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 (immune cells that promote inflammation) they have in their adipose tissue (body fat). And the higher their chances of developing T2D. This article covers the emerging role of inflammation in the pathophysiology of diabetes (how the disease develops). It also looks at the inflammatory pathways involved and the biomarkers (measurable signs) of inflammation in diabetes and metabolic diseases.
- How does metabolic inflammation lead to type 2 diabetes?
Metabolic syndrome often comes before type 2 diabetes and cardiovascular disease. Its signs are high blood pressure, a large waist, high fasting glucose and triglycerides, and low HDL cholesterol. Metabolic inflammation is a hot research topic right now. Researchers are looking at quirks in metabolic and inflammatory pathways. They want to know the possible contribution of these quirks to atherosclerosis, Type 2 diabetes and insulin resistance (IR). In metabolic inflammation, inflammation caused by obesity hinders insulin signaling. Metabolically activated macrophages are key cells in the process. They are believed to spike both pro- and anti-inflammatory pathways. They do this in reaction to lipid spillover (fat overflowing) from adipocytes (fat cells). Diabetes is a complex metabolic disorder that affects the body’s glucose status. The main clinical signs used to diagnose it are impaired glucose tolerance and hyperglycemia (high blood sugar). These occur as the result of an absolute or relative insulin deficiency, or resistance to insulin’s action. Chronic hyperglycemia associated with diabetes can lead to end-organ dysfunction and failure. This can involve the retina, kidneys, nerves, heart and blood vessels. There is a clinical relationship between diabetes and atherosclerotic cardiovascular disease. The risk for cardiovascular disease (CVD) is significantly higher in patients with diabetes. Typically, CVD occurs one to two decades earlier in people with diabetes. It is also more aggressive, severe and widespread. The first WHO Global report on diabetes was published in 2016. It shows that the number of adults living with diabetes has almost quadrupled since 1980, to 422 million adults. This is expected to rise to 552 million by 2030. So there is a need for effective new approaches for the treatment and/or prevention of diabetes and atherosclerotic disease. Various ideas and hypotheses have been put forward to describe the mechanisms behind the propagation (progression) of diabetes. Most focus on T2D. The rise in how common the condition is has been related to well-known risk factors. These include 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. That means they cannot be changed. Other factors can be changed through changes in behavior and environment. These include being overweight or obese, an unhealthy diet, too little physical activity and smoking. However, growing evidence has shown that inflammatory pathways are common in both modifiable and non-modifiable factors.
- When was inflammation first thought to cause diabetes?
Observational studies gave the first evidence for a possible association between inflammation and diabetes. Over a century ago, doctors gave high doses of sodium salicylate to people with a suspected or definite diagnosis of diabetes. It led to less glycosuria (sugar in the urine). Later studies on the role of inflammation in diabetes looked at this hypoglycemic (blood-sugar-lowering) action. They revealed that it was related to blocking the serine kinase IkappaB kinase-beta (IKKbeta). That enzyme correlates with the post-receptor action of insulin. A landmark study to correlate inflammation with diabetes was done in animal models by Hotamisligil et al. in 1993. It revealed the role of tumor necrosis factor-alpha (TNF-alpha) in obesity, and particularly in insulin resistance and diabetes. Epidemiologic associations (links seen across large groups of people) of inflammation with obesity and T2D were also made. They were made when blood levels of inflammation markers, mediators and acute-phase reactants were shown to be elevated in these conditions. These included fibrinogen, C-reactive protein, interleukin (IL)-6, plasminogen activator inhibitor-1, sialic acid, and white cells. Over the next decades, many studies in human and animal models gave further supporting evidence. They pointed to a role for inflammation in the start and progression of diabetes. Cumulative evidence suggests that chronic activation of pro-inflammatory pathways may contribute to obesity, insulin resistance and related metabolic disorders including T2D. This activation happens in target cells of insulin action (the cells insulin acts on). Researchers have identified potential pathways connecting inflammation to diabetes. This has produced growing interest in targeting inflammation to help prevent and control diabetes and related conditions. It has also raised interest in using inflammatory biomarkers as potential indexes. These could improve risk stratification for diabetes (sorting people by their risk).
- What is the relationship between Metabolic Disorders and Inflammation in Type 2 Diabetes?
Several pathophysiological studies (studies of how disease works in the body) have expanded our understanding of insulin resistance and secretion as the disease starts and progresses. Subjects at risk of T2D first show insulin resistance. Their beta cells make up for it with hypersecretion (oversupply) of insulin. Over the course of the disease, this pancreatic functional reserve eventually cannot keep up with the insulin needed. By the time diabetes is diagnosed, beta cells can no longer secrete enough insulin. The relative contribution of beta-cell dysfunction and insulin resistance can vary in people with T2D. Even so, it is generally accepted that abnormal insulin sensitivity comes before the clinical diagnosis of diabetes by up to 15 years. So researchers still run mechanistic studies of what lies beneath insulin resistance. But more recent research has also focused on the pathways leading to beta-cell failure.
- 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. These include the liver, the neural system and possibly skeletal muscle. More research is needed to support this evidence.
- What are the Future Perspectives for the Treatment of Diabetes?
Below are some of the approaches currently being investigated.
- Innovative approaches in T2D are under study. They aim to gauge anti-inflammatory diets and modulate (adjust) an individual’s microbiome.
- Clinical trials have looked at the effects of vitamin D supplementation on blood levels of inflammatory markers. The results have been inconsistent. Most trials showed no evidence of effects. Others showed effects on selected markers.
- There are also studies investigating antagonists (blockers) of leukotriene production enzymes – 5-lipoxygenase (5-LO), 5-LO-activating protein and LTA4 hydrolase – or receptor binding BLT1. They test whether these have cardiometabolic outcome benefits. However, these results have not yet been reported.
- The potential for targeting cholinergic pathways, immune modulation or other mediators of inflammation is also being researched. These mediators include JNK and toll-like receptors (TLRs).
- 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 share higher levels of circulatory cytokines (signaling proteins) as a result of inflammation. Inflammatory cytokines are made by different cell types and released into the blood. There they regulate different tissues through their local, central and peripheral action. We now better understand the mechanisms linking inflammation to diabetes and related complications. That has stirred interest in targeting inflammatory pathways. This would be part of the strategy to prevent or control diabetes and its complications. T1D is considered to be more of an immune response than a metabolic disorder. Some trials have used anti-inflammatory and immunomodulatory (immune-adjusting) medication. Their early results are promising. These treatments, combined with the possible use of stem cells to regrow pancreatic beta cells, could potentially be the key to the permanent treatment of T1D. So, after a holistic review of the possible mechanisms that lead to T1D and T2D, and of the many inflammation pathways already described that are involved, one thing becomes more and more clear. Future research should focus on suppressing various inflammatory response pathways at the same time, rather than one pathway at a time.
Frequently asked questions
How does inflammation cause insulin resistance?
Excess body fat sets off inflammation, and that inflammation gets in the way of insulin signaling. The key cells are metabolically activated macrophages (immune cells) in fat tissue. They react to fat spilling over from overfilled fat cells by switching on inflammatory pathways. The higher a person’s body mass index, the more of these pro-inflammatory macrophages they carry, and the higher their chance of type 2 diabetes.
How long does insulin resistance last before diabetes is diagnosed?
Up to 15 years. People at risk first become insulin resistant, and the pancreas covers for it by pumping out extra insulin. Over time the beta cells can no longer keep up. By the time type 2 diabetes is diagnosed, they cannot secrete enough insulin. That is why abnormal insulin sensitivity is present long before the diagnosis.
What blood markers show inflammation in type 2 diabetes?
Several markers of inflammation run high in people with obesity and type 2 diabetes. They include C-reactive protein, interleukin-6, fibrinogen, plasminogen activator inhibitor-1, sialic acid and white blood cells. Tumor necrosis factor-alpha (TNF-alpha) was the first inflammatory signal tied to obesity and insulin resistance, in a landmark 1993 study.
Is type 1 diabetes caused by inflammation too?
Type 1 diabetes is considered more of an immune reaction than a metabolic disorder, while type 2 is driven by metabolic inflammation. Both involve inflammatory pathways. Early trials of anti-inflammatory and immune-modulating medicines in type 1 diabetes are promising. Pairing them with stem cells to regrow insulin-making beta cells may one day offer a permanent treatment.
Related reading
References
- NCBI (2017): Nutritional modulation of metabolic inflammation. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/28710289
- EM-Consulte (2012): Inflammation and type 2 diabetes. Retrieved from https://www.em-consulte.com/en/article/735580
- 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
Medically reviewed by Dr. Gurpreet Singh Padda, MD, MBA, MHP
Interventional pain physician, addiction medicine specialist and obesity medicine diplomate.
Licensed in Missouri and Illinois.
Last reviewed June 18, 2026
