Immunopathology

Inflammation and type 2 diabetes: from basic science to treatment

Treatment of type 2 diabetes by targeting interleukin-1: a meta-analysis of 2921 patients Abstract With obesity and type 2 diabetes prevalence steadily increasing and no effective means in sight to support the population in obtaining and maintaining stable weight loss, there is an imminent need for pharmacological therapy to treat and prevent type 2 diabetes. Current anti-diabetic treatment is symptomatic, and very few drugs have both a strong preclinical rationale and clinical proof-of-principle as therapies targeting pathogenic processes in type 2 diabetes. The emerging appreciation of low-grade inflammation as a significant cause of insulin resistance and beta cell failure warrants exploring anti-inflammatory compounds as drug candidates. Since recent studies have demonstrated considerable phenotypic heterogeneity in the type 2 diabetic syndrome, the concept of one drug fits all is naïve, and biomarkers for the selection of type 2 diabetes subtypes for differentiated treatment based on genetic and pathogenic stratification are urgently needed. Biologics antagonizing the master pro-inflammatory cytokine interleukin-1 is one of the few principles specifically targeting low-grade inflammation in type 2 diabetes. Although early phase II studies were encouraging, subsequent underpowered studies and phase III studies designed primarily with cardiovascular endpoints have discredited the potential of anti-interleukin-1 approaches to treat the subgroup of patients that may benefit from this treatment. In this meta-analysis of 2921 individuals from eight phase I–IV studies, we demonstrate a significant overall HbA1c-lowering effect of interleukin-1 antagonism. Meta-regression analyses demonstrated a significant correlation between baseline C-reactive protein and C-peptide, and HbA1c outcome. The identification of further biomarkers for future clinical trials to define the potential of anti-interleukin-1 therapies in type 2 diabetes is urgently needed.

The role of inflammation in diabetic eye disease Abstract Mounting evidence suggests that immunological mechanisms play a fundamental role in the pathogenesis of diabetic retinopathy (DR) and diabetic macular edema (DME). Upregulation of cytokines and other proinflammatory mediators leading to persistent low-grade inflammation is believed to actively contribute to the DR-associated damage to the retinal vasculature, inducing breakdown of the blood-retinal barrier, subsequent macular edema formation, and promotion of retinal neovascularization. This review summarizes the current knowledge of the biological processes providing an inflammatory basis for DR and DME. In addition, emerging therapeutic approaches targeting inflammation are discussed, including blockade of angiopoietin 2 and other molecular targets such as interleukin (IL)-6, IL-1β, plasma kallikrein, and integrins.

Chronic low-grade inflammation in polycystic ovary syndrome: is there a (patho)-physiological role for interleukin-1? Abstract The polycystic ovary syndrome (PCOS) is a frequent endocrine disorder in women of reproductive age. Its main characteristics are the ovarian overproduction of androgens and ovulatory dysfunction which lead to severe symptoms such as hirsutism, acne, insulin resistance, and infertility. Despite the frequency and disease burden of PCOS, its underlying causes remain unknown, and no causal therapeutic options are available. In recent years, several studies have shown that women with PCOS present with chronic low-grade inflammation indicating an overactivity of the pro-inflammatory cytokine interleukin-1 (IL-1). We show here how IL-1 might affect the ovarian physiology and pathophysiology in animals and humans by reviewing experimental studies on ovarian IL-1 system gene expression and on the effects of exogenous IL-1 on ovarian functions. Although IL-1 ligands and receptors are expressed within the ovarian cells, IL-1 seems to negatively affect the delicate balance between the sex hormones and dominant follicle development, as well as fertility. Whether blockade of the IL-1 signaling leads to an improvement of PCOS-related hormonal abnormalities and symptoms remains to be elucidated in future interventional studies.

The role of interleukin-6 in glucose homeostasis and lipid metabolism Abstract Low-grade inflammation is recognized as an important factor in the development and progression of a multitude of diseases including type 2 diabetes mellitus and cardiovascular disease. The potential of using antibody-based therapies that neutralize key players of low-grade inflammation has gained scientific momentum as a novel therapeutic strategy in metabolic diseases. As interleukin-6 (IL-6) is traditionally considered a key pro-inflammatory factor, the potential of expanding the use of anti-IL-6 therapies to metabolic diseases is intriguing. However, IL-6 is a molecule of a very pleiotropic nature that regulates many aspects of not only inflammation but also metabolism. In this review, we give a brief overview of the pro- and anti-inflammatory aspects of IL-6 and provide an update on its role in metabolic regulation, with a specific focus on glucose homeostasis and adipose tissue metabolism. Finally, we shall discuss the metabolic implications and clinical potential of blocking IL-6 signaling, focusing on glucose homeostasis and lipid metabolism.

Subclinical inflammation and depressive symptoms in patients with type 1 and type 2 diabetes Abstract Depression is a frequent comorbidity of type 1 diabetes (T1D) and type 2 diabetes (T2D). Depression and diabetes are linked by a bidirectional relationship, but the underlying mechanisms are still incompletely understood. Experimental, observational and intervention studies showed that inflammatory processes contribute to the development of depression in animal models and humans. Given the high risk of morbidity and mortality in patients with the double burden of diabetes and depression, this review provides an overview of epidemiological studies that addressed the relationship between biomarkers of inflammation and depressive symptoms or depression in diabetes patients. In patients with T1D, there is some evidence that higher levels of high-sensitivity C-reactive protein (hsCRP), IL-6, IL-1 receptor antagonist (IL-1RA) and sICAM-1 may be related to depressive symptoms or (for hsCRP) lower treatment response. For T2D, hsCRP, IL-1RA, CCL2 and adiponectin or its isoforms were associated with depressive symptoms in at least two studies, whereas positive associations of IL-1β, IL-6 and IL-18 with depressive symptoms or depression were reported from single cohorts. However, the number of studies is too low for any meaningful meta-analysis. Prospective life course studies including both patients with T1D and T2D, a comprehensive assessment of systemic inflammation and repeated assessment of depressive symptoms should represent a future research priority to clarify to what extent subclinical inflammation affects the risk of depression in patients with diabetes. A better understanding of the role of inflammatory processes may help to identify subtypes of depression with partly different pathogenesis, which could have consequences with respect to therapeutic options including immunomodulation.

Impact of bariatric surgery on type 2 diabetes: contribution of inflammation and gut microbiome? Abstract Obesity is a chronic low-grade inflammatory disease (both at the systemic and adipose tissue level) that continues to rise worldwide. It is associated with an abundance of comorbidities, including type 2 diabetes (T2D). Bariatric surgery, which induces modifications of the intestinal tract, is to date the most successful treatment for obesity. Its use has dramatically increased in number as it enables both weight reduction and metabolic improvements, with 60% of patients even achieving diabetes remission. Several mechanisms are actually demonstrated to be involved in those clinical improvements. Importantly, both obesity and T2D share many phenotypic characteristics, including increased systemic and adipose tissue inflammation, as well as gut microbiota dysbiosis. These characteristics are deeply modulated after bariatric surgery. This review will address the host metabolic changes observed after bariatric surgery, focusing on the induced gut architectural changes, as well as on the modifications of the inflammatory tone and the gut microbiota.

Islet inflammation in type 2 diabetes Abstract Metabolic diseases including type 2 diabetes are associated with meta-inflammation. β-Cell failure is a major component of the pathogenesis of type 2 diabetes. It is now well established that increased numbers of innate immune cells, cytokines, and chemokines have detrimental effects on islets in these chronic conditions. Recently, evidence emerged which points to initially adaptive and restorative functions of inflammatory factors and immune cells in metabolism. In the following review, we provide an overview on the features of islet inflammation in diabetes and models of prediabetes. We separately emphasize what is known on islet inflammation in humans and focus on in vivo animal models and how they are used to elucidate mechanistic aspects of islet inflammation. Further, we discuss the recently emerging physiologic signaling role of cytokines during adaptation and normal function of islet cells.

Transcriptional control of macrophage polarisation in type 2 diabetes Abstract Type-2 diabetes (T2D) is considered today as an inflammatory disease. Inflammatory processes in T2D are orchestrated by macrophage activation in different organs. Macrophages undergo classical M1 pro-inflammatory or alternative M2 anti-inflammatory activation in response to tissue microenvironmental signals. These subsets of macrophages are characterised by their expression of cell surface markers, secreted cytokines and chemokines. Transcriptional regulation is central to the polarisation of macrophages, and several major pathways have been described as essential to promote the expression of specific genes, which dictate the functional polarisation of macrophages. In this review, we summarise the current knowledge of transcriptional control of macrophage polarisation and the role this plays in development of insulin resistance.

Role of innate immune cells in metabolism: from physiology to type 2 diabetes Abstract Growing evidence suggests that components of the innate immune system play a crucial role in regulating metabolic homeostasis. Macrophages were the primary immune cells to be described in both the white adipose tissue and the pancreatic islets. Therein, their functions, beneficial or detrimental, are extending under steady state and in the context of obesity-induced type 2 diabetes. Other populations, including innate lymphoid cells, are emerging as key sentinels of metabolic tissues and privileged partners of macrophages. The present review will thus explore the phenotype and the role of innate immune cells in metabolic physiology and dysfunction. Discussion will tackle pending questions and future perspectives in the field of immunometabolism.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com