Increased plasma proneurotensin levels identify NAFLD in adults with and without type 2 diabetes

Context Neurotensin (NT), an intestinal peptide released by fat ingestion, promotes lipid absorption; higher circulating NT levels are associated with type 2 diabetes (T2D), obesity, and cardiovascular disease. Whether NT is related to nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) has not been fully investigated. Objective To study the relationship between plasma proneurotensin 1 to 117 (pro-NT), a stable fragment of the NT precursor hormone, and the presence/severity of NAFLD/NASH and to unravel correlates of increased pro-NT levels. Design/Setting/Participants For this cross-sectional study, 60 obese individuals undergoing bariatric surgery for clinical purposes were recruited. The association between pro-NT and NAFLD was further investigated in 260 consecutive subjects referred to our outpatient clinics for metabolic evaluations, including liver ultrasonography. The study population underwent complete metabolic characterization; in the obese cohort, liver biopsies were performed during surgery. Main Outcome Measures Plasma pro-NT levels in relation to NAFLD/NASH. Results Obese subjects with biopsy-proven NAFLD (53%) had significantly higher plasma pro-NT than those without NAFLD (183.6 ± 81.4 vs 86.7 ± 56.8 pmol/L, P < 0.001). Greater pro-NT correlated with NAFLD presence (P < 0.001) and severity (P < 0.001), age, female sex, insulin resistance, and T2D. Higher pro-NT predicted NAFLD with an area under receiver operating characteristic curve of 0.836 [95% confidence interval (CI), 0.73 to 0.94; P < 0.001]. Belonging to the highest pro-NT quartile correlated with increased NAFLD risk (odds ratio, 2.62; 95% CI, 1.08 to 6.40) after adjustment for confounders. The association between higher pro-NT and NAFLD was confirmed in the second cohort independently from confounders. Conclusions Increased plasma pro-NT levels identify the presence/severity of NAFLD; in dysmetabolic individuals, NT may specifically promote hepatic fat accumulation through mechanisms likely related to increased insulin resistance. © 2018 Endocrine Society

Hypertension, cardiovascular risk and polymorphisms in genes controlling the cytochrome P450 pathway of arachidonic acid: A sex-specific relation?

Hypertension is a multifactorial disease in which the interplay of genetic and environmental factors that maintain blood pressure stable throughout life is altered. Cytochrome P450 (CYP)-derived metabolites of arachidonic acid such as epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid (20-HETE), active on vascular tone, endothelial function and renal sodium reapportion, have been identified as candidate mediators in the development of hypertension in several animal models, with remarkable sex-specific effect. Several SNPs, some recognized as functional, in human genes implicated in EETs/20-HETE biosynthesis and metabolism, such as CYP2J2 and CYP4A11, have been tested for association with blood pressure, hypertension and its long-term cardiovascular consequences in different populations, with conflicting results. A sex-specific effect, related to CYP4F2 polymorphisms and expression, has been observed in association studies. This finding indicates that altered 20-HETE bioactivity underlay the excess of hypertension and associated vascular events observed in men with respect to women and is consistent with the results from experimental models. Further epidemiological and mechanistic studies are required to confirm the effect of lipid mediators on blood pressure in humans and define the mechanisms of a putative sex-specific effect

High salt intake increases copeptin but salt sensitivity is associated with fluid induced reduction of copeptin in women.

This study investigated if copeptin is affected by high salt intake and whether any salt-induced changes in copeptin are related to the degree of salt sensitivity. The study was performed on 20 men and 19 women. In addition to meals containing 50 mmol NaCl daily, capsules containing 100 mmol NaCl and corresponding placebo capsules were administered during 4 weeks each, in random order. Measurements of 24 h blood pressure, body weight, 24 h urinary volume, and fasting plasma copeptin were performed at high and low salt consumption. Copeptin increased after a high compared to low dietary salt consumption in all subjects 3,59 ± 2,28 versus 3,12 ± 1,95 (P = 0,02). Copeptin correlated inversely with urinary volume, at both low (r = -0,42; P = 0,001) and high (r = -0,60; P < 0,001) salt consumption, as well as with the change in body weight (r = -0,53; P < 0,001). Systolic salt sensitivity was inversely correlated with salt-induced changes of copeptin, only in females (r = -0,58; P = 0,017). As suppression of copeptin on high versus low salt intake was associated with systolic salt sensitivity in women, our data suggest that high fluid intake and fluid retention may contribute to salt sensitivity

Method of Predicting Obesity Comprising Measuring Neurotensin

The presently disclosed subject matter relates to a method for predicting increased risk of obesity on a non-obese subject. More particularly, the presently disclosed subject matter relates to a method of predicting increased risk of obesity in a non-obese subject by determining a level of neurotensin expression in a biological sample from the subject and comparing the level of neurotensin expression in the sample with a control level. The presently disclosed subject matter further relates to a method of preventing and/or treating obesity in a subject in need thereof by administering to the subject an effective amount of an agent that inhibits neurotensin

Family History of Myocardial Infarction Increases Risk of Renal Dysfunction in Middle Age.

Background/Aims: Chronic kidney disease (CKD) is common in the general population, may lead to end-stage renal disease, and is most frequently found among males. Familial clustering of kidney diseases has been observed. We aimed to study a potential association between the family history of myocardial infarction (MI) and renal dysfunction. Methods: 22,297 males and 10,828 females, aged 33-60 years, from a population-based cohort study were studied. Estimated glomerular filtration rate (eGFR) was assessed by the CKD-EPI creatinine equation. Every participant filled in a self-administered questionnaire including family history. Heredity for MI was defined as mother or father having had MI and/or died from MI, and/or brother or sister having had MI. Binary logistic regression and multiple linear regression were used in the analyses. Results: Multiple linear regression revealed a significantly increased risk of renal dysfunction in those with a positive heredity for MI (the whole cohort p = 0.01, males p = 0.000, females p = 0.169). Binary logistic regression showed that males with heredity for MI with a mean age of 43 years have a 2 times higher risk (p = 0.02) of belonging to the group with GFR <45 ml/min/1.73 m(2) compared to those without heredity. For the whole cohort the increased risk was 1.6 times (p = 0.07). There was no significant association for females (p = 0.88). Conclusion: These findings demonstrate that a familial burden of MI is associated with renal dysfunction, in men, already in middle age. Genetic variants may underlie predisposition to CKD in those with heredity for MI. © 2014 S. Karger AG, Basel

Neurotensin is a lipid-induced gastrointestinal peptide associated with visceral adipose tissue inflammation in obesity

Neurotensin (NT) is a 13-amino acid peptide localized in the neuroendocrine cells of the small intestine, which promotes fat absorption and fatty acids translocation in response to lipid ingestion. NT-knock-out mice fed with a high-fat diet are protected from obesity, fatty liver, and the development of insulin-resistance. In humans, higher plasma levels of pro-NT, which is the stable circulating precursor of NT, predict obesity, type 2 diabetes (T2D), and cardiovascular disease. In obesity, the presence of visceral adipose tissue (VAT) inflammation leads to unfavorable metabolic outcomes and is associated with the development of T2D and non-alcoholic fatty liver disease (NAFLD). In this study, we investigated the relationship between plasma pro-NT levels and the presence of VAT inflammation in biopsies from 40 morbidly obese subjects undergoing bariatric surgery. We demonstrated that higher proNT levels are significantly associated with greater macrophages infiltration, HIF-1&alpha;, WISP-1, and UNC5B expression in VAT (all p < 0.01) due to the diagnosis of T2D and NAFLD. The overall results show that, in obesity, pro-NT is a biomarker of VAT inflammation and insulin-resistance. Additionally, NT may be involved in the development of dysmetabolic conditions likely mediated by increased gut fat absorption and the presence of a proinflammatory milieu in the adipose tissue

Polymorphism in the MHC2TA Gene Is Associated with Features of the Metabolic Syndrome and Cardiovascular Mortality

BACKGROUND: Recently, a -168A→G polymorphism in the MHC class II transactivator gene (MHC2TA) was shown to be associated with increased susceptibility to myocardial infarction (MI). AIM: To confirm the association between the MHC2TA -168A→G polymorphism and MI and to study its putative role for microalbuminuria, the metabolic syndrome (MetS) and cardiovascular mortality. MATERIALS AND METHODS: Using an allelic discrimination method we genotyped 11,064 individuals from three study populations: 1) 4,432 individuals from the Botnia type 2 diabetes (T2D) study, 2) 1,222 patients with MI and 2,345 control subjects participating in the Malmö Diet and Cancer study and comprising an MI case-control sample, and 3) 3,065 T2D patients from the Local Swedish Diabetes registry. RESULTS: No association between the -168A→G polymorphism in MHC2TA and MI was observed. However, in the Botnia cohort the AG/GG genotypes were associated with cardiovascular mortality after MI (1.78 [1.09–2.92], p = 0.02). In addition, the AG/GG genotypes were more common in subjects with MetS (40.1% vs. 36.9%, p = 0.03) and in non-diabetic subjects with microalbuminuria (45.4% vs. 36.5%, p = 0.003) compared to control subjects. CONCLUSIONS: A polymorphism in MHC2TA was associated with cardiovascular mortality and predictors of cardiovascular mortality, microalbuminuria and MetS

Multiple anthropometric measures in relation to incidence of diabetes: a Swedish population-based cohort study.

Obesity is the major modifiable risk factor for diabetes. This study investigated the incidence of diabetes in relation to multiple anthropometric measures

Midlife risk factor exposure and incidence of cardiac arrest depending on cardiac or non-cardiac origin

Objective: Little is known about midlife risk factors of future cardiac arrest. Our objective was to evaluate cardiovascular risk factors in midlife in relation to the risk of cardiac arrest (CA) of cardiac and non-cardiac origin later in life. Methods: We cross-matched individuals of the population based Malmö Diet and Cancer study (n = 30,447) with the local CA registry of the city of Malmö. Baseline exposures were related to incident CA. Results: During a mean follow-up of 17.6. ±. 4.6. years, 378 CA occurred, of whom 17.2% survived to discharge. Independent midlife risk factors for CA of cardiac origin included coronary artery disease (HR 2.84 (1.86-4.34) (p 30kg/m2) (HR 2.37 (1.51-3.71) (p <0.001)), smoking (HR 2.05 (1.33-3.15) (p <0.001)) and being on antihypertensive treatment (HR 2.25 (1.46-3.46) (p <0.001)). Conclusion: Apart from smoking, which increases the risk of CA in general, the midlife risk factor pattern differs between CA of cardiac and non-cardiac origin. Whereas CA of cardiac origin is predicted by history of cardiovascular disease, dyslipidemia and diabetes mellitus, the main risk factors for CA of non-cardiac origin are obesity and hypertension. In addition to control of classical cardiovascular risk factors for prevention of CA, our results suggest that prevention of midlife obesity may reduce the risk of CA of non-cardiac origin