Ural researchers have published a fundamental review exploring the inflammatory nature of insulin resistance. Aleksey Sarapultsev, Director of the China-Russia Research and Education Centre for System Pathology, jointly with his Yekaterinburg colleagues Evgeny Gusev and Iuliia Zhuravleva, have authored a review article exceeding 100 pages and citing 1239 references. This paper has been published in the International Journal of Molecular Sciences by the international publisher MDPI, a journal ranked in the first quartile of Scopus.
The “insulin resistance” term is familiar to anyone who has studied the nature of type 2 diabetes. There is type 1 diabetes, often referred to as juvenile diabetes, in which the body stops producing insulin due to genetic causes and can no longer properly process glucose. Type 2 diabetes, by contrast, develops when the pancreas works at its limit producing insulin, but the body's cells become less responsive to it.
For centuries, insulin resistance had been generally attributed to “disorders of carbohydrate metabolism”, a broad explanation that provided little insight into the underlying mechanisms. Physicians typically advised patients to reduce their consumption of sweets and carbohydrates while increasing physical activity, and these measures often produced some improvement.
Our body's cells require glucose as their primary energy source. Doctors typically explain it to patients like this: glucose serves as fuel, while insulin acts as a “connector” or “key” that enables energy to enter the mitochondria, the cell’s power stations. As people age, the “key” appears to fit less effectively, like a worn charging port in an old smartphone. While useful for illustration, this explanation does not reflect the full scientific picture.
The researchers have concluded that low-grade but widespread systemic metabolic inflammation is both a consequence of insulin resistance and a driving force behind its further progression.
Under normal conditions, cells are capable of coping with stress. For example, following physical exercise, muscles recover, the liver becomes more efficient at burning fats, and oxidative processes proceed normally. However, when calories—especially fats and carbohydrates—are consumed in excess, cells experience constant stress. Oxygen utilization becomes impaired, protein synthesis is disrupted, and cells begin producing powerful inflammatory cytokines in response to the imbalance caused by excess glucose and lipids.
“Much like offensive words exchanged between people, these cells can stimulate other cells throughout the body, disrupting their normal state and function. In such cases, activated cells in adipose tissue, liver, and muscles effectively “refuse entry” to glucose by blocking its transporter protein, GLUT4. As a result, the insulin “key” has to work harder and harder with diminishing effect,” explains Aleksey Sarapultsev.
As a consequence, the entire body enters a state of chronic stress. Adipose tissue, particularly visceral fat located around the abdomen, ceases to function merely as an energy reserve and becomes a factory producing inflammatory molecules, including leptin, resistin, and harmful fatty acids.
In response, the liver increases glucose production even when additional glucose is unnecessary. It also accumulates fat and releases substances into the bloodstream that further increase insulin resistance in both muscles and adipose tissue.
Skeletal muscles, the body's primary consumers of glucose, gradually lose their ability to absorb sugar. Physical activity may initially help by stimulating glucose uptake, but over time muscle mass and contractile function begin to decline.
Eventually, inflammation affects the blood vessels, particularly the endothelium—their inner lining—raising the risk of thrombosis, atherosclerosis, hypertension, and other cardiovascular complications.
Unfortunately, this process is not limited to individuals with obesity and type 2 diabetes. Similar mechanisms may be triggered by chronic infections such as tuberculosis, post-COVID syndrome (long COVID), psychological stress and depression, as well as various genetic predispositions.
“To slow down or perhaps even prevent these changes, it is important to maintain a balanced diet, stay physically active, avoid creating stress for yourself and others, refrain from smoking, and limit other harmful habits,” advises Aleksey Sarapultsev.
How can this condition be treated? Metabolic inflammation associated with insulin resistance is highly heterogeneous and complex. Conventional medications that target specific inflammatory pathways are not always effective. For now, the problem remains an open challenge for global science. Future therapies may need to be personalized for each patient, taking into account individual genetic and biochemical characteristics. At present, the most effective medical recommendations remain dietary modification and increased physical activity, particularly in the early stages of the disease.