Insulin resistance in pancreatic cancer
Abstract: The dismal prognosis of pancreatic cancer (PC) is related to metabolic complications of the tumor. Impaired glucose tolerance or diabetes due to insulin resistance, and cachexia are observed early and frequently in these patients. The basic mechanisms of PC-associated insulin resistance and weight loss are not fully understood. A majority of PC patients have obstructive jaundice and elevated plasma concentrations of islet amyloid polypeptide (IAPP), both of which may contribute to these metabolic alterations. Conditions associated with hyperinsulinemia are also of interest as a putative risk factors of PC, since insulin seems to promote carcinogenesis in the pancreas. To investigate the mechanisms of PC-associated insulin resistance, intact skeletal muscle of PC patients were incubated in vitro for assessment of glucose transport and insulin signaling through phosphatidylinositol (PI) 3-kinase. Glucose transporter (GLUT) 4, ATP, phosphocreatine, glycogen, and uncoupling protein (UCP) 2 and 3 mRNA and protein content were determined in other muscle biopsies. Patients with benign gastrointestinal diseases, chronic pancreatitis, and cancer of other sites were investigated as controls. GLUT4 transfected myoblasts were treated with media conditioned by PC cells and expression of UCPs monitored. To investigate metabolic effects of obstructive jaundice, bile duct ligated rats and sham-operated pair- fed and ad libitum fed controls were assessed for skeletal muscle glucose metabolism and UCP2 mRNA expression in muscle and liver. The effects of chronic IAPP exposure on the metabolism of glucose and other nutrients were determined in rats. A cohort of individuals of the Swedish Twin Registry was investigated for certain lifestyle factors and pancreatic cancer risk. Exposure data was obtained prospectively by questionnaires, and PC incidence was ascertained by linkage to the Swedish Cancer Registry. Twenty-six out of 30 PC patients had diabetes or impaired glucose tolerance. Insulinstimulated glucose transport and PI 3-kinase activity were significantly decreased in skeletal muscle in these patients, but GLUT4 content was unchanged. Skeletal muscle insulin resistance was associated with increased expression of UCP2 and UCP3 and decreased ATP and glycogen content. These alterations were not found in patients with cancer of other sites or benign diseases who had a similar degree of weight loss. Conditioned media from PC cells increased the expression of UCPs in myoblasts. Obstructive jaundice and long term IAPP exposure did not result in skeletal muscle insulin resistance. Liver UCP2 expression was markedly upregulated and weight-loss was increased in jaundiced animals compared with pair-fed controls. Feeding was markedly reduced in IAPP-treated animals. Body weight gain was significantly reduced in IAPP-infused rats compared with pair-fed animals. In addition, IAPP-treated rats showed decreased intraabdominal fat mass. 176 cases of PC were found in the Swedish Twin Registry. Cigarette smoking, mild obesity, low physical activity, and high adult weight gain were all significant risk factors of PC. In conclusion, insulin resistance in PC patients includes impaired insulin signaling and glucose transport in skeletal muscle. This skeletal muscle metabolic alteration is associated with upregulation of UCP homologues, which may be triggered by PC cell-derived factor(s). Obstructive jaundice and IAPP exposure do not result in skeletal muscle insulin resistance, but are associated with metabolic alterations resulting in body weight loss. Lifestyle factors associated with peripheral insulin resistance increase the risk of PC development.
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