Type 2 diabetes has long been viewed as a disorder of sugar control in the body, but a new review paper from the University of Arkansas for Medical Sciences summaried recent publications suggests that the disease also disrupts the immune system in ways that may directly harm the heart and blood vessels. The review, led by Dr. Yunmeng Liu and published in Life, shows that changes in hormone levels among people with diabetes may cause the immune system to stay constantly “switched on,” leading to ongoing inflammation that damages blood vessels and increases the risk of heart disease.
Dr. Liu and her team examined how common hormones—such as insulin, leptin, and adiponectin—interact with the body’s defense system and affect cardiovascular health. They found that in diabetes, these hormones may act as strong immune triggers instead of simply controlling metabolism and energy balance. “Individuals with Type 2 diabetes exhibit a skewed immune profile, with an elevated secretion of pro-inflammatory cytokines such as interferon gamma, tumor necrosis factor alpha, interleukin 17, and interleukin 6,” Dr. Liu explained, noting that these substances, which are chemical messengers of the immune system, are “well-established drivers of vascular inflammation and dysfunction”.
Under normal conditions, insulin helps cells absorb sugar from the blood to use for energy, while adiponectin—a hormone made by fat tissue—reduces inflammation and helps the body respond properly to insulin. However, in people with diabetes, insulin and leptin levels often stay high, while adiponectin levels drop. This imbalance sends confusing signals to the immune system. As a result, immune cells such as T cells, the white blood cells that coordinate the body’s immune response, and macrophages, which clean up dead or damaged cells, shift into a chronic activated mode and release more inflammatory molecules. The researchers found that insulin receptors on adaptative immune cells, which allow insulin to regulate the function of these cells, can boost their production of interferon gamma, a molecule known to raise blood pressure and increase strain on blood vessels. Leptin, another hormone elevated in obesity and diabetes, also increases the release of interleukin 6 and tumor necrosis factor alpha, worsening inflammation in the arteries.
Adiponectin, in contrast, acts as a calming influence on the immune system. It helps control the activity of T cells and reduces the release of harmful inflammatory molecules. Recent research discussed in this review indicates that when adiponectin levels are too low, the immune system loses this built-in control, leading to chronic inflammation that damages the heart. In studies with laboratory mice, higher adiponectin levels helped prevent fatty buildup in the arteries and reduced the number of immune cells turning into foam cells—fat-filled cells that clog blood vessels and signal the early stages of heart disease.
The study also explored how the immune system of people with Type 2 diabetes differs from that of healthy individuals. The researchers found that people with diabetes, and diabetic mice in laboratory models, tend to have more aggressive immune cells that promote inflammation and fewer regulatory cells that would normally calm the immune response. In diabetic tissue, macrophages—the immune system’s scavenger cells—were more likely to switch into a harmful inflammatory state, releasing large amounts of tumor necrosis factor alpha and interleukin 6. Meanwhile, natural killer cells, another type of immune cell that destroys infected or abnormal cells, became less effective. “This paradoxical immune state—hyperinflammatory yet infection-prone—defines the immune dysfunction in Type 2 diabetes,” the researchers wrote.
Among the different inflammatory molecules identified, tumor necrosis factor alpha and interleukin 6 were shown to have especially strong links to heart disease. Tumor necrosis factor alpha interferes with the body’s ability to use insulin properly, promotes the buildup of fatty plaques in arteries, and damages the lining of blood vessels, making it harder for them to relax and widen. When researchers blocked tumor necrosis factor alpha in diabetic mice, their blood vessels began to function normally again, and their blood pressure decreased. Interleukin 6, another key molecule, plays a double role: it can help regulate metabolism in small amounts but becomes harmful when present in high levels. The study explained that interleukin 6 can bind to receptors floating in the blood and spread inflammation to many different tissues, including the heart and blood vessels, where it contributes to hardening of the arteries and high blood pressure.
Dr. Liu also looked closely at interleukin 17, a molecule that fuels inflammation in both diabetes and heart disease. People with diabetes who developed heart or kidney complications had especially high levels of interleukin 17 in their blood. Experiments showed that blocking interleukin 17 improved blood sugar levels and prevented kidney and heart damage in diabetic mice. “Interleukin 17 is crucial to promote cardiovascular diseases in Type 2 diabetes through multiple mechanisms,” Dr. Liu noted, suggesting that reducing this molecule could help protect vital organs.
In their discussion, Dr. Liu pointed out that treatments focused only on lowering blood sugar may not fully protect people with diabetes from heart disease. “Patients undergoing intensive glucose treatment experience higher cardiovascular mortality than those receiving conventional therapy,” she said, implying that hidden immune system factors may help explain this puzzle. Dr. Liu’s team proposed that future treatments should aim to rebalance the immune system by blocking excessive inflammation while supporting the body’s natural ability to regulate itself. This could include therapies that encourage the growth of calming immune cells or engineered immune cells designed to remove the overactive ones that cause harm.
The findings mark a shift in how scientists and doctors might think about Type 2 diabetes. Instead of seeing it only as a problem of sugar metabolism, it may be more accurate to understand it as a chronic immune disorder driven by hormonal imbalance. If future therapies can target the link between hormones and immune function, doctors might be able to reduce the high risk of heart disease and stroke faced by people with diabetes.
As Dr. Liu summarized, “The diabetic milieu, characterized by elevated insulin and leptin levels alongside reduced adiponectin, fosters a chronic inflammatory environment via enhanced cytokine production from diverse immune cells.” She added that future treatments must address “the immune dysregulation that underlies the metabolic and vascular complications of Type 2 diabetes”.
Journal Reference
Deck K., Mora C., Deng S., Rogers P., Rafferty T., Palade P.T., Mu S., Liu Y., “Immune Dysregulation Connecting Type 2 Diabetes and Cardiovascular Complications.” Life, 2025. DOI: https://doi.org/10.3390/life15081241
About the Authors
Yunmeng Liu (Assistant Professor, UAMS), metabolic syndrome persists as a leading cause of morbidity and mortality among adults in the United States. Specifically, the co-existence of diabetes and hypertension, hallmark components of metabolic syndrome, stand as primary contributors to cardiovascular disease and subsequent mortality. Thus, it is important to identify the pathogenic connection between diabetes and hypertension. Ample evidence suggested the involvement of immune cells, particularly T cells, in the pathogenesis of diabetes and hypertension. However, the precise mechanisms by which immune dysregulation associated with diabetes contributes to hypertension are not fully understood. Our research centers on investigating new intrinsic cellular mechanisms existing in diabetic conditions, which sustain chronic T cell activation and accentuate the progression of cardiovascular complications.
Katherine Deck is a Ph.D. candidate completing her dissertation at the University of Arkansas for Medical Sciences. Her dissertation work investigates the immune-driven progression and chronicity of salt-sensitive hypertension, in particular, the role of aberrantly activated CD8+ T cells becoming a kidney-resident memory population and anchoring hypertension to the kidney. Katherine has funded herself throughout her time at UAMS, beginning with an NIH T32 Research Training Award, followed by an American Heart Association Predoctoral Fellowship and an NIH F31 Predoctoral Award. Looking forward to the future, Katherine hopes to one day establish her own laboratory and continue investigating the immune system’s role in cardio-renal-metabolic diseases to identify hidden drivers of these persistent syndromes.
