Inflammatory Cytokines and SIRT1 Levels in Subcutaneous Abdominal Fat: Relationship With Cardiac Performance in Overweight Pre-diabetics Patients

Abstract

Objectives: In obese patients the superficial adipose tissue expresses cytokines, and sirtuins, that may affect myocardial function. In this study, we investigated the effect of metformin therapy added to a hypocaloric diet on the inflammatory pattern and cardiac performance (MPI) in obese patients with pre-diabetic condition.Materials and Methods: Fifty-eight obese patients that were enrolled for abdominoplastic surgery were divided into patients with pre-diabetic condition (n 40) and normo-glycemic patients (n18). Patients with pre-diabetic condition were randomly assigned to metformin therapy added to a hypocaloric diet (group 1, n 20) or to a hypocaloric diet therapy alone (group 2, n20). Patients with normo-glycemic condition were assigned to a hypocaloric diet therapy.Results: During enrollment, obese patients with a pre-diabetic condition (group 1 and 2) presented higher glucose values, lower values of insulin, and higher values of the homeostasis model for the assessment of insulin resistance (HOMA-IR) than obese patients with normo-glycemic condition(group 3). In addition, they had higher values of C Reactive protein (CRP), interleukin 6 (IL6), and lower values of sirtuin 1(SIRT1). In the 12th month of the follow-up, metformin therapy induced in patients with pre-diabetic condition (group 1) a significant reduction of glucose values, HOMA-IR, and inflammatory markers such as CRP (1.04 ± 0.48 vs. 0.49 ± 0.02 mmol/L, p < 0.05), IL6 (4.22 ± 0.45 vs. 3.33 ± 0.34 pg/ml, p < 0.05), TNFα (6.95 ± 0.59 vs. 5.15 ± 0.44 pg/ml, p < 0.05), and Nitrotyrosine (5,214 ± 0,702 vs. 2,151 ± 0,351 nmol/l, p < 0.05). This was associated with a significant reduction of Intima-media thickness (1.01 ± 0.15 vs. 0.86 ± 0.15 mm, p < 0.05), Septum (14 ± 2.5 vs. 10.5 ± 2 mm, p < 0.05), Posterior wall (11 ± 1.5 vs. 8 ± 1 mm, p < 0.05), LV mass (192.5 ± 49.5 vs. 133.2 ± 37.6 g, p < 0.05) and of MPI (0.58 ± 0.03 vs. 0.38 ± 0.02, p < 0.05). At 12 months of follow-up, group 2 experienced only a reduction of cholesterol (4.15 ± 0.94 vs. 4.51 ± 0.88 mmol/L, p < 0.05) and triglycerides (1.71 ± 1.18 vs. 1.83 ± 0.54 mmol/L, p < 0.05). At 12 months of follow-up, group 3 experienced a significant reduction of inflammatory markers, and also of echographic parameters, associated with amelioration of myocardial performance. To date, IL6 expression was related to higher values of left ventricle mass (R-value 0.272, p-value 0.039), and to higher IMT (R-value 0.272, p-value 0.039), such as those observed for CRP (R-value 0.308, p-value 0.021), for glucose blood values (R-value 0.449, p-value 0.001), and for HOMA-IR (R-value 0.366, p-value 0.005). An inverse correlation was found between subcutaneous fat expression of SIRT1 and myocardial performance index (R-value−0.236, p-value 0.002).Conclusion: In obese patients with pre-diabetic condition a metformin therapy may reduce inflammation and oxidative stress, and this may be associated with the amelioration of the cardiac performance.Clinical research trial number: NCT03439592.

Metformin improves lipid metabolism and reverses the Warburg effect in a canine model of chronic atrial fibrillation

“…Recent studies have begun to shed light on the immunometabolism regulator role of metformin in cardiovascular disease [6]. C. Sardu and his colleagues proved that the use of metformin can regulate the adipose tissue metabolism and improve the cardiac performance in pre-diabetic patients [22][23][24][25], and these effects are predominantly anti-inflammatory. Moreover, inflammation has long be regarded as a vital contributor to AF [26].…”

Association of Glycemic Indices (Hyperglycemia, Glucose Variability, and Hypoglycemia) with Oxidative Stress and Diabetic Complications

“…On the other hand, OS has been alluded to the pathogenesis of diabetes per se [ 41 ], by leading to insulin resistance, dyslipidemia, β -cell dysfunction, and impaired glucose tolerance [ 42 , 43 ]. As a matter of fact, even at the prediabetic state, visceral fat and superficial adipose tissue overexpress different cytokines (such as tumor necrosis factor- α (TNF- α ) and interleukin 6 (IL-6)) and downregulate sirtuins (antiapoptotic proteins) that leads to increased inflammation and oxidative stress, which is associated to downregulation of mitochondrial biogenesis [ 44 ]. This may affect the cardiovascular functions in patients with diabetes vs. normo-glycemic individuals, leading to an altered myocardial performance and to the development of heart damage [ 45 , 46 ].…”

Adiponectin and insulin resistance are related to restenosis and overall new PCI in subjects with normal glucose tolerance: the prospective AIRE Study

“…Therefore, it is intriguing to evaluate the relationship between inflammation/oxidative stress and cytokines milieu and IHD in NGT patients. In this setting, recent advances established a fundamental role for inflammation as an important component of IHD [11], with a clear association existing between inflammatory cytokines relapsed by adipose tissue, inflammation and atherosclerosis [12–14]. Indeed, adipose tissue secretes many biologically active mediators such as TNF-α, plasminogen activator inhibitor type 1 (PAI-1), IL-6, leptin, adiponectin and resistin [15].…”