Endocrine dysfunction in pancreatic cancer

Over the past 15 years we have studied the intricate, multidirectional association between DM and PC with a goal to developing a rational, evidence-based strategy to detect pre-symptomatic sporadic PC. We have shown that 80% of PC patients have hyperglycemia and 50-65% of patients have DM, majority of which is late-onset. Conversely, we have shown that compared to the general population, subjects with late-onset DM are 8-times more likely to have PC within 3 years of onset of DM. A series of studies by our group and others have now established that PC causes a paraneoplastic DM. We have focused our attention on studying the mechanism of PC-induced DM as it holds the key to identifying novel biomarkers that will distinguish PC-DM from usual type 2 DM. These studies have resulted in the identification of AM as a candidate mediator of PC-DM. We found tissue AM overexpression in PC, more so in PC-DM. We have shown that AM and PC-conditioned media inhibit glucose-stimulated insulin secretion from β cells. Further, plasma AM levels are higher in PC, especially PC-DM, compared to controls. We have observed that PC sheds nanoparticle-sized exosomes. PC-exosomes are abundantly present in PC-conditioned media and in portal and peripheral venous blood of patients with PC; exosomes from both sources contain AM. PC-exosomes from both sources readily enter β cells and inhibited insulin secretion through AM-mediated effects. In a recent editorial on our work, PC-DM was called an "Exosomopathy", the first disease to be caused by exosomes.

Based on over a decade of work we launched the first prospective screening study for sporadic pancreatic cancer in subjects with new-onset DM (EXPAND Trial) (NCT02001337). In this study we identify subjects with late-onset DM and screen those with weight loss or elevated tumor marker CA 19-9 for PC using CT scan and endoscopic ultrasound. This study will now be expanded to an NIH-funded nation-wide multi-center study called the New-onset Diabetes (NoD) Study supported by a 10-center Chronic Pancreatitis, Diabetes and Pancreatic Cancer (CPDC) Consortium. Based on lessons learned from past studies, we are now working on biomarkers that will distinguish the more common type 2 diabetes from diabetes due to PC. We are currently focusing on markers in exosomes from PC. If successful, these biomarkers would be incorporated into the NoD study.