How dysregulation of the immune system promotes diabetes mellitus and cardiovascular risk complications

Abstract

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by persistent hyperglycemia due to insulin resistance or failure to produce insulin. Patients with DM develop microvascular complications that include chronic kidney disease and retinopathy, and macrovascular complications that mainly consist in an accelerated and more severe atherosclerosis compared to the general population, increasing the risk of cardiovascular (CV) events, such as stroke or myocardial infarction by 2- to 4-fold. DM is commonly associated with a low-grade chronic inflammation that is a known causal factor in its development and its complications. Moreover, it is now well-established that inflammation and immune cells play a major role in both atherosclerosis genesis and progression, as well as in CV event occurrence. In this review, after a brief presentation of DM physiopathology and its macrovascular complications, we will describe the immune system dysregulation present in patients with type 1 or type 2 diabetes and discuss its role in DM cardiovascular complications development. More specifically, we will review the metabolic changes and aberrant activation that occur in the immune cells driving the chronic inflammation through cytokine and chemokine secretion, thus promoting atherosclerosis onset and progression in a DM context. Finally, we will discuss how genetics and recent systemic approaches bring new insights into the mechanisms behind these inflammatory dysregulations and pave the way toward precision medicine.

Immune Disorders Connecting Type2 Diabetes and Cardiovascular Complications

“…Excessive production of pro-inflammatory cytokines such as IFNγ from T cells can recruit circulating monocytes to adipose tissue or other tissues like vasculature, leading to localized inflammation [154,155]. This localized inflammation contributes to the widespread tissue-specific damage under diabetic conditions [28,[156][157][158].…”

“…The relationship between T2D, metabolic syndrome, and cardiovascular diseases underscores the urgent need for comprehensive preventive measures and therapeutic interventions targeting lifestyle modifications, glycemic control, and cardiovascular risk reduction strategies [24][25][26][27]. Understanding the intricate interplay between these conditions is essential for addressing the multifaceted challenges of T2D and its associated complications [28][29][30]. and autocrine factors to orchestrate localized inflammation [31].…”

Cardiovascular complications of diabetes: role of non-coding RNAs in the crosstalk between immune and cardiovascular systems

“…Long-term exposure to the diabetic environment can damage the vascular endothelium by inducing post-translational modifications of biological molecules, which damage the endothelium and trigger the innate and adaptive immune system. Leucocytes contribute to the pro-oxidant and pro-inflammatory milieu by continuously infiltrating the endothelium, where they accumulate and are activated in an uncontrolled manner, producing pro-inflammatory molecules [ 56 , 57 ]. Moreover, many studies reported an increased number of circulating leucocytes in T2DM [ 58 , 59 ].…”

“…The chronic inflammation induced by DM dysregulates the constant interaction of immune cells and cardiovascular cells [ 57 ]. CCC in DM has been reported to be driven mainly by sEVs RNA cargo [ 139 – 142 ].…”

Prevalence of type 2 diabetes (T2D) in Lebanon: association with inflammatory and infectious clinical markers

“…These markers can contribute to insulin resistance and other complications associated with the condition. Inflammation plays a crucial role in the development and progression of atherosclerosis, a critical factor in the increased risk of cardiovascular disease in individuals with diabetes [ 13 ]. Clinical markers of inflammation, particularly C-reactive protein (CRP), a protein produced by the liver in response to inflammation, can indicate acute or chronic inflammation and are often used to monitor T2D diabetes and cardiovascular diseases by assessing the presence and severity of inflammation [ 14 , 15 ].…”