| 11. |
- Ludvigsson, Johnny, 1943-, et al.
(author)
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GAD treatment and insulin secretion in recent-onset type 1 diabetes
- 2008
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In: New England Journal of Medicine. - Boston, Mass : Massachusetts medical society. - 0028-4793 .- 1533-4406. ; 359:18, s. 1909-1920
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Journal article (peer-reviewed)abstract
- Background The 65-kD isoform of glutamic acid decarboxylase (GAD) is a major autoantigen in patients with type 1 diabetes mellitus. This trial assessed the ability of alum-formulated GAD (GAD-alum) to reverse recent-onset type 1 diabetes in patients 10 to 18 years of age. Methods We randomly assigned 70 patients with type 1 diabetes who had fasting C-peptide levels above 0.1 nmol per liter (0.3 ng per milliliter) and GAD autoantibodies, recruited within 18 months after receiving the diagnosis of diabetes, to receive subcutaneous injections of 20 μg of GAD-alum (35 patients) or placebo (alum alone, 35 patients) on study days 1 and 30. At day 1 and months 3, 9, 15, 21, and 30, patients underwent a mixed-meal tolerance test to stimulate residual insulin secretion (measured as the C-peptide level). The effect of GAD-alum on the immune system was also studied. Results Insulin secretion gradually decreased in both study groups. The study treatment had no significant effect on change in fasting C-peptide level after 15 months (the primary end point). Fasting C-peptide levels declined from baseline levels significantly less over 30 months in the GAD-alum group than in the placebo group (−0.21 vs. −0.27 nmol per liter [−0.62 vs. −0.81 ng per milliliter], P = 0.045), as did stimulated secretion measured as the area under the curve (−0.72 vs. −1.02 nmol per liter per 2 hours [−2.20 vs. −3.08 ng per milliliter per 2 hours], P = 0.04). No protective effect was seen in patients treated 6 months or more after receiving the diagnosis. Adverse events appeared to be mild and similar in frequency between the two groups. The GAD-alum treatment induced a GAD-specific immune response. Conclusions GAD-alum may contribute to the preservation of residual insulin secretion in patients with recent-onset type 1 diabetes, although it did not change the insulin requirement. (ClinicalTrials.gov number, NCT00435981.)
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| 12. |
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| 13. |
- Mootha, VK, et al.
(author)
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PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes.
- 2003
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 34:3, s. 267-273
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Journal article (peer-reviewed)abstract
- DNA microarrays can be used to identify gene expression changes characteristic of human disease. This is challenging, however, when relevant differences are subtle at the level of individual genes. We introduce an analytical strategy, Gene Set Enrichment Analysis, designed to detect modest but coordinate changes in the expression of groups of functionally related genes. Using this approach, we identify a set of genes involved in oxidative phosphorylation whose expression is coordinately decreased in human diabetic muscle. Expression of these genes is high at sites of insulin-mediated glucose disposal, activated by PGC-1alpha and correlated with total-body aerobic capacity. Our results associate this gene set with clinically important variation in human metabolism and illustrate the value of pathway relationships in the analysis of genomic profiling experiments.
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| 14. |
- Brage, Monica, et al.
(author)
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Osteoclastogenesis is decreased by cysteine proteinase inhibitors.
- 2004
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In: Bone. - : Elsevier BV. - 8756-3282 .- 1873-2763. ; 34:3, s. 412-24
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Journal article (peer-reviewed)abstract
- The effects of cystatin C and other cysteine proteinase inhibitors on osteoclast formation and differentiation have been investigated. Cystatin C decreased osteoclast formation stimulated by parathyroid hormone (PTH), 1,25(OH)2-vitamin D3 or interleukin-6 (IL-6) (in the presence of its soluble receptor) as assessed by the number of tartrate-resistant acid phosphatase (TRAP+) multinucleated cells in mouse bone marrow cultures. The inhibitory effect was associated with decreased mRNA expression for the calcitonin receptor as well as decreased number of specific binding sites for 125I-calcitonin, and without any effect on the mRNA expression of receptor activator of nuclear factor kappaB (NF-kappaB) ligand (RANKL). Similarly, the cysteine proteinase inhibitors leupeptin, E-64 and benzyloxycarbonyl-Phe-Ala-diazomethane (Z-FA-CHN2) decreased PTH-stimulated formation of TRAP+ multinucleated cells and binding of 125I-calcitonin. A peptidyl derivative synthesized to mimic part of the proteinase-binding site of cystatin C (benzyloxycarbonyl-Arg-Leu-Val-Gly-diazomethane, or Z-RLVG-CHN2) also decreased PTH-stimulated osteoclast formation. In a 9-day culture, addition of cystatin C during the last 5 days was sufficient to cause substantial inhibition of osteoclast formation. Cystatin C-induced decrease of osteoclast formation was associated with enhanced number of F4/80-positive macrophages and increased mRNA expression of the macrophage receptor c-fms in the bone marrow culture. Osteoclast formation in mouse bone marrow cultures as well as in mouse spleen cell cultures, stimulated by macrophage colony-stimulating factor (M-CSF) and RANKL was also decreased by different cysteine proteinase inhibitors. In addition, cystatin C inhibited M-CSF/RANKL induction of calcitonin receptor mRNA in spleen cell cultures. The inhibitory effect by cystatin C in spleen cells was associated with decreased mRNA expression of RANK and the transcription factor NFAT2. It is concluded that cysteine proteinase inhibitors decrease formation of osteoclasts by interfering at a late stage of pre-osteoclast differentiation.
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| 15. |
- Brand, H S, et al.
(author)
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Family 2 cystatins inhibit osteoclast-mediated bone resorption in calvarial bone explants.
- 2004
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In: Bone. - : Elsevier BV. - 8756-3282 .- 1873-2763. ; 35:3, s. 689-96
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Journal article (peer-reviewed)abstract
- Osteoclastic bone resorption depends on the activity of various proteolytic enzymes, in particular those belonging to the group of cysteine proteinases. Biochemical studies have shown that cystatins, naturally occurring inhibitors of these enzymes, inhibit bone matrix degradation. Since the mechanism by which cystatins exert this inhibitory effect is not completely resolved yet, we studied the effect of cystatins on bone resorption microscopically and by Ca-release measurements. Calvarial bone explants were cultured in the presence or absence of family 2 cystatins and processed for light and electron microscopic analysis, and the culture media were analyzed for calcium release. Both egg white cystatin and human cystatin C decreased calcium release into the medium significantly. Microscopic analyses of the bone explants demonstrated that in the presence of either inhibitor, a high percentage of osteoclasts was associated with demineralized non-degraded bone matrix. Following a 24-h incubation in the presence of cystatin C, 41% of the cells were adjacent to areas of demineralized non-degraded bone matrix, whereas in controls, this was only 6%. If bone explants were cultured with both PTH and cystatin C, 60% of the osteoclasts were associated with demineralized non-degraded bone matrix, compared to 27% for bones treated with PTH only (P < 0.01). Our study provides evidence that cystatins, the naturally occurring inhibitors of cysteine proteinases, reversibly inhibit bone matrix degradation in the resorption lacunae adjacent to osteoclasts. These findings suggest the involvement of cystatins in the modulation of osteoclastic bone degradation.
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| 16. |
- Elfström, Peter, 1974-, et al.
(author)
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Risk of primary adrenal insufficiency in patients with celiac disease
- 2007
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In: Journal of Clinical Endocrinology and Metabolism. - Chevy Chase, Md. : Endocrine Society. - 0021-972X .- 1945-7197. ; 92:9, s. 3595-3598
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Journal article (peer-reviewed)abstract
- Objectives: Earlier research has suggested a positive association between Addison’s disease (AD) and celiac disease (CD).Wehave here investigated the risk of AD in individuals with CD from a general population cohort.Methods: Through the Swedish national registers we identified 14,366 individuals with a diagnosis of CD (1964–2003) and 70,095 reference individuals matched for age, sex, calendar year, and county of residence. We used Cox regression to estimate hazard ratios (HRs) for subsequent AD. Analyses were restricted to individuals with more than 1 yr of follow-up and without AD prior to study entry or within 1 yr after study entry. Conditional logistic regression estimated the odds ratio for CD in individuals with prior AD.Results: There was a statistically significantly positive association between CD and subsequent AD [HR _ 11.4; 95% confidence interval (CI) _ 4.4 –29.6]. This risk increase was seen in both children and adults and did not change with adjustment for diabetes mellitus or socioeconomic status. When we restricted reference individuals to inpatients, the adjusted HR for AD was 4.6 (95% CI _ 1.9 –11.4). Individuals with prior AD were at increased risk of CD (odds ratio _ 8.6; 95% CI _ 3.4 –21.8).Conclusions: This study found a highly increased risk of AD in individuals with CD. This relationship was independent of temporal sequence. We therefore recommend that individuals with AD should be screened for CD. We also suggest an increased awareness of AD in individuals with CD.
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| 17. |
- Elfström, Peter, 1974-, et al.
(author)
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Risk of Thyroid Disease in Individuals with Celiac Disease
- 2008
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In: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 93:10, s. 3915-3921
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Journal article (peer-reviewed)abstract
- Background: It has been suggested that celiac disease is associated with thyroid disease. Earlier studies, however, have been predominately cross-sectional and have often lacked controls. There is hence a need for further research. In this study, we estimated the risk of thyroid disease in individuals with celiac disease from a general population cohort.Methods: A total of 14,021 individuals with celiac disease (1964–2003) and a matched reference population of 68,068 individuals were identified through the Swedish national registers. Cox regression estimated the risk of thyroid disease in subjects with celiac disease. Analyses were restricted to individuals with a follow-up ofmorethan 1 yr and withnothyroid disease before study entry or within 1 yr after study entry. Conditional logistic regression estimated the odds ratio for subsequent celiac disease in individuals with thyroid disease.Results: Celiac disease was positively associated with hypothyroidism [hazard ratio (HR)_4.4;95% confidence interval (CI) _ 3.4 –5.6; P _ 0.001], thyroiditis (HR _ 3.6; 95% CI _1.9–6.7; P _ 0.001) and hyperthyroidism (HR_2.9;95%CI_2.0–4.2; P_0.001). The highest risk estimates were found in children (hypothyroidism, HR _ 6.0 and 95% CI _ 3.4 –10.6; thyroiditis, HR _ 4.7 and 95% CI _ 2.1–10.5; hyperthyroidism, HR _ 4.8 and 95% CI _ 2.5–9.4). In post hoc analyses, where the reference population was restricted to inpatients, the adjusted HR was 3.4 for hypothyroidism (95% CI_2.7– 4.4; P_0.001), 3.3 for thyroiditis(95%CI_1.5–7.7; P_0.001), and 3.1 for hyperthyroidism (95% CI _ 2.0–4.8; P _ 0.001).Conclusion: Celiac disease is associated with thyroid disease, and these associations were seen regardless of temporal sequence. This indicates shared etiology and that these individuals are more susceptible to autoimmune disease.
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| 18. |
- Grundberg, E, et al.
(author)
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Large-scale association study between two coding LRP5 gene polymorphisms and bone phenotypes and fractures in men
- 2007
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In: Osteoporosis International. - : Springer Science and Business Media LLC. - 0937-941X .- 1433-2965. ; 19:6, s. 829-837
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Journal article (peer-reviewed)abstract
- Summary Herein we investigated the association between polymorphisms in the LRP5 gene and bone phenotypes and fractures in three large male cohorts based on the rationale that mutations in LRP5 cause severe bone phenotypes. Results showed an association of the Val667Met SNP with spine BMD in 3,800 young and elderly men. Introduction The low-density lipoprotein receptor-related protein 5 (LRP5)-Wnt signalling system is of importance for regulating osteoblastic activity, which became clear after findings that inactivating mutations in LRP5 cause osteoporosis. The overall aim of this study was to investigate the association between polymorphisms in the LRP5 gene and bone mineral density (BMD) in three large cohorts of young and elderly men. Methods The cohorts used were MrOS Sweden (n = 3014, aged 69–81 years) and MrOs Hong Kong (n = 2000, aged > 65 years) and the Swedish GOOD study (n = 1068, aged 18–20 years). The polymorphisms Val667Met and Ala1330Val were genotyped using a TaqMan assay. Results When combining the data from the Swedish cohorts in a meta-analysis (n = 3,800), men carrying the 667Met-allele had 3% lower BMD at lumbar spine compared with non-carriers (p < 0.05). The Val667Met SNP was not polymorphic in the Hong Kong population and thus were not included. There were no associations between the Ala1330Val SNP and bone phenotypes in the study populations. No associations between the LRP5 polymorphisms and self-reported fractures were seen in MrOs Sweden. Conclusions Results from these three large cohorts indicate that the Val667Met polymorphism but not the Ala1330Val contributes to the observed variability in BMD in the Swedish populations.
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| 19. |
- Lerner, Ulf H
(author)
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New molecules in the tumor necrosis factor ligand and receptor superfamilies with importance for physiological and pathological bone resorption
- 2004
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In: Critical Reviews in Oral Biology and Medicine. - Alexandria : International association for dental research (IADR). - 1045-4411 .- 1544-1113. ; 15:2, s. 64-81
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Research review (peer-reviewed)abstract
- Osteoclasts are tissue-specific polykaryon bone-resorbing cells derived from the monocyte/macrophage hematopoietic lineage with specialized functions required for the adhesion of the cells to bone and the subsequent polarization of the cell membrane, secretion of acid to dissolve mineral crystals, and release of proteolytic enzymes to degrade the extracellular matrix proteins. Most pathological conditions in the skeleton lead to loss of bone due to excess osteoclastic bone resorption, including periodontal disease, rheumatoid arthritis, and osteoporosis. In rare cases, most of them genetic, patients with osteopetrosis exhibit sclerotic bone due either to a lack of osteoclasts or to non-functional osteoclasts. Mainly because of phenotypic findings in genetically manipulated mice or due to spontaneous mutations in humans, mice, and rats, several genes have been discovered as being crucial for osteoclast formation and activation. Recent breakthroughs in our understanding of osteoclast biology have revealed the critical roles in osteoclast differentiation played by RANKL, RANK, and OPG, three novel members of the tumor necrosis factor ligand and receptor superfamilies. The further study of these molecules and downstream signaling events are likely to provide a molecular basis for the development of new drugs for the treatment of diseases with excess or deficient osteoclastic bone resorption.
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| 20. |
- Marsell, Richard, et al.
(author)
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Relation between fibroblast growth factor-23, body weight and bone mineral density in elderly men
- 2009
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In: Osteoporosis International. - : Springer Science and Business Media LLC. - 0937-941X .- 1433-2965. ; 20:7, s. 1167-1173
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Journal article (peer-reviewed)abstract
- We evaluated the relation between serum FGF23 and bone mineral density (BMD) in a community-based cohort of elderly men. There was a weak correlation between FGF23 and BMD, which was primarily dependent on body weight.INTRODUCTION: FGF23 is a hormonal factor produced in bone and regulates serum levels of phosphate (Pi) and vitamin D. FGF23 over-expression is associated with skeletal abnormalities, including rickets/osteomalacia. The relation between FGF23 and Bone Mineral Density (BMD) in the community remains unexplored.METHODS: We employed a large, population-based cohort of 3014 Swedish men aged 69-80 years, without known renal disease. BMD was measured with dual X-ray absorptiometry (DXA) in the hip and lumbar spine. Serum intact FGF23 was analyzed with a two-site monoclonal ELISA.RESULTS: There was a weak but significant correlation between FGF23 and BMD in femoral neck (r = 0.04, p < 0.05), femoral trochanter (r = 0.05, p = 0.004), total hip (r = 0.06, p = 0.0015) and lumbar spine (r = 0.07, p = 0.0004). The correlations remained significant when adjusting for biochemical covariates (Pi, calcium, PTH, 25(OH)D and renal function). However, the association became insignificant in all regions when adjusting for established confounding variables including age, height, weight and smoking. Further analysis confirmed a significant correlation between FGF23 and body weight (r = 0.13, p < 0.0001).CONCLUSIONS: The weak correlation between FGF23 and BMD in elderly male subjects is mainly due to an association between FGF23 and body weight. Therefore, FGF23 may not play a significant role in the hormonal regulation of BMD.
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