Adrenomedullin is Up-regulated in Patients With Pancreatic Cancer and Causes Insulin Resistance in beta Cells and Mice

作者：Aggarwal Gaurav; Ramachandran Vijaya; Javeed Naureen; Arumugam Thiruvengadam; Dutta Shamit; Klee George G; Klee Eric W; Smyrk Thomas C; Bamlet William; Han Jing Jing; Vittar Natalia B Rumie; De Andrade Mariza; Mukhopadhyay Debabrata; Petersen Gloria M; Fernandez Zapico Martin E; Logsdon Craig D; Chari Suresh T^*

来源：Gastroenterology, 2012, 143(6): 1510-+.

DOI：10.1053/j.gastro.2012.08.044

• Pancreas
• Mechanisms
• Mouse Model
• Tumor

BACKGROUND %26 AIMS: New-onset diabetes in patients with pancreatic cancer is likely to be a paraneoplastic phenomenon caused by tumor-secreted products. We aimed to identify the diabetogenic secretory product(s) of pancreatic cancer. METHODS: Using microarray analysis, we identified adrenomedullin as a potential mediator of diabetes in patients with pancreatic cancer. Adrenomedullin was up-regulated in pancreatic cancer cell lines, in which supernatants reduced insulin signaling in beta cell lines. We performed quantitative reverse-transcriptase polymerase chain reaction and immunohistochemistry on human pancreatic cancer and healthy pancreatic tissues (controls) to determine expression of adrenomedullin messenger RNA and protein, respectively. We studied the effects of adrenomedullin on insulin secretion by beta cell lines and whole islets from mice and on glucose tolerance in pancreatic xenografts in mice. We measured plasma levels of adrenomedullin in patients with pancreatic cancer, patients with type 2 diabetes mellitus, and individuals with normal fasting glucose levels (controls). RESULTS: Levels of adrenomedullin messenger RNA and protein were increased in human pancreatic cancer samples compared with controls. Adrenomedullin and conditioned media from pancreatic cell lines inhibited glucose-stimulated insulin secretion from beta cell lines and islets isolated from mice; the effects of conditioned media from pancreatic cancer cells were reduced by small hairpin RNA-mediated knockdown of adrenomedullin. Conversely, overexpression of adrenomedullin in mice with pancreatic cancer led to glucose intolerance. Mean plasma levels of adrenomedullin (femtomoles per liter) were higher in patients with pancreatic cancer compared with patients with diabetes or controls. Levels of adrenomedullin were higher in patients with pancreatic cancer who developed diabetes compared those who did not. CONCLUSIONS: Adrenomedullin is up-regulated in patients with pancreatic cancer and causes insulin resistance in beta cells and mice.

• 出版日期2012-12