Aim: The objectives of the present study were to compare bone characteristics with quantitative computed tomography (QCT) and other metabolic factors relevant to bone health in subjects with normal glucose tolerance, impaired glucose tolerance (IGT), and diabetes mellitus (DM) and to evaluate the association of various laboratory factors with bone characteristics qualified by QCT. Methods: This cross-sectional population-based survey of diabetes and metabolic syndrome was conducted in Pinggu, China. The oral glucose tolerance test was conducted and QCT was tested. The volumetric bone mineral density (vBMD) of lumbar vertebrae 2 through 4 was measured. Results: Among the 4001 eligible participants, the average age was 47.41 +/- 11.86 years. The prevalence of osteoporosis evaluated by QCT was 10.6% in the normal glucose tolerance group, 14.8% in the IGT group, and 16.9% in the DM group. Multivariate linear regression analysis showed that age was negatively associated with vBMD, whereas body mass index and waisthip ratio were positively associated with vBMD across all participants. However, the levels of hemoglobin A1c, fasting plasma glucose, and postprandial glucose were not associated with vBMD after adjusting for sex, age, systolic and diastolic blood pressure, body mass index, total cholesterol, triglyceride, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, FT4, FT3, thyroid-stimulating hormone, urine albumin-to-creatinine ratio, creatinine, and serum uric acid. Conclusions: We found that the prevalence of osteoporosis evaluated by QCT was 10.6% in the normal glucose tolerance group, 14.8% in the IGT group, and 16.9% in the DM group. The levels of hemoglobin A1c, fasting plasma glucose, and postprandial glucose were not associated with vBMD after adjusting for metabolic factors in a Chinese sample.
Context: Very few studies focused on the association between body mass index (BMI) and stroke risk among patients with diabetes. Objective: We aimed to investigate the association between BMI and stroke risk in patients with type 2 diabetes. Design: Demographic, anthropometric, laboratory, and medication information were extracted from the National Patient-Centered Clinical Research Network common data model. Participants: We performed a retrospective cohort study of 67 086 patients with type 2 diabetes. Main Outcome Measures: Incident stroke including both ischemic and hemorrhagic stroke were defined. Results: During a mean follow up of 3.74 years. 8918 incident stroke events occurred. Multivariable-adjusted hazard ratios across different categories of BMI at baseline (18.5-24.9 [reference group], 25.0-29.9, 30.0-34.9, 35.0-39.9, and >= 40 kg/m(2)) were 1.00, 0.92, 0.85, 0.74, and 0.63 (P-trend < 0.001) for total stroke; 1.00, 0.93, 0.88, 0.77, and 0.65 (P-trend < 0.001) for ischemic stroke; and 1.00, 0.79, 0.50, 0.50, and 0.41 (P-trend < 0.001) for hemorrhagic stroke, respectively. When we used an updated mean value of BMI, the graded inverse association of body mass index with stroke risk did not change. This linear association was consistent among patients of different subgroups. Further sensitivity analysis excluding patients who were diagnosed stroke within 6 months after first diagnosis of type 2 diabetes or including nonsmokers only also confirmed our findings. Conclusion: The present study found an inverse association between BMI and the risk of total, ischemic, and hemorrhagic stroke among patients with type 2 diabetes. More clinical and molecular insights are still needed in explaining these findings.
Context: Observational studies have demonstrated that early menarche is associated with cardiometabolic diseases, but confounding factors make it difficult to infer causality. Objective: We used Mendelian randomization (MR) to examine whether age at menarche (AAM) is causally associated with type 2 diabetes (T2D), coronary artery disease (CAD) and cardiometabolic traits. Design and Methods: A 2-sample MR analysis was conducted using genome-wide association study (GWAS) summary statistics from the Diabetes Genetics Replication and Meta-analysis (DIAGRAM) consortium (n = 159 208) for T2D and the Coronary Artery Disease Genome-wide Replication and Meta-analysis plus the Coronary Artery Disease Genetics (CARDIoGRAMplusC4D) consortium (n = 184 305) for CAD. We used 122 instrumental variables (IVs) extracted from a published GWAS meta-analysis incorporating 182 416 women to determine the causal effect of AAM on cardiometabolic diseases, treating childhood and adult body mass index (BMI) as the confounders. Sensitivity analyses were also performed to detect the pleiotropy of the IVs. Results: Employing the MR approach, we found that later AAM was associated with decreased risk of CAD (OR, 0.92 [95% CI, 0.88-0.96]; P = 2.06 x 10(-4)) in adults, as well as lower blood levels of log fasting insulin, log homeostatic model assessment of insulin resistance (HOMA-IR), log HOMA of beta-cell function (HOMA-B), triglycerides, and diastolic blood pressure, but higher blood level of high-density lipoprotein. However, the associations were substantially attenuated after excluding BMI-related variants. MR analyses provide little evidence on the causal effect between AAM and T2D. Conclusions: Our findings showed that AAM did not appear to have a causal effect on the risk of cardiometabolic diseases in adult life, as their associations observed in epidemiological studies might be largely mediated through excessive adiposity. We propose adiposity might be a primary target in future intervention strategy.
Context: The impact of mild TSH elevation (2.5-4.08 mIU/L) on pregnancy outcomes is unclear. The treatment strategy for mild TSH elevation is dependent on thyroid peroxidase antibody (TPOAb) status according to the guidelines. Objective: To assess the effects of mild thyroid dysfunction combined with TPOAb status in the first trimester on pregnancy outcomes and the impact of levothyroxine (L-T4) treatment on pregnancy outcomes. Design: The study retrospectively evaluated 3562 pregnant women. A total of 3296 untreated women were divided into 4 subgroups: group A: 4.08 < TSH <10 mIU/L, TPOAb(+/-); group B: 2.5 < TSH <= 4.08 mIU/L, TPOAb(+); group C: 2.5 < TSH <= 4.08 mIU/L, TPOAb(-); and group D: 0.23 <= TSH <= 2.5 mIU/L, TPOAb(+/-). The other 266 women with L-T4 treatment were divided into TSH 4.08 to 10 mIU/L and 2.5 to 4.08 mIU/L subgroups. Setting: The study was conducted at Peking University First Hospital in China. Patients: A total of 3562 pregnant women were evaluated. Main Outcome Measures: The incidence of pregnancy outcomes in the untreated subgroups (groups A-D) and treated subgroups were measured. Results: Miscarriage and maternal composite outcome risks were 3.53 (1.85-6.75) and 2.19 (1.26-3.81) times greater in group A; 1.58 (1.17-2.13) and 1.27 (1.04-1.54) times greater in group C than in group D. L-T4 improved the miscarriage risk in the TSH 4.08 to 10 and 2.5 to 4.08 mIU/L groups but doubled the risk of gestational diabetes mellitus in the TSH 2.5 to 4.08 mIU/L treated group compared with the untreated group. Conclusions: TSH 2.5 to 4.08 mIU/L combined with TPOAb- during early pregnancy was associated with miscarriages and maternal composite outcomes. The advantages and disadvantages of L-T4 administration in TSH 2.5 to 4.08 mIU/L pregnant women remain uncertain.
Purpose: The aims of this study were to evaluate the effect of age at menarche (AM) on type 2 diabetes mellitus (T2DM) and to assess whether the fasting plasma glucose (FPG) and homeostasis model assessment (HOMA) index responses to AM and menopause status interact in Chinese rural adults. Methods: A cross-sectional, population-based study including 23 138 participants was performed. Logistic regression and multivariable linear regression were performed to investigate the relationship between AM and glucose status. Generalized linear model was used to calculate the interaction term of AM and menopause status on FPG and the HOMA index. Interaction plot was used to interpret the significant interaction effect. Results: Women in the later menarche age group (>= 18 years) had a 17.7% lower risk of T2DM (95% confidence interval [CI]: 0.712-0.951, P = .008), after adjusting for multiple variables. Further adjustment for body mass index (BMI) completely attenuated this association (odds ratio = 0.884, 95% CI: 0.764-1.024, P = .099). A significant interaction effect of AM and menopause status on T2DM (P = .004) was observed. The adverse effects of menopausal status on FPG and HOMA-2 of insulin resistance decreased with increasing menarche age, and the age ranges were limited to <18 and 9 to 19 years, respectively. Conclusions: Later menarche was associated with a lower risk of T2DM, and the association appears to be mediated by BMI. More importantly, the adverse effect of menopause status on T2DM was decreased along with increasing menarche age.
Context: The long-term safety and benefit of pioglitazone use in combination with insulin are still uncertain. Objective: This study compared the risks of all-cause mortality and major cardiovascular (CV) events between pioglitazone users and nonusers receiving insulin therapy. Design, Setting and Patients: We conducted a 13-year retrospective cohort study by using data from the population-based National Health Insurance Research Database in Taiwan. A total of 20 376 patients with type 2 diabetes mellitus (T2DM) receiving insulin therapy were enrolled during 2000 to 2012. Overall, the incidence rates of all-cause mortality and CV events were compared between 2579 pioglitazone users and 2579 matched nonusers. Results: After adjustment for age, sex, comorbidities, Diabetes Complications Severity Index scores, and drugs used, mortality rates were 30.26 and 15.02 per 1000 person-years for pioglitazone nonusers and users, respectively. The adjusted hazard ratio (aHR) of mortality was 0.47 (95% confidence interval [CI]: 0.38-0.58, P < 0.001) for pioglitazone users compared with nonusers. The aHRs of CV and non-CV deaths were 0.78 (95% CI: 0.51-1.19) and 0.50 (95% CI: 0.38-0.66), respectively. The aHRs of hospitalized coronary artery disease, hospitalized stroke, and incident heart failure were not significantly different between pioglitazone users and nonusers. Conclusions: This nationwide cohort study demonstrated that pioglitazone use reduced the risks of all-cause mortality and non-CV death for patients with T2DM undergoing insulin therapy.
Context: SHBG, a homodimeric glycoprotein produced by hepatocytes has been shown to be associated with metabolic disorders. Whether circulating SHBG levels are predictive of later risk of nonalcoholic fatty liver disease (NAFLD) remains unknown. In this study, we prospectively investigated the association between SHBG and NAFLD progression through a community-based cohort comprising 3389 Chinese adults. Methods: NAFLD was diagnosed using abdominal ultrasonography. Serum SHBG levels were measured by chemiluminescent enzyme immunometric assay, and their relationship with NAFLD development and regression was investigated after a mean follow-up of 3.09 years using multivariable logistic regression. Results: Basal SHBG was negatively associated with NAFLD development, with a fully adjusted odds ratio (OR) and its 95% confidence interval (CI) of 0.22 (0.12-0.40) (P < .001). In contrast, basal SHBG was positively associated with NAFLD regression, with a fully adjusted OR of 4.83 (2.38-9.81) (P <.001). Multiple-stepwise logistic regression analysis showed that SHBG concentration was an independent predictor of NAFLD development (OR, 0.28 [0.18-0.45]; P <.001) and regression (OR, 3.89 [2.43-6.22]; P <.001). In addition, the area under the receiver operating characteristic curves were 0.764 (95% CI, 0.740-0.787) and 0.762 (95% CI, 0.738-0.785) for the prediction models of NAFLD development and regression, respectively. Conclusions: Serum SHBG concentration is associated with the development and regression of NAFLD; moreover, it can be a potential biomarker for predicting NAFLD progression, and also a novel preventive and therapeutic target for NAFLD.
Background Adipocyte-derived hormones play a role in insulin sensitivity and energy homeostasis. However, the relationship between circulating fibroblast growth factor 21 (FGF21), adipocytokines and cold-induced supraclavicular brown adipose tissue (sBAT) activation is underexplored. Objective Our study aimed to investigate the relationships between cold-induced sBAT activity and plasma FGF21 and adipocytokines levels in healthy adults. Design Nineteen healthy participants underwent energy expenditure (EE) and supraclavicular infrared thermography (IRT) within a whole-body calorimeter at baseline and at 2 hours post-cold exposure. F-18-fluorodeoxyglucose (F-18-FDG) positron-emission tomography/magnetic resonance (PET/MR) imaging scans were performed post-cold exposure. PET sBAT mean standardized uptake value (SUV mean), MR supraclavicular fat fraction (sFF), anterior supraclavicular maximum temperature (Tscv max) and EE change (%) after cold exposure were used to quantify sBAT activity. Main Outcome Measures Plasma FGF21, leptin, adiponectin, and tumor necrosis factor alpha (TNF alpha) at baseline and 2 hours post-cold exposure. Body composition at baseline by dual-energy x-ray absorptiometry (DXA). Results Plasma FGF21 and adiponectin levels were significantly reduced after cold exposure in BAT-positive subjects but not in BAT-negative subjects. Leptin concentration was significantly reduced in both BAT-positive and BAT-negative participants after cold exposure. Adiponectin concentration at baseline was positively strongly associated with sBAT PET SUV mean (coefficient, 3269; P = 0.01) and IRT Tscv max (coefficient, 6801; P = 0.03), and inversely correlated with MR sFF (coefficient, -404; P = 0.02) after cold exposure in BAT-positive subjects but not in BAT-negative subjects. Conclusion Higher adiponectin concentrations at baseline indicate a greater cold-induced sBAT activity, which may be a novel predictor for sBAT activity in healthy BAT-positive adults.
Context: The association of the combination of body mass index (BMI) and waist circumference (WC) with the risk of proteinuria has previously not been comprehensively investigated and results have been inconclusive. Objective: To examine BMI and WC in relation to new-onset proteinuria in Chinese hypertensive patients. Design and Setting: Post hoc analysis of the renal substudy of the China Stroke Primary Prevention Trial (CSPPT). Patients: 10 805 hypertensive patients without proteinuria at baseline. Main Outcome Measure: The primary outcome was new-onset proteinuria, defined as a urine dipstick protein reading >= 1 + at the exit visit, after a median follow-up duration of 4.4 years. Results: When analyzed separately, increased BMI (>= 28 kg/m(2), quartile 4; odds ratio [OR], 1.36; 95% confidence interval [CI], 1.08-1.72), or increased WC (>= 91 cm for females, quartile 4; OR, 1.35; 95% CI, 1.01-1.80; and >= 79 cm for males, quartile 2-4; OR, 1.60; 95% CI, 1.03-2.50) were each significantly associated with higher risk of new-onset proteinuria. When analyzed jointly, participants without increased BMI and increased WC had the lowest risk, while those with both increased BMI and increased WC had the highest risk of proteinuria (OR, 1.61; 95% CI, 1.21-2.13). Notably, participants with only increased WC also had significantly increased risk of proteinuria (OR, 1.39; 95% CI, 1.04-1.85). Conclusion: In Chinese hypertensive patients, increased BMI and increased WC were individually and jointly associated with a higher risk of new-onset proteinuria, underscoring the value of monitoring both BMI and WC in assessing proteinuria risk.
Context. The role of serum calcium in bone metabolism is unknown, even though calcium/vitamin D supplementations have been widely used and are expected to improve bone health. We aim to determine the independent role of serum calcium in bone mineral density (BMD). Design and setting. Two epidemiological analyses with 5478 and 5556 participants from the National Health and Nutrition Examination Survey (NHANES) 2003 to 2006 and the Hong Kong Osteoporosis Study (HKOS) to evaluate the cross-sectional association of serum calcium with BMD. Two-sample Mendelian randomization (MR) studies using genetic variations as instrumental variables to infer causality. Summary statistics of genome-wide association study of serum calcium (N = 39 400) and lifelong whole-body BMD (N = 66 628) were used. Main outcome measure: BMD measured by dual-energy X-ray absorptiometry Results. In NHANES 2003-6 and HKOS, each standard deviation (SD) increase in serum calcium was significantly associated with 0.036-0.092 SD decrease in BMD at various sites (all P < .05). In multivariable inverse-variance weighted MR analysis, genetic predisposition to higher serum calcium level was inversely associated with whole-body BMD after adjustment for serum parathyroid hormone, vitamin D, and phosphate (-0.431 SD per SD increase in serum calcium; 95% CI: -0.773 to -0.089, P = .014). Similar estimates were obtained in sensitivity analyses. Conclusions. Our study reveals that genetic predisposition to higher serum calcium level per se may have a negative impact on bone metabolism. Whether increased serum calcium caused by calcium/vitamin D supplementations would have the same negative effect on bone remains unknown, which warrants further investigation. In addition to other adverse clinical outcomes, careful use of high-dose supplementations is required.
Context: The X-linked immunoglobulin superfamily, member 1 (IGSF1), gene is highly expressed in the hypothalamus and in pituitary cells of the POU1F1 lineage. Human loss-of-function mutations in IGSF1 cause central hypothyroidism, hypoprolactinemia, and macroorchidism. Additionally, most affected adults exhibit higher than average IGF-1 levels and anecdotal reports describe acromegaloid features in older subjects. However, somatotrope function has not yet been formally evaluated in this condition. Objective: We aimed to evaluate the role of IGSF1 in human and murine somatotrope function. Patients, Design, and Setting: We evaluated 21 adult males harboring hemizygous IGSF1 loss-of-function mutations for features of GH excess, in an academic clinical setting. Main Outcome Measures: We compared biochemical and tissue markers of GH excess in patients and controls, including 24-hour GH profile studies in 7 patients. Parallel studies were undertaken in male Igsf1-deficient mice and wild-type littermates. Results: IGSF1-deficient adult male patients demonstrated acromegaloid facial features with increased head circumference as well as increased finger soft-tissue thickness. Median serum IGF-1 concentrations were elevated, and 24-hour GH profile studies confirmed 2- to 3-fold increased median basal, pulsatile, and total GH secretion. Male Igsf1-deficient mice also demonstrated features of GH excess with increased lean mass, organ size, and skeletal dimensions and elevated mean circulating IGF-1 and pituitary GH levels. Conclusions: We demonstrate somatotrope neurosecretory hyperfunction in IGSF1-deficient humans and mice. These observations define a hitherto uncharacterized role for IGSF1 in somatotropes and indicate that patients with IGSF1 mutations should be evaluated for long-term consequences of increased GH exposure.
Context: China has the largest number of people with type 2 diabetes mellitus (T2DM) in the world. Data from previous studies have suggested that up to one-fifth of individuals with diabetes would be missed without an oral glucose tolerance test (OGTT). To date, there is little information on the mortality risk of these individuals. Objective: We estimated the association of different indicators of hyperglycemia with mortality in the general Chinese population. Design: Prospective cohort study. Setting: China. Participants: A total of 17 939 participants aged 50+ years. Exposures: Previously diagnosed diabetes and newly detected diabetes defined by fasting glucose (>= 7.0 mmol/L), 2-hour postload glucose (>= 11.1 mmol/L), or hemoglobin A(1c) (HbA(1c), >= 6.5%). Main Outcomes Measures: Deaths from all-cause, cardiovascular disease, and cancer were identified by record linkage with death registration. Results: During 7.8 (SD, 1.5) years' follow-up, 1439 deaths were recorded. Of 3706 participants with T2DM, 2126 (57%) had known T2DM, 118 (3%) were identified by isolated elevated fasting glucose, 1022 (28%) had isolated elevated postload glucose, and 440 (12%) had both elevated fasting and postload glucose. Compared with normoglycemia, the hazard ratio (95% confidence interval) of all-cause mortality was 1.71 (1.46-2.00), 0.96 (0.47-1.93), 1.43 (1.15-1.78), and 1.82 (1.35-2.45) for the 4 groups, respectively. T2DM defined by elevated HbA1c was not significantly associated with all-cause mortality (hazard ratio, 1.17; 95% confidence interval, 0.81-1.69). Conclusion: Individuals with isolated higher 2-h postload glucose had a higher risk of mortality by 43% than those with normoglycemia. Underuse of OGTT leads to substantial underdetection of individuals with a higher mortality risk and lost opportunities for early intervention.
Background: In addition to the controversy regarding the association of hyperuricemia with mortality, uncertainty also remains regarding the association between low serum uric acid (SUA) and mortality. We aimed to assess the relationship between SUA and all-cause and cause-specific mortality. Methods: This cohort study included 9118 US adults from the National Health and Nutrition Examination Survey (1999-2002). Multivariable Cox proportional hazards models were used to evaluate the relationship between SUA and mortality. Our analysis included the use of a generalized additive model and smooth curve fitting (penalized spline method), and 2-piecewise Cox proportional hazards models, to address the nonlinearity between SUA and mortality. Results: During a median follow-up of 5.83 years, 448 all-cause deaths occurred, with 100 cardiovascular disease (CVD) deaths, 118 cancer deaths, and 37 respiratory disease deaths. Compared with the reference group, there was an increased risk of all-cause, CVD, cancer, and respiratory disease mortality for participants in the first and third tertiles of SUA. We further found a nonlinear and U-shaped association between SUA and mortality. The inflection point for the curve was found at a SUA level of 5.7 mg/dL. The hazard ratios (95% confidence intervals) for all-cause mortality were 0.80 (0.65-0.97) and 1.24 (1.10-1.40) to the left and right of the inflection point, respectively. This U-shaped association was observed in both sexes; the inflection point for SUA was 6 mg/dL in males and 4 mg/dL in females. Conclusion: Both low and high SUA levels were associated with increased all-cause and cause-specific mortality, supporting a U-shaped association between SUA and mortality.