Chronic hyperglycemia promotes atherosclerosis

A recent study investigated whether chronic hyperglycemia in type 1 diabetes is associated with a proinflammatory immune signature and arterial wall inflammation that promotes the development of atherosclerosis.

Diabetes mellitus significantly increases the risk of atherosclerotic cardiovascular diseases (CVDs). A large meta-analysis of over 100 prospective studies has shown that diabetes confers a twofold increased risk of developing CVD independent of other risk factors [2]. This is true for both type 1 (T1D) and type 2 (T2D) diabetes. Recent studies have confirmed the increased prevalence of CVD in T1D, which was particularly high in patients with early-onset disease and accounted for ~15 years of lifetime loss [3]. It is likely that this increased risk is related to the presence of chronic hyperglycemia. Prospective studies have confirmed that increased risk of coronary artery disease begins at glucose levels below the threshold for diabetes (<7 mmol/L) and continues to increase with higher glucose levels [4].

^{18F-FDG uptake}can detect vascular wall inflammation

2′-Deoxy-2′-^(18F)-fluoro-D-glucose^(18F-FDG) positron emission tomography/computed tomography (PET/CT) in the arterial wall is related to macrophage content and the degree of inflammatory gene expression in atherosclerotic plaques [5,6]. Moreover, ^{18F-FDG PET/CT uptake}in atherosclerotic plaques clearly predicts future cardiovascular events in patients with atherosclerosis [7]. Previous studies have shown increased ^{18F-FDG uptake}in the arterial walls of patients with T2D and patients with impaired glucose tolerance [8,9]. In patients with T2D, ^{18F-FDG uptake}in arterial walls also correlates with arterial stiffness [10]. Interestingly, ^{18F-FDG PET/CT}also allows assessment of hematopoietic activity in the bone marrow. This is higher in patients with atherosclerosis and predicts future cardiovascular events, suggesting that immune activation in the bone marrow is a critical mechanism in atherosclerosis [11,12]. Similarly, FDG uptake in bone marrow is associated with metabolic syndrome and high arterial metabolic activity in subjects without diabetes [13]. Recently, reprogramming of myeloid progenitor cells in bone marrow has been demonstrated in patients with coronary artery disease [14]. In mice, transient glucose spikes can cause sustained activation of immune cells by promoting myelopoiesis in the bone marrow [15].

Although evidence of systemic inflammation and activation of the innate immune system is accumulating in patients with T1D, inflammation of the vascular walls in these patients has not been studied. In addition, isolated monocytes from patients with poorly controlled T1D show increased epigenetic activation of inflammatory pathways compared with better controlled patients [16]. Functional and metabolic changes in monocytes from patients with T1D related to glycemic load have also been recently demonstrated [17]. These results suggest that chronic hyperglycemia in T1D induces changes in the innate immune system and drives systemic inflammation, which accelerates inflammation of the vessel wall.

Therefore, in a recent study, it was hypothesized that in patients with T1D, chronic hyperglycemia triggers activation of circulating innate immune cells and their bone marrow-derived progenitor cells, as well as an increase in circulating inflammatory proteins, leading to inflammation of the arterial wall. To test this hypothesis, ^{18F-FDG PET/CT imaging}was performed in patients with T1D in an area of glycemic control and in non-diabetic control subjects, and circulating immune cell phenotypes and inflammatory markers were determined [1].

Participants and experimental design of the case-control study.

Between January 2018 and January 2019, 61 subjects were enrolled in a case-control study: 41 subjects with T1D and 20 healthy, age-, sex-, and body mass index (BMI)-matched, non-diabetic control subjects (HC). All study participants were between 20 and 60 years of age, nonsmokers, and not overweight (BMI <30 ^kg/m2). Subjects with T1D had diabetes for at least 10 years but were not allowed to have major comorbidities such as autoinflammation or autoimmune disease, chronic kidney disease (dietary modification for kidney disease <45 ml/min/1.73^m2), or history of cardiovascular events (ischemic stroke/transient ischemic attack (TIA), myocardial infarction, or peripheral arterial disease). In addition, patients were not allowed to take immunosuppressive or immunomodulatory drugs or acetylsalicylic acid. If taking statins, they had to be discontinued at least two weeks before inclusion in the study.

F-FDG PET/CT imaging and analyses of the experimental setup.

^{18F-FDG PET/CT scans}were performed after >6 hours of fasting according to the European Association of Nuclear Medicine guidelines [18]. Subjects with a fasting glucose ≥8.3 mmol/L received a small amount of insulin (mean=2.35; standard deviation (SD)=2.02) to achieve a glucose level <8.3 mmol/L before ^{18F-FDG administration}. The time between insulin and ^{18F-FDG administration}was 60 minutes.

Subjects underwent PET imaging and low-dose noncontrast CT two hours after intravenous administration of ^18F-FDG(2 MBq/kg) according to European guidelines [18]. The ^{18F-FDG uptake}was determined according to the carotid arteries; the wall of the ascending, descending, and abdominal aorta; the iliac arteries; the bone marrow (vertebrae L2-L3); and the spleen (ROIs). The mean and maximum standardized uptake values (SUVs) were measured for each ROI. For the left and right carotid arteries, L2 and L3 vertebrae, and left and right iliac arteries, the SUVs of both regions were averaged. SUVs were corrected for blood glucose as previously described [18,19].

Patients with T1D show increased ^{18F-FDG uptake}in vascular and hematopoietic regions

^{18F-FDG uptake}was higher in T1D patients than in control subjects in all vascular regions (aorta, carotid, and iliac arteries). No differences in ^{18F-FDG uptake}were observed between T1D patients with an _HbA1c ≤64 and an _HbA1c >64 mmol/mol.

Also, in the additional sensitivity analysis, in which the 10 participants with the highest HbA_{1c values} with the 10 participants with the lowest HbA_{1c values} were compared (Figs. 1A-C) [1], there was no effect of _HbA1c level, and there was also no significant correlation between HbA1c _level and FDG uptake within the group of patients with T1D (Figs. 1D-F) [1]. In patients with T1D, ^{18F-FDG uptake}was also higher in bone marrow and spleen compared with healthy controls.

The proportion of non-classical monocytes is lower in patients with T1D

Overall, no differences in white blood cell counts were found between healthy controls and participants with T1D, but the percentage of nonclassical monocytes was lower in T1D compared with healthy controls (Fig. 2A) [1]. The monocyte activation markers CCR2 and CD36 were more highly expressed in T1D compared with healthy controls, and no differences were observed between groups in the levels of CD41 and CD11b (Fig. 2B) [1]. Other cell surface markers did not differ between groups, except for nonclassical CD36+ monocytes, which were higher in healthy controls.

Patients with T1D have higher levels of circulating inflammatory markers

Using a targeted proteomics approach, >90 inflammatory circulating proteins were measured. 11 Circulating inflammatory markers were elevated in patients with T1D compared with HCs (FDR corrected): Leukemia inhibitory factor receptor (LIF-R; also above), C-C motif chemokine 25 (CCL25; also below), CUB domain-containing protein 1 (CDCP1), tumor necrosis factor receptor superfamily member 9 (TNFRSF9), adenosine deaminase (ADA), C-C motif chemokine 28 (CCL28), Delta, and Notch-like epidermal growth factor-related receptor (DNER), Interleukin-15 receptor subunit alpha (IL-15RA), interleukin-10 (IL-10), signaling lymphocytic activation molecule (SLAMF1), and interleukin-18 receptor 1 (IL-18R1).

Circulating inflammatory proteins correlate with ^{18F-FDG uptake}.

To determine whether the extent of vascular wall inflammation in patients with T1D is related to levels of circulating inflammatory proteins, ^{18F-FDG uptake}was correlated with levels of circulating inflammatory proteins in both vascular and hematopoietic regions. A total of four inflammatory proteins showed a positive correlation with at least one vascular region. In addition, three proteins correlated positively with at least one nonvascular region, whereas three proteins correlated negatively. Several proteins that showed a positive correlation with vascular inflammation showed the opposite in hematopoietic regions, although they were not significant.

Take-Home Messages

• Vascular wall inflammation measured by ^{18F-FDG-PET/CT}is higher in patients with T1D compared with nondiabetic controls.
• Hematopoietic activity measured by ^{18F-FDG uptake}in bone marrow and spleen is also higher.
• The higher rate of inflammation in the arterial wall was associated with increased expression of the activation markers CCR2 and CD36 in monocytes and systemic inflammation measured by various circulating inflammatory markers.
• The extent of vessel wall inflammation correlated significantly with several circulating inflammatory proteins, suggesting a direct relationship between specific circulating proteins and the severity of vessel wall inflammation.

Literature:

1. Janssen AWM, et al: Arterial wall inflammation assessed by ^{18F-FDG-PET/CT}is higher in individuals with type 1 diabetes and associated with circulating inflammatory proteins. Cardiovascular Research2023; doi: https://doi.org/10.1093/cvr/cvad058.
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CARDIOVASC 2023; 22(3): 16-18