The Contribution of BMI to a Young Child's Risk of Islet Autoimmunity Is Dependent on HLA-DR4-DQ8 Without HLA-DR3-DQ2

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.