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

直到最近，糖尿病主要被分为两种主要形式，1型和2型糖尿病(T2D)，这种分类不能充分反映T2D的复杂性和异质性。2018年，对瑞典一大群糖尿病患者的特征进行了分析。分为五个亚组：重度自身免疫性糖尿病、严重胰岛素缺乏性糖尿病、严重胰岛素抵抗糖尿病、轻度肥胖相关糖尿病和轻度年龄相关糖尿病。这些亚组有不同的糖尿病相关并发症的进展轨迹，这些并发症与不同的临床、代谢和遗传特征有关。糖尿病和IST并发症有一个共同点，即炎症相关的过程参与了它们的发展。我们联盟(德国合作伙伴)最近在德国糖尿病研究中对新近发病的成人糖尿病患者的研究报告显示，炎症生物标记物、白细胞计数和调节性T细胞频率存在差异，这表明炎症反应的失调可能导致特定亚组中T2D的发病。除了这些开创性的观察，对来自法国队列(法国合作伙伴)的723名糖尿病患者的免疫炎症表型的初步分析显示，T2D参与者被细分为3个主要组，具有不同的炎症特征，包括白细胞计数和单核细胞亚型的频率。我们的初步数据支持这样一个概念，即炎症反应的放松控制了T2D亚组的病因。这个T2D亚群中的免疫异常可能涉及调节性T细胞和单核细胞。我们目前的概念验证项目的目标是基于免疫-炎症循环细胞图谱重新定义T2D的分类，并破译控制糖尿病免疫反应的血液免疫细胞(特别是单核细胞和调节性T细胞)之间的相互作用。将研究三个特定和互补的目标：(I)基于免疫-炎症表型对T2D患者亚群进行分层，并确定他们的临床表型；(Ii)研究已确定的T2D免疫簇中单核细胞和调节性T细胞的功能免疫表型；以及(Iii)通过单细胞分析研究不同T2D免疫簇中单核细胞和调节性T细胞亚群。ANR和DFG之间的通话是一个机会，可以协同来自两个国际公认的炎症和T2D研究小组的专业知识，以解决放松炎症管制在T2D的病因和并发症中的重要性。

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.