| 1. |
|
|
| 2. |
|
|
| 3. |
- Jensen, Richard A., et al.
(author)
-
HLA Genes, Islet Autoantibodies and Residual C-Peptide at the Clinical Onset of Type 1 Diabetes Mellitus and the Risk of Retinopathy 15 Years Later
- 2011
-
In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:3
-
Journal article (peer-reviewed)abstract
- Aims/Hypothesis: HLA genes, islet autoantibodies and residual C-peptide were studied to determine the independent association of each exposure with diabetic retinopathy (DR), 15 years after the clinical onset of type 1 diabetes in 15-34 year old individuals. Methods: The cohort was identified in 1992 and 1993 by the Diabetes Incidence Study in Sweden (DISS), which investigates incident cases of diabetes for patients between 15 and 34 years of age. Blood samples at diagnosis were analyzed to determine HLA genotype, islet autoantibodies and serum C-peptide. In 2009, fundus photographs were obtained from patient records. Study measures were supplemented with data from the Swedish National Diabetes Registry. Results: The prevalence of DR was 60.2% (148/246). Autoantibodies against the 65 kD isoform of glutamate decarboxylase (GADA) at the onset of clinical diabetes increased the risk of DR 15 years later, relative risk 1.12 for each 100 WHO units/ml, [95% CI 1.02 to 1.23]. This equates to risk estimates of 1.27, [95% CI 1.04 to 1.62] and 1.43, [95% CI 1.06 to 1.94] for participants in the highest 25(th) (GADA. 233 WHO units/ml) and 5(th) percentile (GADA. 319 WHO units/ml) of GADA, respectively. These were adjusted for duration of diabetes, HbA(1c), treated hypertension, sex, age at diagnosis, HLA and C-peptide. Islet cell autoantibodies, insulinoma-antigen 2 autoantibodies, residual C-peptide and the type 1 diabetes associated haplotypes DQ2, DQ8 and DQ6 were not associated with DR. Conclusions: Increased levels of GADA at the onset of type 1 diabetes were associated with DR 15 years later. These results, if confirmed, could provide additional insights into the pathogenesis of the most common microvascular complication of diabetes and lead to better risk stratification for both patient screenings and DR treatment trials.
|
|
| 4. |
- Johansson, Jesper, et al.
(author)
-
C-peptide in dried blood spots.
- 2010
-
In: Scandinavian Journal of Clinical and Laboratory Investigation. - : Informa UK Limited. - 1502-7686 .- 0036-5513. ; 70, s. 404-409
-
Journal article (peer-reviewed)abstract
- Abstract The aim was to evaluate if the Dried Blood Spot (DBS)-technique can be used to analyse C-peptide. S-C-peptide and paired whole blood clotted on filters, dried, punched out and eluted were sampled from 198 healthy subjects. Six subjects with S-C-peptide values outside the reference range were excluded. A conversion formula using log-DBS-C-peptide was generated in a subset of 156 ( approximately 80%) subjects with predictions made using also storage time (eluates) and age of subjects: (log S-C-peptide = 1.696 + 1.367 log DBS-C-peptide + 0.058 (storage time/month) + 0.014 (age/10 years). This formula was cross validated into the original population. Using Bland-Altman plots, mean difference between converted log DBS-C-peptide and log S-C-peptide at baseline was 0 and limits of agreements were -0.18 to +0.18. Mean difference between converted log DBS-C-peptide values after six months and log S-C-peptide value from baseline was -0.01 and limits of agreement were -0.20-0.19. The lowest value detected with the DBS-technique corresponded to serum C-peptide 0.44 nmol/L. We concluded that DBS-C-peptide can be used as a first line screening test to monitor normal beta cell function. C-peptide on filters remained stable for six months.
|
|
| 5. |
- Kanatsuna, Norio, et al.
(author)
-
Autoimmunity against INS-IGF2 expressed in human pancreatic islets.
- 2013
-
In: Journal of Biological Chemistry. - 1083-351X. ; 288:40, s. 29013-29023
-
Journal article (peer-reviewed)abstract
- Insulin is a major autoantigen in islet autoimmunity and progression to type 1 diabetes. It has been suggested that the insulin B-chain may be critical to insulin autoimmunity in type 1 diabetes. INS-IGF2 consists of the preproinsulin signal peptide, the insulin B-chain and eight amino acids of the C-peptide in addition to 138 amino acids from the IGF2 gene. We aimed to determine 1) expression of INS-IGF2 in human pancreatic islets and 2) autoantibodies in newly diagnosed type 1 diabetes children and controls. INS-IGF2, expressed primarily in beta cells, showed higher levels of expression in islets from normal compared to donors with either type 2 diabetes (p=0.006) or high HbA1c levels (p<0.001). INS-IGF2 autoantibody levels were increased in newly diagnosed type 1 diabetes patients (n=304) compared to healthy controls (n=355; p<0.001). Displacement with cold insulin and INS-IGF2 revealed that more patients than controls had doubly reactive insulin-INS-IGF2 autoantibodies. These data suggest that INS-IGF2, which contains the preproinsulin signal peptide, the B-chain and eight amino acids of the C-peptide may be an autoantigen in type 1 diabetes. INS-IGF2 and insulin may share autoantibody binding sites, thus complicating the notion that insulin is the primary autoantigen in type 1 diabetes.
|
|
| 6. |
- Oak, Shilpa, et al.
(author)
-
Immunoglobulin subclass profiles of anti-idiotypic antibodies to GAD65Ab differ between type 1 diabetes patients and healthy individuals.
- 2011
-
In: Scandinavian Journal of Immunology. - : Wiley. - 1365-3083 .- 0300-9475. ; 74, s. 363-367
-
Journal article (peer-reviewed)abstract
- Previously we reported the presence of anti-idiotypic antibodies (anti-Id) specific to autoantibodies against GAD65 (GAD65Ab) in healthy individuals while the activity of anti-Id directed to GAD65Ab in T1D patients was significantly lower. These anti-Id recognize the antigen binding site of GAD65Ab, thus preventing their binding to GAD65. Here we characterized the IgG subclass profile of these anti-Id (GAD65Ab-specific) and of the associated GAD65Ab themselves. The IgG subclass response of anti-Id in healthy individuals (n=16) was IgG3-dominated, while in T1D patients (n=8) IgG1 was the major IgG subclass. The GAD65Ab bound by anti-Id in both healthy individuals (n=38) and GAD65Ab-negative T1D patients (n=35) showed a predominant rank order of IgG1>IgG2>IgG4>IgG3. However, the frequency of GAD65Ab of the IgG4 subclass was significantly higher in T1D patients (p<0.05). We conclude that the IgG subclass profile of anti-Id (GAD65Ab-specific) in healthy individuals differs from that in T1D patients. These differences may provide insights in the development of these antibodies.
|
|
| 7. |
- Persson, Anders, et al.
(author)
-
Comparison of measurements of autoantibodies to glutamic acid decarboxylase and islet antigen-2 in whole blood eluates from dried blood spots using the RSR-enzyme linked immunosorbent assay kits and in-house radioimmunoassays.
- 2010
-
In: Experimental Diabetes Research. - : Hindawi Limited. - 1687-5214 .- 1687-5303. ; 2010
-
Journal article (peer-reviewed)abstract
- To evaluate the performance of dried blood spots (DBSs) with subsequent analyses of glutamic acid decarboxylase (GADA) and islet antigen-2 (IA-2A) with the RSR-ELISAs, we selected 80 children newly diagnosed with type 1 diabetes and 120 healthy women. DBSs from patients and controls were used for RSR-ELISAs while patients samples were analysed also with in-house RIAs. The RSR-ELISA-GADA performed well with a specificity of 100%, albeit sensitivity (46%) was lower compared to in RIA (56%; P = .008). No prozone effect was observed after dilution of discrepant samples. RSR-ELISA-IA-2A achieved specificity of 69% and sensitivity was lower (59%) compared with RIA (66%; P < .001). Negative or low positive patients and control samples in the RSR-ELISA-IA-2A increased after dilution. Eluates from DBS can readily be used to analyse GADA with the RSR-ELISA, even if low levels of autoantibodies were not detected. Some factor could disturb RSR-ELISA-IA-2A analyses.
|
|
| 8. |
- Schlosser, M., et al.
(author)
-
Diabetes Antibody Standardization Program: evaluation of assays for insulin autoantibodies
- 2010
-
In: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 53:12, s. 2611-2620
-
Journal article (peer-reviewed)abstract
- Aims/hypothesis Insulin autoantibodies (IAA) are important in type I diabetes risk assessment. However, their determination varies more between laboratories than other diabetes autoantibodies. The Diabetes Antibody Standardization Program (DASP) aims to improve and standardise measurement of autoantibodies associated with type I diabetes. We report the results of measurement of IAA from DASP workshops in 2002, 2003 and 2005. Methods Up to 32 laboratories in 14 countries participated in each workshop. Aliquots of coded sera from 50 patients with newly diagnosed type I diabetes and 100 blood donor controls were circulated to participating laboratories. Reported results were analysed using receiver operator characteristic (ROC) curves. We compared concordance of antibody levels by ranking, IAA and insulin antibody (IA) indices and units derived from an IA standard curve. Results In all three workshops IAA assay performance had improved compared with DASP 2000. The median area under the ROC curve was 0.73 in DASP 2002, 0.78 in 2003 and 0.80 in 2005 (p=0.0012), and median laboratory-assigned sensitivity was 26% in 2002, 36% in 2003 and 45% in 2005 (p<0.0001). There was, however, marked variation between assays. The range of AUC was 0.36-0.91 and that of laboratory-assigned sensitivity was 22-57%. Concordance of ranking of patient serum samples was related to AUC (p<0.001). Using an index related to common IAA and IA-positive or -negative control sera improved the concordance between assays (p<0.0001). Conclusions/interpretation The overall performance of IAA assays has improved but there is still wide variation between laboratories. Concordance between assays would be improved by the use of a common reference reagent.
|
|
| 9. |
- Sterner, Y, et al.
(author)
-
Country-specific birth weight and length in type 1 diabetes high-risk HLA genotypes in combination with prenatal characteristics.
- 2011
-
In: Journal of Perinatology. - : Springer Science and Business Media LLC. - 0743-8346 .- 1476-5543. ; 31, s. 764-769
-
Journal article (peer-reviewed)abstract
- Objective:To examine the relationship between high-risk human leukocyte antigen (HLA) genotypes for type 1 diabetes and birth size in combination with prenatal characteristics in different countries.Study Design:Four high-risk HLA genotypes were enrolled in the Environmental determinants of Diabetes in the Young study newborn babies from the general population in Finland, Germany, Sweden and the United States. Stepwise regression analyses were used to adjust for country, parental physical characteristics and environmental factors during pregnancy.Result:Regression analyses did not reveal differences in birth size between the four type 1 diabetes high-risk HLA genotypes. Compared with DQ 4/8 in each country, (1) DQ 2/2 children were heavier in the United States (P=0.028) mostly explained however, by parental weight; (2) DQ 2/8 (P=0.023) and DQ 8/8 (P=0.046) children were longer in Sweden independent of parents height and as well as (3) in the United States for DQ 2/8 (P=0.023), but again dependent on parental height.Conclusion:Children born with type 1 diabetes high-risk HLA genotypes have comparable birth size. Longitudinal follow-up of these children should reveal whether birth size differences between countries contribute to the risk for islet autoimmunity and type 1 diabetes.Journal of Perinatology advance online publication, 28 April 2011; doi:10.1038/jp.2011.26.
|
|
| 10. |
- Thunander, Maria, et al.
(author)
-
Beta-cell function and metabolic control in Latent Autoimmune Diabetes in Adults with early insulin versus conventional treatment: a 3-year follow-up
- 2011
-
In: European Journal of Endocrinology. - 1479-683X. ; 164:2, s. 239-245
-
Journal article (peer-reviewed)abstract
- Objectives: The optimal treatment of latent autoimmune diabetes in adults (LADA) is not established. We explored whether early insulin treatment, which has shown beneficial effects in rodents and in human pilot studies, would result in better preservation of beta-cell function or metabolic control, compared with conventional treatment. Subjects and methods: Glucagon-stimulated C-peptide and HbAlc were evaluated at baseline and after 12, 24 and 36 months in 37 patients recently diagnosed with diabetes, aged >= 30 years, non-insulin-requiring and GADAb and/or ICA positive. Twenty patients received early insulin and 17 received conventional treatment (diet +/- oral hypoglycaemic agents (OHA), metformin, some and/or sulfonylurea) and insulin when necessary. Results: Level of metabolic control, HbAlc, was preserved in the early insulin treated, while it significantly deteriorated in the conventionally treated. There was no significant difference between the groups in C-peptide after 12, 24 or 36 months, or in the decline of C-peptide. Only baseline C-peptide predicted a C-peptide of >= 0.5 nmol/l at 36 months. Gender, body mass index, antibody titres or HbAlc did not influence the levels of C-peptide or HbAlc at baseline or end-of-study, or the decline in C-peptide. Among the diet +/- OHA-treated, 5/17 (30%) developed insulin dependency during the follow-up. No major hypoglycaemic events occurred. Conclusions: Early insulin treatment in LADA leads to better preservation of metabolic control and was safe. Superior preservation of C-peptide could not be significantly demonstrated. Only baseline level of C-peptide significantly influenced C-peptide level after 3 years. Further studies exploring the best treatment in LADA are warranted. European Journal of Endocrinology 164 239-245
|
|
| 11. |
- Törn, Carina, et al.
(author)
-
Excess mortality in middle-aged men with diabetes aged 15-34 years at diagnosis.
- 2011
-
In: Acta Diabetologia. - : Springer Science and Business Media LLC. - 0940-5429 .- 1432-5233. ; 48:3, s. 197-202
-
Journal article (peer-reviewed)abstract
- The aim of this study is to assess mortality risk and the excess of risk in patients with diabetes. Patients were 15–34 years old at diagnosis of diabetes mellitus (n = 879) in 1992 and 1993 in this national cohort from Sweden. Healthy controls were matched for gender and birth on the same day as the index cases (n = 837). The civic registration number was used to link patients and controls to the Swedish Cause of Death Registry. During follow-up, 3.3% (29/879) of patients and 1.1% (9/837; P = 0.002) of controls died. The risk for a patient with diabetes to die was almost threefold increased compared with healthy controls; hazard ratio, 2.9 (95% CI 1.4–6.2). This increased risk was significant in men; hazard ratio, 2.8 (95% CI 1.2–6.5). Diabetes as the underlying cause of death accounted for 38% (11/29) of deaths among patients. Most patients, 55% (16/29), died at home, remaining patients in hospital, 28% (8/29), or elsewhere 17% (5/29) compared to controls of whom 33% (3/9; P = 0.45) died at home, 33% (3/9; P = 1.0) in hospital, and 33% (3/9; P = 0.36) elsewhere. Only 55% (16/29) of patients had a specified day of death on death certificates compared to 100% (9/9; P = 0.016) of controls. Adult men with diabetes had an almost threefold increased risk to die within 15 years of diagnosis compared to healthy men. Most middle-aged patients with diabetes died at home and often without a specified date of death recorded.
|
|
| 12. |
- Vaziri Sani, Fariba, et al.
(author)
-
ZnT8 autoantibody titers in type 1 diabetes patients decline rapidly after clinical onset.
- 2010
-
In: Autoimmunity. - : Informa UK Limited. - 0891-6934 .- 1607-842X. ; Apr 7, s. 598-606
-
Journal article (peer-reviewed)abstract
- Autoantibodies to the islet-specific zinc transporter isoform 8 (ZnT8) are detected in the majority of type 1 diabetes patients prior to and at clinical diagnosis. The presence of ZnT8Ab after diagnosis has not been investigated. This study analyzed the autoantibody response to ZnT8 in regard to age at onset and disease duration. Two new onset type 1 diabetes patient cohorts with different age distributions at onset (2-17 and 15-34 years of age at onset), a longitudinal subset of the younger type 1 diabetes patient cohort (n = 32), and a cohort of GAD65Ab-positive LADA patients (n = 47) was analyzed for the presence of autoantibodies directed to the two major isoforms, ZnT8-Arginine (ZnT8R) and ZnT8-Tryptophan (ZnT8W). The majority of type 1 diabetes patients tested positive for ZnT8Ab to both isoforms. ZnT8Ab titers were significantly higher in the younger type 1 diabetes patients as compared with the older cohort (ZnT8RAb at a median of 148 and 29 U/ml, respectively, p < 0.001) (ZnT8WAb at a median of 145 and 58 U/ml, respectively, p < 0.01). ZnT8RAb and ZnT8WAb titers were significantly lower in the LADA patients (ZnT8RAb at a median of 14 U/ml, ZnT8WAb at a median of 25 U/ml) as compared with either type 1 diabetes cohorts. In our longitudinal analysis of type 1 diabetes patients after clinical diagnosis, ZnT8Ab levels to both isoforms declined significantly during the initial year of disease (ZnT8RAb from a median of 320-162 U/ml, p = 0.0001; ZnT8WAb from a median of 128-46 U/ml, p = 0.0011). The antibody titers further declined during the following 4 years (p < 0.0001). We conclude that ZnT8Ab presents a useful marker for type 1 diabetes, especially in younger patients at disease diagnosis.
|
|
