Paraneoplastic β Cell Dedifferentiation in Nondiabetic Patients with Pancreatic Cancer

Abstract

Context Beta-cell dedifferentiation was recently proposed as a mechanism of β-cell dysfunction, but whether it can be a trigger of β-cell failure preceding hyperglycemia in humans is uncertain. Pancreatic cancer can cause new-onset diabetes, yet the underlying mechanism is unknown. Objective To investigate whether β-cell dedifferentiation is present in nondiabetic pancreatic ductal adenocarcinoma (PDAC) patients, we examined pancreatic islets from 15 nondiabetic patients with benign tumors (control) and 15 nondiabetic PDAC patients. Design We calculated the number of hormone-negative endocrine cells and evaluated important markers of β-cell dedifferentiation and function in the paraneoplastic islets. We assessed tumor-related inflammatory changes under the pancreatic cancer microenvironment and their influence on β-cell identity. Results We found nearly 10% of nonhormone expressing endocrine cells in nondiabetic PDAC subjects. The PDAC islets were dysfunctional, evidenced by low expression of Glucose transporter 2 (GLUT2) and Urocortin3 (UCN3), and concomitant upregulation of Aldehyde Dehydrogenase 1 Family Member A3 (ALDH1A3) expression and proinsulin accumulation. Pancreatic cancer caused paraneoplastic inflammation with enhanced tissue fibrosis, monocytes/macrophages infiltration, and elevated inflammatory cytokines. Moreover, we detected β-cell dedifferentiation and defects in GSIS in islets exposed to PANC-1 (a cell line established from a pancreatic carcinoma of ductal origin from a 56-year-old Caucasian male)-conditioned medium. In a larger cohort, we showed high prevalence of new-onset diabetes in PDAC subjects, and fasting blood glucose (FBG) was found to be an additional useful parameter for early diagnosis of PDAC. Conclusions Our data provide a rationale for β-cell dedifferentiation in the pathogenesis of pancreatic cancer–associated diabetes. We propose that β-cell dedifferentiation can be a trigger for β-cell failure in humans, before hyperglycemia occurs.

A Brief Review of the Mechanisms of β-Cell Dedifferentiation in Type 2 Diabetes

“…Wang et al, demonstrated that cyclooxygenase-2/prostaglandin E2 (COX-2/PGE2) signaling was involved in the regulation of IL-1β autostimulation in β-cells and inhibition of COX-2 activity prevented IL-1β induced β-cell dysfunction [ 45 ]. Similar to a previous study [ 24 ], a recent study using islets from nondiabetic patients with benign tumors directly proved that β-cell dedifferentiation can be triggered prior to hyperglycemia indicating that inflammation may directly induce β-cell dedifferentiation [ 46 ]. In mouse islets exposed to non-cytotoxic concentrations of IL-1β, the expression of key β-cell identity genes (e.g., MafA and Ucn3 ) decreased with a reduction in their transcription activities, as shown by a decrease in H3K27 acetylation, suggesting that inflammatory cytokines directly affect the epigenome [ 47 ].…”

The Intricate Crosstalk Between Insulin and Pancreatic Ductal Adenocarcinoma: A Review From Clinical to Molecular

“…Interestingly, hyperinsulinemia caused by pancreatic cancer might not effectively lower peripheral blood glucose levels. PDA produces multiple factors to inhibit glucose sensitivity in pancreatic islet beta cells which finally leads to a delayed insulin secretion peak ( Tan et al, 2014 ; Parajuli et al, 2020 ; Wang et al, 2020 ). As a result, hyperinsulinemia couldn’t effectively control blood glucose levels in pancreatic cancer patients.…”

Importance of Intestinal Environment and Cellular Plasticity of Islets in the Development of Postpancreatectomy Diabetes

“…Increased levels of ALDH1A3 in islets are thought to be a marker of b-cell failure (8), and ALDH1A3 is reported to be abundantly expressed in the islets of patients with chronic pancreatitis and without diabetes (35). Furthermore, a recent study in patients without diabetes revealed that islet ALDH1A3 expression is increased in patients with pancreatic ductal adenocarcinomas compared with those with benign tumors (36). Taken together, the findings indicate that a substantial number of islet endocrine cells may gain cellular plasticity and thus express ALDH1A3 and that inflammation may trigger ALDH1A3 expression even during the very early stages of diabetes development.…”