Heterozygous pathogenic variants in POMC are not responsible for monogenic obesity: Implication for MC4R agonist use.

PURPOSE: Recessive deficiency of proopiomelanocortin (POMC) causes childhood-onset severe obesity. Cases can now benefit from the melanocortin 4 receptor agonist setmelanotide. Furthermore, a phase 3 clinical trial is evaluating setmelanotide in heterozygotes for POMC. We performed a large-scale genetic analysis to assess the effect of heterozygous, pathogenic POMC variants on obesity. METHODS: A genetic analysis was performed in a family including 2 cousins with childhood-onset obesity. We analyzed the obesity status of heterozygotes for pathogenic POMC variants in the Human Gene Mutation Database. The association between heterozygous pathogenic POMC variants and obesity risk was assessed using 190,000 exome samples from UK Biobank. RESULTS: The 2 cousins carried a compound heterozygous pathogenic variant in POMC. Six siblings were heterozygotes; only 1 of them had obesity. In Human Gene Mutation Database, we identified 60 heterozygotes for pathogenic POMC variants, of whom 14 had obesity. In UK Biobank, heterozygous pathogenic POMC variants were not associated with obesity risk, but they modestly increased body mass index levels. CONCLUSION: Heterozygous pathogenic POMC variants do not contribute to monogenic obesity, but they slightly increase body mass index. Setmelanotide use in patients with obesity, which would only be based on the presence of a heterozygous POMC variant, can be questioned.

PNPLA3 polymorphism influences liver fibrosis in unselected patients with type 2 diabetes.

CONTEXT: Recently, it has been shown that an allele in the adiponutrin (PNPLA3) gene was strongly associated with increased liver fat content (LFC) and liver fibrosis independent of visceral adiposity and insulin resistance. OBJECTIVE: In this study, we set out to determine whether the PNPLA3 rs738409 polymorphism was associated with liver fibrosis in unselected patients with type 2 diabetes. DESIGN, SETTING AND PARTICIPANTS: Two hundred and thirty-four patients with type 2 diabetes were included in this study. MAIN OUTCOME MEASURES: LFC was evaluated using (1) H-MR spectroscopy; fibrosis was measured using the non-invasive FibroTest(®). RESULTS: Advanced liver fibrosis (stage F2 or above) was observed in 10.2% of the patients while 149 (63.6%) patients had steatosis. The prevalence of steatosis and fibrosis was higher in minor G allele carriers than that in C allele homozygote carriers (70.3 vs 57.1%; P=0.04 and 14.7 vs 7.5%; P=0.07 respectively). In multivariate analysis, the predictive variables for advanced liver fibrosis were age (≥60) (P=0.005), sex (female) (P=0.004) and rs 738409 PNPLA3 polymorphism (P=0.01); body mass index (BMI) and LFC were not associated with liver fibrosis. CONCLUSIONS: This study confirms that in patients with type 2 diabetes who were not selected for liver abnormalities, liver fibrosis was related to the rs738409 polymorphism independent of BMI or LFC.

Uptake in the pancreatic uncinate process on the 111In-octreotide scintigraphy: How to distinguish physiological from pathological uptake?

BACKGROUND: The aim of this study was to assess the relevance of physiological In-octreotide uptake in the head of pancreas and to establish its imaging features in comparison with pathological uptake in patients with neuroendocrine tumors (NET). PATIENTS AND METHODS: We retrospectively reviewed all patients that underwent In-octreotide single-photon emission tomography (SPECT) scintigraphy in our institution. Only patients with an isolated uptake in the head of the pancreas were included. In-octreotidescintigraphy consisted in planar whole-body and abdominal SPECT/computed tomography (CT) images acquired at 6 and 30 h' postinjection. Different imaging features of the pancreatic focalized uptake were assessed: its precise location on the pancreas head, shape, intensity [visually and quantitatively by calculating the pancreatic to hepatic uptake ratio (L/H ratio)] and intensity changes. RESULTS: Thirteen patients out of 230 were included. Among them, a pancreatic NET was confirmed in five patients. On In-octreotide SPECT/CT, two of these had uptake located in the uncinate process, and three had uptake focused in the right lateral borders or in the whole head. SPECT images demonstrated high uptake (L/H ratio >2) in four patients out of five. In the eight remaining patients, pancreatic NET was ruled out. For all of these physiological cases, SPECT/CT acquisitions revealed that the uptake was both located in the uncinate process and with an L/H ratio below 2. CONCLUSION: The simple criteria of localization and uptake quantification can help to discriminate between a possible physiological uptake in the uncinate process of the pancreatic head and a pathological uptake induced by a NET.

Monocyte/macrophage recruitment and expression of endothelial adhesion proteins in human atherosclerotic lesions.

Since mononuclear cells are recruited in atherosclerotic lesions, the expression of adhesion proteins by the arterial endothelium may play a major role in atherogenesis. The relationships between ICAM-1, E-selectin, and VCAM-1 expression on the arterial endothelium and the presence and degree of maturation of intimal macrophages in human atherosclerotic lesions was investigated. By quantitative double immunostaining with a pan-macrophage-specific monoclonal antibody, HAM-56, and a recently developed monoclonal antibody that is specific for mature macrophages, 3MA-B38, arterial sections were classified as (I) normal, (II) thickened without macrophage infiltration, (III) atherosclerotic with recent macrophage infiltration or (IV) atherosclerotic with infiltration of mature differentiated macrophages. A marked increase in the expression of ICAM-1, E-selectin, and VCAM-1 was observed on endothelial cells adjacent to recently recruited macrophages. Endothelial cells overlying differentiated macrophages exhibited a lower but significant increase in VCAM-1 expression, with no difference in ICAM-1 and E-selectin expression with respect to that observed in endothelium of normal arteries. These findings indicate that the endothelium covering the human arterial wall exhibits different states of activation as reflected by the expression of adhesion proteins, and that intimal monocyte/macrophage recruitment appears to depend on the level of expression of adhesion proteins.