New insights into pancreatic cancer-induced paraneoplastic diabetes

Abstract

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.

A clinical prediction model to assess risk for pancreatic cancer among patients with new-onset diabetes.

“…18 Such PDA-associated diabetes may be a paraneoplastic phenomenon caused by the cancer rather than a result of direct destruction by PDA and loss of normal pancreatic tissue. 20,21 Frequent resolution of diabetes mellitus after resection of the tumor provides further evidence for such reverse causality. 13 These data and computational models featuring phylogenetic analysis of pancreatic tumors in the same host suggest that the onset of diabetes mellitus may precede the clinical identification of metastatic spread, in at least some cases.…”

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

“…Accumulating evidence suggests that some circulating proteins or cytokines secreted by the tumor cells may exert a para-neoplastic effect on islets, and cause insulin resistance and β-cell dysfunction, which results in new-onset diabetes in patients with PaC (7).…”

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

“…It is physiologically produced by human organism [16] but its secretion increases in multiple pathological conditions, such as endothelial damage, heart failure, hypertension, renal failure, sepsis and hypoxia [17,18]. 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].…”

“…This urge to seek new diagnostic markers led us to investigate the role of Adrenomedullin in PaC. The interest for AM arises from recent studies that investigated PaCDM mediators [12][13][14]. AM is a 52-amino acid peptide discovered in 1993 [15].…”