Metabolically healthy obese(MHO)individuals are reported to have a lower risk of developing cardiovascular diseases in comparison with individuals with metabolic syndrome.However,the association between MHO and type 2...Metabolically healthy obese(MHO)individuals are reported to have a lower risk of developing cardiovascular diseases in comparison with individuals with metabolic syndrome.However,the association between MHO and type 2 diabetes(T2DM)is still controversial.Some studies indicated that MHO is a favorable phenotype for T2DM,but more studies showed that MHO individuals have an increased risk of developing T2DM compared with metabolically healthy normalweight individuals,especially among those who would acquire metabolically unhealthy obesity.This has been supported by finding insulin resistance and lowgrade inflammatory responses in MHO individuals with a tendency for impaired beta-cell dysfunction.Studies also showed that liver fat accumulation increased the risk of incidence of T2DM in MHO.Here,we reviewed current literature on the relationship between MHO and T2DM,discussed the determinants for the development of diabetes in MHO,and summarized the measures for the prevention of T2DM in MHO.展开更多
BACKGROUND Skeletal muscle,a key insulin target organ,has been reported to be associated with diabetes mellitus(DM).Compared to non-diabetic patients,diabetic patients have decreased muscle mass and a higher prevalenc...BACKGROUND Skeletal muscle,a key insulin target organ,has been reported to be associated with diabetes mellitus(DM).Compared to non-diabetic patients,diabetic patients have decreased muscle mass and a higher prevalence of sarcopenia,and patients with sarcopenia may be at increased risk of developing diabetes.In individuals with nonalcoholic fatty liver disease(NAFLD),sarcopenia is associated with the severity of fibrosis and steatosis.Previous studies have demonstrated that NAFLD is strongly associated with DM and sarcopenia.AIM To determine the relationship between skeletal muscle mass and DM in Chinese middle-aged and elderly men,and whether the association is affected by NAFLD.METHODS Skeletal muscle mass was calculated as appendicular skeletal muscle mass(ASM)in kg/body weight×100%.Liver fat content(LFC)was measured using a quantitative ultrasound method.RESULTS As the ASM decreased,fasting blood glucose(FBG),2-h postprandial blood glucose(2hBG),and LFC increased in both genders,as did the prevalence of DM and NAFLD.Spearman analysis showed that the ASM was negatively correlated with the FBG,2hBG,and LFC.Stepwise logistic regression analysis showed that after adjustments,the ASM quartile was negatively associated with the presence of DM in males,but not in females.Subgroup analysis showed that the ASM quartiles remained negatively correlated with the presence of DM in the non-NAFLD population(including males and females),but no correlation was found between ASM quartiles and the presence of DM in the NAFLD population.When stratified by LFC quartiles,ASM was negatively correlated with the presence of DM in the first and second LFC quartiles in males.CONCLUSION Skeletal muscle mass loss was shown to be associated with the presence of DM in males,but not in females;NAFLD weakens this association.The results suggested that the stratified management of diabetes mellitus should be considered according to skeletal muscle mass and NAFLD.展开更多
AIM:To develop and evaluate a new fundus image optimization software based on red,green,blue channels(RGB) for the evaluation of age-related macular degeneration(AMD) in the Chinese population.METHODS:Fundus images th...AIM:To develop and evaluate a new fundus image optimization software based on red,green,blue channels(RGB) for the evaluation of age-related macular degeneration(AMD) in the Chinese population.METHODS:Fundus images that were diagnosed as AMD from the Shanghai Changfeng Study database were analyzed to develop a standardized optimization procedure.Image brightness,contrast,and color balance were measured.Differences between central lesion area and normal retinal area under different image brightness,contrast,and color balance were observed.The optimal optimization parameters were determined based on the visual system to avoid image distortion.A paired-sample diagnostic test was used to evaluate the enhancement software.Fundus optical coherence tomography(OCT) was used as the gold standard.Diagnostic performances were compared between original images and optimized images using Mc Nemar’s test.RESULTS:A fundus image optimization procedure was developed using 86 fundus images of 74 subjects diagnosed with AMD.By observing gray-scale images,choroid can be best displayed in red channel and retina in green channel was found.There was limited information in blue channel.Totally 104 participants were included in the paired sample diagnostic test to assess the performance of the optimization software.After the image enhancement,sensitivity increased from 74% to 88%(P=0.008),specificity decreased slightly from 88% to 84%(P=0.500),and Youden index increased by 0.11.CONCLUSION:The standardized image optimization software increases diagnostic sensitivity and may help ophthalmologists in AMD diagnosis and screening.展开更多
Background： The clinical significance of metabolic syndrome （MS） score, MS, and its individual components with respect to risk prediction of coronary artery disease （CAD） remains unclear. The objective of this st...Background： The clinical significance of metabolic syndrome （MS） score, MS, and its individual components with respect to risk prediction of coronary artery disease （CAD） remains unclear. The objective of this study was to investigate whether and to what extent MS score, MS, and its individual components were related to the risk of CAD. Methods： Among 1191 participants who underwent coronary angiography for the confirmation of suspected myocardial ischemia, 858 were included in this study according to the inclusion criteria from September 2010 to June 2013. MS was diagnosed with the 2005 National Cholesterol Education Program Adult Treatment Panel III criteria. The severity of coronary atherosclerosis was assessed by Gensini score. Results： The results showed that the age- and sex-adjusted odds ratios （ORs） tbr CAD were as follows： MS score, 1.327; MS, 2.013; elevated waist circumference, 1.447; reduced high-density lipoprotein cholesterol, 1.654： and elevated fasting glucose, 1.782： all P〈 0.05： whereas for elevated triglycerides, 1.324, and elevated blood pressure, 1.342, both P 〉 0.05. Alter multivariate adjustment, results showed that only MS and elevated fasting glucose were significantly associated with CAD （OR, 1.628, 95% confidence interval [CI], 1.151-2.305, P = 0.006 for elevated fasting glucose, and OR, 1.631, 95% CI, 1.208-2.203, P = 0.001 for MS）. The study showed that only MS score and elevated fasting glucose were significantly associated with Gensini score （standardized coefficient, 0.101, P = 0.031 for elevated fasting glucose and standardized coefficient, 0.103, P = 0.009 for MS score）. Conclusions： The present study demonstrated that MS score, MS, and its individual components might have different contributions to CAD prevalence and severity. MS and elevated fasting glucose were independent risk factors for the prevalence of angiographic CAD whereas MS score and elevated fasting glucose were significantly associated with the severity of CAD.展开更多
Metabolic diseases including type 2 diabetes mellitus(T2DM),non-alcoholic fatty liver disease(NAFLD),and metabolic syndrome(MetS)are alarming health burdens around the world,while therapies for these diseases are far ...Metabolic diseases including type 2 diabetes mellitus(T2DM),non-alcoholic fatty liver disease(NAFLD),and metabolic syndrome(MetS)are alarming health burdens around the world,while therapies for these diseases are far from satisfying as their etiologies are not completely dear yet.T2DM,NAFLD,and MetS are all complex and multifactorial metabolic disorders based on the interactions between genetics and environment.Omics studies such as genetics,transcriptomics,epigenetics,proteomics,and metabolomics are all promising approaches in accurately characterizing these diseases.And the most effective treatments for individuals can be achieved via omics pathways,which is the theme of precision medicine.In this review,we summarized the multi-omics studies of T2DM,NAFLD,and MetS in recent years,provided a theoretical basis for their pathogenesis and the effective prevention and treatment,and highlighted the biomarkers and future strategies for precision medicine.展开更多
A small fraction of patients diagnosed with obesity or diabetes mellitus has an underlying monogenic cause.Here,we constructed a targeted gene panel consisting of 83 genes reported to be causative for monogenic obesit...A small fraction of patients diagnosed with obesity or diabetes mellitus has an underlying monogenic cause.Here,we constructed a targeted gene panel consisting of 83 genes reported to be causative for monogenic obesity or diabetes.We performed this panel in 481 patients to detect causative variants and compared these results with whole-exome sequencing(WES)data available for 146 of these patients.The coverage of targeted gene panel sequencing was significantly higher than that of WES.The diagnostic yield in patients sequenced by the panel was 32.9%with subsequent WES leading to three additional diagnoses with two novel genes.In total,178 variants in 83 genes were detected in 146 patients by targeted sequencing.Three of the 178 variants were missed by WES,although the WES-only approach had a similar diagnostic yield.For the 335 samples only receiving targeted sequencing,the diagnostic yield was 32.2%.In conclusion,taking into account the lower costs,shorter turnaround time,and higher quality of data,targeted sequencing is a more effective screening method for monogenic obesity and diabetes compared to WES.Therefore,this approach could be routinely established and used as a first-tier test in clinical practice for specific patients.展开更多
A metabolically healthy status,whether obese or not,is a transient stage with the potential to develop into metabolic disor-ders during the course of life.We investigated the incidence of metabolic disorders in 1078 m...A metabolically healthy status,whether obese or not,is a transient stage with the potential to develop into metabolic disor-ders during the course of life.We investigated the incidence of metabolic disorders in 1078 metabolically healthy Chinese adults from the Shanghai Changfeng Study and looked for metabolites that discriminated the participants who would develop metabolic disorders in the future.Participants were divided into metabolically healthy overweight/obesity(MHO)and meta-bolically healthy normal weight(MHNW)groups according to their body mass index(BMI)and metabolic status.Their serum metabolomic profile was measured using a ^(1)H nuclear magnetic resonance spectrometer(^(1)H-NMR).The prevalence of diabetes,hypertriglyceridemia,hypercholesterolemia and metabolic syndrome was similar between the MHNW and MHO participants at baseline.After a median of 4.2 years of follow-up,more MHO participants became metabolically unhealthy than MHNW participants.However,a subgroup of MHO participants who remained metabolically healthy(MHO→MHO)had a similar prevalence of metabolic disorders as the MHNW participants at the follow-up examination,despite a signifi-cant reduction in their serum concentrations of high-density lipoprotein(HDL)and an elevation in valine,leucine,alanine and tyrosine.Further correlation analysis indicated that serum intermediate-density lipoprotein(IDL)and very low-density lipoprotein cholesterol(VLDL-CH)might be involved in the transition from metabolically healthy to unhealthy status and could be valuable to identify the MHNW and MHO with increased metabolic risks.展开更多
Brain-specific serine/threonine-protein kinase 2(BRSK2)plays critical roles in insulin secretion andβ-cell biology.However,whether BRSK2 is associated with human type 2 diabetes mellitus(T2DM)has not been determined....Brain-specific serine/threonine-protein kinase 2(BRSK2)plays critical roles in insulin secretion andβ-cell biology.However,whether BRSK2 is associated with human type 2 diabetes mellitus(T2DM)has not been determined.Here,we report that BRSK2 genetic variants are closely related to worsening glucose metabolism due to hyperinsulinemia and insulin resistance in the Chinese population.BRSK2 protein levels are significantly elevated inβcells from T2DM patients and high-fat diet(HFD)-fed mice due to enhanced protein stability.Mice with inducibleβ-cell-specific Brsk2 knockout(βKO)exhibit normal metabolism with a high potential for insulin secretion under chow-diet conditions.Moreover,βKO mice are protected from HFD-induced hyperinsulinemia,obesity,insulin resistance,and glucose intolerance.Conversely,gain-of-function BRSK2 in matureβcells reversibly triggers hyperglycemia due toβ-cell hypersecretion-coupled insulin resistance.Mechanistically,BRSK2 senses lipid signals and induces basal insulin secretion in a kinase-dependent manner.The enhanced basal insulin secretion drives insulin resistance andβ-cell exhaustion and thus the onset of T2DM in mice fed an HFD or with gain-of-function BRSK2 inβcells.These findings reveal that BRSK2 links hyperinsulinemia to systematic insulin resistance via interplay betweenβcells and insulin-sensitive tissues in the populations carrying human genetic variants or under nutrient-overload conditions.展开更多
Monognnic diabetes is often misdiagnosed with type 2 diabetes due to overlapping characteristics. This study aimed to discover novel causative mutations of monogenic diabetes in patients with clinically diagnosed type...Monognnic diabetes is often misdiagnosed with type 2 diabetes due to overlapping characteristics. This study aimed to discover novel causative mutations of monogenic diabetes in patients with clinically diagnosed type 2 diabetes and to explore potential molecular mechanisms. Whole-exome sequencing was performed on 31 individuals clinically diagnosed with type 2 diabetes. One novel heterozygnus mutation （p^la2Thr） in INS was identified. It was further gnnotyped in an additional case-control population （6523 cases and 4635 controls）, and this variant was observed in 0.09% of cases. IntraceUular trafficking of insulin proteins was assessed in INSl-E and HEK293T cells, p.Ala2Thr preproinsuUn-GFP was markedly retained in the endoplasmic reticulum （ER） in INS1-E cells. Activation of the PERK-elF2a-ATF4, IREla-XBP1, and ATF6 pathways as well as upregulated ER chaperones were detected in INS1-E cells transfected with the p.Ala2Thr mutant. In conclusion, we identified a causative mutation in IN5 respon- sible for maturity-onset diabetes of the young 10 （MODYIO） in a Chinese population and demonstrated that this mutation affected 13 cell function by inducing ER stress.展开更多
A number of recent studies revealed that DNA methylation plays a central role in the regulation of lipid metabolism.DNA methylation modifications are important regulators of transcriptional networks that do not affect...A number of recent studies revealed that DNA methylation plays a central role in the regulation of lipid metabolism.DNA methylation modifications are important regulators of transcriptional networks that do not affect the DNA sequence and can translate genetic variants and environmental factors into phenotypic traits.Therefore,elucidating the factors that underlie inter-individual DNA methylation variations gives us an opportunity to predict diseases and interfere with the establishment of aberrant DNA methylation early.In this review,we summarize the findings of DNA methylation-related studies focused on unravelling the potential role of genetic and environmental factors in DNA methylation and the regulatory effect of DNA methylation on gene expression in lipid metabolism.展开更多
文摘Metabolically healthy obese(MHO)individuals are reported to have a lower risk of developing cardiovascular diseases in comparison with individuals with metabolic syndrome.However,the association between MHO and type 2 diabetes(T2DM)is still controversial.Some studies indicated that MHO is a favorable phenotype for T2DM,but more studies showed that MHO individuals have an increased risk of developing T2DM compared with metabolically healthy normalweight individuals,especially among those who would acquire metabolically unhealthy obesity.This has been supported by finding insulin resistance and lowgrade inflammatory responses in MHO individuals with a tendency for impaired beta-cell dysfunction.Studies also showed that liver fat accumulation increased the risk of incidence of T2DM in MHO.Here,we reviewed current literature on the relationship between MHO and T2DM,discussed the determinants for the development of diabetes in MHO,and summarized the measures for the prevention of T2DM in MHO.
基金the National Key Basic Research Program of China,No.2012CB524906 and No.2011CB504004the Shanghai Municipal Health Bureau Foundation,No.12GWZX0103and the Science and Technology Commission of Shanghai Municipality,No.10411956400.
文摘BACKGROUND Skeletal muscle,a key insulin target organ,has been reported to be associated with diabetes mellitus(DM).Compared to non-diabetic patients,diabetic patients have decreased muscle mass and a higher prevalence of sarcopenia,and patients with sarcopenia may be at increased risk of developing diabetes.In individuals with nonalcoholic fatty liver disease(NAFLD),sarcopenia is associated with the severity of fibrosis and steatosis.Previous studies have demonstrated that NAFLD is strongly associated with DM and sarcopenia.AIM To determine the relationship between skeletal muscle mass and DM in Chinese middle-aged and elderly men,and whether the association is affected by NAFLD.METHODS Skeletal muscle mass was calculated as appendicular skeletal muscle mass(ASM)in kg/body weight×100%.Liver fat content(LFC)was measured using a quantitative ultrasound method.RESULTS As the ASM decreased,fasting blood glucose(FBG),2-h postprandial blood glucose(2hBG),and LFC increased in both genders,as did the prevalence of DM and NAFLD.Spearman analysis showed that the ASM was negatively correlated with the FBG,2hBG,and LFC.Stepwise logistic regression analysis showed that after adjustments,the ASM quartile was negatively associated with the presence of DM in males,but not in females.Subgroup analysis showed that the ASM quartiles remained negatively correlated with the presence of DM in the non-NAFLD population(including males and females),but no correlation was found between ASM quartiles and the presence of DM in the NAFLD population.When stratified by LFC quartiles,ASM was negatively correlated with the presence of DM in the first and second LFC quartiles in males.CONCLUSION Skeletal muscle mass loss was shown to be associated with the presence of DM in males,but not in females;NAFLD weakens this association.The results suggested that the stratified management of diabetes mellitus should be considered according to skeletal muscle mass and NAFLD.
文摘AIM:To develop and evaluate a new fundus image optimization software based on red,green,blue channels(RGB) for the evaluation of age-related macular degeneration(AMD) in the Chinese population.METHODS:Fundus images that were diagnosed as AMD from the Shanghai Changfeng Study database were analyzed to develop a standardized optimization procedure.Image brightness,contrast,and color balance were measured.Differences between central lesion area and normal retinal area under different image brightness,contrast,and color balance were observed.The optimal optimization parameters were determined based on the visual system to avoid image distortion.A paired-sample diagnostic test was used to evaluate the enhancement software.Fundus optical coherence tomography(OCT) was used as the gold standard.Diagnostic performances were compared between original images and optimized images using Mc Nemar’s test.RESULTS:A fundus image optimization procedure was developed using 86 fundus images of 74 subjects diagnosed with AMD.By observing gray-scale images,choroid can be best displayed in red channel and retina in green channel was found.There was limited information in blue channel.Totally 104 participants were included in the paired sample diagnostic test to assess the performance of the optimization software.After the image enhancement,sensitivity increased from 74% to 88%(P=0.008),specificity decreased slightly from 88% to 84%(P=0.500),and Youden index increased by 0.11.CONCLUSION:The standardized image optimization software increases diagnostic sensitivity and may help ophthalmologists in AMD diagnosis and screening.
文摘Background： The clinical significance of metabolic syndrome （MS） score, MS, and its individual components with respect to risk prediction of coronary artery disease （CAD） remains unclear. The objective of this study was to investigate whether and to what extent MS score, MS, and its individual components were related to the risk of CAD. Methods： Among 1191 participants who underwent coronary angiography for the confirmation of suspected myocardial ischemia, 858 were included in this study according to the inclusion criteria from September 2010 to June 2013. MS was diagnosed with the 2005 National Cholesterol Education Program Adult Treatment Panel III criteria. The severity of coronary atherosclerosis was assessed by Gensini score. Results： The results showed that the age- and sex-adjusted odds ratios （ORs） tbr CAD were as follows： MS score, 1.327; MS, 2.013; elevated waist circumference, 1.447; reduced high-density lipoprotein cholesterol, 1.654： and elevated fasting glucose, 1.782： all P〈 0.05： whereas for elevated triglycerides, 1.324, and elevated blood pressure, 1.342, both P 〉 0.05. Alter multivariate adjustment, results showed that only MS and elevated fasting glucose were significantly associated with CAD （OR, 1.628, 95% confidence interval [CI], 1.151-2.305, P = 0.006 for elevated fasting glucose, and OR, 1.631, 95% CI, 1.208-2.203, P = 0.001 for MS）. The study showed that only MS score and elevated fasting glucose were significantly associated with Gensini score （standardized coefficient, 0.101, P = 0.031 for elevated fasting glucose and standardized coefficient, 0.103, P = 0.009 for MS score）. Conclusions： The present study demonstrated that MS score, MS, and its individual components might have different contributions to CAD prevalence and severity. MS and elevated fasting glucose were independent risk factors for the prevalence of angiographic CAD whereas MS score and elevated fasting glucose were significantly associated with the severity of CAD.
文摘Metabolic diseases including type 2 diabetes mellitus(T2DM),non-alcoholic fatty liver disease(NAFLD),and metabolic syndrome(MetS)are alarming health burdens around the world,while therapies for these diseases are far from satisfying as their etiologies are not completely dear yet.T2DM,NAFLD,and MetS are all complex and multifactorial metabolic disorders based on the interactions between genetics and environment.Omics studies such as genetics,transcriptomics,epigenetics,proteomics,and metabolomics are all promising approaches in accurately characterizing these diseases.And the most effective treatments for individuals can be achieved via omics pathways,which is the theme of precision medicine.In this review,we summarized the multi-omics studies of T2DM,NAFLD,and MetS in recent years,provided a theoretical basis for their pathogenesis and the effective prevention and treatment,and highlighted the biomarkers and future strategies for precision medicine.
基金supported by grants from Shanghai Outstanding Academic Leaders(20XD1433300)Medical-Engineering Cross Foundation of Shanghai Jiao Tong University(YG2021ZD20)+3 种基金Shuguang Project(21SG11),Innovative Research Team of High-level Local Universities in Shanghai(SHSMU-ZDCX20212700)Shanghai Research Center for Endocrine,Metabolic Diseases(2022ZZ01002)Shanghai Sixth People’s Hospital Grant(ynhg202204)Shanghai Municipal Key Clinical Specialty.
文摘A small fraction of patients diagnosed with obesity or diabetes mellitus has an underlying monogenic cause.Here,we constructed a targeted gene panel consisting of 83 genes reported to be causative for monogenic obesity or diabetes.We performed this panel in 481 patients to detect causative variants and compared these results with whole-exome sequencing(WES)data available for 146 of these patients.The coverage of targeted gene panel sequencing was significantly higher than that of WES.The diagnostic yield in patients sequenced by the panel was 32.9%with subsequent WES leading to three additional diagnoses with two novel genes.In total,178 variants in 83 genes were detected in 146 patients by targeted sequencing.Three of the 178 variants were missed by WES,although the WES-only approach had a similar diagnostic yield.For the 335 samples only receiving targeted sequencing,the diagnostic yield was 32.2%.In conclusion,taking into account the lower costs,shorter turnaround time,and higher quality of data,targeted sequencing is a more effective screening method for monogenic obesity and diabetes compared to WES.Therefore,this approach could be routinely established and used as a first-tier test in clinical practice for specific patients.
基金supported by the Shanghai Municipal Science and Technology Major Project(2017SHZDZX01)the Science and Technology Commission of Shanghai Municipality(16JC1400500).
文摘A metabolically healthy status,whether obese or not,is a transient stage with the potential to develop into metabolic disor-ders during the course of life.We investigated the incidence of metabolic disorders in 1078 metabolically healthy Chinese adults from the Shanghai Changfeng Study and looked for metabolites that discriminated the participants who would develop metabolic disorders in the future.Participants were divided into metabolically healthy overweight/obesity(MHO)and meta-bolically healthy normal weight(MHNW)groups according to their body mass index(BMI)and metabolic status.Their serum metabolomic profile was measured using a ^(1)H nuclear magnetic resonance spectrometer(^(1)H-NMR).The prevalence of diabetes,hypertriglyceridemia,hypercholesterolemia and metabolic syndrome was similar between the MHNW and MHO participants at baseline.After a median of 4.2 years of follow-up,more MHO participants became metabolically unhealthy than MHNW participants.However,a subgroup of MHO participants who remained metabolically healthy(MHO→MHO)had a similar prevalence of metabolic disorders as the MHNW participants at the follow-up examination,despite a signifi-cant reduction in their serum concentrations of high-density lipoprotein(HDL)and an elevation in valine,leucine,alanine and tyrosine.Further correlation analysis indicated that serum intermediate-density lipoprotein(IDL)and very low-density lipoprotein cholesterol(VLDL-CH)might be involved in the transition from metabolically healthy to unhealthy status and could be valuable to identify the MHNW and MHO with increased metabolic risks.
基金supported by research grants from the National Natural Science Foundation of China(81420108007 and 81830024 to X.H.,82270844,82070843,and 81870531 to Y.Zhu).
文摘Brain-specific serine/threonine-protein kinase 2(BRSK2)plays critical roles in insulin secretion andβ-cell biology.However,whether BRSK2 is associated with human type 2 diabetes mellitus(T2DM)has not been determined.Here,we report that BRSK2 genetic variants are closely related to worsening glucose metabolism due to hyperinsulinemia and insulin resistance in the Chinese population.BRSK2 protein levels are significantly elevated inβcells from T2DM patients and high-fat diet(HFD)-fed mice due to enhanced protein stability.Mice with inducibleβ-cell-specific Brsk2 knockout(βKO)exhibit normal metabolism with a high potential for insulin secretion under chow-diet conditions.Moreover,βKO mice are protected from HFD-induced hyperinsulinemia,obesity,insulin resistance,and glucose intolerance.Conversely,gain-of-function BRSK2 in matureβcells reversibly triggers hyperglycemia due toβ-cell hypersecretion-coupled insulin resistance.Mechanistically,BRSK2 senses lipid signals and induces basal insulin secretion in a kinase-dependent manner.The enhanced basal insulin secretion drives insulin resistance andβ-cell exhaustion and thus the onset of T2DM in mice fed an HFD or with gain-of-function BRSK2 inβcells.These findings reveal that BRSK2 links hyperinsulinemia to systematic insulin resistance via interplay betweenβcells and insulin-sensitive tissues in the populations carrying human genetic variants or under nutrient-overload conditions.
文摘Monognnic diabetes is often misdiagnosed with type 2 diabetes due to overlapping characteristics. This study aimed to discover novel causative mutations of monogenic diabetes in patients with clinically diagnosed type 2 diabetes and to explore potential molecular mechanisms. Whole-exome sequencing was performed on 31 individuals clinically diagnosed with type 2 diabetes. One novel heterozygnus mutation （p^la2Thr） in INS was identified. It was further gnnotyped in an additional case-control population （6523 cases and 4635 controls）, and this variant was observed in 0.09% of cases. IntraceUular trafficking of insulin proteins was assessed in INSl-E and HEK293T cells, p.Ala2Thr preproinsuUn-GFP was markedly retained in the endoplasmic reticulum （ER） in INS1-E cells. Activation of the PERK-elF2a-ATF4, IREla-XBP1, and ATF6 pathways as well as upregulated ER chaperones were detected in INS1-E cells transfected with the p.Ala2Thr mutant. In conclusion, we identified a causative mutation in IN5 respon- sible for maturity-onset diabetes of the young 10 （MODYIO） in a Chinese population and demonstrated that this mutation affected 13 cell function by inducing ER stress.
基金This work was supported by the grant from Outstanding Academic Leaders of Shanghai Heath System[2017BR008].
文摘A number of recent studies revealed that DNA methylation plays a central role in the regulation of lipid metabolism.DNA methylation modifications are important regulators of transcriptional networks that do not affect the DNA sequence and can translate genetic variants and environmental factors into phenotypic traits.Therefore,elucidating the factors that underlie inter-individual DNA methylation variations gives us an opportunity to predict diseases and interfere with the establishment of aberrant DNA methylation early.In this review,we summarize the findings of DNA methylation-related studies focused on unravelling the potential role of genetic and environmental factors in DNA methylation and the regulatory effect of DNA methylation on gene expression in lipid metabolism.
