RESEARCH ARTICLE Mediterranean Diet
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Mediterranean Diet, Glucose Homeostasis, and Inflammasome Genetic Variants: The CORDIOPREV Study Irene Roncero-Ramos, Oriol A. Rangel-Zu˜niga, Javier Lopez-Moreno, Juan F. Alcala-Diaz, Pablo Perez-Martinez, Rosa Jimenez-Lucena, Justo P. Casta˜no, Helen M. Roche, Javier Delgado-Lista, Jose M. Ordovas, Antonio Camargo, and Jose Lopez-Miranda* 1. Introduction
Scope: Insulin resistance (IR) and chronic low-grade inflammation are hallmarks of type 2 diabetes mellitus (T2DM). The “NOD-like receptor pyrin domain containing-3” (NLRP3) inflammasome component of innate immunity is a metabolic stress sensor modulated by dietary and genetics factors. The aim of this study was to evaluate the effects of the consumption of two diets for 3 years, Mediterranean (Med) and low fat, on glucose homeostasis in the 1002 coronary heart disease patients of the CORDIOPREV study, according to a genetic variant of NLRP3 inflammasome. Methods and results: The study was conducted in the framework of the CORDIOPREV study, a randomized dietary intervention with Med and low-fat diets. Single nucleotide polymorphisms (SNPs) located at inflammasome NLRP3 gene were genotyped by OpenArray platform. Nondiabetic CT+TT carriers of the rs4612666 SNP and AG+AA carriers of the rs10733113 SNP increased insulin sensitivity index (ISI) after 3 years of dietary intervention, whereas no effect was observed in diabetic patients. Further analysis by diet showed that the improvement of the ISI in nondiabetic rs10733113 AG+AA carriers was specific to the consumption of the Med diet. Conclusion: Our results show that the benefits associated with a Med diet regarding glucose homeostasis in non-T2DM patients depend on genetic variation in the inflammasome.
Dr. I. Roncero-Ramos, Dr. O. A. Rangel-Zu˜ niga, J. Lopez-Moreno, Dr. J. F. Alcala-Diaz, Dr. P. Perez-Martinez, R. Jimenez-Lucena, Dr. J. Delgado-Lista, Dr. A. Camargo, Prof. J. Lopez-Miranda Lipids and Atherosclerosis Unit GC9 Nutrigenomics Institute Maimonides for Biomedical Research of Cordoba Reina Sofia University Hospital, University of Cordoba Cordoba 14004, Spain E-mail:
[email protected] Dr. I. Roncero-Ramos, Dr. O. A. Rangel-Zu˜ niga, Dr. J. Lopez-Moreno, Dr. J. F. Alcala-Diaz, Dr. P. Perez-Martinez, R. Jimenez-Lucena, Dr. J. P. Casta˜ no, Dr. J. Delgado-Lista, Dr. A. Camargo, Prof. J. Lopez-Miranda CIBER Fisiopatolog´ıa de la Obesidad y Nutrici´ on Instituto de Salud Carlos III Cordoba 14004, Spain
DOI: 10.1002/mnfr.201700960
Mol. Nutr. Food Res. 2018, 62, 1700960
Type 2 diabetes mellitus (T2DM) is a complex disease characterized by insulin resistance in peripheral tissues followed by beta cell failure.[1] Obesityinduced chronic low-grade activation of inflammatory pathways is linked to the development of IR and T2DM.[2,3] However, despite the association between obesity and T2DM, most obese individuals do not develop T2DM, although most T2DM patients are obese.[4] In addition, patients with myocardial infarction and T2DM have a higher risk of developing a new cardiovascular event than those without T2DM.[5] It is therefore important to establish strategies to prevent the incidence of diabetes in coronary heart disease (CHD) patients. Inflammasomes are central components of the innate immune response which activate inflammation in response to a wide range of signals by producing pro-inflammatory cytokines.[6] Structurally, inflammasomes are commonly
Dr. J. P. Casta˜ no Department of Cell Biology, Physiology, and Immunology Institute Maimonides for Biomedical Research of Cordoba Reina Sofia University Hospital, University of Cordoba Cordoba 14004, Spain Prof. H. M. Roche Nutrigenomics Research Group UCD Conway Institute of Biomolecular Research, and School of Public Health, Physiotherapy and Sports Science University College Dublin Dublin 4, Ireland Prof. J. M. Ordovas Nutrition and Genomics Laboratory Jean Mayer USDA Human Nutrition Research Center on Aging Tufts University Boston, MA 02111, USA Prof. J. M. Ordovas Madrid Institute of Advanced Studies (IMDEA) Alimentacion Madrid 28049, Spain Prof. J. M. Ordovas Spanish National Centre for Cardiovascular Research (CNIC) Madrid 28029, Spain
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formed by an innate pattern recognition receptor, usually a member of the nucleotide-binding oligomerization domain-like receptor (NLR) family, and by the adaptor protein apoptosisassociated speck-like protein containing a caspase-recruitment domain (ASC) and pro-caspase-1.[7] Among the NLR family members, the NLR family pyrin domain-containing 3 (NLRP3) inflammasome plays a significant role in obesity-induced inflammation and IR.[8–10] NLRP3 activates caspase-1 and participates in the synthesis and secretion of IL-1β and IL-18.[11] NLRP3 inflammasome activation and subsequent IL-1β production contribute to islet inflammation induced by chronic exposure to high free fatty acid (FFA) and glucose concentrations, which leads to increased apoptosis and impaired insulin secretion of β-cells.[7,12,13] We have recently demonstrated that consuming a high-fat diet enriched with saturated fatty acids (SFA) specifically induces adipose IL-1β inflammation and insulin resistance. However, if SFA is substituted with monounsaturated fatty acids (MUFA), this attenuates NLRP3-mediated IL-1β activation and insulin resistance despite obesity.[14] NLRP3 activation specifically induces IL-1β inflammation, which, in turn, leads to IR and the progression of T2DM.[15,16] The involvement of NLRP3 in the development of T2DM has been demonstrated in preclinical studies, in which high-fat diet fed NLRP3 knockout mice showed improved glucose tolerance and enhanced insulin sensitivity.[10,17] Moreover, a reduced NLRP3 expression in adipose tissue has also been associated with lower inflammation and improved insulin sensitivity in obese T2DM patients.[8] Moreover, a cross-sectional study showed that genetic variants in NLRP3 are related with IR and an increased risk of T2DM in a Chinese population.[18,19] However, to the best of our knowledge, no longitudinal studies evaluating the diet interaction of NLRP3 SNPs in IR and T2DM subjects have been performed. Furthermore, although a large number of studies have shown the beneficial effect of the consumption of healthy diets such as Mediterranean (Med) and low-fat diets in preventing the risk of T2DM,[20–22] the potential differential effect according to genetic variants in the NLRP3 inflammasome has not been assessed. In this study, we aimed to evaluate the effect of the consumption of two diets, Med or low fat, over a period of 3 years, on glucose homeostasis in the 1002 CHD patients of the CORDIOPREV study, according to a genetic variant of NLRP3 inflammasome.
2. Experimental Section 2.1. Study Subjects The current work was conducted within the framework of the CORDIOPREV study, an ongoing prospective, randomized, opened, controlled trial including 1002 patients with CHD, who had their last coronary event more than 6 months before enrolment. Patients were randomized in two different dietary models, a Med diet and a low-fat diet, over a period of 7 years, in addition to conventional treatment for CHD. Patients were recruited from November 2009 to February 2012, mostly at the Reina Sofia University Hospital (Cordoba, Spain), but patients from other hospital centers from the Cordoba and Jaen provinces were also
Mol. Nutr. Food Res. 2018, 62, 1700960
included. In summary, patients were between 20 and 75 years old, with established CHD without clinical events in the last 6 months, had no other severe diseases or a life expectancy of under 5 years, and were considered able to follow a long-term dietary intervention. Details of the trial design were provided in the Clinicaltrials.gov (NTC00924937). This trial was designed and conducted by the authors, and the protocol and all amendments were approved by the local ethics committees, all of which followed the Helsinki Declaration and good clinical practices. As regards diabetic status at baseline, 540 of the subjects were T2DM patients and 462 were nondiabetics who had not been diagnosed with T2DM in the CORDIOPREV study.[23] Of these, 107 patients developed T2DM according to the American Diabetes Association (ADA) diagnosis criteria[24] after a median follow-up of 59 months. The T2DM population therefore consisted of the 540 T2DM subjects at baseline plus the 107 newly diagnosed T2DM patients (n = 647). The nondiabetic population consisted of those who did not develop T2DM during the followup period (n = 355).
2.2. Study Design The study design has been previously described.[25] Briefly, participants were randomized to receive two diets: a Med diet or a lowfat diet. The low-fat diet consisted of
