| 1. |
- Borg, Henrik, et al.
(författare)
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High levels of antigen-specific islet antibodies predict future beta-cell failure in patients with onset of diabetes in adult age
- 2001
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - 1945-7197. ; 86:7, s. 3032-3038
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Tidskriftsartikel (refereegranskat)abstract
- It is unclear whether high levels of antigen-specific islet antibodies [GADA (glutamic acid decarboxylase 65 antibodies) and IA2-ab (protein tyrosine phosphatase-like protein antibodies)] predict beta-cell failure in patients with onset of diabetes in adult age. Therefore, GADA and IA2-ab levels at the diagnosis of diabetes were related to fasting plasma C-peptide levels 5 yr later in 148 patients with diabetes onset in adult age (age at onset, 20-77 yr; median, 57 yr). Classical islet cell antibodies (ICA) were also determined. Complete beta-cell failure (undetectable fasting plasma C-peptide) was only present in 4 patients at diagnosis of diabetes, but in 21 patients 5 yr thereafter. At diagnosis, ICA were detected in 20 of 21 (95%) patients with beta-cell failure after 5 yr and in only 7 of 127 (5%) without, whereas GADA and/or IA2-ab (>97.5 percentile of healthy controls) were detected in all 21 (100%) with but also in 23 of 127 (18%) patients without beta-cell failure after 5 yr. Thus, ICA had a higher positive predictive value (74%) than GADA and/or IA2-ab (47%; P < 0.05). With high cutoff values for GADA and IA2-ab, however, GADA and/or IA2-ab were detected in 19 of 21 (90%) patients with beta-cell failure vs. only in 5 of 127 (4%) without, giving a positive predictive value of 79%. Slightly elevated GADA levels in IA2-ab-negative patients were associated with progressive but not complete beta-cell failure within the study period. Hence, high GADA and/or IA2-ab levels predict a future complete beta-cell failure, whereas low GADA levels predict slowly progressive beta-cell insufficiency.
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| 2. |
- Christensson, Anders, et al.
(författare)
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Serum cystatin C advantageous compared with serum creatinine in the detection of mild but not severe diabetic nephropathy.
- 2004
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Ingår i: Journal of Internal Medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 256:6, s. 510-518
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To determine whether serum cystatin C is more accurate than serum creatinine in the detection of diabetic nephropathy, also after adjustment for age.METHODS: Forty-one patients with type 1 and 82 patients with type 2 diabetes were evaluated with serum creatinine, serum cystatin C, and (51)Cr-EDTA clearance (reference method). Cystatin C was measured by a particle-enhanced turbidimetric method and creatinine by an enzymatic method. Statistical estimations were performed both without and with age adjustment created by z-scores for (51)Cr-EDTA clearance, creatinine, and cystatin C. The cut-off levels for glomerular filtration rate (GFR) ((51)Cr-EDTA clearance) were 60 and 80 mL min(-1) 1.73 m(-2), respectively, in absolute values and 80, 90 and 95% CIs, respectively, in age-adjusted values (z-scores).RESULTS: Estimations without age adjustment showed significantly (P = 0.0132) closer correlation for cystatin C (r = 0.817) versus (51)Cr-EDTA clearance as compared with creatinine (r = 0.678). However, when using age-adjusted values, the correlation for cystatin C and creatinine, respectively, versus (51)Cr-EDTA clearance did not differ. When comparing the diagnostic utilities for serum cystatin C versus serum creatinine in manifest renal impairment (GFR < 60 mL min(-1) 1.73 m(-2) or z-scores <-1.28 SD), there were no significant differences between the two markers whether age adjusted or not. However, for diagnosing mild nephropathy (GFR < 80 mL min(-1) 1.73 m(-2) or z-score -0.84 SD), serum cystatin C is significantly more useful.CONCLUSIONS: Serum cystatin C performed better compared with serum creatinine even when measured enzymatically, to detect mild diabetic nephropathy. However, serum creatinine was as efficient as serum cystatin C to detect advanced diabetic nephropathy.
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| 3. |
- Nordström, Anna, 1973-, et al.
(författare)
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Interleukin-6 promoter polymorphism is associated with bone quality assessed by calcaneus ultrasound and previous fractures in a cohort of 75-year-old women.
- 2004
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Ingår i: Osteoporosis international. - : Springer Science and Business Media LLC. - 0937-941X .- 1433-2965. ; 15:10, s. 820-6
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Tidskriftsartikel (refereegranskat)abstract
- Interleukin 6 (IL-6) is a multifunctional cytokine and a potent stimulator of bone resorption and has been implicated in the pathogenesis of osteoporosis in postmenopausal women. The aim of this study was to investigate if a functional IL-6 promoter polymorphism (-174) was related to bone mass and fractures in a cohort consisting of 964 postmenopausal Caucasian women aged 75 years. Bone mineral density (BMD; g/cm2) of the femoral neck, lumbar spine and total body was measured using dual energy X-ray absorptiometry (DXA). Quantitative ultrasound (QUS) was also measured in the calcaneus and quantified as speed of sound (SOS; m/s), broadband ultrasound attenuation (BUA; dB/MHz), and stiffness index (SI). IL-6 genotypes was determined by restriction fragment length polymorphism (RFLP) using the restriction enzyme NlaIII. The frequencies of the different IL-6 genotypes were 27.5% (GG), 47.9% (GC), 24.6% (CC). The IL-6 polymorphism (presence of G) was independently related to a lower stiffness (beta=-0.07; P=0.03) and BUA (beta=-0.08; P=0.02), but not to BMD at any site measured by DXA. In the cohort, 420 subjects (44%) reported at least one fracture during their lifetime, and 349 (36%) reported at least one fracture after the age of 50. Using binary logistic regression, the IL-6 polymorphism (presence of G) was significantly related to an increased risk of a previous fracture during life (odds ratio 1.46, 95% CI 1.08-1.97) and to an increased risk of a fracture occurring after 50 years of age (odds ratio 1.37, 95% CI 1.004-1.88). The risk was further increased for fractures grouped as osteoporotic fractures (odds ratio 1.67, 95% CI 1.14-2.45), including forearm fractures (odds ratio 1.59, 95% CI 1.05-2.40). In conclusion, presence of G allele in the IL-6 promoter polymorphism at position -174 is independently related to previous fractures in postmenopausal women. This association may be related primarily to an altered bone quality identified by QUS and not a lower bone mass. This is also the first demonstration of association of IL-6 gene polymorphism to calcaneal QUS.
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| 4. |
- Mootha, VK, et al.
(författare)
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PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes.
- 2003
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 34:3, s. 267-273
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Tidskriftsartikel (refereegranskat)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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| 5. |
- Klannemark, Mia
(författare)
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Genetics of type 2 diabetes and the metabolic syndrome
- 2001
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Type 2 diabetes and the metabolic syndrome are highly prevalent disorders with severe complications such as cardiovascular disease. The aetiology of type 2 diabetes and the metabolic syndrome is not known, but the interaction between genetic factors and environmental triggers is important. The aim this thesis was to identify genetic factors that may increase susceptibility to these disorders by investigating candidate genes regulating lipolysis (hormone-sensitive lipase, HSL, lipoprotein lipase, LPL and phosphodiesterase 3B, PDE3B), thermogenesis (uncoupling protein 2, UCP2) and adipogenesis (peroxisome proliferator-activated receptor gamma, PPARG). Four of the genes were screened for mutations and identified variants were tested for association in large intra-familial and case-control association studies. Variability in the UCP2 gene was not associated with alterations in basal metabolic rate or with obesity. The gene encoding HSL was associated with type 2 diabetes in a case-control study, and the LIPE marker of the HSL gene showed distorted transmission to abdominally obese offspring. The PDE3B gene was associated with hyperinsulinaemia in genotype-discordant siblings. Haplotypes including several variants on chromosome 11 were unequally transmitted to offspring with abnormal glucose tolerance. The studies also provided evidence for an interaction between a variant in the LPL gene and insulin sensitivity. In a large, family-based multi-step study we could show that genetic variability in the gene encoding PPARG is associated with a reduced risk for diabetes, supported by the consistent results in a meta-analysis on the same variant. In conclusion, variability in genes regulating lipolysis and adipogenesis increase susceptibility to type 2 diabetes and the metabolic syndrome. Prospective studies will be helpful to establish the risk associated with the potential genetic riskfactors presented in this thesis.
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| 6. |
- Wahlberg, Jeanette, 1969-, et al.
(författare)
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Vaccinations may induce diabetes-related autoantibodies in one-year-old children
- 2003
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Ingår i: Annals of the New York Academy of Sciences. - : Wiley-Blackwell Publishing Inc.. - 0077-8923 .- 1749-6632. ; 1005:1, s. 404-408
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Tidskriftsartikel (refereegranskat)abstract
- Vaccinations have been discussed as one among many environmental candidates contributing to the immune process that later may lead to type 1 diabetes. ABIS (All Babies in Southeast Sweden) is a prospective cohort study following a nonselected birth cohort of general population. In a randomly selected sample collection from 4400 children, GADA and IA-2A have been determined at the age of 1 year. The information on vaccinations was collected from questionnaires answered by the parents and was related to β cell autoantibodies. When studying the induction of autoantibodies using the autoantibody level of 90th percentile as cutoff level, hemophdus influenza B (HIB) vaccination appeared to be a risk factor for IA-2A [OR 5.9 (CI 1.4-24.4; p = 0.01)] and for GADA [OR 3.4 (CI 1.1-10.8; p = 0.04)] in logistic regression analyses. Furthermore, the titers of IA-2A were significantly higher (p < 0.01 in Mann-Whitney test) in those children who had got HIB vaccination. When 99th percentile was used as cutoff to identify the children at risk of type 1 diabetes, BCG vaccination was associated with increased prevalence of IA-2A (p < 0.01). We conclude that HIB vaccination may have an unspecific stimulatory polyclonal effect increasing the production of GADA and IA-2A. This might be of importance under circumstances when the β cell-related immune response is activated by other mechanisms.
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| 7. |
- Brage, Monica, et al.
(författare)
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Osteoclastogenesis is decreased by cysteine proteinase inhibitors.
- 2004
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Ingår i: Bone. - : Elsevier BV. - 8756-3282 .- 1873-2763. ; 34:3, s. 412-24
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Tidskriftsartikel (refereegranskat)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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| 8. |
- Brand, H S, et al.
(författare)
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Family 2 cystatins inhibit osteoclast-mediated bone resorption in calvarial bone explants.
- 2004
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Ingår i: Bone. - : Elsevier BV. - 8756-3282 .- 1873-2763. ; 35:3, s. 689-96
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Tidskriftsartikel (refereegranskat)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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| 9. |
- Lerner, Ulf H
(författare)
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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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Ingår i: 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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Forskningsöversikt (refereegranskat)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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| 10. |
- Li, Haiyan
(författare)
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Genetic interaction between Type 1 and Type 2 diabetes
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- There are two major types of diabetes, type 1 and type 2 diabetes. Similarly characterized by hyperglycaemia and long term micro- and macrovascular complications, type 1 and type 2 diabetes have different underlying pathophysiologic processes. In Scandinavia, type 1 diabetes is common; type 2 diabetes accounts for 85% of all cases with diabetes. There is emerging evidence that type 1 and type 2 diabetes cluster in the same families. 10% of patients diagnosed with type 2 diabetes have autoantibodies against GAD65 (GADabs). The presence of GADabs predicts the development of insulin deficiency in patients with type 2 diabetes (latent autoimmune diabetes in adults, i.e. LADA). The aim of the thesis was to study whether genetic interaction exists between type 1 and type 2 diabetes. In a population-based study in Finland, the prevalence of families with both type 1 and type 2 diabetes (mixed type 1/type 2 diabetes families, or mixed type 1/2) among type 2 diabetes families was 14%. 5% of type 2 diabetic probands had a first-degree relative with type 1 diabetes. Type 2 diabetic patients from the mixed families had more often GADabs (18% vs. 8%; p<0.0001) and HLA DQB1*0302/X genotype (25% vs. 12%; p=0.005) associated with an increased risk for type 1 diabetes than those from the common type 2 diabetes families. However, compared with adult onset type 1 diabetic patients (GADabs, 65%), mixed type 1/2 patients had lower frequencies of GADabs (p<0.0001) and DQB1*02/0302 genotype (4% vs. 27%, p<0.0001) conferring the highest risk for type 1 diabetes. Despite similar age and lipid profile, type 1/2 patients had a more severe beta cell dysfunction, but less features of metabolic syndrome than the common type 2 diabetic patients. Sharing a risk HLA haplotype at the IDDM1 locus with a type 1 diabetic family member could explain most of the genetic influence of type 1 on type 2 diabetes. Insulin gene VNTR at the IDDM2 locus modified the risk conferred by the HLA locus in patients with type 2 diabetes. The data point to a genetic interaction between type 1 and type 2 diabetes that is mediated by the type 1 diabetes susceptibility genes. Combined information from the clinical and genetic studies in the subgroup of type 1/2 patients could have important therapeutic implications for type 2 diabetes.
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