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Fetal pancreatic islets show a deficiency in insulin secretion in response to glucose, but the underlying mechanism is disputed. By isolating pancreatic islets from 21-day pregnant rats and culturing them with 2.8 or 11.1 mM glucose for 7 days, we attempted to clarify the involvement of low glucokinase activity in the poor glucose response in islets cultured with 2.8 mM glucose relative to the response obtained from those cultured with 11.1 mM glucose. The insulin secretion induced by 10 mM glyceraldehyde or 15 mM leucine, but not that induced by 20 mM glucose, from islets cultured with 2.8 mM glucose was higher than the basal insulin secretion, suggesting that the defect in glucose stimulation in fetal islets may be localized somewhere before the glyceraldehyde 3-phosphate step in the glycolytic pathway. When islets cultured with 11.1 mM glucose as distinct from those cultured with 2.8 mM glucose were incubated with glucose, the glycolytic intermediate contents were increased in a concentration- and time-dependent manner. Utilization of glucose at 20 mM, but not at 5 mM, in islets cultured with 11.1 mM glucose was higher than that in islets cultured with 2.8 mM glucose. The Vmax value of glucokinase, but not that of hexokinase or aldolase, in islets cultured with 11.1 mM glucose was higher by 150% than that in islets cultured with 2.8 mM glucose. The results suggest that the poor secretion of insulin in response to glucose can be explained by insufficient glucose metabolism due to the low glucokinase activity.

The effect of maternal hypoglycemia on early organogenesis was studied in normal and diabetic rats. Female Wistar rats were made diabetic by an intravenous injection of streptozotocin (45 mg/kg) 2-3 weeks before conception. On day 9.5 or 10.5 of embryo development, both control and diabetic dams received saline or Actrapid human insulin (400 mU/rat) intraperitoneally after 19-h starvation. The fasting plasma glucose levels in diabetic dams decreased from approximately 23 to 8 mM. Hypoglycemia as low as 3.5 mM was maintained for 60 min in insulin-treated mother rats. Pregnancy was terminated on day 11.6 of embryo development. A significant growth retardation was found in diabetic embryos as compared with normal embryos. Maternal hypoglycemia lowered the DNA content in normal but not diabetic embryos, while the teratogenic effect of maternal hypoglycemia was not pronounced in either normal or diabetic embryos. These data may suggest that maternal hypoglycemia in vivo in early pregnancy influences the embryogenesis but not teratogenesis of rat embryos.

The purpose of this study was to find appropriate adjuvant therapy following resection of pancreatic head carcinoma according to the histopathological and biological features. There was a significant correlation between histological tumor spread and biological factors. When all three biological factors, proliferating cell nuclear antigen (PCNA), epidermal growth factor (EGF), and tenascin (TN) were positive, the incidence of liver metastases was 78.6%, while it was only 7.1% when all three were negative. With the results of these factors surgical margin of the resected tumor (ew) we have proposed a protocol for adjuvant therapy following resection of the pancreatic head carcinoma.

Decompensated diabetes mellitus (DM) is associated with abnormalities in fluid and electrolyte balance (1,2,3). Alterations in the renin-angiotensin- aldosterone system and vasopressin have been observed both in human with DM (4,5) and in rats treated with the diabetogenic agent, streptozotocin (STZ) (6,7,8).

Diabetes mellitus is thought to be one of the risk factors of coronary heart disease (1,2). It is hard to detect ischemic heart disease in diabetic patients because many of them are asymptomatic. It is also considered that cardiomyopathy more often occurs in diabetic patients than in normal population (3,4,5). Exercise Tl-201 scintigraphy are commonly used to detect myocardial viability in coronary heart disease (6,7,8) and cardiomyopathy (9). We evaluate how often the patients of diabetes mellitus without symptoms suffer from heart disease, using the scintigraphic method.

The incidence of congestive heart failure is increased in patients with diabetes mellitus (1,2,3) and there is evidence that cardiac dysfunction occurs in diabetic patients with normal coronary arteries (4,5), but the causes of these abnormalities are still unclarified. Some authors (6,7) have suggested the existence of a specific diabetic cardiomyopathy. Rubler et al. (6) reported four adult-onset diabetic patients who had cardiomegaly and congestive heart failure in the absence of major coronary artery disease or hypertension. Hamby et al. (7) observed a high incidence of diabetes mellitus in their series of patients with idiopathic cardiomyopathy. On the other hand, it has been proposed that metabolic derangements of diabetes may impair the left ventricular function (4,8). Several investigators have shown that abnormalities of left ventricular systolic (9–14) or diastolic (4,8,15–17) function or both (18,19) are common in diabetics even without coronary artery disease and clinical manifestations of congestive heart failure. Abnormalities of the left ventricular function have been shown in diabetic patients at rest (4,9,20,21) and also during exercise (10-14). Whether these abnormalities result either from microangiopathy in the heart or from metabolic derangements inherent to diabetes mellitus remains unclear.

2585 Background: We have previously shown that tumor lysate-pulsed DC vaccination (TP-DC) elicited therapeutic rejection of established tumor in animal models. Administration of activated T cells was also shown to inhibit tumor relapse in patients (pts) with hepatocellular carcinoma (HCC) after curative operation. In addition, combination of TP-DC with administration of activated T cells elicited more significant therapeutic rejection of established tumor than the single therapy alone in animal models. We therefore sought to examine the therapeutic potency of TP-DC with administration of anti-CD3 activated T cells (CAT) against GI cancers: 3 pts were diagnosed with pancreatic cancer, 7 pts with HCC, 3 pts with intrahepatic cholangiocarcinoma, 2 pts with esophageal sarcoma, 12 pts with colorectal cancer. Methods: Monocyte-derived DC was generated in serum-free medium containing GM-CSF (100 ng/ml) and IL-4 (50 ng/ml). Pts received TP-DC intradermally (i.d.) 4 times every 3 weeks with 1 x 109 CAT activated w...

The activities of the mitochondrial FAD-linked glycerophosphate dehydrogenase (m-GDH), glutamate dehydrogenase, alpha-ketoglutarate dehydrogenase, glutamate-pyruvate transaminase (GPT) and glutamate-oxaloacetate transaminase were measured in islet and liver homogenates from fetal, neonatal, adult male, adult female, pregnant and lactating rats. Either parallel or dissociated ontogenic changes were observed in islet and liver homogenates. The activity of islet m-GDH was slightly, albeit not significantly, lower in neonates than in adult rats, comparable in male and female adult animals, unaffected by pregnancy, and increased during lactation. It was much higher in fetal or adult islets cultured for 7 days than in freshly isolated islets from adult rats. In cultured islets from adult rats, the increase in m-GDH activity coincided with a dramatic decrease of GPT activity, a situation the mirror image of that found in several animal models of non-insulin-dependent diabetes mellitus. The intrinsic properties of m-GDH, as judged by comparison of measurements made by either a radioisotopic or a colorimetric procedure, were not identical in islet and liver homogenates and differed between fetal and adult islets, suggesting the existence of distinct iso-enzymes. These findings illustrate adaptive changes of islet enzymes, with exclusive or partial mitochondrial location, in ontogenic situations characterized by a remodelling of fuel homeostasis.

Glucose stimulation of [32P]-prelabelled pancreatic islets induced an increased incorporation of radioactivity into phosphatidylinositol. Glucagon and agents that increases cAMP in the islet did not affect phosphatidylinositol turnover, in spite of increased release of insulin. Furthermore, the potent inhibitor of insulin release, somatostatin did not alter phospholipid metabolism. Colchicine inhibited glucose-stimulated turnover of phosphatidylinositol as well as insulin release. These results may suggest that: (1) cAMP and phosphatidylinositol turnover are involved in different transmembrane control system for regulating insulin release; and (2) the function of microtubules modulate phospholipid metabolism.

SUMMARY In order to elucidate the abnormality of pancreatic polypeptide (PP) secretion in diabetes mellitus, basal plasma PP levels and their response to oral glucose loading were measured in normal subjects and diabetic patients. Fasting plasma PP levels were significantly elevated in patients with diabetes mellitus. Oral administration of 50g of glucose elicited an exaggerated rise in plasma PP in diabetic patients as compared with the response in normal subjects. This exaggerated PP response to oral glucose loading was partially but significantly improved after the treatment, with an augmented response of plasma insulin. These results indicate the existence of abnormal PP secretion in diabetes mellitus which is possibly caused by metabolic or endocrine derangements.

The effect of 48-hour starvation on the somatostatin contents of the pancreas and gastrointestinal tract was studied in the guinea pig. Somatostatin contents were higher in various portions of the stomach and pancreas of fed guinea pigs than in fed rats and unchanged after 48-hour starvation, in spite of the decreased blood glucose level. These results suggest that somatostatin may not play the same physiological role in nutrient homeostasis of guinea pigs as it does in other species.

We have previously reported occurrence of Ca2+-activated, phospholipid-dependent protein kinase (referred as protein kinase C) in the rat pancreatic islets. It has been suggested that unsaturated diacylglycerol which results from hydrolysis of phosphatidylinositol by phospholipase C-like enzyme activates protein kinase C. Therefore, we studied the effect of exogenous phospholipase C on insulin release from isolated islets of rat pancreas. Bacterial phospholipase C enhanced insulin release induced by glucose in a dose dependent manner. The effect, however, was decreased in the islets pretreated with colchicine. Both phospholipase C and glucose caused an increase in 32p incorporation into phosphatidylinositol. These results indicate that phospholipid metabolism is linked to the insulin release mechanism.

In order to elucidate the effect of glucagon antiserum on the endocrine pancreas, the release of somatostatin, glucagon, and insulin from the isolated perfused rat pancreas was studied following the infusion of arginine both with and without pretreatment by glucagon antiserum. Various concentrations of arginine in the presence of 5.5 mM glucose stimulated both somatostatin and glucagon secretion. However, the responses of somatostatin and glucagon were different at different doses of arginine. The infusion of glucagon antiserum strongly stimulated basal secretion in the perfusate total glucagon (free + antibody bound glucagon) and also enhanced its response to arginine, but free glucagon was undetectable in the perfusate during the infusion. On the other hand, the glucagon antiserum had no significant effect on either insulin or somatostatin secretion. Moreover, electron microscopic study revealed degrannulation and vacuolization in the cytoplasm of the A cells after exposure to glucagon antiserum, suggesting a hypersecretion of glucagon, but no significant change was found in the B cells or the D cells. We conclude that in a single pass perfusion system glucagon antiserum does not affect somatostatin or insulin secretion, although it enhances glucagon secretion.

To study the mechanism of imparied insulin secretion from rat fetal islets, the insulin responsiveness of islets from fetuses (day 21.5 of gestation) to a variety of secretagogues was compared with that of adult rat islets. Forskolin (30 microM)-induced insulin release from fetal and adult islets was 2.7-and 2.5-fold higher, respectively, than that from islets treated with 5.6 mM glucose alone. The effects of 12-O-tetradecanoyl phorbol-13-acetate (TPA) (200 nM) were also similar in fetal and adult islets. Thus, the responsiveness to forskolin and TPA showed no significant difference in adult and fetal islets. A synergistic effect of combinations of various insulin secretagogues was observed in adult islets; however, a weak synergistic effect was present with gliclazide plus TPA only in fetal islets. After islets were cultured in RPMI 1640 (containing 11.1 mM glucose), gliclazide-, forskolin-, and TPA-induced insulin release reached the levels obtained in adult islets. However, the synergistic effect of gliclazide and TPA disappeared after culture of the islets. These results suggest that the poor insulin secretion from fetal islets is not due to a defect in the activating system of either cAMP or C-kinase, but to the immaturity of the interaction of those messenger systems.

Effects of antisomatostatin and antiglucagon sera on insulin secretion were studied in isolated pancreatic islets of rats. Addition of antisomatostatin or antiglucagon serum to the incubation medium containing 5.5 mM glucose significantly increased insulin secretion from the islets. In contrast, these effect were not apparent when the glucose concentration was elevated to 20 mM. In the presence of antiglucagon serum the free glucagon concentration in the medium was decreased, while the total glucagon was markedly increased, suggesting that the antiglucagon serum caused an increase in glucagon secretion. These results suggest that A- and D-cells may play an important role in regulating insulin release at physiologic glucose concentration.