Inflammatory subgroups defining clinical features in type 2 diabetes – the role of monocytes and regulatory T cells

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Until recently, diabetes was primarily classified into two main forms, type 1 and type 2 diabetes (T2D), a classification that does not adequately reflect the complexity and the heterogeneity of T2D. In 2018 the characteristics of people with diabetes in a large Swedish cohort were analyzed. Five subgroups were distinguished: severe autoimmune diabetes, severe insulin-deficient diabetes, severe insulin-resistant diabetes, mild obesity-related diabetes, and mild age-related diabetes. These subgroups had distinct progression trajectories of diabetes-related complications which were associated with different clinical, metabolic, and genetic traits. Diabetes and ist complications have in common that inflammation-related processes are involved in their development. Recent reports from our consortium (German Partner) in individuals with recent adult-onset diabetes from the German Diabetes Study showed differences in inflammatory biomarkers, leukocyte counts and the frequency of regulatory T cells suggesting that dysregulation of the inflammatory response may contribute to the onset of T2D in specific subgroups. Additionally to these pioneer observations, preliminary analyses of immune-inflammatory phenotyping in 723 people with diabetes from the French cohort (French Partner) revealed that T2D participants were subdivided in 3 main clusters with different inflammatory characteristics including leukocyte counts and frequency of monocyte subtypes. Our preliminary data support the concept that deregulation of the inflammatory response is governing the etiology of a subgroup of T2D. Dysimmunity in this T2D subgroup may involve regulatory T cells and monocytes. The objective of our current proof-of-concept project is to redefine the classification of T2D based on the immune-inflammatory circulating cell profiles and to decipher the interplay between blood immune cells (particularly monocytes and regulatory T cells) governing the immune response in diabetes. Three specific and complementary aims will be studied: (i) To stratify subsets of people with T2D based on immune-inflammatory phenotyping in a large group of patients with T2D and a continuum in the disease progression and to identify their clinical phenotypes; (ii) To investigate the functional immunophenotypes of monocytes and regulatory T cells in the identified T2D-immune clusters, and (iii) To study monocyte and regulatory T cell subpopulations in different T2D-immune clusters by single cell analysis. The call between ANR and DFG is an opportunity to synergize expertise from 2 internationally recognized research groups in inflammation and T2D to address the importance of the deregulation of inflammation in the etiology and complications of T2D.