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pubmed: 0021-972X



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Digenic DUOX1 and DUOX2 mutations in cases with congenital hypothyroidism.
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Digenic DUOX1 and DUOX2 mutations in cases with congenital hypothyroidism.

J Clin Endocrinol Metab. 2017 Jun 16;:

Authors: Aycan Z, Cangul H, Muzza M, Bas VN, Fugazzola L, Chatterjee VK, Persani L, Schoenmakers N

Abstract
Context: The DUOX2 enzyme generates hydrogen peroxide (H2O2), a crucial electron acceptor for the TPO-catalyzed iodination and coupling reactions mediating thyroid hormone biosynthesis. DUOX2 mutations result in dyshormonogenetic Congenital Hypothyroidism (CH) which may be phenotypically heterogeneous, leading to the hypothesis that CH severity may be influenced by environmental factors (eg dietary iodine) and oligogenic modifiers (eg variants in the homologous NADPH-oxidase DUOX1). However, loss of function mutations in DUOX1 have not hitherto been described and its role in thyroid biology remains undefined.
Case Description: We previously described a Proband and her brother (P1, P2) with unusually severe CH associated with a DUOX2 homozygous nonsense mutation (p.R434*); P1, P2: TSH >100 µU/mL (reference range, RR: 0.5-6.3), P1: Free T4 (FT4) <0.09 ng/dl (RR: 0.9-2.3). Subsequent studies have revealed a novel, homozygous DUOX1 mutation (c.1823-1G>C) resulting in aberrant splicing and a protein truncation (p.Val607Aspfs*43) which segregates with CH in this kindred.
Conclusion: This is the first report of digenic mutations in DUOX1 and DUOX2 in association with CH and we hypothesize that the inability of DUOX1 to compensate for DUOX2 deficiency in this kindred may underlie the severe CH phenotype. Our studies provide evidence for a novel digenic basis for CH and support the notion that oligogenicity as well as environmental modulators may underlie phenotypic variability in genetically-ascertained CH.

PMID: 28633507 [PubMed - as supplied by publisher]




Markers of adipogenesis, but not inflammation in adipose tissue, are independently related to insulin sensitivity.
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Markers of adipogenesis, but not inflammation in adipose tissue, are independently related to insulin sensitivity.

J Clin Endocrinol Metab. 2017 Jun 16;:

Authors: Matulewicz N, Stefanowicz M, Nikolajuk A, Karczewska-Kupczewska M

Abstract
Context: In obesity, adipose tissue (AT) undergoes dynamic remodeling, including an alternations in adipogenesis, AT-resident cell content, angiogenesis and turnover of extracellular matrix (ECM) components. Studies on AT in humans have been carried out mostly on people with severe metabolic abnormalities, like type 2 diabetes or morbid obesity.
Objective: The purpose of the present study was to investigate subcutaneous AT gene expression of markers of adipogenesis, ECM remodeling and inflammation in young, healthy, overweight or obese subjects.
Design: The study group comprised 83 normal-weight, 48 overweight and 19 obese subjects. Euglycemic hyperinsulinemic clamp, biopsy of subcutaneous AT and isolation of peripheral blood mononuclear cells (PBMC) were performed. Gene expression was measured with Real Time PCR.
Results: Overweight/obese subjects had lower AT expression of markers of adipogenesis, insulin signaling and angiogenesis, higher expression of markers of ECM remodeling, altered expression of genes of NFκB, but not JNK pathway, and higher expression of macrophage markers, but not markers of other immune cells. In multiple regression analysis, the expression of CEBPA, ADIPOQ, IRS1, IRS2, SLC2A4 and MMP9 was associated with insulin sensitivity independently of BMI. No differences were found in inflammatory gene PBMC expression.
Conclusions: Overweight/obesity is associated with altered expression of genes of adipogenesis, insulin signaling, ECM remodeling and inflammation. NFκB seems to be the earliest inflammatory pathway altered at the transcriptional level in AT. Macrophages seem to be the first immune cells to infiltrate AT. Adipogenesis and ECM remodeling are the initial processes in AT which independently associate with insulin sensitivity.

PMID: 28633482 [PubMed - as supplied by publisher]




Threshold Effects of Circulating Angiopoietin-like 3 Levels on Plasma Lipoproteins.
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Threshold Effects of Circulating Angiopoietin-like 3 Levels on Plasma Lipoproteins.

J Clin Endocrinol Metab. 2017 Jun 19;:

Authors: Fazio S, Minnier J, Shapiro MD, Tsimikas S, Tarugi P, Averna MR, Arca M, Tavori H

Abstract
Context: Angiopoietin-like 3 (ANGPTL3) deficiency in plasma due to loss-of-function (LOF) gene mutations causes familial combined hypobetalipoproteinemia (FHBL) type 2 in homozygotes. However, the lipid phenotype in heterozygotes is much milder and does not appear to relate directly to ANGPTL3 levels. Furthermore, the low LDL phenotype in carriers of ANGPTL3 mutations is unexplained.
Objective: To determine whether a reduction below a critical threshold in plasma ANGPTL3 levels is a determinant of lipoprotein metabolism in FHBL2, and to study the whether PCSK9 is involved in determining low LDL levels in this condition.
Design: We studied subjects from 19 families with ANGPTL3 mutations, and subjects with FHBL type 1 due to truncated apolipoprotein B (apoB) species.
Results: Total cholesterol, HDL-c, triglycerides, and HDL and LDL particle concentration correlated with plasma ANGPTL3 levels, but only when this was below 25% of normal (<60 ng/ml); (ii) VLDL particle concentration strongly correlated with plasma ANGPTL3 when this was below 58% of normal; (iii) both FHBL1 and FHBL2 subjects showed low levels of mature and LDL-bound PCSK9, and higher levels of its furin-cleaved form; and (iv) LDL-bound PCSK9 is protected from cleavage by furin, and binds to the LDL receptor more strongly compared to apoB-free PCSK9.
Conclusion: Our studies suggest that the hypolipidemic effects of ANGPTL3 mutations in FHBL2 are dependent on threshold plasma ANGPTL3 levels, with differential effects on various lipoprotein particles. The increased inactivation of PCSK9 by furin in FHBL1 and FHBL2 is likely to cause increased LDL clearance and suggests novel therapeutic avenues.

PMID: 28633452 [PubMed - as supplied by publisher]




Pancreas fat and beta cell mass in humans with and without diabetes: An analysis in the Japanese population.
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Pancreas fat and beta cell mass in humans with and without diabetes: An analysis in the Japanese population.

J Clin Endocrinol Metab. 2017 Jun 14;:

Authors: Murakami R, Saisho Y, Watanabe Y, Inaishi J, Tsuchiya T, Kou K, Sato S, Kitago M, Kitagawa Y, Yamada T, Itoh H

Abstract
Context: The mechanisms by which beta cell mass is reduced in patients with type 2 diabetes (T2DM) remain unclear. It has been postulated that ectopic fat deposits in the pancreas induce beta cell apoptosis, leading to the development of diabetes.
Objective: The aim of this study was to clarify the effects of intra-pancreatic fat on beta and alpha cell mass in humans with and without diabetes.
Design, Subjects and Methods: Using our tissue database, pancreas sections of 72 Japanese non-diabetic (NDM) autopsy cases and 50 diabetic (DM) and 49 age- and BMI-matched NDM patients who underwent pancreatic surgery were analyzed. In addition to histological grading, intra-pancreatic fat area (IPFA) was quantified as fractional intra-, but not inter-, lobular fat area to the whole pancreas area.
Results: While IPFA was positively correlated with age and BMI, there was no significant difference in IPFA between cases with and without diabetes. Moreover, no association was found between IPFA and either beta or alpha cell area, or HbA1c.
Conclusion: These findings suggest that pancreatic fat deposits have little effect on beta cell mass and the development of diabetes in humans.

PMID: 28633420 [PubMed - as supplied by publisher]




Multiple soluble TGF-β receptors in addition to soluble endoglin are elevated in preeclamptic serum and they synergistically inhibit TGF-β signalling.
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Multiple soluble TGF-β receptors in addition to soluble endoglin are elevated in preeclamptic serum and they synergistically inhibit TGF-β signalling.

J Clin Endocrinol Metab. 2017 Jun 14;:

Authors: Wang Y, Chen Q, Zhao M, Walton K, Harrison C, Nie G

Abstract
Context: Preeclampsia (PE) can be classified into early-onset (<34wk of gestation) and late-onset (>34wk) subtypes. Soluble endoglin, an auxiliary receptor for TGF-β ligands, is increased in PE circulation and believed to inhibit TGF-β action by sequestering the ligands. However, soluble endoglin, with a low affinity to TGF-β ligands, is demonstrated to have little effect by itself on TGF-β action.
Objectives: We examined whether multiple soluble TGF-β receptors are elevated in PE circulation and whether they synergistically block TGF-β signalling.
Design: TGF-β receptors were measured by ELISA in sera collected from preeclamptic pregnancies and gestation-age-matched controls. TGF-β signalling was assessed using an in vitro bioassay and a tube formation assay.
Results: TGF-β type I, II and III receptors were all identified in pregnant serum; they were all significantly elevated in early-onset but not late-onset PE. Endoglin was increased in both PE subtypes. At the highest concentrations detected in PE, none of these soluble TGF-β receptors alone, including endoglin, inhibited TGF-β signalling. However, when all four soluble receptors were present, signalling of both TGF-β1 and TGF-β2 was significantly reduced. Removal of anyone of these soluble receptors alleviated TGF-β1 inhibition, but removal of soluble TGFβRIII was necessary to relieve TGF-β2 inhibition.
Conclusions: Multiple soluble TGF-β receptors are present in pregnant circulation and elevated in early-onset PE; they synergistically inhibit TGF-β signalling which may occur more likely in early-onset than late-onset PE. Reducing soluble TGFβRIII rather than endoglin would be more effective to alleviate the inhibition of both TGF-β1 and TGF-β2 signalling in PE.

PMID: 28633389 [PubMed - as supplied by publisher]