No abstract

Obesity induces low-grade chronic inflammation, manifested by proinflammatory polarization of adipose tissue innate and adaptive resident and recruited immune cells that contribute to insulin resistance (IR). The glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone that mediates postprandial insulin secretion and has anabolic effects on the adipose tissue. Importantly, recent evidence suggested that GIP is a potential suppressor of inflammation in several metabolic models. In this study, we aimed to investigate the immunoregulatory role of GIP in a murine model of diet-induced obesity (DIO) using the long-acting GIP analog [d-Ala2]GIP. Administration of [d-Ala2]GIP resulted in adipocytes of increased size, increased levels of adipose tissue lipid droplet proteins, indicating better lipid storage capacity, and reduced adipose tissue inflammation. Flow cytometry analysis revealed reduced numbers of inflammatory Ly6Chi monocytes and F4/80hiCD11c+ macrophages, associated with IR. In addition, [d-Ala2]GIP reduced adipose tissue infiltration of IFN-γ–producing CD8+ and CD4+ T cells. Furthermore, [d-Ala2]GIP treatment induced a favorable adipose tissue adipokine profile, manifested by a prominent reduction in key inflammatory cytokines (TNF-α, IL-1β, IFN-γ) and chemokines (CCL2, CCL8, and CCL5) and an increase in adiponectin. Notably, [d-Ala2]GIP also reduced the numbers of circulating neutrophils and proinflammatory Ly6Chi monocytes in mice fed regular chow or a high-fat diet. Finally, the beneficial immune-associated effects were accompanied by amelioration of IR and improved insulin signaling in liver and adipose tissue. Collectively, our results describe key beneficial immunoregulatory properties for GIP in DIO and reveal that its augmentation ameliorates adipose tissue inflammation and improves IR.

Background: One out of 5 patients undergoing coronary angiography has angiographically normal coronary arteries (ANCA). Some of them have abnormally slow coronary flow (SCF). The prevalence and causes of SCF in these patients are not clear.Methods: We studied 114 consecutive patients with ANCA. Each angiogram was independently evaluated by 2 physicians unaware of all other clinical features of the case. Coronary flow (CF) was graded using the corrected TIMI Frame Count (cTFC) and Coronary Clearance Frame Count (CCFC) methodologies. SCF was defined as a cTFC exceeding the reported normal (mean cTFC + 2 SD) in each of the three major coronary arteries. The association between SCF and various clinical, inflammatory, and metabolic variables was tested using a multivariable analysis model.Results: Thirty-nine (34%) patients had SCF. Inter-individual CF varied substantially among them (range 10-143 frames/sec, mean: 37 ± 22 frames/sec). The intra-individual CF did not vary: CF correlated well in the three major epicardial coronary arteries of a given individual (r = 0.7, p = 0.0001). Multivariable analysis revealed that current smoking was the most significant variable related to SCF (odds ratio = 4.7, p = 0.006, CI 95% 1.6-13.3). The SCF group included significantly more smokers (41% versus 15%, p = 0.002).Conclusions: SCF is a common finding (34%) among patients with angiographically normal coronary arteries. In these patients, slow flow is a systemic phenomenon that involves all three coronary arteries rather than a local event and is associated with current smoking.