Laura Bertoccini

Relationship between adipose tissue dysfunction, vitamin D deficiency and the pathogenesis of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. Its pathogenesis is complex and not yet fully understood. Over the years many studies have proposed various pathophysiological hypotheses, among which the currently most widely accepted is the “multiple parallel hits” theory. According to this model, lipid accumulation in the hepatocytes and insulin resistance increase the vulnerability of the liver to many factors that act in a coordinated and cooperative manner to promote hepatic injury, inflammation and fibrosis. Among these factors, adipose tissue dysfunction and subsequent chronic low grade inflammation play a crucial role. Recent studies have shown that vitamin D exerts an immune-regulating action on adipose tissue, and the growing wealth of epidemiological data is demonstrating that hypovitaminosis D is associated with both obesity and NAFLD. Furthermore, given the strong association between these conditions, current findings suggest that vitamin D may be involved in the relationship between adipose tissue dysfunction and NAFLD. The purpose of this review is to provide an overview of recent advances in the pathogenesis of NAFLD in relation to adipose tissue dysfunction, and in the pathophysiology linking vitamin D deficiency with NAFLD and adiposity, together with an overview of the evidence available on the clinical utility of vitamin D supplementation in cases of NAFLD.

WISP1 Is a Marker of Systemic and Adipose Tissue Inflammation in Dysmetabolic Subjects With or Without Type 2 Diabetes

Context: Wnt1-inducible signaling pathway protein 1 (WISP1) is a novel adipokine participating in adipose tissue (AT) dysfunction; so far, no data on WISP1 in diabetes are available. Objectives: To evaluate plasma WISP1 in subjects with type 2 diabetes (T2D) and its correlates linked to AT inflammation. Design and Participants: For this cross-sectional study, 97 consecutive dysmetabolic patients were recruited at the diabetes outpatient clinics of Sapienza University in Rome; 71 of them had T2D, with (n = 35) or without (n = 36) obesity, and 26 were obese patients without diabetes. Twenty-one normal-weight nondiabetic individuals were enrolled as a control group. Study participants underwent clinical workup and blood sampling for metabolic/inflammatory characterization; magnetic resonance imaging (MRI) data on subcutaneous AT and visceral AT (VAT) area, hepatic fat content, and VAT homogeneity were available for most diabetic patients. Results: Plasma WISP1 significantly increased throughout classes of obesity and correlated with greater VAT area, interleukin-8 (IL-8), and lower adiponectin levels, without differing between diabetic and nondiabetic participants. Higher IL-8 was the main determinant of increased WISP1. MRI-assessed VAT inhomogeneity was associated with higher WISP1, IL-8 and C-reactive protein levels, independent of obesity; high WISP1 strongly predicted VAT inhomogeneity (P < 0.001). Conclusions: WISP1 levels are increased in obese persons and are directly related to adiposity, independent of glycemic status or insulin resistance; moreover, they are strongly associated with increased plasma IL-8 and signal abnormalities of VAT. The overall data add insights to the mechanisms underlying metabolic alterations and may open a scenario for innovative therapeutic approaches for diabetes prevention and care.

The vitamin D receptor functional variant rs2228570 (C>T) does not associate with type 2 diabetes mellitus

ABSTRACT Aim: Vitamin D acts through the binding to the vitamin D receptor (VDR). Several polymorphisms in VDR gene have been studied. Among these, the rs2228570 C>T (FokI) variant has been demonstrated to be functional, leading to a protein with a different size and activity. So far, genetic studies on the association between VDR gene rs2228570 single nucleotide polymorphism (SNP) and type 2 diabetes mellitus (T2DM) showed contradictory results. Thus, we performed an association study in a large cohort of adult Italian subjects with T2DM and in nondiabetic controls. Materials and methods: For this study, 1713 subjects, 883 T2DM patients and 830 controls, were genotyped for the polymorphism. All participants without a diagnosis of diabetes underwent oral glucose tolerance test (OGTT), with measurement of glucose and insulin levels. Indices of insulin resistance (Homeostatic model assessment of insulin resistance, insulin sensitivity index), secretion (homeostatic model assessment for beta-cell, corrected insulin response at 30 minutes) and disposition index were calculated. Results: Genotype distributions and allele frequencies did not show difference between T2DM subjects and controls. We did not find significant differences among the three genotypes regarding gender, age, BMI, waist, hip, waist-to-hip ratio, and blood pressure. There were also no significant differences in lipid parameters, aspartate aminotransferase, and alanine aminotransferase levels. We tested for association with OGTT-derived data and surrogate indices of insulin resistance and secretion. We did not find significant differences among the genotypes in any of above-mentioned parameters. Furthermore, vitamin D levels were measured in a subgroup of subjects. We did not find significant differences among the genotypes. Conclusions: Our study does not provide evidence for the association of the rs2228570 polymorphism with T2DM in a Caucasian population.

The perilipin 2 (PLIN2) gene Ser251Pro missense mutation is associated with reduced insulin secretion and increased insulin sensitivity in Italian obese subjects

Perilipin 2 (PLIN2), a member of the family of perilipin lipid droplets coating proteins, is very widely expressed.

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-1α, 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.

Search for Genetic Variant in the Apelin Gene by Resequencing and Association Study in European Subjects

AIMS Apelin is a peptide produced and secreted by white adipose tissue. It is synthesized as preproapelin, a protein containing 77 aminoacids which is then cleaved to shorter active fragments. As an adipokine, apelin plays a role in the regulation of many biological functions, including body energy homeostasis and glucose metabolism, water balance, and immunity. We have recently demonstrated that subjects with type 2 diabetes (T2D) have significantly higher serum apelin levels compared with controls, and that these levels associate with fasting glucose, basal disposition index, age, and diagnosis of T2D. The first aim of this study was to search for sequence variants in the apelin gene (APLN), located on chromosome Xq25-q26.1 that may associate with serum levels of apelin. The second aim was to analyze the possible association between diabetes and diabetes-related traits and APLN variants. METHODS We designed a two-step genetic association study. Step one consisted of an initial screen of 100 individuals selected from the extremes of the apelin distribution levels wherein we sequenced the APLN gene to identify common variants. In step two, the rs181301686 with a minor allele frequency >0.2 was genotyped in 917 individuals to explore its association with T2D and diabetes-related traits. RESULTS Five sequence variations were found across the APLN gene. To test for association with apelin levels, the rs181301686 and rs2281069 single-nucleotide polymorphisms were genotyped in 256 subjects for whom serum apelin levels were available. No significant differences were observed in apelin levels between genotypes. Association analysis in 917 individuals did not show significant differences between APLN genotypes and diabetes and diabetes-related traits. CONCLUSIONS Resequencing of the apelin gene in subjects stratified by low or high apelin levels identified five APLN variants in an European population. No association was found between the most frequent variant, diabetes, and metabolic parameters.

Variability in genes regulating vitamin D metabolism is associated with vitamin D levels in type 2 diabetes

Mortality rate is increased in type 2 diabetes (T2D). Low vitamin D levels are associated with increased mortality risk in T2D. In the general population, genetic variants affecting vitamin D metabolism (DHCR7 rs12785878, CYP2R1 rs10741657, GC rs4588) have been associated with serum vitamin D. We studied the association of these variants with serum vitamin D in 2163 patients with T2D from the “Sapienza University Mortality and Morbidity Event Rate (SUMMER) study in diabetes”. Measurements of serum vitamin D were centralised. Genotypes were obtained by Eco™ Real-Time PCR. Data were adjusted for gender, age, BMI, HbA1c, T2D therapy and sampling season. DHCR7 rs12785878 (p = 1 x 10–4) and GC rs4588 (p = 1 x 10–6) but not CYP2R1 rs10741657 (p = 0.31) were significantly associated with vitamin D levels. One unit of a weighted genotype risk score (GRS) was strongly associated with vitamin D levels (p = 1.1 x 10–11) and insufficiency (<30 ng/ml) (OR, 95%CI = 1.28, 1.16–1.41, p = 1.1 x 10–7). In conclusion, DHCR7 rs12785878 and GC rs4588, but not CYP2R1 rs10741657, are significantly associated with vitamin D levels. When the 3 variants were considered together as GRS, a strong association with vitamin D levels and vitamin D insufficiency was observed, thus providing robust evidence that genes involved in vitamin D metabolism modulate serum vitamin D in T2D.

Procollagen-III peptide identifies adipose tissue-associated inflammation in type 2 diabetes with or without nonalcoholic liver disease

Procollagen‐III peptide (PIIINP) is a marker of fibrosis associated with increased cardiometabolic risk and progression of chronic liver diseases such as nonalcoholic fatty liver disease (NAFLD) and steatohepatitis; its association with type 2 diabetes mellitus (T2DM) has not been elucidated yet. The aim of this study was to investigate the relationship among circulating PIIINP levels, metabolic traits, and body fat distribution in subjects with T2DM with or without NAFLD.

MODY: quando diagnosticarlo

Il termine MODY (maturity-onset diabetes of the young) indica una forma di diabete monogenico caratterizzato da insorgenza precoce, trasmissione autosomica dominante e alterazione della funzione beta cellulare. E’ la forma più comune di diabete monogenico (1–2% dei casi di diabete in Europa) anche se, per le caratteristiche cliniche simili, spesso i pazienti sono classificati come affetti da Diabete tipo 1 o Diabete tipo 2. In un’analisi nel Regno Unito più dell’80% dei pazienti non sono diagnosticati correttamente, con un ritardo fino a 12 anni per la diagnosi di MODY [1]. Sono stati identificati 13 sottotipi di MODY in base al gene responsabile (Tabella 1) ma mutazioni in GCK (glucokinase), HNF1A, HNF4A e HNF1B (hepatocyte-nuclear factor 1α, 4α e 1β) sono le cause più comuni. Una corretta diagnosi permette di identificare la terapia ottimale, la prognosi, il follow-up e lo screening dei familiari. Il gold standard per la diagnosi di MODY sono i test genetici, altamente sensibili e specifici; sono disponibili in molti laboratori ma sono costosi. E’ necessaria quindi una selezione mirata degli individui da sottoporre ai test [2].

Comment on Elangovan H et al. Vitamin D in liver disease: Current evidence and potential directions. Biochim Biophys Acta 2017;1863(4):907-916

Please cite this article as: I. Barchetta, M. Del Ben, F. Angelico, M. Di Martino, A. Fraioli, G. La Torre, R. Saulle, L. Perri, S. Morini, C. Tiberti, L. Bertoccini, F.A. Cimini, F. Panimolle, C. Catalano, M.G. Baroni, M.G. Cavallo, Comment on Elangovan H et al. Vitamin D in liver disease: Current evidence and potential directions. Biochim Biophys Acta 2017;1863(4):907-916, BBA Molecular Basis of Disease (2017), doi:10.1016/j.bbadis.2017.04.023