Neurotensin Gene rs2234762 C>G Variant Associates with Reduced Circulating Pro-NT Levels and Predicts Lower Insulin Resistance in Overweight/Obese Children.

Neurotensin (NT) is a small protein implicated in the regulation of energy balance which acts as both a neurotransmitter in the central nervous system and as a gastrointestinal peptide. In the gut, NT is secreted after fat ingestion and promotes the absorption of fatty acids. The circulating levels of its precursor, pro-NT, predicts the presence and development of metabolic and cardiovascular diseases. Despite the extensive knowledge on the dynamic changes that occur to pro-NT = after fat load, the determinants of fasting pro-NT are unknown. The aim of this study was to determine the possible genetic regulation of plasma pro-NT. The NT gene (NTS) was sequenced for potential functional variants, evaluating its entire genomic and potentially regulatory regions, in DNA from 28 individuals, stratified by low and high pro-NT levels. The identified variant differently distributed in the two pro-NT subgroups was genotyped in a cohort of nine hundred and thirty-two overweight/obese children and adolescents. A total of seven sequence variations across the NTS gene, none of them located in coding regions, were identified. The rs2234762 polymorphism, sited in the NTS gene promoter, was statistically more frequent in the lowest pro-NTS level group. Carriers of the rs2234762 variant showed lower pro-NT levels, after adjusting for sex, age, BMI, triglycerides and the Tanner stage. Having NTS rs2234762 predicted less pronounced insulin resistance at the 6.5-year follow-up with OR: 0.46 (0.216-0.983), at the logistic regression analysis adjusted for age, sex and BMI. In conclusion, the NTS rs2234762 gene variant is a determinant of reduced circulating pro-NT levels in overweight and obese children, which predisposes this group to a more favorable metabolic profile and a reduced insulin resistance later in life, independently from metabolic confounders.

Reduced High-Density Lipoprotein Cholesterol Is an Independent Determinant of Altered Bone Quality in Women with Type 2 Diabetes.

Type 2 diabetes mellitus (T2DM) is associated with an increased fracture risk. Our study aimed to explore differences in bone alterations between T2DM women and controls and to assess clinical predictors of bone impairment in T2DM. For this observational case control study, we recruited 126 T2DM female patients and 117 non-diabetic, age- and BMI-comparable women, who underwent clinical examination, routine biochemistry and dual-energy X-ray absorptiometry (DXA) scans for bone mineral density (BMD) and trabecular bone score (TBS) assessment-derived indexes. These were correlated to metabolic parameters, such as glycemic control and lipid profile, by bivariate analyses, and significant variables were entered in multivariate adjusted models to detect independent determinants of altered bone status in diabetes. The T2DM patients were less represented in the normal bone category compared with controls (5% vs. 12%; p = 0.04); T2DM was associated with low TBS (OR: 2.47, C.I. 95%: 1.19-5.16, p = 0.016) in a regression model adjusted for age, menopausal status and BMI. In women with T2DM, TBS directly correlated with plasma high-density lipoprotein cholesterol (HDL-c) (p = 0.029) and vitamin D (p = 0.017) levels. An inverse association was observed with menopausal status (p < 0.001), metabolic syndrome (p = 0.014), BMI (p = 0.005), and waist circumference (p < 0.001). In the multivariate regression analysis, lower HDL-c represented the main predictor of altered bone quality in T2DM, regardless of age, menopausal status, BMI, waist circumference, statin treatment, physical activity, and vitamin D (p = 0.029; R2 = 0.47), which likely underlies common pathways between metabolic disease and bone health in diabetes.

Liver fibrosis is associated with impaired bone mineralization and microstructure in obese individuals with non-alcoholic fatty liver disease.

BACKGROUND AND PURPOSE: Chronic liver diseases are associated with increased bone fracture risk, mostly in end-stage disease and cirrhosis; besides, data in non-alcoholic fatty liver disease (NAFLD) are limited. Aim of this study was to investigate bone mineralization and microstructure in obese individuals with NAFLD in relation to the estimated liver fibrosis. METHODS: For this cross-sectional investigation, we analyzed data from 1872 obese individuals (44.6 ± 14.1 years, M/F: 389/1483; BMI: 38.3 ± 5.3 kg/m2) referring to the Endocrinology outpatient clinics of Sapienza University, Rome, Italy. Participants underwent clinical work-up, Dual-Energy X-ray Absorptiometry for assessing bone mineral density (BMD) and microarchitecture (trabecular bone score, TBS). Liver fibrosis was estimated by Fibrosis Score 4 (FIB-4). Serum parathyroid hormone (PTH), 25(OH) vitamin D, osteocalcin and IGF-1 levels were measured. RESULTS: Obese individuals with osteopenia/osteoporosis had greater FIB-4 than those with normal BMD (p < 0.001). FIB-4 progressively increased in presence of degraded bone microarchitecture (p < 0.001) and negatively correlated with the serum osteocalcin (p < 0.001) and IGF-1 (p < 0.001), which were both reduced in presence of osteopenia/osteoporosis. FIB-4 predicted IGF-1 reduction in multivariable regression models adjusted for confounders (ß: - 0.18, p < 0.001). Higher FIB-4 predicted bone fragility with OR 3.8 (95%C.I:1.5-9.3); this association persisted significant after adjustment for sex, age, BMI, diabetes, smoking status and PTH at the multivariable logistic regression analysis (OR 1.91 (95%C.I:1.15-3.17), p < 0.01), with AUROC = 0.842 (95%C.I:0.795-0.890; p < 0.001). CONCLUSION: Our data indicate the presence of a tight relation between NAFLD-related liver fibrosis, lower bone mineral density and degraded microarchitecture in obese individuals, suggesting potential common pathways underlying liver and bone involvement in obesity and insulin resistance-associated disorders.

Dipeptidyl Peptidase 4 (DPP4) as A Novel Adipokine: Role in Metabolism and Fat Homeostasis.

Dipeptidyl peptidase 4 (DPP4) is a molecule implicated in the regulation of metabolic homeostasis and inflammatory processes, and it exerts its main action through its enzymatic activity. DPP4 represents the enzyme most involved in the catabolism of incretin hormones; thus, its activity impacts appetite, energy balance, and the fine regulation of glucose homeostasis. Indeed, DPP4 inhibitors represent a class of antidiabetic agents widely used for the treatment of Type 2 diabetes mellitus (T2DM). DPP4 also acts as an adipokine and is mainly secreted by the adipose tissue, mostly from mature adipocytes of the visceral compartment, where it exerts autocrine and paracrine activities. DPP4 can disrupt insulin signaling within the adipocyte and in other target cells and tissues, where it also favors the development of a proinflammatory environment. This is likely at the basis of the presence of elevated circulating DPP4 levels in several metabolic diseases. In this review, we summarize the most recent evidence of the role of the DPP4 as an adipokine-regulating glucose/insulin metabolism and fat homeostasis, with a particular focus on clinical outcomes associated with its increased secretion in the presence of adipose tissue accumulation and dysfunction.

Biliverdin reductase-A protein levels are reduced in type 2 diabetes and are associated with poor glycometabolic control.

AIM: Biliverdin reductase-A (BVR-A) other than its canonical role in the degradation pathway of heme as partner of heme oxygenase-1 (HO1), has recently drawn attention as a protein with pleiotropic functions involved in insulin-glucose homeostasis. However, whether BVR-A expression is altered in type 2 diabetes (T2D) has never been evaluated. MAIN METHODS: BVR-A protein levels were evaluated in T2D (n = 44) and non-T2D (n = 29) subjects, who underwent complete clinical workup and routine biochemistry. In parallel, levels HO1, whose expression is regulated by BVR-A as well as levels of tumor necrosis factor α (TNFα), which is a known repressor for BVR-A with pro-inflammatory properties, were also assessed. KEY FINDINGS: BVR-A levels were significantly lower in T2D subjects than in non-T2D subjects. Reduced BVR-A levels were associated with greater body mass, systolic blood pressure, fasting blood glucose (FBG), glycated hemoglobin (HbA1c), triglycerides, transaminases and TNFα, and with lower high-density lipoprotein (HDL) levels. Lower BVR-A levels are associated with reduced HO1 protein levels and the multivariate analysis showed that BVR-A represented the main determinant of HO1 levels in T2D after adjustment. In addition, reduced BVR-A levels were able to predict the presence of T2D with AUROC = 0.69. for potential confounders. SIGNIFICANCE: Our results demonstrate for the first time that BVR-A protein levels are reduced in T2D individuals, and that this alteration strictly correlates with poor glycometabolic control and a pro-inflammatory state. Hence, these observations reinforce the hypothesis that reduced BVR-A protein levels may represent a key event in the dysregulation of intracellular pathways finally leading to metabolic disorders.