Protein biomarkers for the future development of dysglycaemia, insulin resistance, and beta cell dysfunction

Other conference contribution, 2025

Background and aims: Dysglycaemia, including type 2 diabetes, impaired fasting glucose, and impaired glucose tolerance arises from a complex interplay between insulin resistance and beta cell dysfunction. This study aimed to identify plasma proteins predictive of incident dysglycemia and to examine their association with future insulin sensitivity and beta cell function, thereby elucidating potential pathophysiological pathways leading to type 2 diabetes.
Materials and methods: In a nested case-control study within the Swedish CArdioPulmonary bioImage Study cohort, we used a targeted proteomics
approach (Olink Target 96 Cardiovascular II and III panels) to identify plasma proteins that predicted the development of dysglycaemia compared
to those remaining normoglycaemic using logistic regression and applying a false discovery rate threshold of 0.05. Further, quantile regression was performed to identify proteins associated with insulin sensitivity (Matsuda index) and beta cell function (oral disposition index) at follow-up.
Results: After a median follow-up of 18.2 years (25-75 th percentile: 10.7-23.5), 347 subjects developed dysglycaemia and were matched by age, sex and BMI with 347 control subjects who remained normoglycaemic. Ten plasma proteins predicted incident dysglycemia: fatty acid binding protein 4 (FABP4), fibroblast growth factor 21 (FGF-21), galectin-3, galectin-4, galectin-9, interleukin-1 receptor antagonist protein (IL-1ra), LDL receptor, P-selectin glycoprotein ligand 1, retinoic acid receptor responder protein 2 (RARRES2) and tissue-type plasminogen activator (t-PA). Conversely, lower levels of insulin-like growth factor-binding protein 2 (IGFBP-2) and paraoxonase 3 (PON3) were associated with an increased risk of dysglycaemia. Among these proteins, RARRES2 was linked to lower beta cell function at follow-up, while FABP4, FGF-21, IL-1ra, PON3 and t-PA were associated with lower future insulin sensitivity. In contrast, IGFBP-2 and PON3 correlated with higher future insulin sensitivity.
Conclusion: This study validates prior cross-sectional findings on protein biomarkers associated with type 2 diabetes and established their predictive role in the development of dysglycaemia. Additionally, eight proteins were identified as key regulators of insulin resistance and beta cell dysfunction, providing novel insights into type 2 diabetes pathophysiology. These findings offer potential targets for early risk assessment and therapeutic intervention.