- Metabolic syndrome
- Beta cells
What is the relationship between metabolic Inflammation and type 2 diabetes?
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 fat tissue and the higher their chances of developing Type 2 diabetes. In this article, we will highlight the emerging role of inflammation in the pathway that leads to 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 and is characterized by high blood pressure, a large waist circumference, elevated fasting glucose and triglycerides, and low HDL cholesterol.
Metabolic inflammation (MI) 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 hindered by obesity-related inflammation. Metabolically activated macrophages are key cells in the process believed to spike both pro- and anti-inflammatory pathways in reaction to excess fat.
Diabetes is a complex metabolic disorder affecting the glucose status of the human body. The main clinical diagnostic features are impaired glucose tolerance and hyperglycaemia which occur as the result of an absolute or relative insulin deficiency or resistance to its action. Chronic hyperglycaemia associated with diabetes can result in end organ dysfunction and failure and may 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 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.Effective novel therapeutic approaches are needed 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 Type 2. The increase in prevalence of the condition has been related to well-recognized risk factors, such as the adoption of a western lifestyle, lack of physical activity, and high sugar diet.
Genetic predisposition, ethnicity, and aging are not modifiable risk factors for Type 2 diabetes, but 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 the 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 salt led to decreased blood sugar 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 an enzyme which is one component in the insulin response pathway.
A landmark study to correlate inflammation with diabetes, conducted in animal models by Hotamisiligil et al. in 1993, revealed that tumor necrosis factor-alpha (TNF-alpha) played a role in obesity and particularly in insulin resistance and diabetes.Causal connections between inflammation and obesity or Type 2 diabetes were made because of these findings.
Over the next decades, many studies provided more supporting evidence for the role of inflammation in the initiation and progression of diabetes.Accumulative evidence suggests that chronic inflammation in target cells of insulin action may contribute to obesity, insulin resistance, and related metabolic disorders including Type 2 diabetes.
What is the relationship between Metabolic Disorders and Inflammation in Type 2 Diabetes?
In several studies, our understanding of insulin resistance and insulin secretion in the onset of Type 2 diabetes and its 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. As it progresses, this shift in pancreatic function 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 Type 2 diabetes, it is generally accepted that abnormal insulin sensitivity precedes the clinical diagnosis of diabetes by up to 15 years.Therefore, along with looking into the mechanism of insulin resistance, studies have investigated the pathways leading to beta cell failure.
3. Is there evidence of Inflammation in Other Organs in People with Type 2 Diabetes?
The evidence is inconclusive whether the inflammatory state in Type 2 diabetes can spread to other organs such as the liver, the neural system, and possibly skeletal muscle. More research is needed to determine this.
4. What are the Future Perspectives for the Treatment of Diabetes?
Below are some of the approaches currently being investigated.
- Gauging anti-inflammatory diets in streamlining an individual’s microbiome through innovative approaches for Type 2 diabetes
- Examining the effects of vitamin D supplementation on serum levels of inflammatory markers through clinical trials; results so far are inconsistent
- investigating whether antagonists of leukotriene production enzymes or receptor binding BLT1 have benefits for metabolic and cardiovascular health; results have not been reported yet
5. What is the future of understanding metabolic inflammation as a cause for diabetes?
Given the increasing prevalence of diabetes, it is crucial that research focuses on its prevention as well as its treatment. Heart disease, the metabolic syndrome and type 2 diabetes (T2D) all have a high level 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.
Type 1 diabetes 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 possible use of stem cells to regenerate pancreatic beta cells could potentially be the key to permanent treatment of Type 1 diabetes. Therefore, after a holistic review of the possible mechanisms that lead to Type 1 and Type 2 diabetes 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.