Diabetes is a complex disease characterized by a combination of different and little understood, causes. The current classification system for the disease characterizes diabetes into three broad types: type 1 diabetes, type 2 diabetes, and gestational diabetes, but these three categories do not adequately reflect its sheer heterogeneity. This has severe negative implications for the planning of treatment regimens and identifying which patients are at risk of developing complications or comorbidities. Building on previous research which identified five novel diabetes subgroups in Scandinavian diabetes patient cohorts, this study sought to comprehensively characterize differences in inflammation biomarkers between these subgroups using Olink’s inflammation biomarker panel.
What are the 5 diabetes subgroups and why could inflammation biomarkers differentiate between them?
Using cluster analysis to analyze data from Scandinavian diabetes patient cohorts, a previous study (find it here) identified the following five diabetes subgroups:
- Severe autoimmune diabetes
- Severe insulin-deficient diabetes
- Severe insulin-resistant diabetes
- Mild obesity-related diabetes
- Mild age-related diabetes
Each subgroup was defined by a distinct progression trajectory of diabetes-related complications related to differences in genetic, clinical, and metabolic factors.
Inflammatory processes play a huge role in complications from diabetes; therefore, it is likely that differences in the levels of these inflammation biomarkers may lead to different complication outcomes. However, to date, there has been little research done on inflammation biomarkers in this context. Using the Olink inflammation biomarker panel, one of the most comprehensive multimarker protein panels available, researchers analyzed 414 individuals with recent-onset diabetes from the German Diabetes Study (GDS) who had been allocated to the above 5 different subgroups. The cross-sectional study also used glucose tolerant individuals as controls.
Researchers then looked at pairwise differences between biomarkers before, and after adjustment for the clustering variables between subgroups, which included age at diagnosis, BMI, and blood sugar levels in the blood (HbA1c test).
Inflammation biomarkers do differentiate between different diabetes subgroups, with varying efficacy
Before adjustment for clustering variables, inflammation biomarker comparison between the five subgroups showed differences in serum levels in 26 out of 74 biomarkers. Biomarker levels were especially high in individuals with severe insulin-resistant diabetes, and lowest in individuals with severe insulin-deficient diabetes. The other three groups showed intermediate levels of inflammation biomarkers.
After adjusting for clustering variables, 13 out of the initial 26 biomarkers were significantly different between the five diabetes subgroups. However, three inflammation biomarkers were particularly pronounced: Casp-8, EN-RAGE, and IL-6. Most differences in serum inflammation biomarker levels were found when comparing individuals with severe insulin-resistant diabetes and those with severe insulin-deficient diabetes, with higher serum levels found in the former subgroup. None of the biomarkers differed after adjustment for the other three subgroups.
Investigation of inflammation biomarkers gives further insight into the pathophysiology of diabetes
The differences in inflammation biomarker profiles in each subgroup complement existing research on the pathophysiology of diabetes. For example, the result that the severe insulin resistance diabetes subgroup showed such high levels of inflammation biomarkers reflects that there is a close relationship between insulin resistance and inflammation evidenced by past studies, especially with regards to obesity. Apart from the high degree of insulin resistance, individuals with this form of diabetes are at higher risk of developing diabetes-related comorbidities. The severe insulin-deficient diabetes subgroup represents the opposite extreme compared to the former subgroup; therefore, it is unsurprising that individuals in this subgroup demonstrated the lowest levels of inflammatory biomarkers compared to the other four subgroups.
Of the 74 inflammation biomarkers for which data was available, significant differences were found for three of them. Casp-8 is a cytosolic cysteine protease that mediates programmed cell death, and in diabetes is involved with B-cell apoptosis. Higher levels of circulating Casp-8 have been associated with a higher risk of type 2 diabetes in previous studies. Higher levels of EN-RAGE have also been linked to type 2 diabetes, as well as incident prediabetes. IL-6 levels have been related to inflammation of adipose tissue but also display pro-inflammatory properties which counteract metabolic stress and insulin resistance. Therefore, IL-6 levels may play different roles in disease progression in the diabetes subgroups, depending on the type.
The researchers conclude that their results demonstrate different inflammation biomarker profiles for the five diabetes subgroups, but further research, especially in a longitudinal cohort, is required to verify the above results as well as determine the extent to which these biomarkers may contribute to differences in diabetes-related complications in the different subgroups.
Read more about this study here.
Herder et al., 2021, Differences in Biomarkers of Inflammation Between Novel Subgroups of recent-onset Diabetes, Diabetes, https://doi.org/10.2337/db20-1054