Context: Diabetes mellitus (DM) has been associated with a 60% to 90% increased risk of fracture but few studies have been performed in African American and Hispanic subjects. Objective: The aim of the present study was to quantify the risk of incident major osteoporotic fractures (MOFs) of the hip, wrist, and humerus in African Americans, Hispanics, and Caucasians with DM compared with those with hypertension (HTN). Methods: We performed a retrospective cohort study of 19,153 subjects with DM (7618 Caucasians, 7456 African Americans, and 4079 Hispanics) and 26,217 with HTN (15,138 Caucasians, 8301 African Americans, and 2778 Hispanics) aged >= 40 years, treated at a large health care system in Philadelphia, Pennsylvania. All information about the subjects was obtained from electronic health records. Results: The unadjusted MOF rates for each race/ethnicity were similar among those with DM and those with HTN (Caucasians, 1.85% vs 1.84%; African Americans, 1.07% vs 1.29%; and Hispanics, 1.69% vs 1.33%; P = NS for all). However, the MOF rates were higher for Caucasians and Hispanics with DM than for African Americans with DM (P< 0.01). In a multivariable model controlled for age, body mass index, sex, and previous MOF, DM was a statistically significant predictor of MOFs only for Caucasians and Hispanics [hazard ratio (HR), 1.23; 95% CI, 1.02 to 1.48; P = 0.026] but not for African Americans (HR, 0.92; 95% CI, 0.68 to 1.23; P = 0.56). Conclusions: Hispanics had a DM-related fracture risk similar to that of Caucasians, but AAs did not have an additional fracture risk conferred by DM.
Context: In individuals with obesity, adipocyte endocrine function is affected by altered a utophagy. Genetic variants in autophagy-related gene 7 (ATG7) correlated with serum chemerin (RARRES2) concentrations. Objectives: To investigate a functional interplay between chemerin and ATG7, how it may relate to autophagy-mediated adipocyte dysfunction in obesity, and the relevance of genetic ATG7 variants in chemerin physiology. Design: Adipose ATG7 mRNA expression and adiposity measures were available in two human study cohorts. The effect of a high-calorie diet on adipose Rarres2 and Atg7 expression was investigated in mice. In 3T3-L1 adipocytes, the effect of Atg7 knockdown on chemerin expression and secretion was studied. The influence of single nucleotide polymorphisms on ATG7 transcription and chemerin physiology was investigated using a luciferase assay. Setting: Mouse model, clinical trials, in vitro studies. Participants: Native American (n = 83) and white (n = 100) cohorts. Main outcome measure: Adipocyte chemerin expression and secretion. Results: In mice fed a high-calorie diet, adipose Atg7 mRNA expression did not parallel an increase in Rarres2 mRNA expression. ATG7 mRNA expression in human subcutaneous adipose tissue correlated with body mass index, fat mass (r > 0.27; P < 0.01), and adipocyte cell size (r > 0.24; P < 0.02). Atg7 knockdown in 3T3-L1 adipocytes decreased chemerin secretion by 22% (P < 0.04). Rs2606729 in ATG7 was predicted to alter ATG7 transcription and induced higher luciferase activity in vitro (P < 0.0001). Conclusions: Human adipose ATG7 mRNA expression relates to measures of adiposity. Atg7 knockdown reduces chemerin secretion from adipocytes in vitro, supportive of a functional interplay between ATG7 and chemerin in autophagy-mediated adipocyte dysfunction.
Objective: Augmenting nicotinamide adenine dinucleotide (NAD(+)) metabolism through dietary provision of NAD(+) precursor vitamins translates to improved glucose handling in rodent models of obesity and diabetes. Preclinical evidence suggests that the NAD(+)/SIRT1 axis may be implicated in modulating important gut-related aspects of glucose regulation. We sought to test whether NAD(+) precursor supplementation with nicotinamide riboside (NR) affects beta-cell function, alpha-cell function, and incretin hormone secretion as well as circulating bile acid levels in humans. Design: A 12-week randomized, double-blind, placebo-controlled, parallel-group trial in 40 males with obesity and insulin resistance allocated to NR at 1000 mg twice daily (n = 20) or placebo (n = 20). Two-hour 75-g oral glucose tolerance tests were performed before and after the intervention, and plasma concentrations of glucose, insulin, C-peptide, glucagon, glucagon-like peptide 1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) were determined. beta-Cell function indices were calculated based on glucose, insulin, and C-peptide measurements. Fasting plasma concentrations of bile acids were determined. Results: NR supplementation during 12 weeks did not affect fasting or postglucose challenge concentrations of glucose, insulin, C-peptide, glucagon, GLP-1, or GIP, and beta-cell function did not respond to the intervention. Additionally, no changes in circulating adipsin or bile acids were observed following NR supplementation. Conclusion: The current study does not provide evidence to support that dietary supplementation with the NAD(+) precursor NR serves to impact glucose tolerance, beta-cell secretory capacity, alpha-cell function, and incretin hormone secretion in nondiabetic males with obesity. Moreover, bile acid levels in plasma did not change in response to NR supplementation.
Context: Thyroid hormones (THs) have direct and indirect effects on hematopoiesis. However, few studies have directly evaluated the effect of THs on incident anemia among euthyroid subjects. This cohort study aimed to explore whether THs under physiological conditions can affect the development of anemia in the general population. Design: A total of 12,310 participants were enrolled in the cohort study (-5-year follow-up period; mean, 3.1 years). A chemiluminescence immunoassay was used to measure free T3 (FT3), free T4 (FT4), and TSH, and anemia was defined according to the World Health Organization recommendation. THs, TSH, and Hb were assessed yearly during follow-up. Multivariable Cox proportional hazards regression models were used to assess the association between THs, TSH, and incident anemia. Results: The fully adjusted hazards ratios (95% CI) of anemia per 1-unit change in FT3, FT4, and TSH concentrations were 0.70 (0.56, 0.87), 0.93 (0.88, 0.98), and 1.19 (0.94, 1.50) (P < 0.01, P < 0.01, and P = 0.14, respectively). Moreover, a significant and positive association between FT3, FT4, and annual changes in Hb (standard regression coefficients of 0.056 and 0.028, respectively; both P < 0.01) was observed. Similar associations were observed when the participants who had thyroid dysfunction upon follow-up were excluded. Conclusions: The current study demonstrated that THs significantly predict future anemia and annual changes in Hb, even in the euthyroid population.
Context: SDHB mutations are found in an increasing number of neoplasms, most notably in paragangliomas and pheochromocytomas (PPGLs). SDHB-PPGLs are slow-growing tumors, but similar to 50% of them may develop metastasis. The molecular basis of metastasis in these tumors is a long-standing and unresolved problem. Thus, a better understanding of the biology of metastasis is needed. Objective: This study aimed to identify gene methylation changes relevant for metastatic SDHB-PPGLs. Design: We performed genome-wide profiling of DNA methylation in diverse clinical and genetic PPGL subtypes, and validated protocadherin gamma-C3 (PCDHGC3) gene promoter methylation in metastatic SDHB-PPGLs. Results: We define an epigenetic landscape specific for metastatic SDHB-PPGLs. DNA methylation levels were found significantly higher in metastatic SDHB-PPGLs than in SDHB-PPGLs without metastases. One such change included long-range de novo methylation of the PCDHA, PCDHB, and PCDHG gene clusters. High levels of PCDHGC3 promoter methylation were validated in primary metastatic SDHB-PPGLs, it was found amplified in the corresponding metastases, and it was significantly correlated with PCDHGC3 reduced expression. Interestingly, this epigenetic alteration could be detected in primary tumors that developed metastasis several years later. We also show that PCDHGC3 down regulation engages metastasis-initiating capabilities by promoting cell proliferation, migration, and invasion. Conclusions: Our data provide a map of the DNA methylome episignature specific to an SDHB-mutated cancer and establish PCDHGC3 as a putative suppressor gene and a potential biomarker to identify patients with SDHB-mutated cancer at high risk of metastasis who might benefit from future targeted therapies.
Context: Assessing thyroid nodules for malignancy is complex. The impact of patient and nodule factors on cancer evaluation is uncertain. Objectives: To determine precise estimates of cancer risk associated with clinical and sonographic variables obtained during thyroid nodule assessment. Design: Analysis of consecutive adult patients evaluated with ultrasound-guided fine-needle aspiration for a thyroid nodule >= 1 cm between 1995 and 2017. Demographics, nodule sonographic appearance, and pathologic findings were collected. Main Outcome Measures: Estimated risk for thyroid nodule malignancy for patient and sonographic variables using mixed-effect logistic regression. Results: In 9967 patients [84% women, median age 53 years (range 18 to 95)], thyroid cancer was confirmed in 1974 of 20,001 thyroid nodules (9.9%). Significant ORs for malignancy were demonstrated for patient age <52 years [OR: 1.82, 95% CI (1.63 to 2.05), P < 0.0001], male sex [OR: 1.68 (1.45 to 1.93), P < 0.0001], nodule size [OR: 1.30 (1.14 to 1.49) for 20 to 19 mm, OR: 1.59 (1.34 to 1.88) for 30 to 39 mm, and OR: 1.71 (1.43 to 2.04) for >= 40 mm compared with 10 to 19 mm, P < 0.0001 for all], cystic content [OR: 0.43 (0.37 to 0.50) for 25% to 75% cystic and OR: 0.21 (0.15 to 0.28) for >75% compared with predominantly solid, P< 0.0001 for both], and the presence of additional nodules >= 1cm [OR: 0.69 (0.60 to 0.79) for two nodules, OR: 0.41 (0.34 to 0.49) for three nodules, and OR: 0.19 (0.16 to 0.22) for greater than or equal to four nodules compared with one nodule, P< 0.0001 for all]. A free online calculator was constructed to provide malignancy-risk estimates based on these variables. Conclusions: Patient and nodule characteristics enable more precise thyroid nodule risk assessment. These variables are obtained during routine initial thyroid nodule evaluation and provide new insights into individualized thyroid nodule care.
Context: Primary aldosteronism (PA) represents a secondary form of arterial hypertension that can be cured by surgery. Evidence of adrenal insufficiency (AI) was recently found in patients with PA who had undergone unilateral adrenalectomy (uADX). Objective: To study the incidence and long-term outcome of postoperative Al after uADX for PA. Design: Prospective registry study (August 2014 until the end of 2018). Setting: Tertiary referral center. Patients: One hundred consecutive patients undergoing uADX for PA were included. All patients underwent postoperative ACTH stimulation testing. Intervention: Postoperative ACTH stimulation testing to identify patients with Al. Main Outcome Measures: Incidence of patients with postoperative Al and definition of long-term outcome. Results: Twenty-seven percent of patients developed postoperative Al. Of these, 48% had postoperative ACTH stimulation serum cortisol levels <= 13.5 mu g/dL (severe AI); 52% were classified into the group with moderate Al (stimulated serum cortisol levels: 13.5 to 17 mu g/dL). Patients with severe Al required significantly longer hydrocortisone replacement therapy than the moderate group (median [25th, 75th percentiles]: 353 [294, 476] days; 95% CI: 284 to 322 days; vs 74 [32, 293] days; 95% CI: 11 to 137 days; P = 0.016). One patient with severe Al was hospitalized for an acute adrenal crisis. With a cumulative follow-up of 14.5 years, this produced an incidence rate of 6.9 adrenal crises per 100 patient-years. Conclusion: We suggest performing postoperative ACTH stimulation tests in all patients who undergo uADX for PA.
Context: Prolonged adrenal stimulation by corticotropin, as in long-standing Cushing disease (CD), leads to diffuse to nodular hyperplasia. Adrenal functional autonomy has been described in a subset of patients with CD, leading to the hypothesis of transition from ACTH-dependent to ACTH-independent hypercortisolism. Objective: With the consideration that the catalytic a subunit of protein kinase A (PKA; PRKACA) somatic mutations are the most common finding in adrenal adenomas associated with ACTH-independent Cushing syndrome, our aim was to analyze PRKACA mutations in adrenals of patients with persistent/long-standing CD. Design: Cross-sectional. Setting: University hospital. Patients: Two patients with long-standing CD and suspicion of coexistence of autonomous adrenal hyperfunction, according to pre and postoperative evaluations, were selected for this study, following an intensive literature search and patient-chart reviewing. Intervention: Clinical data were analyzed. DNA was extracted from adrenal tissue for PRKACA sequencing. PKA activity was assayed. Main Outcome Measure: PRKACA somatic mutations. Results: Both patients showed mutations of PRKACA in the macronodule in the context of micronodular adrenal hyperplasia. One patient harbored the previously described p.Leu206Arg substitution, whereas a p.Ser213Arg missense variation was detected in the adrenal nodule of the second patient. No mutations were detected in the adjacent adrenal cortex of the second patient. In silico analysis predicts that p.Ser213Arg can interfere with the interaction between the regulatory and catalytic subunits of PKA. Conclusions: Our study shows that PRKACA somatic mutations can be found in adrenal nodules of patients with CD. These genetic alterations could represent a possible mechanism underlying adrenal nodule formation and autonomous cortisol hyperproduction in a subgroup of patients with long-standing CD.
Context: Adrenocortical zonation is associated with a markedly complex developmental process, and the pathogenesis and/or etiology of many disorders of adrenocortical zonal development have remained unknown. Cells from the three adrenocortical zones are morphologically and functionally differentiated, and the mature stage of cell development or senescence has been recently reported to be correlated with telomere length. However, the telomere length of each adrenocortical zonal cell has not yet been studied in human adrenal glands. Objective: We aimed to study the telomere lengths of adrenocortical parenchymal cells from three different zones of the adrenal glands present during childhood, adolescence, and adulthood. Methods: Adrenal glands of 30 autopsied subjects, aged between 0 and 68 years, were retrieved from pathology files. The normalized telomere to centromere ratio (NTCR), an index of telomere length, was determined in the parenchymal cells of the zona glomerulosa, zona fasciculata, and zona reticularis (ZR), using quantitative fluorescence in situ hybridization. Results: NTCR of ZR cells was the longest, followed in decreasing order by that of zona glomerulosa and zona fasciculata cells in subjects aged 20 to 68 years, but no substantial differences in NTCR were detected among these three zones in the group <20 years of age. NTCR of ZR increased with age in subjects aged 20 to 68 years, whereas no important age-dependent changes in NTCR were detected in the group <20 years of age. Conclusion: The telomere lengths for three zones in adrenal cortex were correlated with their differentiation in adulthood but not in childhood and adolescence.
Context: The bidirectional relationship between low high-density lipoprotein cholesterol (HDL-C) and glucose intolerance is well established. Recent studies suggested an association of lipid variability with various health outcomes. Objective: To investigate the combined effect of HDL-C levels and their variability on the risk of diabetes. Design: A population-based cohort study. Setting and Participants: In all, 5,114,735 adults without known diabetes in the Korean National Health Insurance System cohort who underwent three or more health examinations from 2009 to 2013 were included. Visit-to-visit HDL-C variability was calculated using variability independent of the mean (VIM) and the coefficient of variation (CV). Low mean and high variability groups were defined as the lowest and highest quartiles of HDL-C mean and variability, respectively. Main Outcome Measures: Newly developed diabetes. Results: There were 122,192 cases (2.4%) of incident diabetes during the median follow-up of 5.1 years. Lower mean or higher variability of HDL-C was associated with higher risk of diabetes in a stepwise manner, and an additive effect of the two measures was noted. In the multivariable-adjusted model, the hazard ratios and 95% Cls for incident diabetes were 1.20 (1.18 to 1.22) in the high mean/high VIM group, 1.35 (1.33 to 1.37) in the low mean/low VIM group, and 1.40 (1.38 to 1.42) in the low mean/high VIM group compared with the high mean/low VIM group. Similar results were observed when modeling the variability using CV and in various subgroup analyses. Conclusions: Low mean and high variability in HDL-C were independent predictors of diabetes with an additive effect. Both elevating and stabilizing HDL-C may be important goals for reducing diabetes risk.
Context: Despite the emerging evidence on the role of oxytocin (OXT) in metabolic diseases, there is a lack of well-powered studies addressing the relationship of circulating OXT with obesity and diabetes. Objectives and Design: Here, we measured OXT in a study cohort (n = 721; 396 women, 325 men; mean age +/- SD, 47.7 +/- 15.2 years) with subphenotypes related to obesity, including anthropometric traits such as body mass index [BMI (mean +/- SD), 26.8 +/- 4.6 kg/m(2)], waist-to-hip ratio (WHR; 0.88 +/- 0.09), blood parameters (glucose, 5.32 +/- 0.50 mmol/L; insulin, 5.3 +/- 3.3 mu U/mL), and oral glucose tolerance test to clarify the association with OXT. We also tested in a genome-wide association study (GWAS) whether the interindividual variation in OXT serum levels might be explained by genetic variation. Results: The OXT concentration was increased in subjects with elevated BMI and positively correlated with WHR, waist circumference, and triglyceride levels. The OXT concentration in subjects with BMI <25 kg/m(2) was significantly lower (n = 256; 78.6 pg/mL) than in subjects with a BMI between 25 and 30 kg/m 2 (n = 314; 98.5 pg/mL, P = 6 x 10(-6)) and with BMI >30 kg/m(2) (n = 137; 106.4 pg/mL, P = 8 x 10 -8 ). OXT levels were also positively correlated with plasma glucose and insulin and were elevated in subjects with impaired glucose tolerance (P = 4.6 x 10(-3)). Heritability of OXT was estimated at 12.8%. In a GWAS, two hits in linkage disequilibrium close (19 kb) to the OXT reached genome-wide significant association (top-hit rs12625893, P = 3.1 x 10(-8), explained variance 3%). Conclusions: Our data show that OXT is genetically affected by a variant near OXT and is associated with obesity and impaired glucose tolerance.
Context: Teriparatide and denosumab are effective treatments for osteoporosis and typically reserved as second-line options after patients have used bisphosphonates. However, limited head-to-head comparative effectiveness data exist between teriparatide and denosumab. Objective: We compared changes in bone mineral density (BMD) between groups treated with teriparatide or denosumab after using bisphosphonates, focusing on the change in BMD while on either drug over 2 years. Design: Observational cohort study using electronic medical records from two academic medical centers in the United States. Participants: The study population included osteoporotic patients >45 years who received bisphosphonates >1 year before switching to teriparatide or denosumab. Outcome Measures: Annualized BMD change from baseline at the lumbar spine, total hip, and femoral neck. Results: Patients treated with teriparatide (n = 110) were compared with those treated with denosumab (n = 105); the mean (SD) age was 70 (10) years and median duration (interquartile range) of bisphosphonate use was 7.0 (5.6 to 9.7) years. Compared with denosumab users, teriparatide users had higher annualized BMD change at the spine by 1.3% (95% CI 0.02, 2.7%) but lower at the total hip by -2.2% (95% CI -2.9 to -1.5%) and the femoral neck by -1.1% (95% CI -2.1 to -0.1 %). Those who switched to teriparatide had a transient loss of hip BMD for the first year, with no overall increase in the total hip BMD over 2 years. Conclusions: Among patients who use long-term bisphosphonates, the decision of switching to teriparatide should be made with caution, especially for patients at high risk of hip fracture.
Context: Conventional treatment of hypoparathyroidism is associated with decreased renal function and increased bone mineral density (BMD). Objective: To evaluate the effects of 8 years of recombinant human parathyroid hormone (1-84) [rhPTH(1-84)] therapy on key biochemical and densitometric indices. Design: Prospective open-label trial. Setting: Tertiary medical center. Participants: Twenty-four subjects with hypoparathyroidism. Intervention: Treatment with rhPTH(1-84) for 8 years. Main Outcome Measures: Supplemental calcium and vitamin D requirements, serum calcium and phosphorus levels, calcium-phosphate product, urinary calcium excretion, estimated glomerular filtration rate (eGFR) and BMD. Results: PTH therapy was associated with progressive reduction in supplemental calcium (57%; P < 0.01) and active vitamin D (76%; P < 0.001) requirements over 8 years. Serum calcium concentration was stable; urinary calcium excretion declined 38% (P < 0.01). eGFR remained stable and was related to baseline eGFR and serum calcium levels. Calcium-phosphate product was below the recommended limit; serum phosphorus remained within normal range. Lumbar spine and total hip BMD increased, peaking at 4 (mean +/- SE, 4.6% +/- 1.5%; P = 0.01) and 8 years (2.6% +/- 1.1%; P = 0.02), whereas femoral neck BMD did not change and one-third radius BMD decreased (mean +/- SE, -3.5% +/- 1.1%; P = 0.001). BMD at all sites was higher throughout the 8 years than in the age- and sex-matched reference population. Hypercalcemia and hypocalcemia were uncommon. Conclusion: rhPTH(1-84) is a safe and effective treatment for hypoparathyroidism for 8 years. Long-term reductions in supplemental requirements and biochemical improvements with stable renal function are maintained.
Context: Elevated circulating parathyroid hormone concentrations have been associated with increased risk of cardiovascular disease in observational studies, but whether the association is causal is unknown. Objective: We used the Mendelian randomization design to test whether genetically increased serum parathyroid hormone (S-PTH) concentrations are associated with coronary artery disease (CAD). Design, Setting, and Participants: Five single-nucleotide polymorphisms robustly associated with S-PTH concentrations were used as instrumental variables to estimate the association of genetically higher S-PTH concentrations with CAD. Summary statistics data for CAD were obtained from a genetic consortium with data from 184,305 individuals (60,801 CAD cases and 123,504 noncases). Main Outcome Measure: OR of CAD per genetically predicted one SD increase of S-PTH concentrations. Results: Genetically higher S-PTH concentration was not associated with CAD as a whole or myocardial infarction specifically (similar to 70% of total cases). The ORs per genetically predicted one SD increase in S-PTH concentration were 1.01 (95% CI: 0.93 to 1.09; P = 0.88) for CAD and 1.02 (95% CI: 0.94 to 1.10; P = 0.64) for myocardial infarction. The lack of association remained in various sensitivity analyses. Conclusion: Genetic predisposition to higher S-PTH concentrations does not appear to be an independent risk factor for CAD.
Context: Characterization of slow progression to type 1 diabetes (T1D) may reveal novel means for prevention of T1D. Slow progressors might carry natural immunomodulators that delay beta-cell destruction and mediate preservation of beta-cell function. Objective: To identify demographic, genetic, and immunological characteristics of slow progression from seroconversion to clinical T1D. Design: H LA-susceptible children (n = 7410) were observed from birth for islet cell antibody (ICA), insulin autoantibody (IAA), glutamic acid decarboxylase (GADA), and islet antigen-2 autoantibodies (IA-2A), and for clinical T1D. Disease progression that lasted >= 7.26 years (slowest) quartile from initial seroconversion to diagnosis was considered slow. Autoantibody and genetic characteristics including 45 non-HLA single nucleotide polymorphisms (SNPs) predisposing to T1D were analyzed. Results: By the end of 2015, 1528 children (21 %) had tested autoantibody positive and 247 (16%) had progressed to T1D. The median delay from seroconversion to diagnosis was 8.7 years in slow (n = 62, 25%) and 3.0 years in other progressors. Compared with other progressors, slow progressors were less often multipositive, had lower ICA and IAA titers, and lower frequency of IA-2A at seroconversion. Slow progressors were born more frequently in the fall, whereas other progressors were born more often in the spring. Compared with multipositive nonprogressors, slow progressors were younger, had higher ICA titers, and higher frequency of IAA and multiple autoantibodies at seroconversion. We found no differences in the distributions of non-HLA SNPs between progressors. Conclusions: We observed differences in autoantibody characteristics and the season of birth among progressors, but no characteristics present at seroconversion that were specifically predictive for slow progression.