Margery K. Herrington

Islet Amyloid Polypeptide in Patients with Pancreatic Cancer and Diabetes

BACKGROUND The diabetes mellitus that occurs in patients with pancreatic cancer is characterized by marked insulin resistance that declines after tumor resection. Islet amyloid polypeptide (IAPP), a hormonal factor secreted from the pancreatic beta cells, reduces insulin sensitivity in vivo and glycogen synthesis in vitro. In this study, we examined the relation between IAPP and diabetes in patients with pancreatic cancer. METHODS We measured IAPP in plasma from 30 patients with pancreatic cancer, 46 patients with other cancers, 23 patients with diabetes, and 25 normal subjects. IAPP immunoreactivity and IAPP messenger RNA were studied in pancreatic cancers, pancreatic tissue adjacent to cancers, and normal pancreatic tissue. RESULTS Plasma IAPP concentrations were elevated in the patients with pancreatic cancer as compared with the normal subjects (mean [+/- SD], 22.3 +/- 13.6 vs. 8.0 +/- 5.0 pmol per liter; P < 0.001), normal in the patients with other cancers, and normal or low in the patients with diabetes. Among the patients with pancreatic cancer, the concentrations were 25.0 +/- 8.7 pmol per liter in the 7 patients with diabetes who required insulin, 31.4 +/- 12.6 pmol per liter in the 11 patients with diabetes who did not require insulin, and 12.2 +/- 2.4 pmol per liter in the 9 patients with normal glucose tolerance (3 patients had impaired glucose tolerance; their mean plasma IAPP concentration was 11.7 +/- 5.5 pmol per liter). Plasma IAPP concentrations decreased after surgery in the seven patients with pancreatic cancer who were studied before and after subtotal pancreatectomy (28.9 +/- 16.4 vs. 5.6 +/- 3.4 pmol per liter, P = 0.01). Pancreatic cancers contained IAPP, but the concentrations were lower than in normal pancreatic tissue (17 +/- 16 vs. 183 +/- 129 pmol per gram, P < 0.001). In samples from the patients with both pancreatic cancer and diabetes, immunostaining for IAPP was reduced in islets of pancreatic tissue surrounding the tumor; in situ hybridization studies suggested that transcription occurred normally in these islets. CONCLUSIONS Plasma IAPP concentrations are elevated in patients with pancreatic cancer who have diabetes. Since IAPP may cause insulin resistance, its overproduction may contribute to the diabetes that occurs in these patients.

Effects of dietary menhaden oil on mucosal adaptation after small bowel resection in rats

BACKGROUND/AIMS Adaptive hyperplasia of the small intestine is important in the outcome of short bowel syndrome. Previous studies have shown that long-chain fats stimulate this process. In the present study, the trophic effects of dietary menhaden oil, a highly unsaturated fat source, on mucosal adaptation following small bowel resection in rats was evaluated. METHODS Thirty weanling Sprague-Dawley rats and their controls were fed diets containing fats provided primarily as menhaden oil, safflower oil, or beef tallow. After 4 weeks, animals underwent a 70% jejunoileal resection. Mucosal mass, DNA, protein, and sucrase levels were assessed 14 days after a 70% jejunoileal resection or control feeding. Serum fatty acid composition and several gastrointestinal hormone levels were measured. RESULTS Resected animals fed menhaden oil showed a marked increase in mucosal weight, DNA, and protein levels compared with rats fed the other fat sources. Enteroglucagon level was increased in all resected groups, but least increased in the menhaden-fed animals. In contrast, peptide YY concentrations were most increased in animals fed menhaden oil. CONCLUSIONS Menhaden oil appears more effective in inducing intestinal adaptation than less highly unsaturated fats. Analysis of gastrointestinal hormones revealed no clear-cut explanation for this finding, other than a modest but associated increase in peptide YY levels.

Impaired insulin action on phosphatidylinositol 3-kinase activity and Glucose transport in skeletal muscle of pancreatic cancer patients

Introduction Glucose intolerance or overt diabetes occurs in 80% of patients with pancreatic cancer (PC). This associated metabolic disorder includes peripheral insulin resistance, which may be caused by factors produced by the PC. The mechanism underlying PC-associated insulin resistance has not been clearly defined. Aim To characterize basal and insulin-stimulated glucose transport, phosphatidylinositol (PI) 3-kinase activity, and glucose transporter 4 (GLUT4) in skeletal muscles of PC patients. Methodology Skeletal muscle samples were obtained from the abdominal wall of 17 PC patients during surgery. Control muscles were sampled in the same way from 11 donors undergoing abdominal surgery for benign diseases. PI 3-kinase activity, glucose transport, and GLUT4 were assessed in vitro in these muscles. Results In the presence of physiologic concentrations of insulin, glucose transport and PI 3-kinase activity were significantly decreased in the PC group compared with controls. At supraphysiologic insulin concentrations, glucose transport was significantly decreased but PI 3-kinase activity was normalized. In the absence of insulin, these parameters were not significantly different between PC and control groups. Muscle GLUT4 contents were similar between PC and control groups. Conclusion Defects in insulin-mediated PI 3-kinase activity and glucose transport contribute to the insulin resistance in patients with PC.

Early changes in islet hormone secretion in the hamster pancreatic cancer model.

The diabetic state that is seen at a high frequency in association with pancreatic cancer is characterized by elevated plasma levels of several islet hormones and by marked insulin resistance. Both the diabetic state and insulin sensitivity improve after tumor removal by sub-total pancreatectomy. Impaired glucose tolerance has also been found in the hamster pancreatic cancer model, but conflicting data regarding islet function have been reported. In order to further investigate islet function and secretion during early development of pancreatic cancer, we measured the concentrations of insulin, glucagon, somatostatin, and islet amyloid polypeptide (IAPP) in plasma, pancreatic tissue, and secretin-stimulated pancreatic juice at 12 and 27 weeks after the ductal-cell-specific carcinogen, BOP had been used to induce tumors in Syrian golden hamsters. At 12 weeks after BOP, plasma glucagon levels were significantly increased. An exaggerated plasma-glucose response and concomitant hyperinsulinemia were observed at 27 but not 12 weeks after BOP. Plasma IAPP concentrations, but not glucagon or somatostatin, were elevated at 27 weeks. Tissue concentrations of IAPP were substantially reduced in BOP-treated hamsters at 27 weeks. No differences in hormone concentrations were seen in pancreatic juice from the two groups at either of the two time points investigated. The study showed that islet hormone changes accompany the early development of pancreatic tumors in the hamster pancreatic model. The hormone changes and apparent insulin resistance resemble the metabolic changes found in humans with pancreatic cancer.

Postnatal development of circulating cholecystokinin and secretin, pancreatic growth, and exocrine function in guinea pigs

SummaryConcentrations of cholecystokinin (CCK) and secretin from neonatal guinea pig plasma were evaluated in relation to pancreatic growt, and secretion from dispersed pancreatic acini. Plasma CCK was low at birth (3.1±0.8 pmol/L) but rose markedly by day 15 (11.0±0.8 pmol/L,p<0.001). Plasma secretin was also low at birth (3.8±0.8 pmol/L) but peaked on day 4 (17.0±1.4 pmol/L,p<0.001) and remained elevated through d 15. Adult nonfasting plasma CCK and secretin levels were 12.3±0.8 and 8.9±1.5 pmol/L, respectively. Pancreatic weight more than doubled during the first week of life, with the greatest increase during the first 4 d (156±4 to 262±10 mg/100g body wt,p<0.001). Body weight increased most dramatically during the second week (126±9 to 190±7 gp<0.001). Amylase secretion from isolated acini stimulated by CCK-8, carbachol, phorbol ester, forskolin, and calcium ionophore (A23187) was present at birth. The percentage of total amylase content secreted in response to CCK, carbamylcholine, and secretin did not change during the first 2 wk of neonatal life, and was independent of surges in circulating CCK and secretin. These results indicate that functional maturity of the guinea pig pancreas for amylase secretion occurs early and is different from the rat, mouse, pig, and human. Since results can readily be compared between animals of different postnatal ages, the neonatal guinea pig is ideally suited for the study of hormonal effects on acinar cell function.

On the role of cholecystokinin in pancreatic cancer

Pancreatic cancer is the fourth leading cause of cancer death for both men and women in the United States (1). There are no effective treatments for the disease, and no screening techniques are available for detecting tumors at an early stage. In most patients, the diagnosis is made too late for curative surgery; the tumor has often already spread beyond the pancreas or has metastasized at the time of the first symptoms (2). Over 90% of the patients die within 1 yr after the disease is diagnosed, and the 5-yr survival rate is negligible (1, 3). The reason for the aggressive nature of pancreatic cancer is unknown, but hormonal growth factors are likely to be important. In the past few years, considerable attention has been given to the possible hormone responsiveness of pancreatic cancer. Much of this work has focused on the gastrointestinal hormone cholecystokinin (CCK). Recent reviews on the role of CCK in pancreatic cancer (4-15) have emphasized the experiments that suggest that CCK receptors are present on pancreatic cancer cells, that CCK stimulates growth of tumor cells, and that CCK receptor blockade retards tumor development. However, the results of many other experiments do not support the hypothesis that CCK plays an important role in pancreatic cancer. The current review gives an overview of this controversial subject. Some investigations of CCK and pancreatic cancer have been conducted using fresh human pancre-

Effects of raw soya diet and cholecystokinin receptor blockade on pancreatic growth and tumor initiation in the hamster

Raw soya diet in the hamster had short-term trophic effects on the pancreas, causing significant increases in pancreatic weight, DNA, RNA, and protein. These changes appear to be mediated by cholecystokinin (CCK) because the increases were blocked by infusion of the CCKA receptor antagonist, MK329. Raw soya diet significantly increased plasma levels of CCK in both the short-term and long-term studies. However, raw soya did not potentiate pancreatic cancer in hamsters treated with N-nitrosobis(2-oxopropyl)amine (BOP). Infusion of MK329 during the initiation period of carcinogenesis did not change tumor incidence or yield, suggesting that endogenous CCK does not influence tumor induction during the initiation period in the hamster.

Effects of epidermal growth factor on neonatal pancreatic growth in the guinea pig

SummaryConclusionEGF and/or transforming growth factor-α (TGF-α) are likely to be important in the rapid pancreatic growth that occurs in the neonatal guinea pig.BackgroundRapid pancreatic growth is observed during the neonatal period in the guinea pig. The growth factors that are involved are not known but may include members of the EGF family.MethodsMini-osmotic pumps were implanted on the day of birth for continuous infusion of EGF (30 μg/d). Pancreatic DNA, RNA, and protein contents were determined at 4 and 15 d, along with wet weights of the pancreas, duodenum, jejunoileum, colon, and gallbladder. Pancreatic EGF and TGF-α concentrations were measured in adult controls, in control neonates at 1, 4, 8, and 15 d, and also at d 4 and 15 in guinea pigs receiving either EGF or the cholecystokinin receptor antagonist devazepide (25 nmol/kg/h).ResultsEGF infusion significantly increased the weight of the stomach and duodenum at 4 d and all the gastrointestinal organs, including the pancreas, at 15 d. Exogenous EGF increased pancreatic DNA, RNA, and protein content at 4 and 15 d. Endogenous EGF and TGF-α concentrations in the pancreas were significantly higher at birth than in adults (P<0.001 andP<0.01, respectively) and declined during the first 2 wk postpartum. At 15 d, EGF concentrations remained significantly higher than adult levels (P<0.01), but TGF-α concentrations had declined to adult values. Infusion of EGF decreased concentrations of endogenous EGF in the pancreas at 4 and 15 d (bothP<0.05) and decreased TGF-α concentrations at 4 d (P<0.001). Devazepide infusion caused a significant decrease in endogenous pancreatic EGF concentrations at 15 d (P<0.05).

On the importance of cholecystokinin in neonatal pancreatic growth and secretory development in guinea pigs.

The role of cholecystokinin (CCK) in pancreatic growth and secretory development in fetal and neonatal guinea pigs was investigated by CCK receptor blockade. For the last 20 days of gestation, sows received the CCKA receptor antagonist, MK329 (25 nmol/kg/h) by continuous subcutaneous infusion. Alternatively, neonates from untreated females received an MK329 infusion for the first 4 or 15 days following birth. Pancreatic weight, DNA, RNA, protein, and amylase content per 100 g body weight and secretory responses to CCK, car-bamylcholine, and phorbol ester were determined at birth and 4 days in animals receiving MK329 in utero and were measured at 4 and 15 days in neonatally infused animals. No significant changes in pancreatic growth parameters were seen in MK329-treated animals compared to controls, except for a small (14%; p < 0.02) decrease in weight after 15 days of neonatal exposure. Enhanced amylase secretion in response to CCK and carbamylcholine was seen in all groups receiving MK329 (all p values < 0.00001). Pancreatic growth and secretion were not inhibited by CCKA receptor blockade, which suggests that the effects of CCK mediated by the CCKA receptor are not essential for growth or development of the pancreatic amylase secretory response in the neonatal guinea pig.

Effects of Epidermal Growth Factor, Cholecystokinin, and Secretin on Growth of the Alimentary Tract in the Neonatal Guinea Pig

Gut hormones and growth factors are likely to be involved in the functional changes and substantial growth of the alimentary tract that occurs during early neonatal life. The present experiments investigated the effects of continuous subcutaneous infusion of cholecystokinin (CCK), secretin, and epidermal growth factor (EGF) in neonatal guinea pigs for 4 or 15 days. At doses of 20, 100 or 500 pmol/kg/h, CCK and secretin had no effect on alimentary tract organs except for an increase in pancreatic weight at 4 days with the highest dose of CCK and an increase in stomach weight at 4 days with the highest dose of secretin. In contrast, EGF showed dose-dependent and time-dependent effects on all the alimentary tract organs when infused at 70, 210 and 630 pmol/kg/h. These results suggest that EGF, but not CCK or secretin, is likely to be an important trophic factor during the neonatal period.