Diabetes: An Inflammatory Disease, where do we stand?
Inflammation and Diabetes – General Perspective
Human bodies have evolved inflammation mechanisms to fight infection and heal the damage caused by internal or external stimuli. The normal inflammatory response is determined by key factors like perturbed energy status that is prevalent in state of obesity. In addition, individuals with obesity are known to have lipid abnormalities, such as elevated serum triacylglycerols, very low density lipoprotein, apolipoprotein B, and non-high density lipoprotein cholesterol, which can all substantially accelerate inflammatory pathways (1). Inflammatory and metabolic pathways are dependent on one another and under certain conditions, such as malnourishment, this relationship can be compromised. In last 10-15 years, investigators have noticed chronic metabolic overload (i.e. high-sugar diets) in certain individuals has caused aberrant activation of numerous inflammatory pathways that can lead to fatal outcomes in obesity-associated syndromes (2).
Diabetes is a complex metabolic disorder and elevated blood glucose level is the most common causative factor responsible for multiple organ failure, which can involve the retina, kidneys, nerves, heart, and blood vessels. Conventionally, diabetes falls under two major categories: type 1 (T1D) and type 2 (T2D). In T1D, an autoimmune response is responsible for the targeted killing of pancreatic beta cells. Pancreatic beta cells are required for controlling blood glucose levels by secreting stored insulin in the blood and increasing its production. Thus, loss of functional beta cells results in increases in blood glucose concentrations.
Throughout the 2000’s, T2D has become the most prevalent form of chronic hyperglycemia or hyperlipidemia. T2D is prominently a manifestation of western lifestyle, lack of physical activity, and over nourishment with foods high in glycemic index. However, recent research data has suggested that unregulated accentuation of inflammatory pathways are central in the pathogenesis of obesity mediated organ failure.
Role of Inflammation in Pathophysiology of Type 1 Diabetes
The role of tumor necrosis factor-alpha (TNF-alpha) in obesity mediated inflammation was discovered in early 1990 (3). Increased levels of TNF-α are directly correlated with amount of adipose tissue and it plays pivotal role in development of progression of T1D. Acute phase reactants including fibrinogen, C-reactive protein, IL-6, plasminogen activator inhibitor-1, and sialic acid are known to be elevated in the serum of individuals in a diabetic state. In recent years, there has been an increased interest in understanding and researching the role of inflammation in the progression of diabetes. Prominent inflammatory molecules, such as interleukins 6, 10, 17, 23, 1β are involved in exacerbation of pathophysiology of diabetes. These proinflammatory cytokines have been identified as potential biomarkers and used as therapeutic targets to limit the progression of diabetes and its related disorders (Figure 1).
T1D is a well characterized autoimmune disorder. It is a T cell mediated autoimmune disorder which results in the killing of pancreatic beta cells. T cells can generally be categorized into two main subsets: regulatory T cells (Tregs) and effector T cells (Teffs). Balance in the level of these two types of cells is very important for immune homeostasis. Imbalance in the activity of Teffs and Tregs is the prominent cause of T1D. As the name suggests, Tregs have role in regulating other cells in immune system. Tregs regulate immune response to self and foreign antigens, therefore protecting against autoimmune diseases. Destruction of pancreatic beta cells is mainly an attribute of pathogenic autoreactive Teffs, but apparent failure of Tregs to counterbalance the activity of Teffs leads to development of T1D. It is still unclear what prompts release of beta cells autoantigens (endogenous beta cells defects or exogenous viral infection); regardless of factors, CD4+ T cells in pancreatic lymph nodes proliferate and differentiate to become CD4+ Teffs that specifically respond to beta cell autoantigens. Within pancreas, autoreactive CD4+ Teffs release cytokines including IFN-γ, IL-1β, TNF-α, which result in recruitment of macrophages and CD8+T lymphocytes.
Cytotoxic inflammatory cells infiltrate and damage the islets of pancreas in a process called “insulitis”. In addition, chemokine released from damaged beta cells accentuate further mononuclear cell recruitment, increase burst of inflammation, and exacerbate oxidant stress further injuring pancreatic beta cells. In addition to CD4+ cells, both CD8+ T cells and CD20+ B cells are also involved in the progression of diabetes (4). Interestingly, invariant natural killer T (iNK) cells demonstrated protective effect against T1D in mouse models by increasing the secretion of IL-4. However, their clinical relevance is questionable as iNKT cells represents less than 0.1% of total peripheral blood lymphocytes (5).
Recent Clinical Trials on Type 1 Diabetes Targeting Inflammatory Pathways
Given the impact of inflammatory pathways and potential molecules that are involved in pathophysiology of T1D, it has become increasingly important to curatively target inflammatory pathways for preserving the functions of remaining beta cells. Rituximab, a monoclonal antibody targeting CD20+ cells were found to be partially successful (6, 7). A plasmid vaccine containing a transgene that encodes proinsulin has been described and has shown very encouraging results. Interestingly, the mechanism of action in a proinsulin vaccination is to induce tolerance to proinsulin to help prevent future autoimmune reactions against insulin (8). With the usage of antigen (pro-insulin) specific vaccine, we can reduce immune response against insulin in individuals with T1D, while leaving other immune cells intact maintaining immune regulatory functions of the body. A patient with newly diagnosed T1D was reported to have significantly reduced loss of β cell functioning when treated with teplizumab and otelixizumab (anti-CD3 monoclonal antibodies) (9).
Cytokine blocking therapies are promising for patients with T1D. Etanercept (anti-TNF alpha) has shown improved endogenous insulin production and controlled metabolism. IL-1β is a master cytokine that regulates many other proinflammatory cytokines such as TNF-α and IL-6. IL-1β contributes to apoptosis and beta cell functioning impairment by enhancing the production of cytokines, chemokines and local attraction of macrophages. In view of this, alpha anti-trypsin is a known anti-inflammatory serum protein has shown to reduced production of IL-1β in circulating monocytes, hence improved β-cell functioning (10). The anti-inflammatory role of vitamin D is ambiguous because of its limited effect on sustaining beta cell protection (11). Canakinumab (IL-1 receptor antagonist) and anakinra (human monoclonal IL-1β) were not found to be effective in maintaining endogenous insulin production (12). Presently, Salsalate (NCT02936843) and Difluoromethylornithine (DFMO) (NCT02384889) are currently being tested in clinical trials.
Role of Inflammation in Progression of Type 2 Diabetes
T2D was initially characterized by insulin resistance and followed by the inability of the pancreas to respond to an increased insulin demand, eventually rendering beta cells incapable of secreting insulin. T2D is a manifestation of excess consumption of glucose dense diets, typically in individuals with obesity. Imbalance in energy expenditure due to sedentary lifestyle and lack of physical activity leads to deposition of fat in subcutaneous tissues and in different vital organs.
White adipose tissue is known to be the major driver for production of cytokines and bioactive substance which are involved in various inflammatory pathways, involving cytokines such as TNF-α, Il-6, IL-10, leptin, and others. Stress activated Jun N-terminal Kinases (JNK) and the transcription factor NF-kappaB are the most common and major inflammatory pathways found to be activated in individuals with obesity. One hypothesis is that in individuals with obesity, there are similar immune response signatures between hyperlipidemia stress and infection, as both JNK and NF-ƙB are activated in both pathways. Accumulating evidence suggests that macrophages and free fatty acids (FFA) play key roles in accentuating the inflammation in T2D. Dysregulated IL-1β and TNF-α signaling is prominently responsible for loss of beta cell functioning in T2D.
In addition, FFA also initiates the production of IL-1 β in pancreatic islets cells, and then IL-1β regulates it own production by auto stimulation. However, this pathophysiologic process can lead to accentuation in the generation of reactive oxygen species. Moreover, this increased oxidant stress along with inflammatory chemokines can defunct the beta cell functioning (Figure 2).
On-going Clinical Trials on Type 2 diabetes Targeting Inflammatory Pathways
Conventionally, statins, thiazolidinedione’s, and sodium-glucose cotransporter-2 inhibitors have been used for the amelioration of T2D and its associated disorders. For the last few decades, salicylates and methotrexate have also heavily used to treat cardio-metabolic disorders and can result in a modest control on hyperglycemia (13, 14). However, biological agents have also been used as anti-inflammatory agents in treatment of T2D. In recent therapies, cytokines production and secretion has been targeted to abolish the progression of T2D. TNF-α and IL-1β antagonists have been used to block the progression of inflammatory pathway which are closely associated with diabetes. Antagonist of IL-1β anakinra and gevokizumab (anti-IL1β) (15, 16) have demonstrated reduced serum levels of inflammatory proteins such as C-reactive protein and IL-6. However, large randomized clinical trials failed to reproduce the above-mentioned similar results.
Take Home Message
Diabetes and its associated disorders have become a pandemic. Moreover, it is becoming increasingly important to focus research on its prevention, as well as treatment. Comprehensive analyses of the inflammatory pathways linking to diabetes may be a promising strategy to prevent or control diabetes and its related complications.
Bio about the author:
Dr. Isha Sharma is currently a senior postdoctoral research associate in the Department of Pathology, Northwestern University Feinberg School of Medicine, and Chicago, USA. As a postdoctoral fellow, she has been working on impact of diabetes on kidney functions since January 2015. She received her Ph.D from India and later on she moved to USA to pursue her passion for research. Currently, she is involved in investigating the role of renal tubular specific enzyme, myo-inositol oxygenase (MIOX), in progression of diabetes related renal disorders. Her findings revealed that genetic deletion of MIOX enzyme alone or in the background of natural model of diabetes, alleviate the burden of tubular damage in mice. Her research findings have been published in Journal of Clinical Investigation, Journal of American Society of Nephrology, Diabetes, and American Journal of Pathology. To acknowledge her research and mentorship credentials, Proteintech (a biotechnology company) awarded her the best postdoc mentor award 2019. She has presented her work at various international platforms. She sincerely wishes to work in the field of kidney disorders. She hopes that her findings will lead to discovery of novel biomarkers and therapeutic strategies that would help to manage diabetes related renal disorders in the world more effectively.
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