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Up to 85% of patients with pancreatic cancer have diabetes or hyperglycaemia, which frequently manifests as early as 2–3 years before a diagnosis of pancreatic cancer. Conversely, patients with new-onset diabetes have a 5–8-fold increased risk of being diagnosed with pancreatic cancer within 1–3 years of developing diabetes. Emerging evidence now indicates that pancreatic cancer causes diabetes. As in type 2 diabetes, β-cell dysfunction and peripheral insulin resistance are seen in pancreatic cancer-induced diabetes. However, unlike in patients with type 2 diabetes, glucose control worsens in patients with pancreatic cancer in the face of ongoing, often profound, weight loss. Diabetes and weight loss, which precede cachexia onset by several months, are paraneoplastic phenomena induced by pancreatic cancer. Although the pathogenesis of these pancreatic cancer-induced metabolic alterations is only beginning to be understood, these are likely mechanisms to promote the survival and growth of pancreatic cancer in a hostile and highly desmoplastic microenvironment. Interestingly, these metabolic changes could enable early diagnosis of pancreatic cancer, if they can be distinguished from the ones that occur in patients with type 2 diabetes. One such possible biomarker is adrenomedullin, which is a potential mediator of β-cell dysfunction in pancreatic cancer-induced diabetes.

No single serologic marker is diagnostic of ISD. Serum IgG4 elevation has convincing diagnostic utility when combined with other disease features although its value in disease monitoring may be limited.

Background & Aims The role of trypsinogen activation in pathogenesis of acute pancreatitis (AP) has not been clearly established. Methods We generated and characterized mice with disruption in the gene that encodes trypsinogen7 (T7; T−/− mice), the mouse correlate of human cationic trypsinogen. The effects of pathologic activation of trypsinogen were studied in these mice, during induction of AP with caerulein. Acinar cell death, tissue damage, early intra-acinar activation of the transcription factor NF-κB, and local and systemic inflammation were compared between T−/− and wild-type mice with AP. Results Deletion of T7 reduced the total trypsinogen content by 60%, and resulted in total loss of cationic trypsinogen, but did not affect physiologic function. T−/− mice lacked pathologic activation of trypsinogen, which occurs within acinar cells early during AP progression. Absence of trypsinogen activation in T−/− mice led to near complete inhibition of acinar cell death in vitro and a 50% reduction in acinar necrosis during AP progression. However, T−/− mice had similar degrees of local and systemic inflammation during AP progression, as well as comparable intra-acinar levels of NF-κB activation—which was previously shown to occur concurrently with trypsinogen activation during early stages of pancreatitis. Conclusions T7 is activated during pathogenesis of AP in mice. Intra-acinar trypsinogen activation leads to acinar death during early stages of pancreatitis, which is responsible for 50% of the pancreatic damage in AP. However, progression of local and systemic inflammation in AP does not require trypsinogen activation. NF-κB is activated early in acinar cells, independently of trypsinogen activation, and might be responsible for progression of AP.

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Background and Objectives New-onset diabetes and concomitant weight loss occurring several months before the clinical presentation of pancreatic cancer (PC) appear to be paraneoplastic phenomena caused by tumor-secreted products. Our recent findings have shown exosomal adrenomedullin (AM) is important in development of diabetes in PC. Adipose tissue lipolysis might explain early onset weight loss in PC. We hypothesize that lipolysis-inducing cargo is carried in exosomes shed by PC and is responsible for the paraneoplastic effects. Therefore, in this study we investigate if exosomes secreted by PC induce lipolysis in adipocytes and explore the role of AM in PC exosomes as the mediator of this lipolysis. Design Exosomes from patient derived cell lines and from plasma of PC patients and non-PC controls were isolated and characterized. Differentiated murine (3T3-L1) and human adipocytes were exposed to these exosomes to study lipolysis. Glycerol assay and western blotting were used to study lipolysis. Duolink assay was used to study AM and AM receptor (ADMR) interaction in adipocytes treated with exosomes. Results In murine and human adipocytes we found that both AM and PC-exosomes promoted lipolysis, which was abrogated by AM receptor blockade. AM interacted with its receptor on the adipocytes, activated p38 and ERK1/2 MAPKs and promoted lipolysis by phosphorylating hormone sensitive lipase. PKH67 labeled PC-exosomes were readily internalized into adipocytes and involved both caveolin and macropinocytosis as possible mechanisms for endocytosis. Conclusions Pancreatic cancer secreted exosomes induce lipolysis in subcutaneous adipose tissue; exosomal adrenomedullin is a candidate mediator of this effect.

Purpose of review The pathogenesis of acute pancreatitis (AP) is still not well understood. This articles reviews recent advances in our understanding of AP with emphasis on literature published during the last year. Recent Findings Zymogen activation was shown to be sufficient to induce AP. Another key early event, NFkB activation has previously been shown to induce AP. The relationship between these two key early steps is beginning to be clarified. The mechanisms responsible for zymogen activation- pathologic calcium signaling, pH changes, colocalization and autophagy; mechanisms of NFkB activation and potential therapeutic targets both upstream and downstream of these key events have been explored. Additional key findings have been elucidation of the dual role of oxidative stress in AP and role of bioenergetics in determining mode of cell death, recognition of endoplasmic reticulum stress as an early step and duct cells as important players in pancreatic injury. Summary Current findings have provided further insight into the roles and mechanisms of zymogen activation and inflammatory pathways in pancreatic injury. Future studies are being undertaken to establish the relative contributions of these pathways during acute pancreatitis which will be critical to identifying successful therapeutic targets.

Purpose of review In this article, we review important advances in our understanding of the mechanisms of pancreatitis. Recent Findings The relative contribution of intra-pancreatic trypsinogen activation and NFκB activation, the two major early independent cellular events in the etiology of pancreatitis, have been investigated using novel genetic models. Trypsinogen activation has traditionally held the spotlight for many decades as it is believed to be the central pathogenic event of pancreatitis However, recent experimental evidence points to the role of trypsin activation in early acinar cell damage but not in the inflammatory response of acute pancreatitis through NFκB activation. Further, chronic pancreatitis in the caerulein model develops independently of typsinogen activation. Sustained activation of the NFκB pathway, but not persistent intra-acinar expression of active trypsin, was shown to result in chronic pancreatitis. Calcineurin-NFAT signaling was shown to mediate downstream effects of pathologic rise in intracellular calcium. IL-6 was identified as a key cytokine mediating pancreatitis-associated lung injury. Summary Recent advances challenge the long-believed trypsin-centered understanding of pancreatitis. It is becoming increasingly clear that activation of intense inflammatory signaling mechanisms in acinar cells is crucial to the pathogenesis of pancreatitis, which may explain the strong systemic inflammatory response in pancreatitis.