate the relationship between pancreatic hormone content and the pattern of hormone secretion in diabetic Chinese hamsters of the Asahikawa colony (CHA). Isolated islets of normals and diabetics from the CHA were perifused. When the medium was changed to high glucose (500 mg/dl), a low insulin response and paradoxical glucagon response were seen in diabetics compared with normals. Positive correlations were found between pancreatic insulin and the amount of perifusate insulin, and glucagon content and glucagon release, respectively. It is suggested, accordingly, that pancreatic hormone content is related to the amount of hormone release in CHA. A negative correlation between the amount of perifusate insulin and glucagon release was found. It is suggested, therefore, that an impaired suppression of glucagon release in the diabetic CHA animals could be attributed at least to insulin deficiency. These findings agree with the histological discovery of decreased B-cells and increased A-cells in the diabetic islets. Both decreased B-cells and islet numbers could be the cause of the low insulin response to glucose. Increased numbers of A-cells with hyperfunction resulting from local insulin deficiency could be the cause of the paradoxical glucagon response.

Experimental study on multidisciplinary treatment of pancreatic cancer.

SummaryWe investigated the antitumor effects of intratumoral (IT) injection of mitomycin-C (MMC), 5-fluorouracil (5FU), adriamycin (ADR), cisplatin (CDDP), streptozotocin (STZ), and interleukin-2 (IL-2) on well-differentiated pancreatic ductal adenocarcinoma (WD PaCa), a solid tumor model in the Syrian golden hamster. The growth of established palpable WD PaCa was not suppressed by intraperitoneal (IP) injection of these anticancer agents, whereas IT injection of MMC (1.0 mg/kg or more), 5FU (12.5 mg/kg or more), and CDDP (2.5 mg/kg or more) caused significant and marked suppression. The growth of established palpable WD PaCa was transiently suppressed by 50 Gy of local irradiation. The antitumor effect of irradiation was not enhanced by it injection of MMC before irradiation, whereas it was significantly enhanced by it injection after irradiation. Intraperitoneal injection of IL-2 (5 or 10 µg/d, 18 d) slightly suppressed the growth of established palpable tumors, but it injection of IL-2 caused significant and marked suppression, eliminating the tumor in 10–20% of the animals. Findings in this animal model of pancreatic cancer suggest that it treatment of anticancer agents or IL-2 might become an effective therapy for advanced pancreatic cancer.

Non-selective inhibition of insulin and glucagon release by xenogeneic islet cell surface antibodies.

The influence of xenogeneic islet cell surface antibodies (ICSA) on the hormonal secretion of non-B islet cells has not been completely elucidated. Accordingly, we investigated the influence of xenogeneic antiserum on glucagon release from A cells, as representative of non-B islet cells, together with other characteristics of the antiserum. Anti-islet cell sera were produced in rabbits by xenogeneic immunization with dispersed hamster islet cells. Rabbit anti-hamster islet cell surface antibodies were detected both qualitatively by indirect immunofluorescence analyses and quantitatively by 125I-protein A radioligand assay. However, antiserum did not induce cell surface immunofluorescence on rat or mouse islet cells. As a result of evaluation of the specific cytotoxicity using 51Cr release assay, antiserum was observed to induce a significantly higher release of 51Cr compared with that of normal rabbit serum in complement-dependent antibody-mediated cytotoxicity. Both glucose-stimulated insulin and arginine-stimulated glucagon release were suppressed by xenogeneic antiserum not only in the presence but also in the absence of complement. It is concluded, therefore, that xenogeneic antiserum has a relative species specificity and non-selectively binds to islet cells in contrast with the non-species specificity and preferential binding to pancreatic B cells of human ICSA, although heterogeneity in ICSA-positive sera has been suggested.

The usefulness of serum paba measurement after bt-paba administration in the diagnosis of chronic pancreatitis

SummaryWe examined the maximal serum PABA concentration within 3 hrs (MS-PABA) and the 6 hr urinary PABA recovery (6 hr U-PABA) after BT-PABA administration, PABA excretion index, and chymotrypsin secretory response to caeruleinsecretin stimulation in ten control subjects and fifteen patients with chronic pancreatitis diagnosed on the basis of pancreatograms. The results suggested that MS-PABA can distinguish the patients with definite irregular dilatation of the main pancreatic duct from the controls, but not those with localized irregular dilatations of the side branches from the controls. MS-PABA showed a significant correlation with 6 hr U-PABA, PABA excretion index, chymotrypsin output and bicarbonate output. This modified method was shown to be useful in the diagnosis of chronic pancreatitis with unequivocally abnormal pancreatograms and/or markedly decreased chymotrypsin secretion. This modification will serve to simplify the BT-PABA test by eliminating urinary collection and shortening the procedure time.

Proceedings of the 64th annual meeting from May 22 to 24, 1978—Sapporo, Japan

The Ist presumptive evidence that gastrointestinal hormones influence growth is found in a number of studies describing the long term effects of antrectomy on the remaining oxyntic gland mucosa. And, it is reported that gastrin stimulates protein and DNA synthesis, this effect is specific to certain tissue of the digestive tract, and it is dependent of secretory phenomena. From this experiment, it is concluded that the effect of gastrin is mediated by cyclic GMP and in gastric atrophy, the responses of cyclic GMP and protein synthesis to gastrin is diminished.

Reserve capacity of bicarbonate secretion in chronic pancreatitis

SummaryWhen secretin was given by continuous intravenous infusion in the control subjects, the dose of secretin inducing maximal bicarbonate output was found to be around 6.0 CHR U/kg/hr. Then the pancreatic exocrine secretory response to sequential standard (1.2 CHR U/kg/hr) and augmented (6.0 CHR U/kg/hr) dose of secretin was studied in the controls, in patients with chronic pancreatitis and in its suspected cases. This new method for exocrine pancreatic function did not offer advantage for the diagnosis of well established chronic pancreatitis. But from the results obtained in suspected chronic pancreatitis it was supposed that the decline of increasing rate of bicarbonate output with augmentation of dose and the decrease of response to augmented dose of secretin might be one of functional disorders occurred in the early stage of chronic pancreatitis.