Modulation of GLP-1 levels by a genetic variant that regulates the cardiovascular effects of intensive glycemic control in ACCORD

OBJECTIVE A genome-wide association study in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial identified two markers (rs57922 and rs9299870) that were significantly associated with cardiovascular mortality during intensive glycemic control and could potentially be used, when combined into a genetic risk score (GRS), to identify patients with diabetes likely to derive benefit from intensive control rather than harm. The aim of this study was to gain insights into the pathways involved in the modulatory effect of these variants. RESEARCH DESIGN AND METHODS Fasting levels of 65 biomarkers were measured at baseline and at 12 months of follow-up in the ACCORD-Memory in Diabetes (ACCORD- MIND) MRI substudy (n = 562). Using linear regression models, we tested the association of the GRS with baseline and 12-month biomarker levels, and with their difference (D), among white subjects, with genotype data (n = 351) stratified by intervention arm. RESULTS A significant association was observed between GRS and DGLP-1 (glucagon-like peptide 1, active) in the intensive arm (P = 3 3 1024). This effect was driven by rs57922 (P = 5 3 1024). C/C homozygotes, who had been found to derive cardiovascular benefits from intensive treatment, showed a 22% increase in GLP-1 levels during follow-up. By contrast, T/T homozygotes, who had been found to experience increased cardiac mortality with intensive treatment, showed a 28% reduction in GLP-1 levels. No association between DGLP-1 and GRS or rs57922 was observed in the standard treatment arm. CONCLUSIONS Differences in GLP-1 axis activation may mediate the modulatory effect of variant rs57922 on the cardiovascular response to intensive glycemic control. These findings highlight the importance of GLP-1 as a cardioprotective factor

Genetic tools for coronary risk assessment in type 2 diabetes: A cohort study from the ACCORD clinical trial

OBJECTIVE We evaluated whether the increasing number of genetic loci for coronary artery disease (CAD) identified in the general population could be used to predict the risk of major CAD events (MCE) among participants with type 2 diabetes at high cardiovascular risk. RESEARCH DESIGN AND METHODS A weighted genetic risk score (GRS) derived from 204 variants representative of all the 160 CAD loci identified in the general population as of December 2017 was calculated in 5,360 and 1,931 white participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Outcome Reduction With Initial Glargine Intervention (ORIGIN) studies, respectively. The association between GRS and MCE (combining fatal CAD events, nonfatal myocardial infarction, and unstable angina) was assessed by Cox proportional hazards regression. RESULTS The GRS was associated with MCE risk in both ACCORD and ORIGIN (hazard ratio [HR] per SD 1.27, 95% CI 1.18–1.37, P = 4 3 10210, and HR per SD 1.35, 95% CI 1.16–1.58, P = 2 3 1024, respectively). This association was independent from interventions tested in the trials and persisted, though attenuated, after adjustment for classic cardiovascular risk predictors. Adding the GRS to clinical predictors improved incident MCE risk classification (relative integrated discrimination improvement +8%, P = 7 3 1024). The performance of this GRS was superior to that of GRS based on the smaller number of CAD loci available in previous years. CONCLUSIONS When combined into a GRS, CAD loci identified in the general population are associated with CAD also in type 2 diabetes. This GRS provides a significant improvement in the ability to correctly predict future MCE, which may increase further with the discovery of new CAD loci

PPARA polymorphism influences the cardiovascular benefit of fenofibrate in type 2 diabetes: Findings from accord-lipid

The cardiovascular benefits of fibrates have been shown to be heterogeneous and to depend on the presence of atherogenic dyslipidemia. We investigated whether genetic variability in the PPARA gene, coding for the pharmacological target of fibrates (PPAR-a), could be used to improve the selection of patients with type 2 diabetes who may derive cardiovascular benefit from addition of this treatment to statins. We identified a common variant at the PPARA locus (rs6008845, C/T) displaying a study-wide significant influence on the effect of fenofibrate on major cardiovascular events (MACE) among 3,065 self-reported white subjects treated with simvastatin and randomized to fenofibrate or placebo in the ACCORD-Lipid trial. T/T homozygotes (36% of participants) experienced a 51% MACE reduction in response to fenofibrate (hazard ratio 0.49; 95% CI 0.34–0.72), whereas no benefit was observed for other genotypes (Pinteraction 5 3.7 3 1024). The rs6008845-by-fenofibrate interaction on MACE was replicated in African Americans from ACCORD (N 5 585, P 5 0.02) and in external cohorts (ACCORD-BP, ORIGIN, and TRIUMPH, total N 5 3059, P 5 0.005). Remarkably, rs6008845 T/T homozygotes experienced a cardiovascular benefit from fibrate even in the absence of atherogenic dyslipidemia. Among these individuals, but not among carriers of other genotypes, fenofibrate treatment was associated with lower circulating levels of CCL11—a proinflammatory and atherogenic chemokine also known as eotaxin (P for rs6008845-by-fenofibrate interaction 5 0.003). The GTEx data set revealed regulatory functions of rs6008845 on PPARA expression in many tissues. In summary, we have found a common PPARA regulatory variant that influences the cardiovascular effects of fenofibrate and that could be used to identify patients with type 2 diabetes who would derive benefit from fenofibrate treatment, in addition to those with atherogenic dyslipidemia

Lung cancer presenting with gastrointestinal symptoms: a tricky diagnosis

Lung cancer presenting with gastrointestinal symptoms: a tricky diagnosi

Severe multi-organ complications in young adult after bariatric surgery

Case report: A 36 years old girl was referred to Ophthalmology Emergency Room (O.E.R.) for progressive loss of virus, with intensive xerophthalmia and itching, she had almost total blindness on right eye, and a 7/10 loss of visual acuity in left eye; the discharge diagnosis was bilateral keratoconjunctivitis sicca and right corneal ulceration

Effect of 14 days experimental horizontal bed rest on lipid and inflammatory profile.

Objectives: Physical inactivity reduces quality of life and implies higher healthcare costs. Experimental bed-Rest (BR) model allows to analyze metabolic consequences of physical inactivity. The PANGeA group set 14-day horizontal BR to evaluate the effect of bed confinement on body composition, lipid and inflammatory profile. Methods: 23 healthy male subjects were enrolled, divided in 'YOUNG'(n=7;18-25 years) and 'Olders'(n=16;55-65 years). Body composition was assessed by BIA and blood samples were collected at baseline (BDC) and after 14-day BR (BR14). Among the 'OLD', 8 subjects underwent daily specific visual-spatial brain-training during BR (OLDBT). Results: At BDC body mass index was similar in the two groups while OLD showed higher levels of total- (204±39mg/dl vs. 151±15mg/dl;P: 0,002) and LDL-cholesterol (137±34mg/dl vs. 89±12mg/dl;P:0,002). At BR14, a significant decrease of body mass, free-fat Mass (FFM), total body water (TBW), body cell mass (BCM) and muscular mass (MM) was observed. Moreover, OLD showed a total- and LDL-cholesterol reduction (13% and 16%;P: 0,002) while the reduction in the YOUNG was not significant (4.3% and 4%). HDL-cholesterol was significantly reduced only in YOUNG (-17%; P=0,065). Both groups showed a significant increase in serum TNF-a. Althout not significant OLDBT showed an increase in HDL-c (+10%) opposite to the trend observed in OLD without brain traning (OLDNO-BT -10%). Similarly, Total-C/HDL-c ratio was 7% reduced in Old [OLDBT -18%; OLDNO-BT +2%] and 15% increased in YOUNG (P:0, 03). Conclusion: As expected BR was associated with a reduction in body mass, FFM, TBW, BCM and MM. This 'catabolic state' was associated with an increase inflammatory response and, in YOUNG, with a worsened lipid profile. Conversely, OLD showed an apparent lipid profile improvement which seems to be further modulated by brain-training. Further analysis are needed to investigate whether: 1) these changes are associated with decreased cardiovascular risk. 2) Brain-training might have a role in preventing BR associated modifications