| 1. |
- Dalin, Frida, 1984-, et al.
(författare)
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Clinical and immunological characteristics of Autoimmune Addison's disease : a nationwide Swedish multicenter study
- 2017
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : Oxford University Press. - 0021-972X .- 1945-7197. ; 102:2, s. 379-389
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Studies on clinical and immunological features of Autoimmune Addison's disease (AAD) are needed to understand the disease burden and increased mortality.OBJECTIVE: To provide upgraded data on autoimmune comorbidities, replacement therapy, autoantibody profiles and cardiovascular risk factors.DESIGN, SETTING AND PARTICIPANTS: Cross sectional, population-based study. 660 AAD patients were included utilizing the Swedish Addison Registry (SAR) 2008-2014. When analyzing cardiovascular risk factors, 3,594 individuals from the population-based survey in Northern Sweden, MONICA (MONItoring of Trends and Determinants of CArdiovascular Disease), served as controls.MAIN OUTCOME MEASURE: Prevalence of autoimmune comorbidities and cardiovascular risk factors. Autoantibodies against 13 autoantigens were determined.RESULTS: Sixty percent of the SAR cohort consisted of females. Mean age at diagnosis was significantly higher for females than for males (36.8 vs. 31.1 years). The proportion of 21-hydroxylase autoantibody positive patients was 83% and 62% of patients had one or more associated autoimmune diseases, more frequently coexisting in females (p<0.0001). AAD patients had lower BMI (p<0.0001) and prevalence of hypertension (p=0.027) compared with controls. Conventional hydrocortisone tablets were used by 89% of patients; with the mean dose 28.1±8.5 mg/day. The mean hydrocortisone equivalent dose normalized to body surface was 14.8±4.4 mg/m(2)/day. Higher hydrocortisone equivalent dose was associated with higher incidence of hypertension (p=0.046).CONCLUSIONS: Careful monitoring of AAD patients is warranted to detect associated autoimmune diseases. Contemporary Swedish AAD patients do not have increased prevalence of overweight, hypertension, T2DM or hyperlipidemia. However, high glucocorticoid replacement doses may be a risk factor for hypertension.
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| 2. |
- Gustafsson, Stefan, et al.
(författare)
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Associations of circulating adiponectin with measures of vascular function and morphology
- 2010
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 95:6, s. 2927-2934
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Some previous studies have reported an association between circulating adiponectin and selected measures of vascular function and morphology, but most of these studies have been performed in small samples of patients with preexisting disease. OBJECTIVE: We aimed to evaluate associations between circulating adiponectin and comprehensive measures of vascular function and morphology in a large sample of individuals from the community. DESIGN, SETTINGS, AND PARTICIPANTS: We conducted a cross-sectional investigation of 981 70-yr-old participants (50% women) of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS). MAIN OUTCOME MEASURES: Measures of outcome included vascular function [common carotid artery (CCA) distensibility, flow-mediated dilation, endothelium-dependent and endothelium-independent vasodilation using invasive methods] and vascular morphology [intima-media (IM) thickness, plaque presence, gray scale median (GSM) in the IM and plaques]. RESULTS: In age- and sex-adjusted models, adiponectin was positively associated with IM-GSM, plaque GSM, CCA distensibility, endothelium-dependent and endothelium-independent vasodilation. In multivariable models (with additional adjustment for body mass index; systolic blood pressure; antihypertensive, antidiabetic, and lipid-lowering medication; fasting blood glucose; total cholesterol; high-density lipoprotein cholesterol; creatinine; and smoking), adiponectin remained positively associated with IM-GSM [beta = 2.06; 95% confidence interval (CI), 0.54, 3.58], plaque GSM (beta = 3.11; 95% CI, 0.36, 5.86), and CCA distensibility (beta = 0.04; 95% CI, 0.00, 0.07). CONCLUSIONS: Serum levels of adiponectin were positively associated with IM-GSM and plaque GSM (indicating lower fat content in the IM and plaques) and CCA distensibility (indicating higher wall elasticity), independent of potential confounders. Our results imply that adiponectin is associated with less arterial pathology.
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| 3. |
- Michaëlsson, Karl, et al.
(författare)
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Serum adiponectin in elderly men does not correlate with fracture risk
- 2008
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 93:10, s. 4041-7
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Recent evidence suggests that adiponectin may play a role in bone metabolism, but studies of the correlation between serum adiponectin and bone mineral density (BMD) have given conflicting results, and the impact on fracture risk is unknown. OBJECTIVE: Our objective was to investigate the association between serum adiponectin levels and BMD and fracture risk. DESIGN, SETTING, PARTICIPANTS, MAIN OUTCOME MEASURES: We used regression analyses to estimate the relationship between adiponectin and BMD in the Prospective Investigation of the Vasculature in Uppsala Seniors cohort of 441 men and 457 women aged 70 yr. The association was thereafter analyzed in the Uppsala Longitudinal Study of Adult Men (ULSAM), in which adiponectin was analyzed at age 70 yr and BMD at 82 yr in 507 men. Fractures in the ULSAM were documented in 314 men during 15 yr follow-up. Cox regression analysis was used to determine the risk of fracture according to serum adiponectin levels. RESULTS: In multivariable analysis a negative association between adiponectin and BMD was found in both cohorts. When individuals in the highest quintile of adiponectin were compared with those in the lowest quintile, adjusted BMD was 9.7% lower at the lumbar spine, 7.1% lower at the proximal femur, and 5.2% lower for total body in the Prospective Investigation of the Vasculature in Uppsala Seniors (P < 0.001 for all three), and 8.1, 5.1, and 4.1% (P < 0.003 for all three), respectively, in the ULSAM. However, the hazard ratio for fracture per 1 sd of serum adiponectin was 0.99 (95% confidence interval 0.89-1.11). CONCLUSION: Although adiponectin was a negative determinant of BMD in two independent cohorts, it was not associated with fracture risk in men.
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| 4. |
- Rask, Eva, 1958-, et al.
(författare)
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Tissue-specific changes in peripheral cortisol metabolism in obese women : increased adipose 11beta-hydroxysteroid dehydrogenase type 1 activity
- 2002
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : Williams & Wilkins Co.. - 0021-972X .- 1945-7197. ; 87:7, s. 3330-6
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Tidskriftsartikel (refereegranskat)abstract
- Cushing's syndrome and the metabolic syndrome share clinical similarities. Reports of alterations in the hypothalamic-pituitary-adrenal (HPA) axis are inconsistent, however, in the metabolic syndrome. Recent data highlight the importance of adipose 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which regenerates cortisol from cortisone and, when overexpressed in fat, produces central obesity and glucose intolerance. Here we assessed the HPA axis and 11beta-HSD1 activity in women with moderate obesity and insulin resistance. Forty women were divided into tertiles according to body mass index (BMI; median, 22.0, 27.5, and 31.4, respectively). Serum cortisol levels were measured after iv CRH, low dose dexamethasone suppression, and oral cortisone administration. Urinary cortisol metabolites were measured in a 24-h sample. A sc abdominal fat biopsy was obtained in 14 participants for determination of 11beta-HSD type 1 activity in vitro. Higher BMI was associated with higher total cortisol metabolite excretion (r = 0.49; P < 0.01), mainly due to increased 5alpha- and, to a lesser extent, 5beta-tetrahydrocortisol excretion, but no difference in plasma cortisol basally, after dexamethasone, or after CRH, and only a small increase in the ACTH response to CRH. Hepatic 11beta-HSD1 conversion of oral cortisone to cortisol was impaired in obese women (area under the curve, 147,736 +/- 28,528, 115,903 +/- 26,032, and 90,460 +/- 18,590 nmol/liter.min; P < 0.001). However, 11beta-HSD activity in adipose tissue was positively correlated with BMI (r = 0.55; P < 0.05). In obese females increased reactivation of glucocorticoids in fat may contribute to the characteristics of the metabolic syndrome. Increased inactivation of cortisol in liver may be responsible for compensatory activation of the HPA axis. These alterations in cortisol metabolism may be a basis for novel therapeutic strategies to reduce obesity-related complications.
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| 5. |
- Rask, Eva, et al.
(författare)
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Tissue-specific dysregulation of cortisol metabolism in human obesity.
- 2001
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 86:3, s. 1418-1421
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Tidskriftsartikel (refereegranskat)abstract
- Cortisol has been implicated as a pathophysiological mediator in idiopathic obesity, but circulating cortisol concentrations are not consistently elevated. The tissue-specific responses to cortisol may be influenced as much by local prereceptor metabolism as by circulating concentrations. For example, in liver and adipose tissue cortisol is regenerated from inactive cortisone by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). In obese Zucker rats 11beta-HSD1 activity is reduced in liver but enhanced in adipose tissue. This study addressed whether the same tissue-specific disruption of cortisol metabolism occurs in human obesity. 34 men were recruited from the MONICA population study in Northern Sweden to represent a wide range of body composition and insulin insensitivity. Plasma cortisol was measured at 0830h and 1230h, after overnight low-dose dexamethasone suppression, after intravenous corticotropin releasing hormone (CRH), and after oral cortisone administration. Urinary cortisol metabolites were measured in a 24 h sample. A subcutaneous fat biopsy was obtained from 16 participants to measure cortisol metabolism in vitro. Higher body mass index was associated with increased total cortisol metabolite excretion (r = 0.47, p < 0.01), but lower plasma cortisol at 1230 h and after dexamethasone, and no difference in response to CRH. Obese men excreted a greater proportion of glucocorticoid as metabolites of cortisone rather than cortisol (r = 0.43, p < 0.02), and converted less cortisone to cortisol after oral administration (r = 0.49, p < 0.01), suggesting impaired hepatic 11beta-HSD1 activity. By contrast, in vitro 11beta-HSD1 activity in subcutaneous adipose tissue was markedly enhanced in obese men (r = 0.66, p < 0.01). We conclude that in obesity, reactivation of cortisone to cortisol by 11beta-HSD1 in liver is impaired, so that plasma cortisol levels tend to fall, and there may be a compensatory increase in cortisol secretion mediated by a normally functioning hypothalamic-pituitary-adrenal axis. However, changes in 11beta-HSD1 are tissue-specific: strikingly enhanced reactivation of cortisone to cortisol in subcutaneous adipose tissue may exacerbate obesity; and it may be beneficial to inhibit this enzyme in adipose tissue in obese patients.
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| 6. |
- Stattin, P, et al.
(författare)
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Leptin is associated with increased prostate cancer risk : a nested case-referent study.
- 2001
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 86:3, s. 1341-1345
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Tidskriftsartikel (refereegranskat)abstract
- A Western lifestyle has been implicated in the pathogenesis of prostate cancer. However, no clear association between obesity and prostate cancer has been shown. Leptin may stimulate prostate growth and angiogenesis, and receptors for leptin are present in the prostate. Leptin may, thus, be associated with increased risk of prostate cancer. One hundred forty-nine men with prostate cancer were identified (together with 298 matched referents) who, before diagnosis, had participated in population-based health surveys in Northern Sweden. Blood pressure, body mass index, and use of tobacco were recorded. Leptin, insulin, insulin-like growth factor I (IGF-I), IGF-I-binding proteins 1-3, testosterone, and sex hormone-binding globulin were analyzed in stored samples. Their influences on prostate cancer were estimated by conditional logistic regression analysis. Prostate cancer specimens were investigated for immunoreactivity for the leptin receptor. Relative risk (95% confidence intervals) estimates of prostate cancer over the quintiles of leptin were 1.0, 2.1 (1.1-4.1), 2.6 (1.4-4.8), 1.4 (0.7-2.7), and 1.6 (0.8-3.2). Adjustments for metabolic variables, testosterone, and IGF-I and its binding proteins did not attenuate this increased risk. Immunoreactivity for the leptin receptor was detected in normal, high-grade prostatic intraepithelial neoplasia lesions and malignant prostatic epithelium. Moderately elevated plasma leptin concentrations are associated with later development of prostate cancer. This may be due to direct effects of leptin on prostatic intraepithelial neoplasia lesions, or to indirect actions through other mechanisms. A critical fat mass related to an interior milieu favorable for prostate cancer development seems to exist, because intermediate but not high leptin levels are related to prostate cancer risk.
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| 7. |
- Wake, Deborah J, et al.
(författare)
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Local and systemic impact of transcriptional up-regulation of 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue in human obesity.
- 2003
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 88:8, s. 3983-3988
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Tidskriftsartikel (refereegranskat)abstract
- In idiopathic obesity circulating cortisol levels are not elevated, but high intraadipose cortisol concentrations have been implicated. 11beta-Hydroxysteroid dehydrogenase type 1 (11HSD1) catalyzes the conversion of inactive cortisone to active cortisol, thus amplifying glucocorticoid receptor (GR) activation. In cohorts of men and women, we have shown increased ex vivo 11HSD1 activity in sc adipose tissue associated with in vivo obesity and insulin resistance. Using these biopsies, we have now validated this observation by measuring 11HSD1 and GR mRNA and examined the impact on intraadipose cortisol concentrations, putative glucocorticoid regulated adipose target gene expression (angiotensinogen and leptin), and systemic measurements of cortisol metabolism. From aliquots of sc adipose biopsies from 16 men and 16 women we extracted RNA for real-time PCR and steroids for immunoassays. Adipose 11HSD1 mRNA was closely related to 11HSD1 activity [standardized beta coefficient (SBC) = 0.58; P < 0.01], and both were positively correlated with parameters of obesity (e.g. for BMI, SBC = 0.48; P < 0.05 for activity, and SBC = 0.63; P < 0.01 for mRNA) and insulin sensitivity (log fasting plasma insulin; SBC = 0.44; P < 0.05 for activity, and SBC = 0.33; P = 0.09 for mRNA), but neither correlated with urinary cortisol/cortisone metabolite ratios. Adipose GR-alpha and angiotensinogen mRNA levels were not associated with obesity or insulin resistance, but leptin mRNA was positively related to 11HSD1 activity (SBC = 0.59; P < 0.05) and tended to be associated with parameters of obesity (BMI: SBC = 0.40; P = 0.09), fasting insulin (SBC = 0.65; P < 0.05), and 11HSD1 mRNA (SBC = 0.40; P = 0.15). Intraadipose cortisol (142 +/- 30 nmol/kg) was not related to 11HSD1 activity or expression, but was positively correlated with plasma cortisol. These data confirm that idiopathic obesity is associated with transcriptional up-regulation of 11HSD1 in adipose, which is not detected by conventional in vivo measurements of urinary cortisol metabolites and is not accompanied by dysregulation of GR. Although this may drive a compensatory increase in leptin synthesis, whether it has an adverse effect on intraadipose cortisol concentrations and GR-dependent gene regulation remains to be established.
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| 8. |
- Zhang, Lei, et al.
(författare)
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Distinct ethnic differences in lipid profiles across glucose categories
- 2010
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 95:4, s. 1793-1801
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Tidskriftsartikel (refereegranskat)abstract
- Context: Dyslipidemia coexists with hyperglycemia. However, little is known about the ethnic differences in lipid profiles at comparable glucose tolerance status. Objective: The aim was to study ethnic differences in lipid profiles stratified by glucose levels. Design and Setting: Data from 31 study cohorts of 12 countries, consisting of 24,760 men and 27,595 women aged 25–74 yr, were compared. The odds ratio for having dyslipidemia was estimated for each ethnic group stratified by glucose categories. Results: Compared with central and northern Europeans, multivariable adjusted odds ratios (95% confidence intervals) for having lower high-density lipoprotein-cholesterol were 4.74 (4.19–5.37), 5.05 (3.88–6.56), 3.07 (2.15–4.40), and 2.37 (1.67–3.35) in Asian Indian men, but 0.12 (0.09–0.16), 0.07 (0.04–0.13), 0.11 (0.07–0.20), and 0.16 (0.08–0.32) in Chinese men who had normoglycemia, prediabetes, and undiagnosed and diagnosed diabetes, respectively. Similar results were obtained for women. The prevalence of low high-density lipoprotein-cholesterol remained higher in Asian Indians (62.8% of the nondiabetic and 67.4% of the diabetic) than in central and northern Europeans (20.3 and 37.3%), Japanese (25.7 and 34.1%), or Qingdao Chinese (15.7 and 17.0%), even in individuals with low-density lipoprotein-cholesterol of less than 3 mmol/liter. Conclusion: There are distinct patterns of lipid profiles associated with ethnicity regardless of the glucose levels, suggesting that ethnic-specific strategies and guidelines on risk assessment and prevention of cardiovascular disease are required.
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