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

Abstract

Background & 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 β cells and mice.

Osteoprotegerin is up-regulated in pancreatic cancers and correlates with cancer-associated new-onset diabetes

“…Except for diabetes history, no significant association found several diabetogenic secretory products of pancreatic cancer, such as adrenomedullin, macrophage migration inhibitory factor (9)(10)(11).…”

New-onset hyperglycemia: A potential clue to detect early pancreatic cancer

“…Clinical and laboratory evidence supports the hypothesis that PaC-associated DM is a paraneoplastic phenomenon but its biochemical mediator(s) are not well-known [4]. One such possible biomarker is adrenomedullin, which is a potential mediator of b-cell dysfunction in PaC-associated DM [10]. New-onset DM provides a high-risk group that could be screened for PaC at a time when the cancer is asymptomatic.…”

Adrenomedullin in pancreatic carcinoma: A case-control study of 22 patients

“…Physiologically AM is recognized as a regulator of the pancreatic secretion [14,19,20], while in pancreatic cancer, it is overexpressed in both neoplastic and peritumoral tissues. Circulating levels are increased too [9]. Recently new-onset diabetes mellitus has been investigated as a possible early manifestation of pancreatic cancer (PaCDM).…”

“…Currently, CA 19-9 is the only marker acknowledged worldwide for PaC diagnosis [2,6], and the main limitations to its use are low specificity [6][7][8] and late increase on disease progression [2]. Adrenomedullin (AM) is up-reguleted in pancreatic cancer [9] and it is investigated as a possible diabetogenic mediator [9]. Both cancer cells and neighboring pancreatic tissue show AM overexpression independently from the stage of the neoplastic disease [9].…”

“…Adrenomedullin (AM) is up-reguleted in pancreatic cancer [9] and it is investigated as a possible diabetogenic mediator [9]. Both cancer cells and neighboring pancreatic tissue show AM overexpression independently from the stage of the neoplastic disease [9]. The aim of this study was to evaluate serum AM levels with cytological and/or histological diagnosis of PaC compared to non-cancer controls.…”