# Impaired insulin secretion via the Wnt5a/β-catenin pathway contributes to diabetes development in pancreatic cancer

## TL;DR

Pancreatic cancer patients often develop diabetes due to a disrupted Wnt5a/β-catenin pathway that impairs insulin production, offering new insights into the condition.

## Contribution

The study identifies the Wnt5a/β-catenin pathway as a novel mechanism linking pancreatic cancer and diabetes.

## Key findings

- Patients with pancreatic cancer showed impaired insulin secretion and severe hyperglycemia before surgery.
- Wnt5a levels in blood and β-catenin in pancreatic islets correlated with hyperglycemia and tumor size.
- Inhibiting β-catenin reversed Wnt5a's suppression of insulin release in rodent islets.

## Abstract

Diabetes is highly prevalent in individuals with pancreatic ductal adenocarcinoma (PDAC) and even precedes diagnosis of PDAC; however, the mechanisms of pancreatic cancer-associated blood glucose deterioration remain largely unknown. Here, we constructed a prospective cohort of patients undergoing pancreatectomy to investigate the underlying mechanism of PDAC-associated hyperglycemia. A total of 160 patients who underwent pancreatectomy (72 patients with PDAC and 88 patients without PDAC) were enrolled at a tertiary care hospital. Glucometabolic parameters under oral glucose tolerance test were assessed in both pre- and postoperative periods, and patient-derived blood and pancreatic tissue samples were collected. Compared with patients without PDAC, patients with PDAC showed severe hyperglycemia with impaired insulin secretion before surgery. However, despite identical type of pancreatectomy in both groups, hyperglycemia improved more significantly and insulin secretory function declined less after pancreatectomy in patients with PDAC. Plasma Wnt5a and pancreatic islet β-catenin levels were higher in patients with PDAC and correlated with the degree of hyperglycemia and insulin deficiency. Plasma Wnt5a levels also correlated with tumor size and pancreatic islet β-catenin expression in patients with PDAC. In rodent islets, Wnt5a treatment suppressed insulin release, which was recovered by inhibition of β-catenin. Collectively, impaired pancreatic insulin secretion by aberrant Wnt5a/β-catenin activation may underlie the hyperglycemia associated with PDAC. Our finding provides insights into the unique molecular mechanism of pancreatic cancer-associated hyperglycemia, paving the way for the identification of potential biomarker and therapeutic targets for this condition.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with low survival. Many patients with PDAC also develop diabetes, but the connection between the two is still unclear. Researchers aimed to explore this link by studying 160 patients, including those with PDAC and those without PDAC, who had surgery to remove part of their pancreas. The study involved measuring blood sugar and insulin levels before and after surgery. Patients with PDAC had higher blood sugar levels and lower insulin production than those without PDAC before surgery. After the surgery, patients with PDAC showed greater improvement in blood sugar control and a smaller decrease in insulin secretion than patients without PDAC. A protein called Wnt5a secreted by cancer was higher in patients with PDAC and might be linked to reduced insulin production. This protein could serve as a marker for early detection of PDAC-related diabetes.

This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.