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Background and Aims: Neurotensin (NT) is an intestinal peptide released after fat ingestion, which regulates appetite and facilitates lipid absorption. Elevated plasma levels of its stable precursor pro-neurotensin (pro-NT) are associated with type 2 diabetes, obesity and cardiovascular mortality in adult populations; no data on pro-NT and metabolic disease are available in children. Aim of the study was to evaluate plasma pro-NT in relation to the presence of obesity in children, and to test if high pro-NT associates with the development of metabolic impairment later in life., Methods and Results: For this longitudinal retrospective study, we studied 151 overweight/obese children undergoing metabolic evaluations at University of Cagliari, Italy. Pro-NT was also assessed in 46 normal-weight, age-, sex-comparable normal-weight children, selected as a reference group. At the baseline, pro-NT was comparable between overweight/obese and normal-weight children and correlated positively with age (p < 0.001), triglycerides (p < 0.001) and inversely with HDL levels (p = 0.008). Plasma pro-NT associated with high triglycerides with OR = 5.9 (95%CI: 1.24-28.1; p = 0.026) after adjustment for multiple confounders. At the 6.5-year follow-up, high basal pro-NT associated with impaired β-cell function to compensate for insulin-resistance (disposition index: r = -0.19, p = 0.035) and predicted bodyweight increase, as indicated by percentage change of standard deviation score BMI (median(95%CI) = +20.8(+4.9-+27.5)% in the highest tertile), independently from age, sex, triglycerides and insulin-resistance (standardized β = 0.24; p = 0.036)., Conclusions: Elevated pro-NT levels in children are significantly associated with weight gain later in life and may represent a marker of susceptibility to metabolic impairment in presence of obesity., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this study., (Copyright © 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background and Aim: Dipeptidyl peptidase 4 (DPP4) is a key enzyme involved in the regulation of the incretin system exerted by cleaving the glucagon-like peptide 1 (GLP-1); the blockage of DPP4, exerted by the antidiabetic agents DPP4-inhibitors (DPP4-I), results in greater GLP-1 concentration and improved glycaemic control. DPP4 acts also as a pro-inflammatory molecule and mediates vascular damage in experimental models. The relationship between DPP4 activity and endothelial function in diabetes has not been explored yet. Aim of this study was to investigate systemic plasma DPP4 activity in relation to endothelial function in patients with type 2 diabetes mellitus (T2DM)., Methods and Results: Sixty-two T2DM individuals were recruited in our Diabetes outpatient clinics, Sapienza University, Rome, Italy. All participants underwent complete clinical work-up; endothelial function was evaluated by flow-mediated dilatation (FMD) test; plasma DPP4 activity was assessed by measuring the 7-amino-4-methylcoumarin (AMC) cleavage rate from the synthetic substrate H-glycyl-prolyl-AMC and compared with DPP4 activity measured in sixty-two age-, sex-, BMI-matched non-diabetic subjects. Patients with T2DM had significantly higher DPP4 activity than non-diabetic individuals (211,466 ± 87657 vs 158,087 ± 60267 nmol/min/ml, p < 0.001); in T2DM patients, greater DPP4 activity significantly correlated with lower FMD whereas was not associated with BMI and metabolic control. Greater systemic DPP4 activity was an independent predictor of reduced FMD after adjusting for age, gender and other confounders., Conclusions: Circulating DPP4 activity is increased in individuals with T2DM and associated with signs of endothelial dysfunction such as impaired FMD. DPP4 may negatively affect endothelial function through mechanisms beyond glucose homeostasis and metabolic control., (Copyright © 2019 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. All rights reserved.)

Background and Aims: 1α,25-dihydroxyvitamin-D3, the biologically active vitamin D, plays a central role in several metabolic pathways through the binding to the vitamin D receptor (VDR). VDR has been shown to be involved in cardiovascular diseases, cancer, autoimmunity and type 2 diabetes mellitus (T2DM). Several polymorphisms in the VDR gene have been described. Among these, the rs11568820 G-to-A nucleotide substitution was found to be functional, modulating the transcription of the VDR gene. Objective of this study was to perform an association study between rs11568820 polymorphism and T2DM in a cohort of Italian adults with T2DM and in non-diabetic controls. To add further insight into the role of VDR gene we explored whether this association begins early in life in overweight/obese children, or becomes manifest only in adulthood., Methods and Results: As many as 1788 adults and 878 children were genotyped for the rs11568820 polymorphism. All participants underwent oral glucose tolerance tests (OGTT), with measurement of glucose and insulin levels. Indices of insulin-resistance and secretion were also calculated. The AA genotype was significantly more frequent in adults with T2DM compared to controls (7.5% vs. 4.6%, P = 0.037), and conferred a higher risk of T2DM (ORHom = 1.69C.I. = [1.13-2.53], P = 0.011). In the adult cohort, rs11568820 was also associated with reduced indices of β-cell insulin secretion. In children, the AA genotype was associated with 2 h high-normal glucose, a marker of cardio-metabolic risk., Conclusions: Our study demonstrates for the first time that VDR gene AA carriers have higher risk of T2DM and impaired insulin secretion. In children, the association between AA homozygous and high-normal 2h glucose suggests that mild alterations associated with this genotype may appear early in life., (Copyright © 2016 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Hypoadiponectinemia has been reported in patients with familial combined hyperlipidemia (FCHL) presenting increased waist circumference and insulin resistance. However, no studies have evaluated this association in non-obese FCHL patients. Moreover, it is unclear whether correction of lipoprotein abnormalities may influence adiponectin levels in FCHL., Methods and Results: We have compared serum levels of adiponectin in 199 non-obese FCHL patients (BMI 25.96+/-3.7), 116 normolipaemic (NL) non-affected relatives (BMI 24.4+/-4.0) and 192 controls (BMI 28.0+/-7.4). In a subgroup of FCHL patients, changes in adiponectin levels after treatment with atorvastatin (n=22) or fenofibrate (n=26) were also evaluated. FCHL patients as well as their NL relatives showed lower serum adiponectin levels compared to controls (9.7+/-5.4 microg/mL, 10.7+/-5.3 microg/mL and 17.3+/-13.7microg/mL, respectively; p<0.0001 for all comparisons). After controlling for confounders, the strongest association with hypoadiponectinemia was observed with family history of FCHL, followed by HDL-C (negatively) and age (positively). These variables jointly explained 15% of the total variance of serum adiponectin levels. After 24-week of treatment, adiponectin was increased by 12.5% (p<0.05) by atorvastatin and was reduced by 10% by fenofibrate, resulting in a treatment difference of 22.5% in favor of atorvastatin (p<0.017)., Conclusions: FCHL patients showed lower serum adiponectin levels compared to controls. Also normolipaemic relatives of FCHL patients presented decreased levels of adiponectin, suggesting a possible common background in the determination of this abnormality. Overall, these observations indicate that hypoadiponectinemia may be an inherent characteristic of the FCHL phenotype. In FCHL patients hypoadiponectinemia may be partially corrected by atorvastatin but not by fenofibrate treatment.

Background and Aim: Oxidized low-density lipoproteins (OxLDLs) play a critical role in endothelial dysfunction, which is implicated in the pathogenesis of atherosclerosis. Vascular endothelial cells internalize and degrade oxLDL through the endothelial lectin-like oxidized LDL receptor 1 (OLR1). OLR1 is up-regulated in several pathological conditions, including hypertension, hyperlipidemia, diabetes, atherosclerosis and inflammation, and represents therefore a good candidate for coronary artery disease (CAD). Recently, a 3'-UTR (188 C>T) SNP in the OLR1 gene has been reported to be associated with coronary artery stenosis and myocardial infarction. In the present study we investigated whether the OLR1 gene 188 C>T SNP is a genetic risk marker for CAD in Italian patients with angiographically defined coronary atherosclerosis, and assessed its relation with clinical and metabolic abnormalities, including severity of disease (classified as restenosis, single- or multiple coronary vessels disease, and MI)., Methods: The 3'-UTR C>T SNP was detected in real-time PCR in 351 subjects with CAD and in 215 control subjects., Results: The OLR1-T allele frequencies were 48.9% in the CAD subjects and 47.7% in controls, with no significant difference between the two groups. Also, the 3'-UTR C>T SNP did not associate with any of the parameters of severity of disease. Furthermore, none of the other clinical and metabolic parameters were associated with the OLR1 gene SNP., Conclusions: Our observations suggest that, in our population, the 3'-UTR C>T polymorphism of the OLR1 gene is unlikely to play a role in the pathogenesis of coronary artery disease.