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![Venn diagram of candidate gene lists. Abbreviations relate to the following references: TiffinHide2006 [22], DiabetesGenomeCG [23], ParikhGroop2004 [47] and LiuKasif2007 [24]. One gene in TiffinHide2006 has been neglected for the count since no transcriptional information was available for that gene. (*) Two genes are counted twice because the intersection of LiuKasif2007 and our study shares those genes with ParikhGroop2004.](profile/Ralf-Herwig/publication/5262119/figure/fig2/AS:213875157934086@1428003219924/Venn-diagram-of-candidate-gene-lists-Abbreviations-relate-to-the-following-references.png)
Venn diagram of candidate gene lists. Abbreviations relate to the following references: TiffinHide2006 [22], DiabetesGenomeCG [23], ParikhGroop2004 [47] and LiuKasif2007 [24]. One gene in TiffinHide2006 has been neglected for the count since no transcriptional information was available for that gene. (*) Two genes are counted twice because the intersection of LiuKasif2007 and our study shares those genes with ParikhGroop2004.
Source publication
Multiple functional genomics data for complex human diseases have been published and made available by researchers worldwide. The main goal of these studies is the detailed analysis of a particular aspect of the disease. Complementary, meta-analysis approaches try to extract supersets of disease genes and interaction networks by integrating and com...
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Citations
... [20][21][22] SOCS2 gene as risk gene was identified to be associated with the molecular networks of T2DM. 23 The increasing evidence reveals that SOCS2 protein plays an important role in T2DM development, involving regulation of the insulin signaling and pancreatic β-cell function. 24 However, little is known about the impact of SOCS2 genetic variants on the occurrence of T2DM. ...
Background
SOCS2 is downregulated in diabetes, which might be related to diabetes. We explored the effect of SOCS2 polymorphisms on the development of type 2 diabetes mellitus (T2DM) and diabetic complications.
Methods
The subjects consisted of 500 patients with T2DM and 501 healthy controls. Five variants in SOCS2 were genotyped by Agena MassARRAY system. RT-qPCR profiling was performed to detect the expression of SOCS2 mRNA. Logistic regression analysis was utilized to calculate odds ratio (OR) and 95% confidence intervals (95% CIs).
Results
Rs3825199 (OR = 1.44, p = 0.007), rs11107116 (OR = 1.39, p = 0.014) and rs10492321 (OR = 1.48, p = 0.004) had an increased T2DM risk of T2DM. Moreover, the contribution of SOCS2 polymorphisms to T2DM risk was associated with age, gender, smoking, drinking, and BMI. SOCS2 variants also had a reduced risk for T2DM patients with diabetic nephropathy, diabetic retinopathy and coronary heart disease. SOCS2 rs10492321 was the best single locus model. SOCS2 mRNA was downregulated in patients with T2DM compared to healthy controls (p = 0.029).
Conclusion
This study firstly reported that rs3825199, rs11107116 and rs10492321 in SOCS2 conferred to an increased risk for the occurrence of T2DM in the Chinese Han population. Moreover, SOCS2 mRNA was downregulated in patients with T2DM, suggesting that SOCS2 might have an important role in the occurrence of T2DM.
... As such, transcriptomic meta-analysis offers a judicious strategy to overcome these limitations and aid biomarker discovery within disuse/(ageing) RET muscle adaptation. Indeed, the integration of multiple related transcriptomic data sets into a single analysis has improved the power to confirm/detect novel biosignatures in other societally important pathophysiological scenarios such as cancer and diabetes 29,30 and recently, to identify global transcriptional responses to exercise and inactivity 28 and genes that correlate with exercise-induced changes in muscle mass. 26 As a statistical approach, transcriptomic meta-analysis has been routinely applied to identify robust gene-level expression changes. ...
Background:
Skeletal muscle atrophy manifests across numerous diseases; however, the extent of similarities/differences in causal mechanisms between atrophying conditions in unclear. Ageing and disuse represent two of the most prevalent and costly atrophic conditions, with resistance exercise training (RET) being the most effective lifestyle countermeasure. We employed gene-level and network-level meta-analyses to contrast transcriptomic signatures of disuse and RET, plus young and older RET to establish a consensus on the molecular features of, and therapeutic targets against, muscle atrophy in conditions of high socio-economic relevance.
Methods:
Integrated gene-level and network-level meta-analysis was performed on publicly available microarray data sets generated from young (18-35 years) m. vastus lateralis muscle subjected to disuse (unilateral limb immobilization or bed rest) lasting ≥7 days or RET lasting ≥3 weeks, and resistance-trained older (≥60 years) muscle.
Results:
Disuse and RET displayed predominantly separate transcriptional responses, and transcripts altered across conditions were mostly unidirectional. However, disuse and RET induced directly inverted expression profiles for mitochondrial function and translation regulation genes, with COX4I1, ENDOG, GOT2, MRPL12, and NDUFV2, the central hub components of altered mitochondrial networks, and ZMYND11, a hub gene of altered translation regulation. A substantial number of genes (n = 140) up-regulated post-RET in younger muscle were not similarly up-regulated in older muscle, with young muscle displaying a more pronounced extracellular matrix (ECM) and immune/inflammatory gene expression response. Both young and older muscle exhibited similar RET-induced ubiquitination/RNA processing gene signatures with associated PWP1, PSMB1, and RAF1 hub genes.
Conclusions:
Despite limited opposing gene profiles, transcriptional signatures of disuse are not simply the converse of RET. Thus, the mechanisms of unloading cannot be derived from studying muscle loading alone and provides a molecular basis for understanding why RET fails to target all transcriptional features of disuse. Loss of RET-induced ECM mechanotransduction and inflammatory profiles might also contribute to suboptimal ageing muscle adaptations to RET. Disuse and age-dependent molecular candidates further establish a framework for understanding and treating disuse/ageing atrophy.
... • The work in [12][13][14][15] which demonstrated the involvement of genetics and tissue interaction networks in the development of type 2 diabetes mellitus (T2DM) and the genetic relationship between type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD) [16] . • Insufficient lifestyle alone and the need for medical intervention [17] . ...
In this article, we study a predictive model of the risk of cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) in obese populations and investigate its impact on the evolution of their health, terms related to lifestyle and risk factors are also incorporated. This model represented mathematically by a nonlinear temporal system of ordinary differential equations. An analysis of the stability of stationary solutions is also obtained to theoretically confirm the mathematical validity. Numerical simulations presented to explain the usefulness of the developed model; they show the role of a healthy lifestyle (diet, regular exercise, smoking, and increasing alcohol consumption above moderate levels) in alleviating the burden of cardiovascular disease (CVD) and can significantly reduce the risk to develop type 2 diabetes mellitus (T2DM). On the other hand, risk factors management of obesity with complications greatly decreases the risk of developing other complications.
... 5 Given the adipose tissue and skeletal muscle phenotypes we observed in Asnsd1 À/À mice, it is interesting that ASNSD1 was included in a set of 213 candidate genes linked to type 2 diabetes mellitus. 44 Future studies in Asnsd1 À/À mice may lead to a more complete understanding of the underlying pathomechanisms involved in myopathies that culminate in the transdifferentiation of myoblasts into adipocytes. Studies on these mice might also help elucidate the effects of sarcopenia and myosteatosis on metabolism, both being conditions that are of major clinical significance in aged humans. ...
Mice with an inactivating mutation in the gene encoding asparagine synthetase domain containing 1 (ASNSD1) develop a progressive degenerative myopathy that results in severe sarcopenia and myosteatosis. ASNSD1 is conserved across many species, and whole body gene expression surveys show maximal expression levels of ASNSD1 in skeletal muscle. However, potential functions of this protein have not been previously reported. Asnsd1 −/− mice demonstrated severe muscle weakness, and their normalized body fat percentage on both normal chow and high fat diets was greater than 2 SD above the mean for 3651 chow-fed and 2463 high-fat-diet–fed knockout (KO) lines tested. Histologic lesions were essentially limited to the muscle and were characterized by a progressive degenerative myopathy with extensive transdifferentiation and replacement of muscle by well-differentiated adipose tissue. There was minimal inflammation, fibrosis, and muscle regeneration associated with this myopathy. In addition, the absence of any signs of lipotoxicity in Asnsd1 −/− mice despite their extremely elevated body fat percentage and low muscle mass suggests a role for metabolic dysfunctions in the development of this phenotype. Asnsd1 −/− mice provide the first insight into the function of this protein, and this mouse model could prove useful in elucidating fundamental metabolic interactions between skeletal muscle and adipose tissue.
... Several studies reported that SOCS2 genetic variants were associated with some diseases, including acromegaly, growth hormone de ciency and extreme obesity [15][16][17]. SOCS2 gene as risk gene was identi ed to be associated with molecular networks for T2DM [18]. The increasing evidence reveals that SOCS2 protein plays an important role in T2DM development, involving regulation of the insulin signaling and pancreatic β-cell function [19]. ...
Propose: We explored the effect of SOCS2 polymorphisms on the development of type 2 diabetes mellitus (T2DM) and diabetic complications.
Methods: The subjects consisted of 500 T2DM patients and 501 healthy volunteers. Five variants in SOCS2 were genotyped by Agena MassARRAY system. Logistic regression analysis was utilized to calculate the odds ratio (OR) and 95% confidence intervals (95% CI).
Results: Rs3825199 (OR = 1.44, p = 0.007), rs11107116 (OR = 1.39, p = 0.014) and rs10492321 (OR = 1.48, p = 0.004) had the increased T2DM risk. Moreover, the contribution of SOCS2 polymorphisms to T2DM risk was associated with age, gender, smoking and drinking and BMI. SOCS2 variants also had the reduced risk for T2DM patients with diabetic nephropathy, diabetic retinopathy and coronary heart disease.
Conclusions: This study firstly reported that rs3825199, rs11107116 and rs10492321 in SOCS2 conferred to the increased risk for T2DM occurrence in the Chinese Han population.
... It is found that natural killer cell-mediated cytotoxicity is associated with both anti-thyroid peroxidase antibody and type 2 diabetes [27,29]. In addition, those genes involved in antigen processing and presentation are related to anti-thyroid peroxidase antibody and type 2 diabetes [29,30]. There-fore, we deduced that the prevalence of type 2 diabetes might be associated with subclinical hypothyroidism, and the regulation of PAX-AS1 on KIR3DL1 might function in this process. ...
Introduction:
The pathology mechanism of subclinical hypothyroidism and subclinical hypothyroidism complicated with type 2 diabetes remained uncertain. We aimed to find potential related long non-coding RNAs (lncRNAs) and mRNAs in the above diseases.
Material and methods:
Transcriptome sequencing was performed in three patients with subclinical hypothyroidism (S), three patients with subclinical hypothyroidism complicated with type 2 diabetes (SD), and three healthy controls (N). Differentially expressed mRNAs (DEmRNAs) and differentially expressed lncRNAs (DElncRNAs) were screened in S vs. N, SD vs. N, and SD vs. S group, and the nearby and co-expressed DEmRNAs of DElncRNAs were screened in S vs. N and SD vs. N. Moreover, functional analysis of DEmRNAs was then performed by Metascape.
Results:
In total, 465, 1058, and 943 DEmRNAs were obtained in S vs. N, SD vs. N, SD vs. S, respectively, and 191 overlapping genes were obtained in S vs. N and SD vs. N group. Among which, LAIR2, PNMA6A, and SFRP2 were deduced to be involved in subclinical hypothyroidism, and GPR162, APOL4, and ANK1 were deduced to be associated with subclinical hypothyroidism complicated with type 2 diabetes. A total of 50, 100, and 88 DElncRNAs were obtained in S vs. N, SD vs. N and SD vs. S, respectively. Combining with the interaction network of DElncRNA-DEmRNA, PAX8-AS1, co-expressed with KIR3DL1, was identified to function in subclinical hypothyroidism, and JHDM1D-AS1, co-expressed with ANK1, was deduced to play a role in subclinical hypothyroidism complicated with type 2 diabetes.
Conclusions:
Dysfunctional lncRNAs and mRNAs may be involved in the development of subclinical hypothyroidism and subclinical hypothyroidism complicated with type 2 diabetes.
... The JAK-STAT signalling pathway regulates body growth and lipid and glucose metabolism [121]. In contrast, the suppressors of cytokine signalling (SOCS) protein family is involved in the negative regulation of JAK-STAT-dependent activities [122][123][124]. SOCS-2 plays a key role in body growth and development, lipid and glucose metabolism [125,126]. ...
Maternal diabetes is associated with an increased risk of complications for the mother and her offspring. The latter have an increased risk of foetal macrosomia, hypoglycaemia, respiratory distress syndrome, preterm delivery, malformations and mortality but also of life-long development of obesity and diabetes. Epigenetics have been proposed as an explanation for this long-term risk, and microRNAs (miRNAs) may play a role, both in short- and long-term outcomes. Gestation is associated with increasing maternal insulin resistance, as well as β-cell expansion, to account for the increased insulin needs and studies performed in pregnant rats support a role of miRNAs in this expansion. Furthermore, several miRNAs are involved in pancreatic embryonic development. On the other hand, maternal diabetes is associated with changes in miRNA both in maternal and in foetal tissues. This review aims to summarise the existing knowledge on miRNAs in gestational and pre-gestational diabetes, both as diagnostic biomarkers and as mechanistic players, in the development of gestational diabetes itself and also of short- and long-term complications for the mother and her offspring.
... This reaction is catalyzed by the pivotal lipid metabolism enzyme stearoyl-CoA desaturase (SCD) encoded by two murine genes (Scd1 and Scd2) the products of which reside on the ER membrane. Interestingly, polymorphisms in SCD1 have been associated with DM [51] while we found that both SCD1 and SCD2 were significantly upregulated in PAX4 conditionally expressing b-cells correlating with improved survival under stress conditions (Table 1) [6]. Expression levels of both SCD1 and SCD2 were shown to be increased in prediabetic hyperinsulinemic Zucker diabetic fatty (ZDF) rats whereas levels were suppressed with transition to frank diabetes [52]. ...
The high prevalence of diabetes mellitus (DM) in our society, together with the fact that current treatments are only palliative and do not prevent the development of life threatening side effects, highlights the urgent need for novel therapies targeting the root cause of the disease. Independent of the etiology of DM, the definitive therapeutic approach will imply the restitution of an adequate functional β-cell mass capable of compensating for the insulin demand of the organism. The recent demonstration of heterogeneity within the islets as well as their innate plasticity has encouraged the development of studies aiming at potentiation of the regenerative capacity of islets. In this regard, factors implicated in pancreas ontogeny as well as in the adaptation processes that take place in the islets under situations of increased insulin demand have gained much interest. One of these factors is the transcription factor PAX4, required for β-cell formation during embryonic development and implicated in adult β-cell adaptation under stress situations. Here we review the therapeutic potential of PAX4 as well as its downstream targets for the development of novel treatments for DM.
... miR-137 expression was decreased in women with gestational diabetes at risk of fetal macrosomia. 28 Furthermore, the GPD2 gene, which was identified as a candidate for T2DM, 29 is a potential target of miR-137 (http://www.mirdb.org). Changes in the methylation profiles of the target genes of these miRs have previously been reported in a number of pathological conditions. ...
... Genetic predispositions determine the likelihood of individual diabetes-related complications, just as the genetic predisposition of b cells determines b cell exhaustion and damage. Dozens, even hundreds, of susceptibility loci map to the diabetic state, allowing for a multitude of potential contributing genes and gene interactions [13][14][15]. Some loci track b cell function with complication risk, others with the risk factors of complications, such as hypertension, obesity, and inflammation [13]. ...
... As mentioned, oxidative stress/ROS ubiquitously mediate hyperglycemia-induced tissue damage, and are generated mainly by increased free fatty acid (FFA) oxidation [10,11]. Oxidative stress-mediated regulation cascades have been found to map to the 'epicenter' of type 2 DM genetic interaction networks, as well as to the development of complications [13][14][15]. ...
Advances in understanding diabetes mellitus (DM) through basic and clinical research have helped clarify and reunify a disease state fragmented into numerous etiologies and subtypes. It is now understood that a common pathophysiology drives the diabetic state throughout its natural history and across its varied clinical presentations, a pathophysiology involving metabolic insults, oxidative damage, and vicious cycles that aggravate and intensify organ dysfunction and damage. This new understanding of the disease requires that we revisit existing diagnostics and treatment approaches, which were built upon outmoded assumptions. ‘The Common Pathophysiologic Origins of Diabetes Mellitus and its Complications Construct’ is presented as a more accurate, foundational, and translatable construct of DM that helps make sense of the hitherto ambiguous findings of long-term outcome studies.
