BackgroundCeliac disease (CD) is an autoimmune enteropathy triggered by the ingestion of gluten. Gluten-sensitive individuals (GS) cannot tolerate gluten and may develop gastrointestinal symptoms similar to those in CD, but the overall clinical picture is generally less severe and is not accompanied by the concurrence of tissue transglutaminase autoantibodies or autoimmune comorbidities. By studying and comparing mucosal expression of genes associated with intestinal barrier function, as well as innate and adaptive immunity in CD compared with GS, we sought to better understand the similarities and differences between these two gluten-associated disorders.MethodsCD, GS and healthy, gluten-tolerant individuals were enrolled in this study. Intestinal permeability was evaluated using a lactulose and mannitol probe, and mucosal biopsy specimens were collected to study the expression of genes involved in barrier function and immunity.ResultsUnlike CD, GS is not associated with increased intestinal permeability. In fact, this was significantly reduced in GS compared with controls (P = 0.0308), paralleled by significantly increased expression of claudin (CLDN) 4 (P = 0.0286). Relative to controls, adaptive immunity markers interleukin (IL)-6 (P = 0.0124) and IL-21 (P = 0.0572) were expressed at higher levels in CD but not in GS, while expression of the innate immunity marker Toll-like receptor (TLR) 2 was increased in GS but not in CD (P = 0.0295). Finally, expression of the T-regulatory cell marker FOXP3 was significantly reduced in GS relative to controls (P = 0.0325) and CD patients (P = 0.0293).ConclusionsThis study shows that the two gluten-associated disorders, CD and GS, are different clinical entities, and it contributes to the characterization of GS as a condition associated with prevalent gluten-induced activation of innate, rather than adaptive, immune responses in the absence of detectable changes in mucosal barrier function.

The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic patients is unknown. We evaluated SIRT6 expression and the effect of incretin-based therapies in carotid plaques of asymptomatic diabetic and nondiabetic patients. Plaques were obtained from 52 type 2 diabetic and 30 nondiabetic patients undergoing carotid endarterectomy. Twenty-two diabetic patients were treated with drugs that work on the incretin system, GLP-1 receptor agonists, and dipeptidyl peptidase-4 inhibitors for 26 6 8 months before undergoing the endarterectomy. Compared with nondiabetic plaques, diabetic plaques had more inflammation and oxidative stress, along with a lesser SIRT6 expression and collagen content. Compared with non-GLP-1 therapy-treated plaques, GLP-1 therapy-treated plaques presented greater SIRT6 expression and collagen content, and less inflammation and oxidative stress, indicating a more stable plaque phenotype. These results were supported by in vitro observations on endothelial progenitor cells (EPCs) and endothelial cells (ECs). Indeed, both EPCs and ECs treated with high glucose (25 mmol/L) in the presence of GLP-1 (100 nmol/L liraglutide) presented a greater SIRT6 and lower nuclear factor-kB expression compared with cells treated only with high glucose. These findings establish the involvement of SIRT6 in the inflammatory pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin, the effect of which is associated with morphological and compositional characteristics of a potential stable plaque phenotype.Cardiovascular disease represents the leading cause of death in patients with type 2 diabetes (1). Diabetes leads to increased vulnerability for plaque disruption, and mediates increased incidence and severity of clinical events (2). Inflammation, particularly in diabetes, plays a central role in the cascade of events that result in plaque erosion and fissuring (2). There is now increasing evidence that a number of transcription factors, including the Sir2 family of enzymes, namely sirtuins (SIRTs), regulate multiple genes whose products are putatively involved in the regulation of inflammation and endothelial cell (EC) function (3). The Sir2 family consists of seven enzymes (SIRT1 to SIRT7) that share a conserved core catalytic domain, but differ in their cellular localization and tissue distribution (4). Among the SIRTs, SIRT6, a chromatinassociated deacetylase, is considered to have a leading role in regulating genomic stability, cellular metabolism, stress response, and aging (5-8). A recent study (9) in mice suggested a role for SIRT6 in inflammation. Moreover, the knockdown of SIRT6 resulted in the increased expression of proinflammatory cytokines (interleukin [IL]-1b, IL-6, and IL-8), extracellular matrix remodeling enzymes (matrix metalloproteinase [MMP]-2, MMP-9, and plasminogen activator inhibitor 1), and intracellular adhesion molecule-1 (4). In ECs, the loss of SIRT6 was associated with an increased expression of nuclear factor-kB (NF-kB), whereas o...

This article is available online at http://www.jlr.org tural basis of the progression from well-compensated hypertrophy to HF is still largely unknown in MS patients. Emerging evidence suggests that inherited and acquired cardiomyopathies, such as impaired glucose tolerance and diabetes, are associated with marked intracellular lipid accumulation in the heart ( 2, 3 ). In the normal body, most triglyceride is stored in adipocytes; the amount of triglyceride stored in nonadipocyte tissues (liver, and myocardium) is minimal and very tightly regulated. However, several-fold increased cardiomyocyte triglyceride stores are observed in animal models of obesity and diabetes ( 4 ). This lipid accumulation may contribute to cardiomyocyte death by nonoxidative and oxidative ( 5 ) metabolic pathways and to HF. Even in humans, myocardial lipid content was recently reported to increase with the degree of adiposity and contribute to cardiac dysfunction ( 6 ), suggesting that myocardial lipid content may be a biomarker and putative therapeutic target for cardiac disease in patients with MS.Genes involved in lipid metabolism are nutritionally regulated at the transcriptional level in a coordinated fashion ( 7 ). Sterol-regulatory element binding protein (SREBP)-1c is a transcription factor that controls lipogenesis and is induced during overnutrition to facilitate the conversion of glucose to fatty acids and triglycerides for the storage of excess energy ( 8 ). Uncontrolled activation of nuclear SREBP-1c in the liver can cause hepatosteatosis Metabolic syndrome (MS) is strongly associated with left ventricular (LV) hypertrophy and cardiac function derangements that lead to heart failure (HF) ( 1 ). The struc-

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