Manon Jaffredo, Nicole A. J. Krentz, Benoite Champon, Claire E. Duff, Sameena Nawaz, Nicola Beer, Christian Honore, Anne Clark, Patrik Rorsman, Jochen Lang, Anna L. Gloyn, Matthieu Raoux, Benoit Hastoy
iPSC-derived human β-like cells (BLC) hold promise for both therapy and disease modelling, but their generation remains challenging and their functional analyses beyond transcriptomic and morphological assessments remain limited. Here, we validate an approach using multicellular and single cell electrophysiological tools to evaluate function of BLCs from pioneer protocols that can be easily adapted to more differentiated BLCs. The Multi-Electrode Arrays (MEAs) measuring the extracellular electrical activity revealed that BLCs are electrically coupled, produce slow potential (SP) signals like primary β-cells that are closely linked to insulin secretion. We also used high-resolution single-cell patch-clamp measurements to capture the exocytotic properties, and characterise voltage-gated sodium and calcium currents and found that they were comparable to those in primary β and EndoC-βH1 cells. The KATP channel conductance is greater than in human primary β-cells which may account for the limited glucose responsiveness observed with MEA. We used MEAs to study the impact of the type 2 diabetes protective SLC30A8 allele (p.Lys34Serfs*50) and found that BLCs with this allele have stronger electrical coupling activity. Our data suggest that BLCs can be used to evaluate the functional impact of genetic variants on β-cell function and coupling.
{"title":"Electrophysiological characterisation of iPSC-derived human β-like cells and an SLC30A8 disease model.","authors":"Manon Jaffredo, Nicole A. J. Krentz, Benoite Champon, Claire E. Duff, Sameena Nawaz, Nicola Beer, Christian Honore, Anne Clark, Patrik Rorsman, Jochen Lang, Anna L. Gloyn, Matthieu Raoux, Benoit Hastoy","doi":"10.2337/db23-0776","DOIUrl":"https://doi.org/10.2337/db23-0776","url":null,"abstract":"iPSC-derived human β-like cells (BLC) hold promise for both therapy and disease modelling, but their generation remains challenging and their functional analyses beyond transcriptomic and morphological assessments remain limited. Here, we validate an approach using multicellular and single cell electrophysiological tools to evaluate function of BLCs from pioneer protocols that can be easily adapted to more differentiated BLCs. The Multi-Electrode Arrays (MEAs) measuring the extracellular electrical activity revealed that BLCs are electrically coupled, produce slow potential (SP) signals like primary β-cells that are closely linked to insulin secretion. We also used high-resolution single-cell patch-clamp measurements to capture the exocytotic properties, and characterise voltage-gated sodium and calcium currents and found that they were comparable to those in primary β and EndoC-βH1 cells. The KATP channel conductance is greater than in human primary β-cells which may account for the limited glucose responsiveness observed with MEA. We used MEAs to study the impact of the type 2 diabetes protective SLC30A8 allele (p.Lys34Serfs*50) and found that BLCs with this allele have stronger electrical coupling activity. Our data suggest that BLCs can be used to evaluate the functional impact of genetic variants on β-cell function and coupling.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141165342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Liana K. Billings, Kathleen A. Jablonski, Qing Pan, Paul W. Franks, Ronald B. Goldberg, Marie-France Hivert, Steven E. Kahn, William C. Knowler, Christine G. Lee, Jordi Merino, Alicia Huerta-Chagoya, Josep M. Mercader, Sridharan Raghavan, Zhuqing Shi, Shylaja Srinivasan, Jianfeng Xu, Jose C. Florez, Miriam S. Udler
Partitioned polygenic scores (pPS) have been developed to capture pathophysiologic processes underlying type 2 diabetes (T2D). We investigated the influence of T2D pPS on diabetes-related traits and T2D incidence in the Diabetes Prevention Program. We generated five T2D pPS (β-cell, proinsulin, liver/lipid, obesity, lipodystrophy) in 2,647 participants randomized to intensive lifestyle, metformin or placebo arms. Associations were tested using general linear models and Cox regression adjusted for age, sex, and principal components. Sensitivity analyses included adjustment for BMI. Higher β-cell pPS was associated with lower insulinogenic index and corrected insulin response at one year follow-up adjusted for baseline measures (effect per pPS standard deviation (SD) -0.04, P=9.6 x 10-7; -8.45 uU/mg, P=5.6 x 10-6, respectively) and with increased diabetes incidence adjusted for BMI at nominal significance (HR 1.10 per SD, P=0.035). The liver/lipid pPS was associated with reduced one-year baseline-adjusted triglyceride levels (effect per SD -4.37, P=0.001). There was no significant interaction between T2D pPS and randomized groups. The remaining pPS were associated with baseline measures only. We conclude that despite interventions for diabetes prevention, participants with a high genetic burden of the β-cell cluster pPS had worsening in measures of β-cell function.
{"title":"Increased genetic risk for β-cell failure is associated with β-cell function decline in people with prediabetes","authors":"Liana K. Billings, Kathleen A. Jablonski, Qing Pan, Paul W. Franks, Ronald B. Goldberg, Marie-France Hivert, Steven E. Kahn, William C. Knowler, Christine G. Lee, Jordi Merino, Alicia Huerta-Chagoya, Josep M. Mercader, Sridharan Raghavan, Zhuqing Shi, Shylaja Srinivasan, Jianfeng Xu, Jose C. Florez, Miriam S. Udler","doi":"10.2337/db23-0761","DOIUrl":"https://doi.org/10.2337/db23-0761","url":null,"abstract":"Partitioned polygenic scores (pPS) have been developed to capture pathophysiologic processes underlying type 2 diabetes (T2D). We investigated the influence of T2D pPS on diabetes-related traits and T2D incidence in the Diabetes Prevention Program. We generated five T2D pPS (β-cell, proinsulin, liver/lipid, obesity, lipodystrophy) in 2,647 participants randomized to intensive lifestyle, metformin or placebo arms. Associations were tested using general linear models and Cox regression adjusted for age, sex, and principal components. Sensitivity analyses included adjustment for BMI. Higher β-cell pPS was associated with lower insulinogenic index and corrected insulin response at one year follow-up adjusted for baseline measures (effect per pPS standard deviation (SD) -0.04, P=9.6 x 10-7; -8.45 uU/mg, P=5.6 x 10-6, respectively) and with increased diabetes incidence adjusted for BMI at nominal significance (HR 1.10 per SD, P=0.035). The liver/lipid pPS was associated with reduced one-year baseline-adjusted triglyceride levels (effect per SD -4.37, P=0.001). There was no significant interaction between T2D pPS and randomized groups. The remaining pPS were associated with baseline measures only. We conclude that despite interventions for diabetes prevention, participants with a high genetic burden of the β-cell cluster pPS had worsening in measures of β-cell function.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140954258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ibrahim Choucair, Deepthi P. Mallela, James R. Hilser, Jaana A. Hartiala, Ina Nemet, Valentin Gogonea, Lin Li, Aldons J. Lusis, Michael A. Fischbach, W. H. Wilson Tang, Hooman Allayee, Stanley L. Hazen
Bile acids (BAs) are cholesterol-derived compounds that regulate glucose, lipid, and energy metabolism. Despite their significance in glucose homeostasis, the association between specific BA molecular species and their synthetic pathways with diabetes mellitus (DM) is unclear. Here, we used a recently validated stable-isotope dilution highperformance liquid chromatography with tandem mass spectrometry (LC-MS/MS) method to quantify a panel of BAs in fasting plasma from subjects (n=2,145) and explored structural and genetic determinants of BAs linked to DM, insulin resistance and obesity. Multiple 12α-hydroxylated BAs were associated with DM [adjusted odds ratios (aORs):1.3-1.9 (all P<0.05)] and insulin resistance [aORs:1.3-2.2 (all P<0.05)]. Conversely, multiple 6a-hydroxylated BAs and isolithocholic acid (Iso-LCA) were inversely associated with DM and obesity [aORs:0.3-0.9 (all P<0.05)]. Genome-wide association studies (GWAS) revealed multiple genome-wide significant loci linked with nine of the 14 DM-associated BAs, including a locus for Iso-LCA (rs11866815). Mendelian randomization analyses showed genetically elevated DCA levels were causally associated with higher BMI, and Iso-LCA levels were causally associated with reduced BMI and DM risk. In conclusion, comprehensive large-scale quantitative mass spectrometry and genetics analyses show circulating levels of multiple structurally specific BAs, especially DCA and Iso-LCA, are clinically associated with and genetically linked to obesity and DM.
胆汁酸（BA）是一种胆固醇衍生化合物，可调节葡萄糖、脂质和能量代谢。尽管胆汁酸在葡萄糖稳态中具有重要作用，但特定胆汁酸分子种类及其合成途径与糖尿病（DM）之间的关系尚不清楚。在这里，我们使用最近验证的稳定同位素稀释高效液相色谱-串联质谱（LC-MS/MS）方法定量检测了受试者（n=2,145）空腹血浆中的一组 BAs，并探讨了与 DM、胰岛素抵抗和肥胖有关的 BAs 结构和遗传决定因素。多种 12α- 羟基化 BA 与糖尿病[调整后的几率比（aORs）：1.3-1.9（均为 P<0.05）]和胰岛素抵抗[aORs：1.3-2.2（均为 P<0.05）]有关。相反，多种 6a- 羟基化 BA 和异LCA 与 DM 和肥胖成反比[aORs:0.3-0.9（均为 P<0.05）]。全基因组关联研究（GWAS）揭示了与14种DM相关BA中的9种相关的多个全基因组显著位点，其中包括一个异LCA位点（rs11866815）。孟德尔随机分析表明，DCA水平的遗传升高与较高的BMI有因果关系，而Iso-LCA水平的遗传升高与较低的BMI和DM风险有因果关系。总之，全面的大规模定量质谱分析和遗传学分析表明，循环中多种结构特殊的BA（尤其是DCA和Iso-LCA）水平与肥胖和DM有临床相关性和遗传相关性。
{"title":"Comprehensive clinical and genetic analyses of circulating bile acids and their associations with diabetes and its indices","authors":"Ibrahim Choucair, Deepthi P. Mallela, James R. Hilser, Jaana A. Hartiala, Ina Nemet, Valentin Gogonea, Lin Li, Aldons J. Lusis, Michael A. Fischbach, W. H. Wilson Tang, Hooman Allayee, Stanley L. Hazen","doi":"10.2337/db23-0676","DOIUrl":"https://doi.org/10.2337/db23-0676","url":null,"abstract":"Bile acids (BAs) are cholesterol-derived compounds that regulate glucose, lipid, and energy metabolism. Despite their significance in glucose homeostasis, the association between specific BA molecular species and their synthetic pathways with diabetes mellitus (DM) is unclear. Here, we used a recently validated stable-isotope dilution highperformance liquid chromatography with tandem mass spectrometry (LC-MS/MS) method to quantify a panel of BAs in fasting plasma from subjects (n=2,145) and explored structural and genetic determinants of BAs linked to DM, insulin resistance and obesity. Multiple 12α-hydroxylated BAs were associated with DM [adjusted odds ratios (aORs):1.3-1.9 (all P&lt;0.05)] and insulin resistance [aORs:1.3-2.2 (all P&lt;0.05)]. Conversely, multiple 6a-hydroxylated BAs and isolithocholic acid (Iso-LCA) were inversely associated with DM and obesity [aORs:0.3-0.9 (all P&lt;0.05)]. Genome-wide association studies (GWAS) revealed multiple genome-wide significant loci linked with nine of the 14 DM-associated BAs, including a locus for Iso-LCA (rs11866815). Mendelian randomization analyses showed genetically elevated DCA levels were causally associated with higher BMI, and Iso-LCA levels were causally associated with reduced BMI and DM risk. In conclusion, comprehensive large-scale quantitative mass spectrometry and genetics analyses show circulating levels of multiple structurally specific BAs, especially DCA and Iso-LCA, are clinically associated with and genetically linked to obesity and DM.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140821790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Karen C. Shen, Kelsey H. Collins, Jeremie L.A. Ferey, Alan Fappi, Jeremy J. McCormick, Bettina Mittendorfer, Farshid Guilak, Gretchen A. Meyer
Observational studies show correlations between intramyocellular lipid (IMCL) content and muscle strength and contractile function in people with “metabolically abnormal” obesity. However, a clear physiologic mechanism for this association is lacking and causation is debated. We combined immunofluorescent confocal imaging with force measurements on permeabilized muscle fibers from metabolically normal and metabolically abnormal mice and metabolically normal (defined as normal fasting plasma glucose and glucose tolerance) and metabolically abnormal (defined as pre-diabetes and type 2 diabetes) people with overweight/obesity to evaluate relationships among myocellular lipid droplet characteristics (droplet size and density) and biophysical (active contractile and passive viscoelastic) properties. The fiber type specificity of lipid droplet parameters varied between metabolically abnormal and normal mice and among metabolically normal and metabolically abnormal people. However, despite considerable quantities of IMCL in the metabolically abnormal groups, there were no significant differences in peak active tension or passive viscoelasticity between the metabolically abnormal groups and the control group in mice or people. Additionally, there were no significant relationships among IMCL parameters and biophysical variables. Thus, we conclude that IMCL accumulation per se does not impact muscle fiber biophysical properties or physically impede contraction.
{"title":"Excess Intramyocellular Lipid Does Not Affect Muscle Fiber Biophysical Properties in Mice or People with Metabolically Abnormal Obesity","authors":"Karen C. Shen, Kelsey H. Collins, Jeremie L.A. Ferey, Alan Fappi, Jeremy J. McCormick, Bettina Mittendorfer, Farshid Guilak, Gretchen A. Meyer","doi":"10.2337/db23-0991","DOIUrl":"https://doi.org/10.2337/db23-0991","url":null,"abstract":"Observational studies show correlations between intramyocellular lipid (IMCL) content and muscle strength and contractile function in people with “metabolically abnormal” obesity. However, a clear physiologic mechanism for this association is lacking and causation is debated. We combined immunofluorescent confocal imaging with force measurements on permeabilized muscle fibers from metabolically normal and metabolically abnormal mice and metabolically normal (defined as normal fasting plasma glucose and glucose tolerance) and metabolically abnormal (defined as pre-diabetes and type 2 diabetes) people with overweight/obesity to evaluate relationships among myocellular lipid droplet characteristics (droplet size and density) and biophysical (active contractile and passive viscoelastic) properties. The fiber type specificity of lipid droplet parameters varied between metabolically abnormal and normal mice and among metabolically normal and metabolically abnormal people. However, despite considerable quantities of IMCL in the metabolically abnormal groups, there were no significant differences in peak active tension or passive viscoelasticity between the metabolically abnormal groups and the control group in mice or people. Additionally, there were no significant relationships among IMCL parameters and biophysical variables. Thus, we conclude that IMCL accumulation per se does not impact muscle fiber biophysical properties or physically impede contraction.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140821497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Caroline Frørup, Mathias Høj Jensen, Martin Haupt-Jorgensen, Karsten Buschard, Joachim Størling, Flemming Pociot, Tina Fløyel
Accumulating data suggest a role for the lysosomal protease cathepsin S (CTSS) in type 1 diabetes. Circulating CTSS is increased in type 1 diabetes; however, whether CTSS has protective or deleterious effects is unclear. The study’s objectives were to examine the biomarker potential of CTSS in new-onset type 1 diabetes, and to investigate the expression and secretion of CTSS in human islets and β cells. The CTSS level was analyzed in serum from children with new-onset type 1 diabetes and autoantibody-positive and -negative siblings by ELISA. The expression and secretion of CTSS were evaluated in isolated human islets and EndoC-βH5 cells by real-time qPCR, immunoblotting, and ELISA. The CTSS serum level was elevated in children with new-onset type 1 diabetes and positively associated with autoantibody status in healthy siblings. Human islets and EndoC-βH5 cells demonstrated induction and secretion of CTSS after exposure to pro-inflammatory cytokines, a model system of islet inflammation. Analysis of publicly available single-cell RNA sequencing data on human islets showed that elevated CTSS expression was exclusive for the β cells in donors with type 1 diabetes as compared to non-diabetic donors. These findings suggest a potential of CTSS as a diagnostic biomarker in type 1 diabetes.
{"title":"Elevated cathepsin S serum levels in new-onset type 1 diabetes and autoantibody-positive siblings","authors":"Caroline Frørup, Mathias Høj Jensen, Martin Haupt-Jorgensen, Karsten Buschard, Joachim Størling, Flemming Pociot, Tina Fløyel","doi":"10.2337/db23-0911","DOIUrl":"https://doi.org/10.2337/db23-0911","url":null,"abstract":"Accumulating data suggest a role for the lysosomal protease cathepsin S (CTSS) in type 1 diabetes. Circulating CTSS is increased in type 1 diabetes; however, whether CTSS has protective or deleterious effects is unclear. The study’s objectives were to examine the biomarker potential of CTSS in new-onset type 1 diabetes, and to investigate the expression and secretion of CTSS in human islets and β cells. The CTSS level was analyzed in serum from children with new-onset type 1 diabetes and autoantibody-positive and -negative siblings by ELISA. The expression and secretion of CTSS were evaluated in isolated human islets and EndoC-βH5 cells by real-time qPCR, immunoblotting, and ELISA. The CTSS serum level was elevated in children with new-onset type 1 diabetes and positively associated with autoantibody status in healthy siblings. Human islets and EndoC-βH5 cells demonstrated induction and secretion of CTSS after exposure to pro-inflammatory cytokines, a model system of islet inflammation. Analysis of publicly available single-cell RNA sequencing data on human islets showed that elevated CTSS expression was exclusive for the β cells in donors with type 1 diabetes as compared to non-diabetic donors. These findings suggest a potential of CTSS as a diagnostic biomarker in type 1 diabetes.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140821542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yaling Tang, Lynn Ang, Mamta Jaiswal, Brendan R Dillon, Nazanene H Esfandiari, Hetal S Shah, Cathie Spino, Cindy Plunkett, Bruce A Perkins, Rodica Pop-Busui, Alessandro Doria
Results of previous studies have suggested that cardiovascular autonomic neuropathy (CAN) may predict rapid kidney function decline among people with diabetes. We analyzed the association between baseline CAN and subsequent glomerular filtration rate (GFR) decline among individuals with type 1 diabetes (T1D) from the Preventing Early Renal Loss in Diabetes (PERL) study (N = 469) and with type 2 diabetes (T2D) from Action to Control Cardiovascular Risk in Diabetes (ACCORD) (N = 7,973). Baseline CAN was ascertained with electrocardiogram-derived heart rate variability indices. Its association with GFR slopes, rapid kidney function decline (GFR loss of ≥5 mL/min/1.73 m2/year), and ≥40% GFR loss was evaluated by linear mixed-effects, logistic, and Cox regression, respectively. Participants with CAN experienced more rapid GFR decline, by an excess 1.15 mL/min/1.73 m2/year (95% CI -1.93 to -0.37; P = 4.0 × 10-3) in PERL and 0.34 mL/min/1.73 m2/year (95% CI -0.49 to -0.19; P = 6.3 × 10-6) in ACCORD. This translated to 2.11 (95% CI 1.23-3.63; P = 6.9 × 10-3) and 1.39 (95% CI 1.20-1.61; P = 1.1 × 10-5) odds ratios of rapid kidney function decline in PERL and ACCORD, respectively. Baseline CAN was also associated with a greater risk of ≥40% GFR loss events during follow-up (hazard ratio 2.60 [95% CI 1.15-5.45], P = 0.02, in PERL and hazard ratio 1.54 [95% CI 1.28-1.84], P = 3.8 × 10-6, in ACCORD). These associations remained significant after adjustment for potential confounders, including baseline GFR and albuminuria. Our findings indicate that CAN is a strong, independent predictor of rapid kidney function decline in both T1D and T2D. Further studies of the link between these two complications may help with development of new therapies to prevent kidney function decline in patients with diabetes.
Article highlights:
以往的研究结果表明，心血管自主神经病变（CAN）可能预示着糖尿病患者肾功能的快速下降。我们分析了 "预防糖尿病早期肾功能丧失"（PERL）研究中的 1 型糖尿病（T1D）患者（469 人）和 "控制糖尿病心血管风险行动"（ACCORD）研究中的 2 型糖尿病（T2D）患者（7973 人）基线 CAN 与随后肾小球滤过率（GFR）下降之间的关系。基线 CAN 是通过心电图得出的心率变异性指数确定的。通过线性混合效应、逻辑回归和 Cox 回归分别评估了 CAN 与 GFR 斜率、肾功能快速下降（GFR 下降≥5 mL/min/1.73 m2/年）和 GFR 下降≥40% 的关系。CAN 患者的 GFR 下降速度更快，在 PERL 中超过 1.15 mL/min/1.73 m2/year (95% CI -1.93 to -0.37; P = 4.0 × 10-3)，在 ACCORD 中超过 0.34 mL/min/1.73 m2/year (95% CI -0.49 to -0.19; P = 6.3 × 10-6)。这在 PERL 和 ACCORD 中分别转化为 2.11 (95% CI 1.23-3.63; P = 6.9 × 10-3) 和 1.39 (95% CI 1.20-1.61; P = 1.1 × 10-5) 的肾功能快速下降几率比。基线 CAN 还与随访期间 GFR 下降≥40% 事件的更大风险相关（PERL 的危险比为 2.60 [95% CI 1.15-5.45]，P = 0.02；ACCORD 的危险比为 1.54 [95% CI 1.28-1.84]，P = 3.8 × 10-6）。在对包括基线肾小球滤过率和白蛋白尿在内的潜在混杂因素进行调整后，这些相关性仍然显著。我们的研究结果表明，CAN 是 T1D 和 T2D 肾功能快速下降的一个强有力的独立预测因子。对这两种并发症之间联系的进一步研究可能有助于开发新的疗法，防止糖尿病患者肾功能衰退：
{"title":"Cardiovascular Autonomic Neuropathy and Risk of Kidney Function Decline in Type 1 and Type 2 Diabetes: Findings From the PERL and ACCORD Cohorts.","authors":"Yaling Tang, Lynn Ang, Mamta Jaiswal, Brendan R Dillon, Nazanene H Esfandiari, Hetal S Shah, Cathie Spino, Cindy Plunkett, Bruce A Perkins, Rodica Pop-Busui, Alessandro Doria","doi":"10.2337/db23-0247","DOIUrl":"10.2337/db23-0247","url":null,"abstract":"<p><p>Results of previous studies have suggested that cardiovascular autonomic neuropathy (CAN) may predict rapid kidney function decline among people with diabetes. We analyzed the association between baseline CAN and subsequent glomerular filtration rate (GFR) decline among individuals with type 1 diabetes (T1D) from the Preventing Early Renal Loss in Diabetes (PERL) study (N = 469) and with type 2 diabetes (T2D) from Action to Control Cardiovascular Risk in Diabetes (ACCORD) (N = 7,973). Baseline CAN was ascertained with electrocardiogram-derived heart rate variability indices. Its association with GFR slopes, rapid kidney function decline (GFR loss of ≥5 mL/min/1.73 m2/year), and ≥40% GFR loss was evaluated by linear mixed-effects, logistic, and Cox regression, respectively. Participants with CAN experienced more rapid GFR decline, by an excess 1.15 mL/min/1.73 m2/year (95% CI -1.93 to -0.37; P = 4.0 × 10-3) in PERL and 0.34 mL/min/1.73 m2/year (95% CI -0.49 to -0.19; P = 6.3 × 10-6) in ACCORD. This translated to 2.11 (95% CI 1.23-3.63; P = 6.9 × 10-3) and 1.39 (95% CI 1.20-1.61; P = 1.1 × 10-5) odds ratios of rapid kidney function decline in PERL and ACCORD, respectively. Baseline CAN was also associated with a greater risk of ≥40% GFR loss events during follow-up (hazard ratio 2.60 [95% CI 1.15-5.45], P = 0.02, in PERL and hazard ratio 1.54 [95% CI 1.28-1.84], P = 3.8 × 10-6, in ACCORD). These associations remained significant after adjustment for potential confounders, including baseline GFR and albuminuria. Our findings indicate that CAN is a strong, independent predictor of rapid kidney function decline in both T1D and T2D. Further studies of the link between these two complications may help with development of new therapies to prevent kidney function decline in patients with diabetes.</p><p><strong>Article highlights: </strong></p>","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11043059/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9892156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Soyoung Park, Hye-Na Cha, Min-Gyeong Shin, Sanghee Park, Yeongmin Kim, Min-Seob Kim, Kyung-Hoon Shin, Themis Thoudam, Eun Ju Lee, Robert R. Wolfe, Jinmyoung Dan, Jin-Ho Koh, Il-Young Kim, Inho Choi, In-kyu Lee, Hoon-Ki Sung, So-Young Park
Forkhead box protein O1 (FoxO1) regulates muscle growth, but the metabolic role of FoxO1 in skeletal muscle and its mechanisms remain unclear. To explore the metabolic role of FoxO1 in skeletal muscle, we generated skeletal muscle-specific FoxO1 inducible knockout (mFoxO1 iKO) mice and fed them a high-fat diet to induce obesity. We measured insulin sensitivity, fatty acid oxidation, mitochondrial function, and exercise capacity in obese mFoxO1 iKO mice, and assessed the correlation between FoxO1 and mitochondrial-related protein in the skeletal muscle of diabetic patients. Obese mFoxO1 iKO mice exhibited improved mitochondrial respiratory capacity, which was followed by attenuated insulin resistance, enhanced fatty acid oxidation, and improved skeletal muscle exercise capacity. Transcriptional inhibition of FoxO1 in peroxisome proliferator-activated receptor δ (PPARδ) expression was confirmed in skeletal muscle and deletion of PPARδ abolished the beneficial effects of FoxO1 deficiency. FoxO1 protein levels were higher in the skeletal muscle of diabetic patients and negatively correlated with PPARδ and electron transport chain protein levels. These findings highlight FoxO1 as a new repressor in PPARδ gene expression in skeletal muscle and suggest that FoxO1 links insulin resistance and mitochondrial dysfunction in skeletal muscle via PPARδ.
{"title":"Inhibitory regulation of FoxO1 in PPARδ expression drives mitochondria dysfunction and insulin resistance","authors":"Soyoung Park, Hye-Na Cha, Min-Gyeong Shin, Sanghee Park, Yeongmin Kim, Min-Seob Kim, Kyung-Hoon Shin, Themis Thoudam, Eun Ju Lee, Robert R. Wolfe, Jinmyoung Dan, Jin-Ho Koh, Il-Young Kim, Inho Choi, In-kyu Lee, Hoon-Ki Sung, So-Young Park","doi":"10.2337/db23-0432","DOIUrl":"https://doi.org/10.2337/db23-0432","url":null,"abstract":"Forkhead box protein O1 (FoxO1) regulates muscle growth, but the metabolic role of FoxO1 in skeletal muscle and its mechanisms remain unclear. To explore the metabolic role of FoxO1 in skeletal muscle, we generated skeletal muscle-specific FoxO1 inducible knockout (mFoxO1 iKO) mice and fed them a high-fat diet to induce obesity. We measured insulin sensitivity, fatty acid oxidation, mitochondrial function, and exercise capacity in obese mFoxO1 iKO mice, and assessed the correlation between FoxO1 and mitochondrial-related protein in the skeletal muscle of diabetic patients. Obese mFoxO1 iKO mice exhibited improved mitochondrial respiratory capacity, which was followed by attenuated insulin resistance, enhanced fatty acid oxidation, and improved skeletal muscle exercise capacity. Transcriptional inhibition of FoxO1 in peroxisome proliferator-activated receptor δ (PPARδ) expression was confirmed in skeletal muscle and deletion of PPARδ abolished the beneficial effects of FoxO1 deficiency. FoxO1 protein levels were higher in the skeletal muscle of diabetic patients and negatively correlated with PPARδ and electron transport chain protein levels. These findings highlight FoxO1 as a new repressor in PPARδ gene expression in skeletal muscle and suggest that FoxO1 links insulin resistance and mitochondrial dysfunction in skeletal muscle via PPARδ.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140642312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
We aimed to clarify the relationship between intra- and peri-organ fat, visceral fat, and subcutaneous fat. We used abdominal CT to evaluate intra- and peri-organ fat accumulations in the pancreas, liver, spleen, renal parenchyma, renal sinus, and skeletal muscle. The relationships between these fats, visceral fat, and subcutaneous fat were examined by using the partial correlation and covariance analysis, adjusting for BMI. We found that visceral fat and each intraand peri-organ fat accumulation were positively correlated, whereas subcutaneous fat and the accumulation of each intra- and peri-organ fat and visceral fat were negatively correlated. Pancreas fat, liver fat, renal sinus fat, and skeletal muscle fat accumulated significantly more in people with excessive visceral fat accumulation than in those without excessive visceral fat accumulation (p = 0.01, 0.006, 0.008, 0.02, respectively). In conclusion, intra- and peri-organ fat accumulation in each organ shows a positive correlation with visceral fat and a negative correlation with subcutaneous fat, independent of BMI.
{"title":"Interrelationships among accumulations of intra- and peri-organ fat, visceral fat, and subcutaneous fat","authors":"Kento Mitsushio, Megu Y Baden, Takuya Kagisaki, Sarasa Kato, Akiko Niki, Risa Takayama, Tomomi Horii, Harutoshi Ozawa, Chisaki Ishibashi, Yoshiya Hosokawa, Yukari Fujita, Junji Kozawa, Iichiro Shimomura","doi":"10.2337/db24-0035","DOIUrl":"https://doi.org/10.2337/db24-0035","url":null,"abstract":"We aimed to clarify the relationship between intra- and peri-organ fat, visceral fat, and subcutaneous fat. We used abdominal CT to evaluate intra- and peri-organ fat accumulations in the pancreas, liver, spleen, renal parenchyma, renal sinus, and skeletal muscle. The relationships between these fats, visceral fat, and subcutaneous fat were examined by using the partial correlation and covariance analysis, adjusting for BMI. We found that visceral fat and each intraand peri-organ fat accumulation were positively correlated, whereas subcutaneous fat and the accumulation of each intra- and peri-organ fat and visceral fat were negatively correlated. Pancreas fat, liver fat, renal sinus fat, and skeletal muscle fat accumulated significantly more in people with excessive visceral fat accumulation than in those without excessive visceral fat accumulation (p = 0.01, 0.006, 0.008, 0.02, respectively). In conclusion, intra- and peri-organ fat accumulation in each organ shows a positive correlation with visceral fat and a negative correlation with subcutaneous fat, independent of BMI.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140642103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hak Joo Lee, Liang Min, Jingli Gao, Shane Matta, Viktor Drel, Afaf Saliba, Ian Tamayo, Richard Montellano, Leila Hejazi, Soumya Maity, Guogang Xu, Brian I. Grajeda, Sourav Roy, Kenneth R. Hallows, Goutam Ghosh Choudhury, Balakuntalam S. Kasinath, Kumar Sharma
Reduced kidney AMPK activity is associated with nutrient stress-induced chronic kidney disease (CKD) in male mice. In contrast, female mice resist nutrient stress-induced CKD. The role of kidney AMPK in sex-related organ protection against nutrient stress and metabolite changes were evaluated in diabetic kidney tubule-specific AMPKγ2KO (KTAMPKγ2KO) male and female mice. In WT males, diabetes increased albuminuria, urinary kidney injury molecule-1, hypertension, kidney p70S6K phosphorylation, and kidney matrix accumulation; these features were not exacerbated with KTAMPKγ2KO. Whereas WT females had protection against diabetes induced kidney injury, KTAMPKγ2KO led to loss of female protection against kidney disease. 17β-estradiol ameliorated high glucose-induced AMPK inactivation, p70S6K phosphorylation and matrix protein accumulation in kidney tubule cells. The mechanism for female protection against diabetes-induced kidney injury is likely via an estrogen-AMPK pathway, as inhibition of AMPK led to loss of estrogen protection to glucose-induced mTORC1 activation and matrix production. RNA-seq and metabolomic analysis identified a decrease in the degradation pathway of phenylalanine and tyrosine resulting in increased urinary phenylalanine and tyrosine levels in females. The metabolite levels correlated with loss of female protection. The findings provide new insights to explain evolutionary advantages to females during states of nutrient challenges.
{"title":"Female protection against diabetic kidney disease is regulated by kidney-specific AMPK activity","authors":"Hak Joo Lee, Liang Min, Jingli Gao, Shane Matta, Viktor Drel, Afaf Saliba, Ian Tamayo, Richard Montellano, Leila Hejazi, Soumya Maity, Guogang Xu, Brian I. Grajeda, Sourav Roy, Kenneth R. Hallows, Goutam Ghosh Choudhury, Balakuntalam S. Kasinath, Kumar Sharma","doi":"10.2337/db23-0807","DOIUrl":"https://doi.org/10.2337/db23-0807","url":null,"abstract":"Reduced kidney AMPK activity is associated with nutrient stress-induced chronic kidney disease (CKD) in male mice. In contrast, female mice resist nutrient stress-induced CKD. The role of kidney AMPK in sex-related organ protection against nutrient stress and metabolite changes were evaluated in diabetic kidney tubule-specific AMPKγ2KO (KTAMPKγ2KO) male and female mice. In WT males, diabetes increased albuminuria, urinary kidney injury molecule-1, hypertension, kidney p70S6K phosphorylation, and kidney matrix accumulation; these features were not exacerbated with KTAMPKγ2KO. Whereas WT females had protection against diabetes induced kidney injury, KTAMPKγ2KO led to loss of female protection against kidney disease. 17β-estradiol ameliorated high glucose-induced AMPK inactivation, p70S6K phosphorylation and matrix protein accumulation in kidney tubule cells. The mechanism for female protection against diabetes-induced kidney injury is likely via an estrogen-AMPK pathway, as inhibition of AMPK led to loss of estrogen protection to glucose-induced mTORC1 activation and matrix production. RNA-seq and metabolomic analysis identified a decrease in the degradation pathway of phenylalanine and tyrosine resulting in increased urinary phenylalanine and tyrosine levels in females. The metabolite levels correlated with loss of female protection. The findings provide new insights to explain evolutionary advantages to females during states of nutrient challenges.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140642385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lisa Smeehuijzen, Anouk Gijbels, Joline P. Nugteren-Boogaard, Frank Vrieling, Mehdi Boutagouga Boudjadja, Inez Trouwborst, Kelly M. Jardon, Gabby B. Hul, Edith J.M. Feskens, Ellen E. Blaak, Gijs H. Goossens, Lydia A. Afman, Rinke Stienstra
Obesity is associated with chronic inflammation and metabolic complications, including insulin resistance (IR). Immune cells drive inflammation through the rewiring of intracellular metabolism. However, the impact of obesity-related IR on the metabolism and functionality of circulating immune cells, like monocytes, remains poorly understood. To increase insight into the inter-individual variation of immunometabolic signatures among individuals and their role in the development of IR, we assessed systemic and tissue-specific IR and circulating immune markers, and we characterized metabolic signatures and cytokine secretion of circulating monocytes from 194 individuals with a BMI≥25kg/m2. Monocyte metabolic signatures were defined using extracellular acidification rates (ECAR) to estimate glycolysis and oxygen consumption rates (OCR) for oxidative metabolism. Although monocyte metabolic signatures and function based on cytokine secretion varied greatly among subjects, they were strongly associated with each other. The ECAR/OCR ratio, representing the balance between glycolysis and oxidative metabolism, was negatively associated with fasting insulin, systemic IR, and liver-specific IR. These results indicate that monocytes from individuals with IR were relatively more dependent on oxidative metabolism, while monocytes from more insulinsensitive individuals were more dependent on glycolysis. Additionally, circulating CXCL11 was negatively associated with the degree of systemic IR and positively with the ECAR/OCR ratio in monocytes, suggesting that individuals with high IR and a monocyte metabolic dependence on oxidative metabolism also have lower levels of circulating CXCL11. Our findings suggest that monocyte metabolism is related to obesity-associated IR progression and deepen insights into the interplay between innate immune cell metabolism and IR development in humans.
肥胖与慢性炎症和代谢并发症有关，包括胰岛素抵抗（IR）。免疫细胞通过重构细胞内代谢驱动炎症。然而，人们对肥胖相关的 IR 对单核细胞等循环免疫细胞的新陈代谢和功能的影响仍然知之甚少。为了更深入地了解个体间免疫代谢特征的差异及其在内分泌失调发展过程中的作用，我们评估了全身和组织特异性内分泌失调和循环免疫标记物，并对体重指数≥25kg/m2的194人的循环单核细胞的代谢特征和细胞因子分泌进行了表征。单核细胞代谢特征是通过细胞外酸化率（ECAR）估算糖酵解和耗氧率（OCR）估算氧化代谢来定义的。虽然不同受试者的单核细胞代谢特征和基于细胞因子分泌的功能差异很大，但它们之间存在密切联系。代表糖酵解和氧化代谢平衡的ECAR/OCR比率与空腹胰岛素、全身IR和肝脏特异性IR呈负相关。这些结果表明，IR 患者的单核细胞相对更依赖氧化代谢，而对胰岛素更敏感的患者的单核细胞则更依赖糖酵解。此外，循环中的 CXCL11 与全身红外程度呈负相关，而与单核细胞中的 ECAR/OCR 比率呈正相关，这表明红外程度高且单核细胞代谢依赖氧化代谢的个体，其循环中的 CXCL11 水平也较低。我们的研究结果表明，单核细胞代谢与肥胖相关的IR进展有关，并加深了对人类先天免疫细胞代谢与IR发展之间相互作用的了解。
{"title":"Immunometabolic Signatures of Circulating Monocytes in Humans with Obesity and Insulin Resistance","authors":"Lisa Smeehuijzen, Anouk Gijbels, Joline P. Nugteren-Boogaard, Frank Vrieling, Mehdi Boutagouga Boudjadja, Inez Trouwborst, Kelly M. Jardon, Gabby B. Hul, Edith J.M. Feskens, Ellen E. Blaak, Gijs H. Goossens, Lydia A. Afman, Rinke Stienstra","doi":"10.2337/db23-0970","DOIUrl":"https://doi.org/10.2337/db23-0970","url":null,"abstract":"Obesity is associated with chronic inflammation and metabolic complications, including insulin resistance (IR). Immune cells drive inflammation through the rewiring of intracellular metabolism. However, the impact of obesity-related IR on the metabolism and functionality of circulating immune cells, like monocytes, remains poorly understood. To increase insight into the inter-individual variation of immunometabolic signatures among individuals and their role in the development of IR, we assessed systemic and tissue-specific IR and circulating immune markers, and we characterized metabolic signatures and cytokine secretion of circulating monocytes from 194 individuals with a BMI≥25kg/m2. Monocyte metabolic signatures were defined using extracellular acidification rates (ECAR) to estimate glycolysis and oxygen consumption rates (OCR) for oxidative metabolism. Although monocyte metabolic signatures and function based on cytokine secretion varied greatly among subjects, they were strongly associated with each other. The ECAR/OCR ratio, representing the balance between glycolysis and oxidative metabolism, was negatively associated with fasting insulin, systemic IR, and liver-specific IR. These results indicate that monocytes from individuals with IR were relatively more dependent on oxidative metabolism, while monocytes from more insulinsensitive individuals were more dependent on glycolysis. Additionally, circulating CXCL11 was negatively associated with the degree of systemic IR and positively with the ECAR/OCR ratio in monocytes, suggesting that individuals with high IR and a monocyte metabolic dependence on oxidative metabolism also have lower levels of circulating CXCL11. Our findings suggest that monocyte metabolism is related to obesity-associated IR progression and deepen insights into the interplay between innate immune cell metabolism and IR development in humans.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140642441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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