Pancreatic Cancer-Related Diabetes and Type 2 Diabetes Differ in Multiple Aspects of Glucose Homeostasis

Authors

Frederico G S Toledo
Yisheng Li
Fuchenchu Wang
Melena D Bellin
Randall Brand
Kenneth Cusi
William Fisher
Yogish C Kudva
Walter G Park
Zeb I Saeed
Dhiraj Yadav
Robert V Considine
Sarah C Graham
Dana K Andersen
Jose Serrano
Mark O Goodarzi
Phil A Hart

Language

English

Publication Date

12-1-2025

Journal

Diabetologia

DOI

10.1007/s00125-025-06543-y

PMID

40991017

PMCID

PMC12579526

PubMedCentral® Posted Date

11-2-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Aims/hypothesis: Pancreatic ductal adenocarcinoma-related diabetes mellitus (PDAC-DM) is a paraneoplastic syndrome with a poorly understood pathophysiology. PDAC-DM is often clinically confused with type 2 diabetes, resulting in delayed cancer detection and poorly individualised hyperglycaemia treatment. We investigated whether these forms of diabetes can be distinguished at the metabolic level.

Methods: Adults with either cancer treatment-naive PDAC-DM (n=28) or type 2 diabetes (n=97), and with diabetes onset within 3 years, underwent mixed-meal tolerance tests to investigate glucose metabolism. Outcomes included insulin sensitivity (Matsuda index), insulin secretion (insulinogenic index), beta cell function (oral disposition index), insulin clearance, and postprandial glucagon, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) responses.

Results: Compared with type 2 diabetes, individuals with PDAC-DM showed ~2.5-fold greater insulin sensitivity, ~81% lower insulin secretion and ~40% lower beta cell function. Insulin clearance was higher in the PDAC-DM group than the type 2 diabetes group, with and without adjustment for insulin sensitivity. Glucagon and GLP-1 levels increased after a meal in both groups, but levels were higher in the PDAC-DM group. GIP levels were similar between groups. The metabolic differences between groups persisted after adjustment for age, sex and BMI.

Conclusions/interpretation: PDAC-DM and type 2 diabetes are metabolically distinct, with different defects responsible for hyperglycaemia. PDAC-DM is characterised predominantly by insulin deficiency and displays higher insulin sensitivity than type 2 diabetes. There are also differences in alpha cell regulation and insulin clearance compared with type 2 diabetes. These findings identify biological characteristics that may have implications for individualised treatment of PDAC-DM and guide diagnostic biomarker discovery for early PDAC diagnosis.

Keywords

Humans, Diabetes Mellitus, Type 2, Male, Female, Pancreatic Neoplasms, Middle Aged, Aged, Insulin, Blood Glucose, Glucagon-Like Peptide 1, Insulin Resistance, Glucagon, Homeostasis, Gastric Inhibitory Polypeptide, Insulin-Secreting Cells, Carcinoma, Pancreatic Ductal, Glucose Tolerance Test, Insulin Secretion, Adult, Diabetes, Insulin secretion, Pancreatic cancer, Pancreatic ductal adenocarcinoma

Published Open-Access

yes

Recommended Citation

Toledo, Frederico G S; Li, Yisheng; Wang, Fuchenchu; et al., "Pancreatic Cancer-Related Diabetes and Type 2 Diabetes Differ in Multiple Aspects of Glucose Homeostasis" (2025). Faculty, Staff and Student Publications. 6099.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6099