Chronic inflammation is increasingly being observed in a range of long-term diseases, including many of the largest global causes of ill health. The triggers and consequences of such inflammation are under investigation by many research teams around the world.

This article will examine our current knowledge on the role of inflammation in three forms of diabetes: type 1, type 2, and gestational diabetes.

The majority of people with diabetes fall into the first two broad categories, type 1 or type 2. For many years, scientists have looked at the role of pancreatic beta cell function in diabetes, as well as factors such as obesity, physical activity, genes, and age.

However, the emerging role of inflammation in both type 1 and type 2 diabetes is generating increasing interest, as targeting inflammation could help both the prevention and control of the disease.

Type 1 diabetes (T1D) is related to an absolute lack of insulin caused by immune-mediated destruction of pancreatic beta cells. Type 2 diabetes (T2D), the most common form of diabetes, develops following a relative insulin deficiency linked to insulin resistance. Rates of T2D are rising and are associated with a range of modifiable and non-modifiable risk factors.

In a 2019 review by experts at the University of Athens, Greece, the authors write, "Increasing evidence has shown that inflammatory pathways are the principal, common pathogenetic mediators in the natural course of diabetes under the stimulus of common risk factors."

They describe the emerging role of inflammation in the development of diabetes, including the related pathways and biomarkers. This work goes back over a century, they state, beginning with observational studies in which the level of sugar in patients' urine was reduced with high doses of the salt sodium salicylate, known for its anti-inflammatory properties.

They write, "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."

Returning to T1D - an autoimmune disorder - one major theory is that insulin-producing cells in the pancreas are inflamed, triggering the growth of defective T cells. Further immune cells called macrophages are also critical to this inflammation as they secrete cytokines, such as Interleukin 1 beta and tumour necrosis factor alpha, as well as reactive oxygen species. Overall, the interaction among various cell types determines the progression of T1D.

This suggests that many pathways can contribute to pancreatic beta cell death. The activity of cytokines is likely to be a critical factor in both inflammatory and autoimmune-mediated pancreatic cell death, which perhaps work in a vicious cycle.

In a 2017 paper, a research team from the University of North Carolina at Chapel Hill, NC, describe T1D as "A chronic anti-self inflammatory response". They explain, "Autoimmunity arises when aberrant immune responses target self-tissues causing inflammation. In T1D, T cells attack the insulin producing beta cells in the pancreatic islets.

"Unlike protective immunity where inflammation is terminated, autoimmunity is sustained by chronic inflammation." Compared with healthy people, they report that individuals with T1D show higher expression of proinflammatory cytokines "consistent with ongoing B cell autoimmunity".

They conclude that T1D involves genetic and environmental factors that cause cellular changes that culminate in pathological, chronic inflammation. The nature of this inflammation varies between patients and determines individual outcomes.

For T2D, the situation is different in many ways. A very common risk factor, obesity, and its associated conditions such as metabolic syndrome, raise levels of inflammatory biomarkers. Low-level chronic inflammation occurs alongside two major inflammatory pathways, both increasing pro-inflammatory cytokines, which leads to insulin resistance, then T2D itself.

Although brown adipose tissue is important in regulating energy and glucose, and is linked to insulin resistance and glucose levels, it is white adipose tissue especially around the trunk, upper body or abdomen that seems to be the major source of inflammation in T2D.

It produces cytokines and several other inflammatory substances, and can be infiltrated by macrophages and B and T immune cells, further triggering local and systemic chronic low-grade inflammation.

Turning to gestational diabetes mellitus (GDM), this is a condition also closely linked to obesity, which can be thought of as a chronic inflammatory state. Pregnancy causes an altered inflammatory state with a balance between pro- and anti-inflammatory cytokines needed for normal fetal development.

This altered inflammatory environment, plus the heightened inflammatory response from obesity, may together lead to the development of GDM.

Specifically, obesity is linked to changed levels of adipokines, proteins that are used to make certain hormones. Some of these can trigger adipose tissue to become inflamed, and decrease insulin sensitivity, a precursor state to both GDM and T1D. Furthermore, pregnancy hormones including progesterone, relaxin and oxytocin also have a direct impact on inflammatory pathways.

Insulin resistance increases even in normal pregnancies in the late second trimester, to levels similar to those in T2D. Usually this is compensated by higher insulin secretion, but if this response is inadequate, GDM can result.

In a 2015 review of this issue, Dr Sally Abell of Monash University, Australia, and colleagues explain that GDM is linked to the down-regulation of anti-inflammatory cytokines and up-regulation of pro-inflammatory cytokines implicated in insulin resistance.

This contributes to impaired glucose control via direct and indirect mechanisms, they state. "Direct mechanisms include regulation of insulin secretion and insulin sensitivity; indirect mechanisms relate to inflammation, regulation of adipogenesis, chemoattraction of immune cells and subsequent effects on glucose metabolism."

In terms of pharmaceuticals that may help reduce the inflammation behind all forms of diabetes, trials have so far looked at rituximab, a monoclonal anti-CD20 antibody, and drugs that target cytokines, in particular interleukin 1 beta and tumour necrosis factor alpha. However, these trials tend to provide treatment after diabetes has already developed and may be more effective as preventative measures in high-risk individuals.

Other approaches include focusing on diet and physical activity, both to lower a high body mass index and as a non-pharmacological approach to control elevated blood glucose.

The identification of pathways that connect inflammation to the various forms of diabetes has led to widespread interest in the area, and highlights a number of possible avenues through which inflammation could be tackled to help prevent and control diabetes.

Research has begun to focus on methods of suppressing these inflammatory pathways, and in parallel, to allow the use of biomarkers of inflammation to improve risk stratification in diabetes.

References and Resources

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6523054/ Tsalamandris, S. et al. The Role of Inflammation in Diabetes: Current Concepts and Future Perspectives. European Cardiology Review, April 2019 doi: 10.15420/ecr.2018.33.1
2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5743904/ Clark, M. et al. Type 1 Diabetes: A Chronic Anti-Self-Inflammatory Response. Frontiers in immunology, 22 December 2017 doi: 10.3389/fimmu.2017.01898
3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4466145 Pantham, P. et al. Inflammation in Maternal Obesity and Gestational Diabetes Mellitus. Placente, 28 April 2015 doi: 10.1016/j.placenta.2015.04.006
4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4490503/ Abell, S. K. et al. Inflammatory and Other Biomarkers: Role in Pathophysiology and Prediction of Gestational Diabetes Mellitus. International Journal of Molecular Sciences, 11 June 2015 doi: 10.3390/ijms160613442

About the Author:

Jane Collingwood is a medical journalist with 17 years experience reporting on all areas of medical research for online and print publications. Jane has also worked on a range of medical studies funded by the UK National Health Service within the University of Bristol in the South West of England. Jane has an academic background in psychology and has authored books on stress management and respiratory infections. Currently she is combining journalism with a national coordinating role on the UK's largest surgical research trial.