Susanna D Mitro,L Elaine Waetjen,Catherine Lee,Lauren A Wise,Eve Zaritsky,Siobán D Harlow,Samar R El Khoudary,Nanette Santoro,Daniel H Solomon,Rebecca C Thurston,Monique M Hedderson
BACKGROUNDFibroids are non-cancerous uterine tumors potentially associated with cardiovascular risk factors. We examined prospectively associations of glucose, insulin, sex hormone binding globulin (SHBG), and diabetes with incidence of fibroid diagnoses in midlife.METHODSParticipants in the Study of Women's Health Across the Nation (SWAN) cohort (n=2570) reported fibroid diagnoses at enrollment (1996-1997) and 13 follow-up visits (1996-2013). At all visits, we measured glucose, insulin, and SHBG in fasting blood samples and calculated homeostatic model assessment for insulin resistance (HOMA-IR). Diabetes was defined using glucose levels, self-reported diabetes, or diabetes medication use. We used discrete-time survival models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations of time-varying biomarkers and diabetes with incident fibroid diagnoses, adjusted for demographics and healthcare utilization. We also evaluated effect modification by menopausal status.RESULTSAt baseline, 2.7% of participants (n=70) were using diabetes medication. Time-varying glucose, insulin, HOMA-IR, and SHBG were not associated with fibroid diagnosis. However, diabetes was associated with a 28% lower incidence of fibroid diagnosis (adjusted HR: 0.72, 95% CI: 0.44, 1.17), driven by participants using metformin (adjusted HR: 0.49, 95% CI: 0.21, 1.12), though precision was limited. After stratification by menopausal status, higher HOMA-IR and insulin were associated with greater incidence of fibroid diagnosis during premenopause but not perimenopause, while the inverse association between diabetes and fibroids was strongest during perimenopause.CONCLUSIONThe effect of diabetes and biomarkers on fibroids may vary by menopausal status. Fibroid risk may increase with insulin resistance and decrease with diabetes treatment.
{"title":"Diabetes and uterine fibroid diagnosis in midlife: Study of Women's Health Across the Nation (SWAN).","authors":"Susanna D Mitro,L Elaine Waetjen,Catherine Lee,Lauren A Wise,Eve Zaritsky,Siobán D Harlow,Samar R El Khoudary,Nanette Santoro,Daniel H Solomon,Rebecca C Thurston,Monique M Hedderson","doi":"10.1210/clinem/dgae625","DOIUrl":"https://doi.org/10.1210/clinem/dgae625","url":null,"abstract":"BACKGROUNDFibroids are non-cancerous uterine tumors potentially associated with cardiovascular risk factors. We examined prospectively associations of glucose, insulin, sex hormone binding globulin (SHBG), and diabetes with incidence of fibroid diagnoses in midlife.METHODSParticipants in the Study of Women's Health Across the Nation (SWAN) cohort (n=2570) reported fibroid diagnoses at enrollment (1996-1997) and 13 follow-up visits (1996-2013). At all visits, we measured glucose, insulin, and SHBG in fasting blood samples and calculated homeostatic model assessment for insulin resistance (HOMA-IR). Diabetes was defined using glucose levels, self-reported diabetes, or diabetes medication use. We used discrete-time survival models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations of time-varying biomarkers and diabetes with incident fibroid diagnoses, adjusted for demographics and healthcare utilization. We also evaluated effect modification by menopausal status.RESULTSAt baseline, 2.7% of participants (n=70) were using diabetes medication. Time-varying glucose, insulin, HOMA-IR, and SHBG were not associated with fibroid diagnosis. However, diabetes was associated with a 28% lower incidence of fibroid diagnosis (adjusted HR: 0.72, 95% CI: 0.44, 1.17), driven by participants using metformin (adjusted HR: 0.49, 95% CI: 0.21, 1.12), though precision was limited. After stratification by menopausal status, higher HOMA-IR and insulin were associated with greater incidence of fibroid diagnosis during premenopause but not perimenopause, while the inverse association between diabetes and fibroids was strongest during perimenopause.CONCLUSIONThe effect of diabetes and biomarkers on fibroids may vary by menopausal status. Fibroid risk may increase with insulin resistance and decrease with diabetes treatment.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142215590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Dedifferentiation as a stealthy disruptor of β-cell function in diabetes.","authors":"Jinsook Son,Domenico Accili","doi":"10.1210/clinem/dgae624","DOIUrl":"https://doi.org/10.1210/clinem/dgae624","url":null,"abstract":"","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142215589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rachel E Elam,Karen C Johnson,Hongyan Xu,Carlos M Isales,Yanbin Dong,Laura D Carbone
CONTEXTPersons with type 2 diabetes have increased fracture risk that existing fracture risk assessment tools underestimate.OBJECTIVEIdentify fracture predictors in persons with type 2 diabetes and overweight or obesity, considering traditional and diabetes-related risk factors.DESIGNSecondary analysis of the Look AHEAD: Action for Health in Diabetes randomized clinical trial, with randomization from 2001-2004 and fracture follow-up until 2015.SETTINGMulticenter U.S. study.PARTICIPANTSMen and women 45-75 years old with type 2 diabetes and body mass index≥25 kg/m2.EXPOSURESPotential fracture predictors ascertained at randomization included traditional and diabetes-related risk factors (diabetes duration, diabetic neuropathy, antidiabetic medication use, hemoglobin A1c, and renal function). Total hip bone mineral density (BMD) was measured in a subcohort.MAIN OUTCOME MEASUREAll incident clinical fractures, ascertained by self-report and centrally adjudicated with medical records review.RESULTSOver a median 12.2 years follow-up, 649 of the 4,703 participants experienced at least one clinical fracture. Thiazolidinedione use [hazard ratio (HR):1.22, 95% confidence interval (CI):1.02-1.46] and insulin use [HR:1.34, 95% CI:1.08-1.66] were significant diabetes-related predictors of all clinical fractures. When measured in a subcohort (n=1,285), total hip BMD was the strongest modifiable predictor of all clinical fractures [Per 1 standard deviation (SD)=0.1 g/cm2 increase, HR:0.47, 95% CI:0.39-0.58].CONCLUSIONSThiazolidinedione and insulin use predict clinical fracture in middle-aged and older persons with type 2 diabetes and overweight or obesity. Evaluating BMD is advisable if these medications are prescribed. Fracture risk prediction tools may consider including thiazolidinedione and insulin use to refine prediction in this population.
{"title":"Predictors of fracture in middle-aged and older adults with type 2 diabetes and overweight or obesity.","authors":"Rachel E Elam,Karen C Johnson,Hongyan Xu,Carlos M Isales,Yanbin Dong,Laura D Carbone","doi":"10.1210/clinem/dgae623","DOIUrl":"https://doi.org/10.1210/clinem/dgae623","url":null,"abstract":"CONTEXTPersons with type 2 diabetes have increased fracture risk that existing fracture risk assessment tools underestimate.OBJECTIVEIdentify fracture predictors in persons with type 2 diabetes and overweight or obesity, considering traditional and diabetes-related risk factors.DESIGNSecondary analysis of the Look AHEAD: Action for Health in Diabetes randomized clinical trial, with randomization from 2001-2004 and fracture follow-up until 2015.SETTINGMulticenter U.S. study.PARTICIPANTSMen and women 45-75 years old with type 2 diabetes and body mass index≥25 kg/m2.EXPOSURESPotential fracture predictors ascertained at randomization included traditional and diabetes-related risk factors (diabetes duration, diabetic neuropathy, antidiabetic medication use, hemoglobin A1c, and renal function). Total hip bone mineral density (BMD) was measured in a subcohort.MAIN OUTCOME MEASUREAll incident clinical fractures, ascertained by self-report and centrally adjudicated with medical records review.RESULTSOver a median 12.2 years follow-up, 649 of the 4,703 participants experienced at least one clinical fracture. Thiazolidinedione use [hazard ratio (HR):1.22, 95% confidence interval (CI):1.02-1.46] and insulin use [HR:1.34, 95% CI:1.08-1.66] were significant diabetes-related predictors of all clinical fractures. When measured in a subcohort (n=1,285), total hip BMD was the strongest modifiable predictor of all clinical fractures [Per 1 standard deviation (SD)=0.1 g/cm2 increase, HR:0.47, 95% CI:0.39-0.58].CONCLUSIONSThiazolidinedione and insulin use predict clinical fracture in middle-aged and older persons with type 2 diabetes and overweight or obesity. Evaluating BMD is advisable if these medications are prescribed. Fracture risk prediction tools may consider including thiazolidinedione and insulin use to refine prediction in this population.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"276 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142215587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rocío Martínez-Aguilar,Bethan M Rowley,Catherine Walker,Hilary O D Critchley,Peter Carmeliet,Jacqueline A Maybin
CONTEXTHeavy menstrual bleeding (HMB) is common and debilitating, but the precise endometrial mechanisms causing increased menstrual blood loss (MBL) remain undefined. We have previously identified a role for hypoxia in endometrial repair following progesterone withdrawal.OBJECTIVEAs hypoxia inducible factor 2 alpha (HIF2A) is known to alter vascular function in other tissues, we hypothesised that endometrial HIF2A is involved in pre-menstrual optimisation of endometrial function during the secretory phase to limit MBL.RESULTSWomen with objective HMB had higher endometrial HIF2A during the mid-secretory phase when compared to those with normal MBL (p=0.0269). In a mouse model of simulated menses, genetic or pharmacological manipulation of HIF2A did not significantly affect endometrial breakdown/repair, volume of MBL or endometrial hypoxia. However, 88% of Hif2a heterozygote mice reached early-full repair by 24h versus only 65% of wild-type mice. Mean MBL was 0.39 μl (±0.67) in Hif2a heterozygote mice versus 0.98 μl (±0.79) in wild-type mice. Conversely, when we increased HIF2A pre-menstrually, 11% reached early repair at by 8h versus 30% of vehicle-treated mice. Mean MBL was 2.61 μl (±1.10) in mice with HIF2A stabilisation and 2.24 μl (±1.14) in vehicle-treated mice. These non-significant but consistent trends indicate that increased endometrial HIF2A may contribute to delayed endometrial repair and HMB.CONCLUSIONSIncreased HIF2A in the secretory endometrium is unlikely to be sufficient to account for the phenotype of HMB, but limitation of HIF2 levels may optimise endometrial function at menstruation.
{"title":"Limiting pre-menstrual endometrial Hypoxia Inducible Factor 2 Alpha may fine-tune endometrial function at menstruation.","authors":"Rocío Martínez-Aguilar,Bethan M Rowley,Catherine Walker,Hilary O D Critchley,Peter Carmeliet,Jacqueline A Maybin","doi":"10.1210/clinem/dgae630","DOIUrl":"https://doi.org/10.1210/clinem/dgae630","url":null,"abstract":"CONTEXTHeavy menstrual bleeding (HMB) is common and debilitating, but the precise endometrial mechanisms causing increased menstrual blood loss (MBL) remain undefined. We have previously identified a role for hypoxia in endometrial repair following progesterone withdrawal.OBJECTIVEAs hypoxia inducible factor 2 alpha (HIF2A) is known to alter vascular function in other tissues, we hypothesised that endometrial HIF2A is involved in pre-menstrual optimisation of endometrial function during the secretory phase to limit MBL.RESULTSWomen with objective HMB had higher endometrial HIF2A during the mid-secretory phase when compared to those with normal MBL (p=0.0269). In a mouse model of simulated menses, genetic or pharmacological manipulation of HIF2A did not significantly affect endometrial breakdown/repair, volume of MBL or endometrial hypoxia. However, 88% of Hif2a heterozygote mice reached early-full repair by 24h versus only 65% of wild-type mice. Mean MBL was 0.39 μl (±0.67) in Hif2a heterozygote mice versus 0.98 μl (±0.79) in wild-type mice. Conversely, when we increased HIF2A pre-menstrually, 11% reached early repair at by 8h versus 30% of vehicle-treated mice. Mean MBL was 2.61 μl (±1.10) in mice with HIF2A stabilisation and 2.24 μl (±1.14) in vehicle-treated mice. These non-significant but consistent trends indicate that increased endometrial HIF2A may contribute to delayed endometrial repair and HMB.CONCLUSIONSIncreased HIF2A in the secretory endometrium is unlikely to be sufficient to account for the phenotype of HMB, but limitation of HIF2 levels may optimise endometrial function at menstruation.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142215586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nicole L Spartano,Naznin Sultana,Honghuang Lin,Huimin Cheng,Sophia Lu,David Fei,Joanne M Murabito,Maura E Walker,Howard A Wolpert,Devin W Steenkamp
CONTEXTContinuous glucose monitor (CGM) companies are beginning to market these sensors to populations without diabetes, but the range of CGM values clinicians should expect to see for this population is unclear because there have been no large studies reporting these ranges.OBJECTIVETo report the physiological range of continuous glucose monitor (CGM) time in range values observed across glycemic status, including individuals without diabetes, to serve as a reference for clinicians.DESIGNThe Framingham Heart Study, a prospective cohort study.SETTINGCommunity-dwelling individuals.PATIENTS OR PARTICIPANTSAdults with normoglycemia (n=560), prediabetes (n=463), and diabetes (n=152).INTERVENTIONWe conducted a cross-sectional investigation in participants who wore a Dexcom G6 Pro CGM for ≥7 complete days.MAIN OUTCOME MEASURESCGM metrics including mean glucose and time spent in glucose ranges.RESULTSNormoglycemic participants (mean age 58.5y, 64.5% women, 93.3% non-Hispanic white) spent 87.0% time in the 70-140mg/dL CGM range, and, on average, >15min/day (1.2% time) >180mg/dL. Furthermore, normoglycemic participants spent ∼3 hours/day (12.1% time) with CGM glucose >140mg/dL. On average, participants with prediabetes and diabetes spent 77.1% and 46.2% time in 70-140mg/dL, respectively.CONCLUSIONSOur results contribute to the understanding of the physiological CGM range in >1000 participants without diabetes. These results are also important for clinicians to reference as CGM sensors become more widely accessible to people without known diabetes.
CONTEXTC 连续血糖监测仪 (CGM) 公司开始向无糖尿病人群销售这些传感器，但临床医生在这一人群中应该看到的 CGM 值范围尚不清楚，因为还没有大型研究报告这些范围。OBJECTIVETO report the physiological range of continuous glucose monitor (CGM) time in range values observed across glycemic status, including individuals without diabetes, to serve as a reference for clinicians.设计弗雷明汉心脏研究，一项前瞻性队列研究。患者或参与者成人血糖正常者（560 人）、糖尿病前期者（463 人）和糖尿病患者（152 人）.干预我们对佩戴 Dexcom G6 Pro CGM≥7 天的参与者进行了横断面调查。结果正常血糖参与者（平均年龄 58.5 岁，64.5% 为女性，93.3% 为非西班牙裔白人）87.0% 的时间在 70-140mg/dL CGM 范围内，平均 >180mg/dL >15 分钟/天（1.2% 的时间）。此外，血糖正常的参与者每天有 3 小时（12.1% 的时间）在 CGM 血糖 >140mg/dL 的范围内。结论我们的研究结果有助于了解 1000 多名无糖尿病参与者的 CGM 生理范围。随着 CGM 传感器越来越广泛地应用于未发现糖尿病的人群，这些结果对于临床医生来说也具有重要的参考价值。
{"title":"Defining continuous glucose monitor time in range in a large community-based cohort without diabetes.","authors":"Nicole L Spartano,Naznin Sultana,Honghuang Lin,Huimin Cheng,Sophia Lu,David Fei,Joanne M Murabito,Maura E Walker,Howard A Wolpert,Devin W Steenkamp","doi":"10.1210/clinem/dgae626","DOIUrl":"https://doi.org/10.1210/clinem/dgae626","url":null,"abstract":"CONTEXTContinuous glucose monitor (CGM) companies are beginning to market these sensors to populations without diabetes, but the range of CGM values clinicians should expect to see for this population is unclear because there have been no large studies reporting these ranges.OBJECTIVETo report the physiological range of continuous glucose monitor (CGM) time in range values observed across glycemic status, including individuals without diabetes, to serve as a reference for clinicians.DESIGNThe Framingham Heart Study, a prospective cohort study.SETTINGCommunity-dwelling individuals.PATIENTS OR PARTICIPANTSAdults with normoglycemia (n=560), prediabetes (n=463), and diabetes (n=152).INTERVENTIONWe conducted a cross-sectional investigation in participants who wore a Dexcom G6 Pro CGM for ≥7 complete days.MAIN OUTCOME MEASURESCGM metrics including mean glucose and time spent in glucose ranges.RESULTSNormoglycemic participants (mean age 58.5y, 64.5% women, 93.3% non-Hispanic white) spent 87.0% time in the 70-140mg/dL CGM range, and, on average, >15min/day (1.2% time) >180mg/dL. Furthermore, normoglycemic participants spent ∼3 hours/day (12.1% time) with CGM glucose >140mg/dL. On average, participants with prediabetes and diabetes spent 77.1% and 46.2% time in 70-140mg/dL, respectively.CONCLUSIONSOur results contribute to the understanding of the physiological CGM range in >1000 participants without diabetes. These results are also important for clinicians to reference as CGM sensors become more widely accessible to people without known diabetes.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"100 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142215588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
AIMSNon-alcoholic fatty liver disease (NAFLD) with advanced liver fibrosis is associated with cardiovascular disease (CVD). To examine if markers of vascular injury mediate the link between liver fibrosis non-invasive tests (LFNITs) and CVD events, and to compare the incremental predictive value of LFNITs over established CVD risk scores.METHODSConsecutively recruited individuals (n=1,692) with or without clinically overt coronary artery disease (CAD) from the Athens Cardiometabolic Cohort, were analysed. Fibrosis-4 index (FIB-4), NAFLD Fibrosis score (NFS), and BARD score were evaluated for direct and indirect associations with indices of subclinical arterial injury including carotid maximal wall thickness (maxWT) and pulse wave velocity (PWV) and with a composite of major adverse cardiovascular events (MACE) that consisted of cardiac death, acute myocardial infarction, or coronary revascularization (39-month median follow-up).RESULTSFIB-4 was the only LFNIT which consistently associated with multiple markers of vascular injury, irrespective of CAD presence and after controlling for traditional risk factors, surrogates of insulin resistance or obesity (adjusted p<0.05 for all). FIB-4 also independently associated with CAD presence (adjusted OR 6.55 (3.48-12.3), p<0.001). Increased FIB-4>2.67 was incrementally associated with increased risk for MACE (OR (95% CI) 2.00(1.12, 3.55), deltaAUC (95% CI) 0.014(0.002-0.026)). These associations were mediated by maxWT rather than PWV. Only FIB-4 (>3.25) was independently and incrementally associated with all-cause mortality (adjusted p<0.05).CONCLUSIONSIn a cardio-metabolically diverse population, the incremental associations of LFNITs with CVD outcomes were mediated by atherosclerotic burden rather than arterial stiffening. FIB-4 consistently demonstrated associations with all study endpoints. These findings provide mechanistic insights and support the clinical applicability of FIB-4 in CVD prevention.
{"title":"Incremental value of blood-based markers of liver fibrosis in cardiovascular risk stratification.","authors":"Georgios Georgiopoulos,Stavros Athanasopoulos,Georgios Mavraganis,Christina Konstantaki,Maria Papaioannou,Dimitrios Delialis,Lasthenis Angelidakis,Marco Sachse,Dimitrios Papoutsis,Beyza Cavlan,Simon Tual-Chalot,Georgios Zervas,Kateryna Sopova,Asimina Mitrakou,Konstantinos Stellos,Kimon Stamatelopoulos","doi":"10.1210/clinem/dgae619","DOIUrl":"https://doi.org/10.1210/clinem/dgae619","url":null,"abstract":"AIMSNon-alcoholic fatty liver disease (NAFLD) with advanced liver fibrosis is associated with cardiovascular disease (CVD). To examine if markers of vascular injury mediate the link between liver fibrosis non-invasive tests (LFNITs) and CVD events, and to compare the incremental predictive value of LFNITs over established CVD risk scores.METHODSConsecutively recruited individuals (n=1,692) with or without clinically overt coronary artery disease (CAD) from the Athens Cardiometabolic Cohort, were analysed. Fibrosis-4 index (FIB-4), NAFLD Fibrosis score (NFS), and BARD score were evaluated for direct and indirect associations with indices of subclinical arterial injury including carotid maximal wall thickness (maxWT) and pulse wave velocity (PWV) and with a composite of major adverse cardiovascular events (MACE) that consisted of cardiac death, acute myocardial infarction, or coronary revascularization (39-month median follow-up).RESULTSFIB-4 was the only LFNIT which consistently associated with multiple markers of vascular injury, irrespective of CAD presence and after controlling for traditional risk factors, surrogates of insulin resistance or obesity (adjusted p<0.05 for all). FIB-4 also independently associated with CAD presence (adjusted OR 6.55 (3.48-12.3), p<0.001). Increased FIB-4>2.67 was incrementally associated with increased risk for MACE (OR (95% CI) 2.00(1.12, 3.55), deltaAUC (95% CI) 0.014(0.002-0.026)). These associations were mediated by maxWT rather than PWV. Only FIB-4 (>3.25) was independently and incrementally associated with all-cause mortality (adjusted p<0.05).CONCLUSIONSIn a cardio-metabolically diverse population, the incremental associations of LFNITs with CVD outcomes were mediated by atherosclerotic burden rather than arterial stiffening. FIB-4 consistently demonstrated associations with all study endpoints. These findings provide mechanistic insights and support the clinical applicability of FIB-4 in CVD prevention.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"38 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142215592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CONTEXTIn recent studies of childhood cancer survivors, diabetes has been considered a late effect associated with high therapeutic doses of radiation therapy. Our recent study of atomic bomb (A-bomb) survivors also suggested an association between radiation dose and diabetes incidence, with exposure city and age at exposure as radiation dose effect modifiers. Insulin resistance mediated by systemic inflammation and abnormal body composition has been suggested as a possible primary mechanism for the incidence of diabetes after total body irradiation, however, no studies have examined low-to- moderate radiation exposure (<4 Gy) and insulin resistance in A-bomb survivors.OBJECTIVESTo examine the association between radiation dose and markers of inflammation and insulin resistance.METHODSThis study investigated 3,152 survivors who underwent a health examination between 2008 and 2012 and who were younger than 15 years at exposure. Multivariate linear regression analyses were used to evaluate the radiation effects on levels of markers of inflammation and insulin resistance.RESULTSRadiation dose was significantly and positively associated with levels of CRP, triglycerides, homeostasis model assessment of β-cell function (HOMA-β), and HOMA of insulin resistance (HOMA-IR) after adjustment for relevant covariates including sex, city, and age at exposure. Adiponectin and HDL cholesterol levels were also associated significantly and negatively with radiation dose. However, city was not a dose modifier of the radiation response on these markers of inflammation and insulin resistance.CONCLUSIONSInsulin resistance might be a possible factor in the radiation related diabetes incidence in the A-bomb survivors.
{"title":"Relationship between radiation dose and markers of insulin resistance and inflammation in atomic bomb survivors.","authors":"Yoshimi Tatsukawa,Richard Sposto,Michiko Yamada,Waka Ohishi,Misa Imaizumi,Ayumi Hida,Ritsu Sakata,Saeko Fujiwara,Shuhei Nakanishi,Haruya Ohno","doi":"10.1210/clinem/dgae621","DOIUrl":"https://doi.org/10.1210/clinem/dgae621","url":null,"abstract":"CONTEXTIn recent studies of childhood cancer survivors, diabetes has been considered a late effect associated with high therapeutic doses of radiation therapy. Our recent study of atomic bomb (A-bomb) survivors also suggested an association between radiation dose and diabetes incidence, with exposure city and age at exposure as radiation dose effect modifiers. Insulin resistance mediated by systemic inflammation and abnormal body composition has been suggested as a possible primary mechanism for the incidence of diabetes after total body irradiation, however, no studies have examined low-to- moderate radiation exposure (<4 Gy) and insulin resistance in A-bomb survivors.OBJECTIVESTo examine the association between radiation dose and markers of inflammation and insulin resistance.METHODSThis study investigated 3,152 survivors who underwent a health examination between 2008 and 2012 and who were younger than 15 years at exposure. Multivariate linear regression analyses were used to evaluate the radiation effects on levels of markers of inflammation and insulin resistance.RESULTSRadiation dose was significantly and positively associated with levels of CRP, triglycerides, homeostasis model assessment of β-cell function (HOMA-β), and HOMA of insulin resistance (HOMA-IR) after adjustment for relevant covariates including sex, city, and age at exposure. Adiponectin and HDL cholesterol levels were also associated significantly and negatively with radiation dose. However, city was not a dose modifier of the radiation response on these markers of inflammation and insulin resistance.CONCLUSIONSInsulin resistance might be a possible factor in the radiation related diabetes incidence in the A-bomb survivors.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142215591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bobbie-Jo M Webb-Robertson,Wenting Wu,Javier E Flores,Lisa M Bramer,Farooq Syed,Sarah A Tersey,Sarah C May,Emily K Sims,Carmella Evans-Molina,Raghavendra G Mirmira
CONTEXTAlterations in RNA splicing may influence protein isoform diversity that contributes to or reflects the pathophysiology of certain diseases. Whereas specific RNA splicing events in pancreatic islets have been investigated in models of inflammation in vitro, how RNA splicing in the circulation correlates with or is reflective of T1D disease pathophysiology in humans remains unexplored.OBJECTIVETo use machine learning to investigate if alternative RNA splicing events differ between individuals with and without new-onset type 1 diabetes (T1D) and to determine if these splicing events provide insight into T1D pathophysiology.METHODSRNA deep sequencing was performed on whole blood samples from two independent cohorts: a training cohort consisting of 12 individuals with new-onset T1D and 12 age- and sex-matched nondiabetic controls and a validation cohort of the same size and demographics. Machine learning analysis was used to identify specific isoforms that could distinguish individuals with T1D from controls.RESULTSDistinct patterns of RNA splicing differentiated participants with T1D from unaffected controls. Notably, certain splicing events, particularly involving retained introns, showed significant association with T1D. Machine learning analysis using these splicing events as features from the training cohort demonstrated high accuracy in distinguishing between T1D subjects and controls in the validation cohort. Gene Ontology pathway enrichment analysis of the retained intron category showed evidence for a systemic viral response in T1D subjects.CONCLUSIONSAlternative RNA splicing events in whole blood are significantly enriched in individuals with new-onset T1D and can effectively distinguish these individuals from unaffected controls. Our findings also suggest that RNA splicing profiles offer the potential to provide insights into disease pathogenesis.
{"title":"RNA Splicing Events in Circulation Distinguish Individuals with and without New-Onset Type 1 Diabetes.","authors":"Bobbie-Jo M Webb-Robertson,Wenting Wu,Javier E Flores,Lisa M Bramer,Farooq Syed,Sarah A Tersey,Sarah C May,Emily K Sims,Carmella Evans-Molina,Raghavendra G Mirmira","doi":"10.1210/clinem/dgae622","DOIUrl":"https://doi.org/10.1210/clinem/dgae622","url":null,"abstract":"CONTEXTAlterations in RNA splicing may influence protein isoform diversity that contributes to or reflects the pathophysiology of certain diseases. Whereas specific RNA splicing events in pancreatic islets have been investigated in models of inflammation in vitro, how RNA splicing in the circulation correlates with or is reflective of T1D disease pathophysiology in humans remains unexplored.OBJECTIVETo use machine learning to investigate if alternative RNA splicing events differ between individuals with and without new-onset type 1 diabetes (T1D) and to determine if these splicing events provide insight into T1D pathophysiology.METHODSRNA deep sequencing was performed on whole blood samples from two independent cohorts: a training cohort consisting of 12 individuals with new-onset T1D and 12 age- and sex-matched nondiabetic controls and a validation cohort of the same size and demographics. Machine learning analysis was used to identify specific isoforms that could distinguish individuals with T1D from controls.RESULTSDistinct patterns of RNA splicing differentiated participants with T1D from unaffected controls. Notably, certain splicing events, particularly involving retained introns, showed significant association with T1D. Machine learning analysis using these splicing events as features from the training cohort demonstrated high accuracy in distinguishing between T1D subjects and controls in the validation cohort. Gene Ontology pathway enrichment analysis of the retained intron category showed evidence for a systemic viral response in T1D subjects.CONCLUSIONSAlternative RNA splicing events in whole blood are significantly enriched in individuals with new-onset T1D and can effectively distinguish these individuals from unaffected controls. Our findings also suggest that RNA splicing profiles offer the potential to provide insights into disease pathogenesis.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142215632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Ehlers, A. Kuebart, H. Hautzel, J. Enczmann, A. Reis, M. Haase, S. Allelein, T. Dringenberg, C. Schmid, M. Schott
Context Papillary thyroid cancer (PTC) is characterized by a lymphocytic infiltration. PTC patients with lymphocytic infiltration may have a better clinical outcome. Objective Characterization of tumor epitope-specific immunity and correlation analyses with the clinical outcome. Patients 150 PTC patients; 40 Hashimoto thyroiditis (HT) patients; 21 healthy controls; 27,239 healthy whites (for HLA typing). Main Outcome Measures HLA class I restricted thyroperoxidase (TPO) and thyroglobulin (Tg) epitope-specific T cells (tetramer analyses), correlation analyses between HLA class II phenotypes, T cell immunity, and the clinical course. Results The frequency of TPO- and Tg-specific CD8+ T cells in PTC patients was largely increased compared with healthy controls (TPO and Tg, P < 0.005 and P < 0.005) and was similar to those in HT patients. HLA-DQB1*03-positive PTC patients had a significantly lower risk [risk ratio (RR), 0.170; 95% confidence interval (CI), 0.037 to 0.755; P < 0.05] and HLA-DRB1*03-positive and HLA-DQB1*02-positive PTC patients a significantly higher risk (HLA-DRB1*03: RR, 4.400; 95% CI, 1.378 to 14.05; P < 0.05; HLA-DQB1*02: RR, 3.692; 95% CI, 1.102 to 12.38; P < 0.05) for distant metastases, compared with patients with other haplotypes. HLA-DQB1*03-positive PTC patients revealed an increased responsiveness of tumor epitopes in vitro. These tumor epitope-specific CD8+ T cells were also found in lymph node metastases of HLA-DQB1*03-positive PTC patients. Conclusion We demonstrate a tumor epitope-specific immunity in PTC patients and the protective role of HLA-DQB1*03 against metastatic spread. These results have direct implications for new treatment options with immune checkpoint inhibitors.
{"title":"Epitope-Specific Antitumor Immunity Suppresses Tumor Spread in Papillary Thyroid Cancer","authors":"M. Ehlers, A. Kuebart, H. Hautzel, J. Enczmann, A. Reis, M. Haase, S. Allelein, T. Dringenberg, C. Schmid, M. Schott","doi":"10.1210/jc.2016-2469","DOIUrl":"https://doi.org/10.1210/jc.2016-2469","url":null,"abstract":"Context\u0000Papillary thyroid cancer (PTC) is characterized by a lymphocytic infiltration. PTC patients with lymphocytic infiltration may have a better clinical outcome.\u0000\u0000\u0000Objective\u0000Characterization of tumor epitope-specific immunity and correlation analyses with the clinical outcome.\u0000\u0000\u0000Patients\u0000150 PTC patients; 40 Hashimoto thyroiditis (HT) patients; 21 healthy controls; 27,239 healthy whites (for HLA typing).\u0000\u0000\u0000Main Outcome Measures\u0000HLA class I restricted thyroperoxidase (TPO) and thyroglobulin (Tg) epitope-specific T cells (tetramer analyses), correlation analyses between HLA class II phenotypes, T cell immunity, and the clinical course.\u0000\u0000\u0000Results\u0000The frequency of TPO- and Tg-specific CD8+ T cells in PTC patients was largely increased compared with healthy controls (TPO and Tg, P < 0.005 and P < 0.005) and was similar to those in HT patients. HLA-DQB1*03-positive PTC patients had a significantly lower risk [risk ratio (RR), 0.170; 95% confidence interval (CI), 0.037 to 0.755; P < 0.05] and HLA-DRB1*03-positive and HLA-DQB1*02-positive PTC patients a significantly higher risk (HLA-DRB1*03: RR, 4.400; 95% CI, 1.378 to 14.05; P < 0.05; HLA-DQB1*02: RR, 3.692; 95% CI, 1.102 to 12.38; P < 0.05) for distant metastases, compared with patients with other haplotypes. HLA-DQB1*03-positive PTC patients revealed an increased responsiveness of tumor epitopes in vitro. These tumor epitope-specific CD8+ T cells were also found in lymph node metastases of HLA-DQB1*03-positive PTC patients.\u0000\u0000\u0000Conclusion\u0000We demonstrate a tumor epitope-specific immunity in PTC patients and the protective role of HLA-DQB1*03 against metastatic spread. These results have direct implications for new treatment options with immune checkpoint inhibitors.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"28 1","pages":"2154–2161"},"PeriodicalIF":0.0,"publicationDate":"2017-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75026597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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