Glucose metabolism in patients with exocrine pancreatic adenocarcinoma

Sammanfattning: Carc.inoma of the exocrine pancreas is the fifth leading cause of cancer death in the Western world and the survival rate is one of the lowest for cancers of any site. Pancreatic cancer is characterized by pronounced, early cachexia and frequent metabolic complications. An increased incidence of diabetes or impaired glucose tolerance have been reported in pancreatic cancer patients. Two different hypotheses for this association have been presented, one suggesting that diabetes is a predisposing factor for pancreatic cancer and the other suggesting that the diabetic state is a consequence of the malignant disease.In the present study, 50 patients with exocrine pancreatic adenocarcinoma were studied, 11 of whom were found suitable for radical surgery. These eleven patients were studied both preoperatively and 3 months after subtotal pancreatectomy. Healthy subjects, patients with cancer of other sites and diabetic patients without any malignancy were investigated as controls. The incidence of diabetes and impaired glucose tolerance was investigated. Insulin secretion from pancreatic cancer patients was evaluated in the basal state, during hyperglycemia and after glucagon stimulation. Whole-body and peripheral insulin sensitivity were determined. The abundance and distribution pattern of endocrine cells, and the concentration of pancreatic islet hormones were investigated in control tissues ·and human exocrine pancreatic adenocarcinomas. The metabolic effect of extracts of these tumors on muscle glycogen synthesis was studied in vitro. Concentrations of islet hormones were determined in plasma in the basal state, during hyperglycemia and after stimulation by glucagon. Production of islet amyloid polypeptide (IAPP) was evaluated by studies of mRNA expression and peptide immunoreactivity in pancreatic adenocarcinomas, in tissue adjacent to the tumor and in normal pancreas.Diabetes or impaired glucose tolerance was found in 74% of the patients with pancreatic cancer, and this high frequency resulted mainly from newly-diagnosed diabetes. The diabetic state was more a consequence of profound insulin resistance rather than an impaired insulin secretion. After subtotal pancreatectomy, the diabetic state, glucose tolerance and insulin sensitivity were improved despite a marked decrease in insulinsecretion. Endocrine cells were found in 80% of the adenocarcinomas, predominantly in well-differentiated adenocarcinomas. Extracts from the tumors contained islet hormones, but in varying concentrations and without any correlation to diabetic state. Tumor extracts from diabetic but not from non-diabetic pancreatic cancer patients inhibited glycogen synthesis in skeletal muscle. This metabolic effect could not be explained by the concentrations of the diabetogenic peptides in the extracts. Plasma IAPP, glucagon and somatostatin were normalized after subtotal pancreatectomy. The pattern of hormonal changes seen was suggestive of a paracrine action of pancreatic adenocarcinomas on the adjacent pancreatic islets. This was supported by the normal IAPP mRNA-staining in the absence of IAPP-immunoreactivity in endocrine pancreatic tissues adjacent to the tumor. In conclusion, diabetes occurs with an increased frequency in patients with exocrine pancreatic adenocarcinoma. The diabetic state is closely related to the tumor itself and is a consequence rather then the cause of the malignant disease. Overall the results indicate that the diabetic state results from the tumor acting either directly or indirectly.