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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.

Pancreatic carcinoma is characterized by poor prognosis and lack of response to conventional therapy for reasons that are not clear. Because of the structural relationship between the exocrine and endocrine pancreas and high concentrations of islet hormones bathing pancreatic tissue, we hypothesized that pancreatic cancer cell proliferation and glucose utilization are regulated by pancreatic islet hormones, particularly insulin. Based on this, the effect of islet hormones on pancreatic cancer cells in vitro was investigated. Five pancreatic cancer cell lines, CD11, CD18, HPAF, PANC-1, and MiaPaCa2 were used to investigate the effect of islet hormones on cell proliferation, glucose utilization, and GLUT-1 expression. Insulin, but not somatostatin and glucagon, induced pancreatic cancer cell growth in a concentration- and time-dependent manner. At concentrations within the range of those in the intrapancreatic vasculature, insulin (10(-10)-10(-8) mol/L) markedly increased [3H]-thymidine incorporation. Insulin significantly enhanced glucose utilization of pancreatic cancer cells before it enhanced cell proliferation. The MAPK kinase inhibitor PD 098059 abolished insulin-stimulated DNA synthesis and partially reduced insulin-stimulated glucose uptake. In contrast, the PI3 kinase inhibitor wortmannin substantially inhibited insulin-induced glucose uptake and partially blocked thymidine incorporation. Furthermore, after 24-hour treatment with insulin, GLUT-I expression in pancreatic cancer cells was markedly increased, indicating that insulin enhances glucose utilization partly through increasing glucose transport. These findings suggest that insulin stimulates proliferation and glucose utilization in pancreatic cancer cells by two distinct pathways. Insulin augments DNA synthesis mainly by MAP kinase activation and glucose uptake mainly by PI3 kinase activation and enhancement of GLUT-I expression. High intrapancreatic concentrations of insulin are likely to play an important role in stimulating pancreatic cancer growth indirectly by increasing substrate availability as well as by direct action as a trophic factor.

The diabetes or impaired glucose tolerance that occurs in most patients with pancreatic cancer is characterized by profound insulin resistance. Recent evidence suggests that the diabetes may result from the presence of the tumor rather than being a predisposing factor to development of the malignancy. Some islet hormones have been shown to exhibit diabetogenic effects. To investigate the potential role of these hormones in the diabetic state associated with pancreatic cancer, we measured islet hormones during fasting in pancreatic cancer patients (n = 30), patients with other malignancies (n = 43), and healthy controls (n = 25). Preoperative pancreatic cancer patients were classified as normal glucose tolerance (NGTT), impaired glucose tolerance (IGTT), non-insulin-requiring diabetes (NIRD), and insulin-requiring diabetes (IRD). Nine pancreatic cancer patients were studied after tumor removal by subtotal pancreatectomy. Some preoperative pancreatic cancer patients (n = 19), postoperative patients (n = 9), and controls (n = 8) were also studied during hyperglycemia and following glucagon injection. Fasting plasma C-peptide was elevated in NIRD pancreatic cancer patients compared to controls. Fasting levels of islet amyloid polypeptide (IAPP), glucagon, and somatostatin were elevated in NIRD and IRD patients. IAPP and glucagon, but not somatostatin, normalized following subtotal pancreatectomy. During hyperglycemia, increases in C-peptide and IAPP were seen only in controls and in NGTT and postoperative pancreatic cancer patients. After glucagon infusion, IAPP levels increased in controls and nondiabetic cancer patients; C-peptide levels increased in controls, nondiabetic patients, and NIRD. Responses of C-peptide and IAPP to glucagon normalized after pancreatectomy. During hyperglycemia, glucagon levels fell in all groups except IGTT patients and a decrease in somatostatin concentrations was seen in controls.

Islet amyloid polypeptide (IAPP) is produced in pancreatic beta cells. Intraislet function of IAPP is still uncertain. In the present study, we investigated effects of IAPP and somatostatin on stimulus-secretion coupling of beta cells in isolated rat pancreatic islets. Insulin secretion induced by 22.2 mM glucose was increased by an IAPP antiserum (0.1%) or an IAPP antagonist (IAPP8-37, 10 microM). Pretreatment of islets with pertussis toxin (PTX) abolished the stimulating effect of IAPP8-37 on glucose-induced insulin secretion. In contrast, IAPP antiserum and IAPP8-37 did not change insulin secretion induced by 30 mM KCl. Somatostatin (1 nM) inhibited insulin secretion induced by 22.2 mM glucose, 10 mM L-arginine, 25 microM forskolin, and 200 microM carbachol. IAPP (10 microM) enhanced the inhibitory effect of somatostatin on insulin secretion induced by L-arginine or forskolin. PTX pretreatment abolished the effects of somatostatin and IAPP on arginine-induced insulin secretion. In conclusion, IAPP regulates multiple steps in signal transductions of beta cells. The effects of IAPP on beta cells are mediated by PTX-sensitive regulatory G proteins.

Abnormal insulin and islet amyloid polypeptide (IAPP) secretion are usually seen in patients with exocrine pancreatic cancer. The beta-cell dysfunction is a characteristic of the glucose intolerance found in pancreatic cancer patients. The effects of pancreatic cancer cells on insulin and IAPP secretion from beta cells are unclear. In this study, isolated rat pancreatic islets were cocultured with two human pancreatic adenocarcinoma cell lines (Panc-1 and HPAF) and a human colonic adenocarcinoma cell line (HT-29). As a control, islets were incubated in the absence of malignant cells. The accumulation of insulin and IAPP in culture media was measured by radioimmunoassay. Output of insulin and IAPP was decreased in islets cocultured with each malignant cell line. Molar ratio of secreted IAPP and insulin (IAPP/insulin) was increased in the islets cocultured with Panc-1 or HPAF cells, but not HT-29 cells. The decreased insulin and IAPP secretion were partly recovered after Panc-1, HPAF, or HT-29 cells were removed. The IAPP/insulin ratio was normalized after the removal of Panc-1 or HPAF cells. This study indicates that insulin and IAPP secretion are altered by the human adenocarcinoma cells investigated. The impairment induced by pancreatic adenocarcinoma cells is associated with a hypersecretion of IAPP relative to insulin on a molar basis.

We have investigated whether a possible dysregulation of the storage and function of islet amyloid polypeptide (IAPP) in the endocrine pancreas of 4-month-old spontaneously diabetic Goto-Kakizaki (GK) rats might contribute to the impairment of glucose-induced insulin secretion previously reported in these rats. Immunocytochemical studies indicated a significantly lower degree of labeling per beta-cell granule of insulin but not of IAPP in GK islets compared to control islets. Further, the GK rats displayed lower plasma levels of both insulin and IAPP in the fasting state. The pancreatic concentrations of both IAPP and insulin were also significantly lower in the GK rats than in the controls. Following an intraperitoneal glucose injection, the plasma IAPP and insulin concentration of the GK rats did not increase at all, whereas a significant increase in both IAPP and insulin concentration was recorded in the control animals. However, the plasma IAPP/insulin ratio was significantly higher in the GK rats at both 30 and 60 min after glucose injection, which may be a reflection of an increased negative feedback effect of IAPP on insulin release. A relative hypersecretion of IAPP might be one of several factors contributing to the impairment of glucose-induced insulin secretion in this rat model of non-insulin-dependent diabetes mellitus. This is further supported by our electron microscopic observations showing disproportionate IAPP/insulin labeling of beta-cell granules in the GK islets.