Aims/hypothesis
Wolfram syndrome is a rare, autosomal recessive syndrome characterised by juvenile-onset diabetes and optic atrophy and is caused by bi-allelic mutations in the
WFS1
gene. In a recent ...sequencing study, an individual with juvenile-onset diabetes was observed to be homozygous for a rare missense variant (c.1672C>T, p.R558C) in the
WFS1
gene. The aim of this study was to perform the genetic characterisation of this variant and to determine whether it is causal for young-onset diabetes and Wolfram syndrome.
Methods
We analysed the allele frequency of the missense variant in multiple variant databases. We genotyped the variant in 475 individuals with type 1 diabetes and 2237 control individuals of Ashkenazi Jewish ancestry and analysed the phenotypes of homozygotes. We also investigated the association of this variant with risk for type 2 diabetes using genotype and sequence data for type 2 diabetes cases and controls.
Results
The missense variant demonstrated an allele frequency of 1.4% in individuals of Ashkenazi Jewish ancestry, 60-fold higher than in other populations. Genotyping of this variant in 475 individuals diagnosed with type 1 diabetes identified eight homozygotes compared with none in 2237 control individuals (genotype relative risk 135.3,
p
= 3.4 × 10
−15
). The age at diagnosis of diabetes for these eight individuals (17.8 ± 8.3 years) was several times greater than for typical Wolfram syndrome (5 ± 4 years). Further, optic atrophy was observed in only one of the eight individuals, while another individual had the Wolfram syndrome-relevant phenotype of neurogenic bladder. Analysis of sequence and genotype data in two case–control cohorts of Ashkenazi ancestry demonstrated that this variant is also associated with an increased risk of type 2 diabetes in heterozygotes (OR 1.81,
p
= 0.004).
Conclusions/interpretation
We have identified a low-frequency coding variant in the
WFS1
gene that is enriched in Ashkenazi Jewish individuals and causes a mild form of Wolfram syndrome characterised by young-onset diabetes and reduced penetrance for optic atrophy. This variant should be considered for genetic testing in individuals of Ashkenazi ancestry diagnosed with young-onset non-autoimmune diabetes and should be included in Ashkenazi carrier screening panels.
Exosomes released into the extracellular matrix have been reported to contain metabolic biomarkers of various diseases. These intraluminal vesicles are typically found in blood, urine, saliva, breast ...milk, cerebrospinal fluid, semen, amniotic fluid, and ascites. Analysis of exosomal content with specific profiles of DNA, microRNA, proteins, and lipids can mirror their cellular origin and physiological state. Therefore, exosomal cargos may reflect the physiological processes at cellular level and can potentially be used as biomarkers. Herein, we report an optical detection method for assaying exosomal biomarkers that supersedes the state-of-the-art time consuming and laborious assays such as ELISA and NTA. The proposed assay monitors the changes in optical properties of poly(3-(4-methyl-3'-thienyloxy) propyltriethylammonium bromide) upon interacting with aptamers/peptide nucleic acids in the presence or absence of target biomarkers. As a proof of concept, this study demonstrates facile assaying of microRNA, DNA, and advanced glycation end products in exosomes isolated from human plasma with detection levels of ~1.2, 0.04, and 0.35 fM/exosome, respectively. Thus, the obtained results illustrate that the proposed methodology is applicable for rapid and facile detection of generic exosomal biomarkers for facilitating diseases diagnosis.
Pathogenic variants in more than 14 genes have been implicated in monogenic diabetes; however, a significant fraction of individuals with young-onset diabetes and a strong family history of diabetes ...have unknown genetic etiology. To identify novel pathogenic alleles for monogenic diabetes, we performed whole-genome sequencing (WGS) on four related individuals with type 2 diabetes - including one individual diagnosed at the age of 31 years - that were negative for mutations in known monogenic diabetes genes. The individuals were ascertained from a large case-control study and had a multi-generation family history of diabetes. Identity-by-descent (IBD) analysis revealed that the four individuals represent two sib-pairs that are third-degree relatives. A novel missense mutation (p.P81S) in the PAX6 gene was one of eight rare coding variants across the genome shared IBD by all individuals and was inherited from affected mothers in both sib-pairs. The mutation affects a highly conserved amino acid located in the paired-domain of PAX6 - a hotspot for missense mutations that cause aniridia and other eye abnormalities. However, no eye-related phenotype was observed in any individual. The well-established functional role of PAX6 in glucose-induced insulin secretion and the co-segregation of diabetes in families with aniridia provide compelling support for the pathogenicity of this mutation for diabetes. The mutation could be classified as "likely pathogenic" with a posterior probability of 0.975 according to the ACMG/AMP guidelines. This is the first PAX6 missense mutation that is likely pathogenic for autosomal-dominant adult-onset diabetes without eye abnormalities.
It is known that the SARS‐CoV virus infects the hosts through angiotensin converting enzyme‐2 (ACE‐2) enzymes and transmembrane serine protease 2 (TMPRSS2) expressed in the alveolar cells. Other ...receptors used by the virus include sialic acid receptors, and extracellular matrix metalloproteinase inducer (CD147).12, 13 The receptor TMPRSS2 is also expressed in cardiac endothelial cells14 and CD147 is minimally expressed in normal vessels, but its expression increases following inflammation and vascular injury.15In an autopsy study, a significantly greater number of ACE‐2 positive endothelial cells with significant changes in the morphology has been reported. It is possible that through the use of ACE‐2 the virus is causing unique and distinctive sequelae.16 The virus by itself has the potential to cause significant epithelial and endothelial injury. The ACE‐2 receptors are also expressed in pericytes which communicate with endothelial cells via the angiopoietin ligands (ANGPT1/2). This dynamic interplay is vital for the endothelial cell survival.17 Viral invasion of pericytes potentially disrupts this milieu potentially increasing endothelial cell injury. In a recent histopathological study, the authors have reported endothelial cell involvement across vascular beds of different organs with severe lymphocytic endothelialitis, viral inclusion bodies and apoptosis of varying degrees in the lungs, heart, kidneys, liver and submucosal vessels of the intestines.18 Recent observational reports of higher frequency of Chilblains (‘COVID toes’) in children and young adults during the COVID‐19 pandemic have also revealed the presence of Severe Acute Respiratory Syndrome‐Coronavirus‐2 (SARS‐CoV‐2) particles in the endothelial and epithelial cells of the eccrine glands and likely being causative.19
Crossing the intestinal epithelial cell barrier safely and reaching the blood with therapeutic levels of bioactive insulin have been the ultimate goal of oral insulin delivery. The optimum way to ...overcome the barrier lies in the design of an efficient high drug loading carrier, that can protect insulin from the harsh Gastrointestinal (GI) environment and enhance its uptake and transport by epithelial cells. In the present study, we developed a multi-layered insulin loading strategy on an anionic nanoliposome surface based on electrostatic interaction with chitosan. The layer-by-layer (LbL) coated nanoliposomes achieved high insulin loading (10.7% by weight) and offered superior protection with limited release in simulated gastric fluid (SGF) (about 6% in 1 h), simulated intestinal fluid (SIF) (2% in two weeks), and phosphate buffered saline (PBS) (5% in two weeks). Intracellular imaging revealed that the LbL coated liposomes were internalized and intracellularly trafficked towards the basolateral side of the Caco-2 monolayer. Transported insulin demonstrated retention of bioactivity while crossing the epithelial barrier in the glucose uptake study in 3T3 L1-MBX adipocytes. In rat studies, oral administration of the formulation resulted in rapid absorption with a peak in plasma insulin levels 0.5 h post oral gavaging. This technology thus serves as a promising platform for potential oral insulin applications.
Nanosulin - a highly stable multilayer insulin-coated nanoliposome, enhanced insulin permeation across the intestinal epithelium and maintained bioactivity
via
oral administration
in vivo
.
The ACE-2 in COVID-19: Foe or Friend? Dalan, Rinkoo; Bornstein, Stefan R; El-Armouche, Ali ...
Hormone and metabolic research,
05/2020, Letnik:
52, Številka:
5
Journal Article
Recenzirano
Odprti dostop
COVID-19 is a rapidly spreading outbreak globally. Emerging evidence demonstrates that older individuals and people with underlying metabolic conditions of diabetes mellitus, hypertension, and ...hyperlipidemia are at higher risk of morbidity and mortality. The SARS-CoV-2 infects humans through the angiotensin converting enzyme (ACE-2) receptor. The ACE-2 receptor is a part of the dual system renin-angiotensin-system (RAS) consisting of ACE-Ang-II-AT
R axis and ACE-2-Ang-(1-7)-Mas axis. In metabolic disorders and with increased age, it is known that there is an upregulation of ACE-Ang-II-AT
R axis with a downregulation of ACE-2-Ang-(1-7)-Mas axis. The activated ACE-Ang-II-AT1R axis leads to pro-inflammatory and pro-fibrotic effects in respiratory system, vascular dysfunction, myocardial fibrosis, nephropathy, and insulin secretory defects with increased insulin resistance. On the other hand, the ACE-2-Ang-(1-7)-Mas axis has anti-inflammatory and antifibrotic effects on the respiratory system and anti-inflammatory, antioxidative stress, and protective effects on vascular function, protects against myocardial fibrosis, nephropathy, pancreatitis, and insulin resistance. In effect, the balance between these two axes may determine the prognosis. The already strained ACE-2-Ang-(1-7)-Mas in metabolic disorders is further stressed due to the use of the ACE-2 by the virus for entry, which affects the prognosis in terms of respiratory compromise. Further evidence needs to be gathered on whether modulation of the renin angiotensin system would be advantageous due to upregulation of Mas activation or harmful due to the concomitant ACE-2 receptor upregulation in the acute management of COVID-19.
•Cerebral vein sinus thrombosis reported after COVID-19 infection and vaccination•COVID-19 vaccine thrombosis reports more common after ChAdOx1 than mRNA vaccines.•COVID-19 vaccine thrombosis more ...common in arteries than veins with mRNA vaccines•COVID-19 vaccine thrombosis may be related to dysregulation of ACE pathways.•COVID-19 vaccine thrombosis may be related to genetic mutations ACE/ACE2.
Type 1 diabetes: A new vision of the disease based on endotypes Weston, Craig Sinclair; Boehm, Bernhard O.; Pozzilli, Paolo
Diabetes/metabolism research and reviews,
February 2024, 2024-Feb, 2024-02-00, 20240201, Letnik:
40, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Diagnosis and management of type 1 diabetes (T1D) have remained largely unchanged for the last several years. The management of the disease remains primarily focused on its phenotypical presentation ...and less on endotypes, namely the specific biological mechanisms behind the development of the disease. Furthermore, the treatment of T1D is essentially universal and indiscriminate—with patients administering insulin at varying dosages and frequencies to maintain adequate glycaemic control. However, it is now well understood that T1D is a heterogeneous disease with many different biological mechanisms (i.e. endotypes) behind its complex pathophysiology. A range of factors, including age of onset, immune system regulation, rate of β‐cell destruction, autoantibodies, body weight, genetics and the exposome are recognised to play a role in the development of the condition. Patients can be classified into distinct diabetic subtypes based on these factors, which can be used to categorise patients into specific endotypes. The classification of patients into endotypes allows for a greater understanding of the natural progression of the disease, giving rise to more accurate and patient‐centred therapies and follow‐up monitoring, specifically for other autoimmune diseases. This review proposes 6 unique endotypes of T1D based on the current literature. The recognition of these endotypes could then be used to direct therapeutic modalities based on patients' individual pathophysiology.
Monozygotic (MZ) twin pair discordance for childhood-onset Type 1 Diabetes (T1D) is ∼50%, implicating roles for genetic and non-genetic factors in the aetiology of this complex autoimmune disease. ...Although significant progress has been made in elucidating the genetics of T1D in recent years, the non-genetic component has remained poorly defined. We hypothesized that epigenetic variation could underlie some of the non-genetic component of T1D aetiology and, thus, performed an epigenome-wide association study (EWAS) for this disease. We generated genome-wide DNA methylation profiles of purified CD14+ monocytes (an immune effector cell type relevant to T1D pathogenesis) from 15 T1D-discordant MZ twin pairs. This identified 132 different CpG sites at which the direction of the intra-MZ pair DNA methylation difference significantly correlated with the diabetic state, i.e. T1D-associated methylation variable positions (T1D-MVPs). We confirmed these T1D-MVPs display statistically significant intra-MZ pair DNA methylation differences in the expected direction in an independent set of T1D-discordant MZ pairs (P = 0.035). Then, to establish the temporal origins of the T1D-MVPs, we generated two further genome-wide datasets and established that, when compared with controls, T1D-MVPs are enriched in singletons both before (P = 0.001) and at (P = 0.015) disease diagnosis, and also in singletons positive for diabetes-associated autoantibodies but disease-free even after 12 years follow-up (P = 0.0023). Combined, these results suggest that T1D-MVPs arise very early in the etiological process that leads to overt T1D. Our EWAS of T1D represents an important contribution toward understanding the etiological role of epigenetic variation in type 1 diabetes, and it is also the first systematic analysis of the temporal origins of disease-associated epigenetic variation for any human complex disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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