Mitochondrial alteration in type 2 diabetes and obesity: An epigenetic link

The growing epidemic of type 2 diabetes mellitus (T2DM) and obesity is largely attributed to the current lifestyle of over-consumption and physical inactivity. As the primary platform controlling metabolic and energy homeostasis, mitochondria show aberrant changes in T2DM and obese subjects. While the underlying mechanism is under extensive investigation, epigenetic regulation is now emerging to play an important role in mitochondrial biogenesis, function, and dynamics. In line with lifestyle modifications preventing mitochondrial alterations and metabolic disorders, exercise has been shown to change DNA methylation of the promoter of PGC1α to favor gene expression responsible for mitochondrial biogenesis and function. In this article we discuss the epigenetic mechanism of mitochondrial alteration in T2DM and obesity, and the effects of lifestyle on epigenetic regulation. Future studies designed to further explore and integrate the epigenetic mechanisms with lifestyle modification may lead to interdisciplinary interventions and novel preventive options for mitochondrial alteration and metabolic disorders.     

Identification of shared genetic susceptibility locus for coronary artery disease, type 2 diabetes and obesity: a meta-analysis of genome-wide studies

ABSTRACT: Type 2 diabetes (2DM), obesity, and coronary artery disease (CAD) are frequently coexisted being as key components of metabolic syndrome. Whether there is shared genetic background underlying these diseases remained unclear. We performed a meta-analysis of 35 genome screens for 2DM, 36 for obesity or body mass index (BMI)-defined obesity, and 21 for CAD using genome search meta-analysis (GSMA), which combines linkage results to identify regions with only weak evidence and provide genetic interactions among different diseases. For each study, 120 genomic bins of approximately 30 cM were defined and ranked according to the best linkage evidence within each bin. For each disease, bin 6.2 achieved genomic significanct evidence, and bin 9.3, 10.5, 16.3 reached suggestive level for 2DM. Bin 11.2 and 16.3, and bin 10.5 and 9.3, reached suggestive evidence for obesity and CAD respectively. In pooled all three diseases, bin 9.3 and 6.5 reached genomic significant and suggestive evidence respectively, being relatively much weaker for 2DM/CAD or 2DM/obesity or CAD/obesity. Further, genomewide significant evidence was observed of bin 16.3 and 4.5 for 2DM/obesity, which is decreased when CAD was added. These findings indicated that bin 9.3 and 6.5 are most likely to be shared by 2DM, obesity and CAD. And bin 16.3 and 4.5 are potentially common regions to 2DM and obesity only. The observed shared susceptibility regions imply a partly overlapping genetic aspects of disease development. Fine scanning of these regions will definitely identify more susceptibility genes and causal variants.     

Molecular genetic analysis of the Idd4 locus implicates the IFN response in type 1 diabetes susceptibility in nonobese diabetic mice

High-resolution mapping and identification of the genes responsible for type 1 diabetes (T1D) has proved difficult because of the multigenic etiology and low penetrance of the disease phenotype in linkage studies. Mouse congenic strains have been useful in refining Idd susceptibility loci in the NOD mouse model and providing a framework for identification of genes underlying complex autoimmune syndromes. Previously, we used NOD and a nonobese diabetes-resistant strain to map the susceptibility to T1D to the Idd4 locus on chromosome 11. Here, we report high-resolution mapping of this locus to 1.4 megabases. The NOD Idd4 locus was fully sequenced, permitting a detailed comparison with C57BL/6 and DBA/2J strains, the progenitors of T1D resistance alleles found in the nonobese diabetes-resistant strain. Gene expression arrays and quantitative real-time PCR were used to prioritize Idd4 candidate genes by comparing macrophages/dendritic cells from congenic strains where allelic variation was confined to the Idd4 interval. The differentially expressed genes either were mapped to Idd4 or were components of the IFN response pathway regulated in trans by Idd4. Reflecting central roles of Idd4 genes in Ag presentation, arachidonic acid metabolism and inflammation, phagocytosis, and lymphocyte trafficking, our combined analyses identified Alox15, Alox12e, Psmb6, Pld2, and Cxcl16 as excellent candidate genes for the effects of the Idd4 locus.     

Geographic and haplotype structure of candidate type 2 diabetes susceptibility variants at the calpain-10 locus

Recently, a positional cloning study proposed that haplotypes at the calpain-10 locus (CAPN10) are associated with increased risk of type 2 diabetes, or non-insulin-dependent diabetes mellitus, in Mexican Americans, Finns, and Germans. To inform the interpretation of the original mapping results and to look for evidence for the action of natural selection on CAPN10, we undertook a population-based genotyping survey of the candidate susceptibility variants. First, we genotyped sites 43, 19, and 63 (the haplotype-defining variants previously proposed) and four closely linked SNPs, in 561 individuals from 11 populations from five continents, and we examined the linkage disequilibrium among them. We then examined the ancestral state of these sites by sequencing orthologous portions of CAPN10 in chimpanzee and orangutan (the identity of sites 43 and 19 was further investigated in a limited sample of other great apes and Old World and New World monkeys). Our survey suggests larger-than-expected differences in the distribution of CAPN10 susceptibility variants between African and non-African populations, with common, derived haplotypes in European and Asian samples (including one of two proposed risk haplotypes) being rare or absent in African samples. These results suggest a history of positive natural selection at the locus, resulting in significant geographic differences in polymorphism frequencies. The relationship of these differences to disease risk is discussed.     

An in vivo cis-regulatory screen at the type 2 diabetes associated TCF7L2 locus identifies multiple tissue-specific enhancers

Genome-wide association studies (GWAS) have repeatedly shown an association between non-coding variants in the TCF7L2 locus and risk for type 2 diabetes (T2D), implicating a role for cis-regulatory variation within this locus in disease etiology. Supporting this hypothesis, we previously localized complex regulatory activity to the TCF7L2 T2D-associated interval using an in vivo bacterial artificial chromosome (BAC) enhancer-trapping reporter strategy. To follow-up on this broad initial survey of the TCF7L2 regulatory landscape, we performed a fine-mapping enhancer scan using in vivo mouse transgenic reporter assays. We functionally interrogated approximately 50% of the sequences within the T2D-associated interval, utilizing sequence conservation within this 92-kb interval to determine the regulatory potential of all evolutionary conserved sequences that exhibited conservation to the non-eutherian mammal opossum. Included in this study was a detailed functional interrogation of sequences spanning both protective and risk alleles of single nucleotide polymorphism (SNP) rs7903146, which has exhibited allele-specific enhancer function in pancreatic beta cells. Using these assays, we identified nine segments regulating various aspects of the TCF7L2 expression profile and that constitute nearly 70% of the sequences tested. These results highlight the regulatory complexity of this interval and support the notion that a TCF7L2 cis-regulatory disruption leads to T2D predisposition.     

MicroRNAs and type 2 diabetes/obesity

MicroRNAs belong to a newly identified class of small non-coding RNAs that have been widely implicated in the fine-tuning of many physiological processes such as the pathogenesis of type 2 diabetes(T2D) and obesity.Microarray studies have highlighted an altered profile of miRNA expression in insulin target tissues in diabetic and obese models.Emerging evidences suggest that miRNAs play significant roles in insulin production,secretion and actions,as well as in diverse aspects of glucose homeostasis and adipocyte differentiation. The identification of tissue-specific miRNAs implicated in T2D and obesity might be useful for the future development of effective strategies for early diagnosis and therapeutic intervention of obesity-related medical complications.     

Genome-wide methylation analysis identifies differentially methylated CpG loci associated with severe obesity in childhood

Childhood obesity is a major public health issue. Here we investigated whether differential DNA methylation was associated with childhood obesity. We studied DNA methylation profiles in whole blood from 78 obese children (mean BMI Z-score: 2.6) and 71 age- and sex-matched controls (mean BMI Z-score: 0.1). DNA samples from obese and control groups were pooled and analyzed using the Infinium HumanMethylation450 BeadChip array. Comparison of the methylation profiles between obese and control subjects revealed 129 differentially methylated CpG (DMCpG) loci associated with 80 unique genes that had a greater than 10% difference in methylation (P-value < 0.05). The top pathways enriched among the DMCpGs included developmental processes, immune system regulation, regulation of cell signaling, and small GTPase-mediated signal transduction. The associations between the methylation of selected DMCpGs with childhood obesity were validated using sodium bisulfite pyrosequencing across loci within the FYN, PIWIL4, and TAOK3 genes in individual subjects. Three CpG loci within FYN were hypermethylated in obese individuals (all P < 0.01), while obesity was associated with lower methylation of CpG loci within PIWIL4 (P = 0.003) and TAOK3 (P = 0.001). After building logistic regression models, we determined that a 1% increase in methylation in TAOK3, multiplicatively decreased the odds of being obese by 0.91 (95% CI: 0.86 – 0.97), and an increase of 1% methylation in FYN CpG3, multiplicatively increased the odds of being obese by 1.03 (95% CI: 0.99 – 1.07). In conclusion, these findings provide evidence that childhood obesity is associated with specific DNA methylation changes in whole blood, which may have utility as biomarkers of obesity risk.     

Genome‐wide promoter methylation analysis identifies epigenetic silencing of MAPK13 in primary cutaneous melanoma

The involvement of epigenetic alterations in the pathogenesis of melanoma is increasingly recognized. Here, we performed genome‐wide DNA methylation analysis of primary cutaneous melanoma and benign melanocytic nevus interrogating 14 495 genes using BeadChip technology. This genome‐wide view of promoter methylation in primary cutaneous melanoma revealed an array of recurrent DNA methylation alterations with potential diagnostic applications. Among 106 frequently hypermethylated genes, there were many novel methylation targets and tumor suppressor genes. Highly recurrent methylation of the HOXA9, MAPK13, CDH11, PLEKHG6, PPP1R3C, and CLDN11 genes was established. Promoter methylation of MAPK13, encoding p38δ, was present in 67% of primary and 85% of metastatic melanomas. Restoration of MAPK13 expression in melanoma cells exhibiting epigenetic silencing of this gene reduced proliferation, indicative of tumor suppressive functions. This study demonstrates that DNA methylation alterations are widespread in melanoma and suggests that epigenetic silencing of MAPK13 contributes to melanoma progression.     

Effects of short chain fatty acid producing bacteria on epigenetic regulation of FFAR3 in type 2 diabetes and obesity

The human gut microbiota and microbial influences on lipid and glucose metabolism, satiety, and chronic low-grade inflammation are known to be involved in metabolic syndrome. Fermentation end products, especially short chain fatty acids, are believed to engage the epigenetic regulation of inflammatory reactions via FFARs (free fatty acid receptor) and other short chain fatty acid receptors.     

Ⅱ型糖尿病易感基因研究的进展

Ⅱ型糖尿病是由基因和环境共同作用所引起的多基因遗传病,随着人类基因组计划的完成和单核苷酸多态性(single-nu-clcotide polymorphisms,SNP)扫描技术的发展,许多SNP位点被证实与Ⅱ型糖尿病相关,因此易感基因的检测是未来糖尿病预防和治疗的关键.本文主要介绍了目前Ⅱ型糖尿病易感基因的检测策略、方法、研究进展及今后的研究方向.     

Evaluation of glutathione S-transferase genetic variants affecting type 2 diabetes susceptibility: A meta-analysis

Genetic polymorphisms of glutathione S-transferases (GSTs) and type 2 diabetes mellitus (T2DM) risk have been widely studied, however, the results were somewhat conflicting. To evaluate the association of GSTs (GSTM1, GSTT1 and GSTP1) gene polymorphisms with T2DM, a meta-analysis was performed before October, 2012. ORs were pooled according to random-effects model. There were a total of 1354/1666 (n = 9) cases/controls (studies) for GSTM1, 1271/1470 (n = 8) for GSTT1, and 1205/1250 (n = 7) for GSTM1. There were significant associations between GSTM1 polymorphism, GSTT1 polymorphism and T2DM in the contrast of present genotype vs. null genotype, with pooled OR = 1.99 (95%CI = 1.46–2.71) and OR = 1.61 (95%CI = 1.19–2.17), respectively. Yet no significant association of GSTP1 polymorphism and T2DM was showed. When stratified by ethnicity, the significant associations were also existed in Asians for GSTM1 and GSTT1, but not GSTP1. No publication bias but some extent of heterogeneity was observed. Finally, the accumulated evidence proved the obvious associations of GSTM1 and GSTT1 polymorphisms with an increased risk of T2DM.     

A proteomic approach to obesity and type 2 diabetes

The incidence of obesity and type diabetes 2 has increased dramatically resulting in an increased interest in its biomedical relevance. However, the mechanisms that trigger the development of diabetes type 2 in obese patients remain largely unknown. Scientific, clinical and pharmaceutical communities are dedicating vast resources to unravel this issue by applying different omics tools. During the last decade, the advances in proteomic approaches and the Human Proteome Organization have opened and are opening a new door that may be helpful in the identification of patients at risk and to improve current therapies. Here, we briefly review some of the advances in our understanding of type 2 diabetes that have occurred through the application of proteomics. We also review, in detail, the current improvements in proteomic methodologies and new strategies that could be employed to further advance our understanding of this pathology. By applying these new proteomic advances, novel therapeutic and/or diagnostic protein targets will be discovered in the obesity/Type 2 diabetes area.     

Mouse models of type 1 and type 2 diabetes derived from the same closed colony: genetic susceptibility shared between two types of diabetes

Except for rare subtypes of diabetes, both type 1 and type 2 diabetes are multifactorial diseases in which genetic factors consisting of multiple susceptibility genes and environmental factors contribute to the disease development. Due to complex interaction among multiple susceptibility genes and between genetic and environmental factors, genetic analysis of multifactorial diseases is difficult in humans. Inbred animal models, in which the genetic background is homogeneous and environmental factors can be controlled, are therefore valuable in genetic dissection of multifactorial diseases. We are fortunate to have excellent animal models for both type 1 and type 2 diabetes--the nonobese diabetic (NOD) mouse and the Nagoya-Shibata-Yasuda (NSY) mouse, respectively. Congenic mapping of susceptibility genes for type 1 diabetes in the NOD mouse has revealed that susceptibility initially mapped as a single locus often consists of multiple components on the same chromosome, indicating the importance of congenic mapping in defining genes responsible for polygenic diseases. The NSY mouse is an inbred animal model of type 2 diabetes established from Jcl:ICR, from which the NOD mouse was also derived. We have recently mapped three major loci contributing to type 2 diabetes in the NSY mouse. Interestingly, support intervals where type 2 diabetes susceptibility genes were mapped in the NSY mouse overlapped the regions where type 1 diabetes susceptibility genes have been mapped in the NOD mouse. Although additional evidence is needed, it may be possible that some of the genes predisposing to diabetes are derived from a common ancestor contained in the original closed colony, contributing to type 1 diabetes in the NOD mouse and type 2 diabetes in the NSY mouse. Such genes, if they exist, will provide valuable information on etiological pathways common to both forms of diabetes, for the establishment of effective methods for prediction, prevention, and intervention in both type 1 and type 2 diabetes.     

Mapping of the murine type 1 diabetes locus Idd20 by genetic interaction

In the nonobese diabetes mouse, the murine type 1 diabetes susceptibility locus Idd20 interacts genetically with the diabetes resistance locus Idd19. Both Idds are located on distal mouse Chromosome 6, and previous studies on NOD.C3H congenic strains have shown that C3H alleles at Idd20 can suppress the disease-promoting effects of C3H alleles at Idd19 in both spontaneous and cyclophosphamide-induced diabetes. In this article we present the construction of novel congenic strains which, while maintaining the C3H alleles at Idd19, have allowed the candidate interval of Idd20 to be reduced from 4 to 1.8 cM. The analysis of these strains shows that Idd20 controls the progression of insulitis. Idd20 also increases the suppressive but not the pathogenic activity of splenocytes in diabetes transfer experiments. Our results suggest that the two Chromosome 6 susceptibility loci, Idd6 and Idd20, interact with the resistance locus Idd19 by regulating the activity of suppressor cells in the peripheral immune system.     

Protective mechanisms of the Mediterranean diet in obesity and type 2 diabetes

The prevalence of obesity has grown to an alarming level of at least 300 million people worldwide. Additionally, a diabetes epidemic is underway, with an estimate of 217 million people with diabetes worldwide. There are many links between excessive body weight and type 2 diabetes, and one common and fundamental cause of both epidemics is an unhealthy diet. Research to identify and promote diets that protect individuals from obesity and type 2 diabetes is urgently needed. The Mediterranean diet, a concept developed in the 1950s, refers to dietary habits of individuals from the Mediterranean basin. The Mediterranean diet is an eating pattern that successfully combines pleasant taste and positive health effects. The Mediterranean diet does not stand for a homogenous and exclusive model among the Mediterranean basin population but rather represents a set of healthy dietary habits, including high consumption of vegetables and fresh fruits and the use of olive oil as the main source of fat. Evidence from epidemiological studies supports a protective effect of this dietary pattern on weight gain and the development of type 2 diabetes. Several mechanistic explanations link characteristic components of the Mediterranean diet with obesity and type 2 diabetes. This review will discuss potential mechanisms by which the Mediterranean diet protects individuals from both diseases.