Impact of Antidiabetic Medications on IgG and Plasma Protein N-Glycosylation in Type 2 Diabetes Patients
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Introduction
Diabetes is a growing global health challenge, necessitating effective management strategies. Glycosylation, a highly regulated post-translational protein modification, has emerged as a pivotal factor in diabetes pathophysiology. However, the modulation of protein glycosylation by antidiabetic treatment is still largely unknown. This study explored the longitudinal effects of four distinct antidiabetic therapies – metformin, insulin, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and glucagon-like peptide-1 receptor agonists (GLP-1RA) – on plasma protein and immunoglobulin G (IgG) glycosylation in patients with type 2 diabetes (T2D).
Research Design and Methods
Plasma protein and IgG N-glycans were enzymatically released, purified and chromatographically profiled in a cohort of 124 patients, examined at four time points, to assess therapy-induced glycan alterations. Linear mixed models adjusting for covariates and multiple testing (FDR<0.05) were used to investigate the associations between plasma protein and IgG N-glycosylation and antidiabetic therapy.
Results
Our findings reveal that metformin, SGLT2 inhibitors, and GLP-1RA induce significant alterations in IgG glycosylation, including the increased core fucosylation and galactosylation, features associated with a reduced inflammatory IgG potential. Notably, IgG monogalactosylation, previously linked to cardioprotective effects in women, was elevated in response to GLP-1RA and SGLT2 inhibitor treatments. Plasma protein glycosylation changes were more limited, with distinct alterations observed for each therapy. Metformin and GLP-1RA similarly reduced certain fucosylated and sialylated glycans, while SGLT2 inhibitors decreased a high-mannose glycan, previously positively associated with diabetes progression. Insulin therapy had a minimal effect on protein glycosylation, with only one plasma glycan significantly altered.
Conclusions
Our findings emphasise the importance of protein glycosylation as a dynamic and responsive marker in T2D treatment. The distinct glycan alterations observed in response to metformin, SGLT2 inhibitors, and GLP-1 receptor agonists provide novel insights into the molecular effects of these therapies, potentially contributing to the development of glycan-based biomarkers for personalized diabetes management.
What is already known on this topic?
Protein glycosylation is known to regulate multiple processes related to glucose homeostasis.
Previous studies have shown that the IgG and plasma protein N-glycome (the entire set of N-glycans covalently attached to the IgG and plasma proteins, respectively) can help identify individuals at increased cardiometabolic risk.
Despite most T2D patients receiving antidiabetic treatment, research on its effects on protein glycosylation remains scarce.
What this study adds?
It is the first study to explore the effects of SGLT2 inhibitor and GLP-1RA therapy on protein glycosylation.
The cardioprotective effects of these drug classes were also reflected in IgG glycosylation, demonstrated by increased monogalactosylation.
Metformin, SGLT2 inhibitors, and GLP-1RA induce significant increase in IgG core fucosylation, a feature associated with reduced inflammatory IgG potential, possibly suggesting a shared pathway in suppressing inflammatory response.
How this study might affect research, practice or policy?
The observed alterations in protein glycosylation across different therapeutic groups highlight its dynamic nature in response to metabolic interventions.
Given the role of glycans in modulating immune function and inflammation, these findings suggest that glycan alterations could serve as potential biomarkers for assessing therapeutic response and disease progression in T2D.
Future studies involving protein glycosylation should account for the potential confounding effects of antidiabetic medications to ensure accurate interpretations.
