A growing body of data shows that type 2 diabetes is at least in part rooted in inflammation. The higher a person’s body mass index, the more pro-inflammatory macrophages they have in their adipose tissue, and the higher their chances of developing T2D. In this article, we will highlight the emerging role of inflammation in the pathophysiology of diabetes. We will also analyze the implicated inflammatory pathways and biomarkers of inflammation in diabetes and metabolic diseases.

1. The metabolic syndrome and metabolic Inflammation

Metabolic syndrome often precedes type 2 diabetes and cardiovascular disease. It is characterized by high blood pressure, a large waist circumference, elevated fasting glucose and triglycerides, and low HDL cholesterol.

Metabolic inflammation is currently a hot research topic, wherein peculiarities in metabolic and inflammatory pathways are looked into for their possible contribution to atherosclerosis, Type 2 diabetes and insulin resistance (IR). In MI, insulin signaling is impeded by inflammation caused by obesity. Metabolically activated macrophages are key cells in the process. They are believed to spike both pro- and anti-inflammatory pathways in reaction to lipid spillover from adipocytes.

Diabetes is a complex metabolic disorder affecting the glucose status of the human body. The main clinical diagnostic features are impaired glucose tolerance and hyperglycemia. These occur as the result of an absolute or relative insulin deficiency or resistance to its action. Chronic hyperglycemia associated with diabetes can result in end-organ dysfunction and failure which can involve the retina, kidneys, nerves, heart and blood vessels. There is a  clinical relationship between diabetes and atherosclerotic cardiovascular disease, with the risk for cardiovascular disease (CVD) being significantly elevated in patients with diabetes.

Typically, CVD occurs one to two decades earlier in people with diabetes, with the more aggressive, severe and diffuse distribution. The first WHO Global report on diabetes published in 2016 demonstrates that the number of adults living with diabetes has almost quadrupled since 1980 to 422 million adults and this is expected to rise to 552 million by 2030. There is, therefore, a need for effective novel therapeutic approaches for the treatment and/or prevention of diabetes and atherosclerotic disease.

Various proposals and hypotheses have been developed to describe the mechanisms involved in the propagation of diabetes, mainly focusing on T2D. The increase in the prevalence of the condition has been related to well-recognized risk factors, such as the adoption of a western lifestyle, sedentary lives, lack of physical activity and an energy-dense diet.

Genetic predisposition, ethnicity, and aging are not modifiable risk factors for T2D. Other factors such as being overweight or obese, an unhealthy diet, insufficient physical activity and smoking are modifiable through behavioral and environmental changes. However, increasing evidence has shown that inflammatory pathways are common in both modifiable and non-modifiable factors.

2. When was inflammation first thought to cause diabetes?

Observational studies provided the first evidence for the possible association between inflammation and diabetes. Over a century ago, the administration of high doses of sodium salicylate led to decreased glycosuria in people with a suspected or definite diagnosis of diabetes.  Later studies on the role of inflammation in diabetes revealed that this hypoglycaemic action was related to the inhibition of the serine kinase IkappaB kinase-beta (IKKbeta), which correlates with the post-receptor action of insulin.

A landmark study to correlate inflammation with diabetes was conducted in animal models by Hotamisiligil et al., in 1993 and it revealed that the role of tumor necrosis factor-alpha (TNF-alpha) in obesity and particularly in insulin resistance and diabetes. Epidemiologic associations of inflammation with obesity and T2D were made when circulating concentrations of markers and mediators of inflammation and acute-phase reactants including fibrinogen, C-reactive protein, interleukin (IL)-6, plasminogen activator inhibitor-1, sialic acid, and white cells, have been shown to be elevated in these conditions.

Over the next decades, numerous studies on human and animal models provided further supporting evidence for the role of inflammation in the initiation and progression of diabetes. Accumulative evidence suggests that chronic activation of pro-inflammatory pathways in target cells of insulin action may contribute to obesity, insulin resistance and related metabolic disorders including T2D. The identification of potential pathways connecting inflammation to diabetes has produced growing interest in targeting inflammation to help prevent and control diabetes and related conditions, as well as improving risk stratification for diabetes by using inflammatory biomarkers as potential indexes.

3. What is the relationship between Metabolic Disorders and Inflammation in Type 2 Diabetes?

In several pathophysiological studies carried out, our understanding of insulin resistance and secretion in the course of disease onset and progression has been expanded. Subjects at risk of T2D display an initial state of insulin resistance compensated by hypersecretion of insulin in the beta cells. In the clinical course of the disease this pancreatic functional reserve is eventually unable to cope with the required insulin secretion and by the time diabetes is diagnosed, beta cells are no longer able to secrete enough insulin.

Although the relative contribution of beta-cell dysfunction and insulin resistance can vary in people with T2D, it is generally accepted that abnormal insulin sensitivity precedes the clinical diagnosis of diabetes by up to 15 years. Therefore, along with mechanistic studies investigating mechanisms forming the basis of insulin resistance, more recent research has also focused on the pathways leading to beta-cell failure.

4. Is there evidence of Inflammation in Other Organs in People with Type 2 Diabetes?

There is inconclusive evidence that the inflammatory state in T2D can spread to other organs such as the liver, the neural system and possibly skeletal muscle. More research is needed to support this evidence.

5. What are the Future Perspectives for the Treatment of Diabetes?

Below are some of the approaches currently being investigated.

1. Innovative approaches on T2D to gauge anti-inflammatory diets and moderate an individual’s microbiome are under study.
2. Clinical trials examining the effects of vitamin D supplementation on serum levels of inflammatory markers have provided inconsistent results, with no evidence of effects in most trials, or effects on selected markers in others.
3. There are also studies investigating whether antagonists of leukotriene production enzymes – 5-lipoxygenase (5-LO), 5-LO-activating protein and LTA4 hydrolase – or receptor binding BLT1 have cardiometabolic outcome benefits, however, these results have not yet been reported.
4. The potential for targeting cholinergic pathways, immune modulation or other mediators of inflammation such as JNK and toll-like receptors (TLRs) are also being researched.
    

6. What is the future of understanding metabolic inflammation as a cause of diabetes?

Given the increasing prevalence of diabetes, it is crucial that research focuses on its prevention as well as its treatment. Heart disease, metabolic syndrome and type 2 diabetes (T2D) all have in common the increased concentration of circulatory cytokines as a result of inflammation. Inflammatory cytokines are produced by different cell types and secreted into the circulation, where they regulate different tissues through their local, central and peripheral action.

An improved understanding of the mechanisms linking inflammation to diabetes and related complications has stimulated interest in targeting inflammatory pathways as part of the strategy to prevent or control diabetes and its complications.

T1D is considered to be more of an immunological response rather than a metabolic disorder and the preliminary results of trials using anti-inflammatory and immunomodulatory medication are promising. These treatments in combination with the possible use of stem cells to regenerate pancreatic beta cells could potentially be the key to the permanent treatment of T1D. Therefore, after a holistic review of the possible mechanisms that lead to T1D and T2D and the numerous already described inflammation pathways that are involved, it becomes more and more clear that future research should focus on simultaneous suppression of various inflammatory response pathways rather than focusing on one pathway at a time.

References

1. NCBI (2017): Nutritional modulation of metabolic inflammation. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/28710289

2. EM-Consulte (2012): Inflammation and type 2 diabetes. Retrieved from https://www.em-consulte.com/en/article/735580

3. ECR (2019): The Role Of Inflammation In Diabetes: Current Concepts And Future Perspectives. Retrieved from https://www.ecrjournal.com/articles/role-inflammation-diabetes-concepts-future