| 1. |
- Andersson, C, et al.
(författare)
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The three ZNT8 autoantibody variants together improve the diagnostic sensitivity of childhood and adolescent type 1 diabetes
- 2011
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Ingår i: Autoimmunity. - : Taylor & Francis. - 0891-6934 .- 1607-842X. ; 44:5, s. 394-405
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Tidskriftsartikel (refereegranskat)abstract
- Aims: We tested whether autoantibodies to all three ZnT8RWQ variants, GAD65, insulinoma-associated protein 2 (IA-2), insulin and autoantibodies to islet cell cytoplasm (ICA) in combination with human leukocyte antigen (HLA) would improve the diagnostic sensitivity of childhood type 1 diabetes by detecting the children who otherwise would have been autoantibody-negative.Methods: A total of 686 patients diagnosed in 1996–2005 in Skåne were analyzed for all the seven autoantibodies [arginin 325 zinc transporter 8 autoantibody (ZnT8RA), tryptophan 325 zinc transporter 8 autoantibody (ZnT8WA), glutamine 325 Zinc transporter 8 autoantibody (ZnT8QA), autoantibodies to glutamic acid decarboxylase (GADA), Autoantibodies to islet-antigen-2 (IA-2A), insulin autoantibodies (IAA) and ICA] in addition to HLA-DQ genotypes.Results: Zinc transporter 8 autoantibody to either one or all three amino acid variants at position 325 (ZnT8RWQA) was found in 65% (449/686) of the patients. The frequency was independent of age at diagnosis. The ZnT8RWQA reduced the frequency of autoantibody-negative patients from 7.5 to 5.4%—a reduction by 28%. Only 2 of 108 (2%) patients who are below 5 years of age had no autoantibody at diagnosis. Diagnosis without any islet autoantibody increased with increasing age at onset. DQA1-B1*X-0604 was associated with both ZnT8RA (p = 0.002) and ZnT8WA (p = 0.01) but not with ZnT8QA (p = 0.07). Kappa agreement analysis showed moderate (>0.40) to fair (>0.20) agreement between pairs of autoantibodies for all combinations of GADA, IA-2A, ZnT8RWQA and ICA but only slight ( < 0.19) agreement for any combination with IAA.Conclusions: This study revealed that (1) the ZnT8RWQA was common, independent of age; (2) multiple autoantibodies were common among the young; (3) DQA1-B1*X-0604 increased the risk for ZnT8RA and ZnT8WA; (4) agreement between autoantibody pairs was common for all combinations except IAA. These results suggest that ZnT8RWQA is a necessary complement to the classification and prediction of childhood type 1 diabetes as well as to randomize the subjects in the prevention and intervention of clinical trials.
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| 2. |
- Kanatsuna, N, et al.
(författare)
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Doubly reactive INS-IGF2 autoantibodies in children with newly diagnosed autoimmune (type 1) diabetes
- 2015
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Ingår i: Scandinavian Journal of Immunology. - : Wiley-Blackwell. - 0300-9475 .- 1365-3083. ; 82:4, s. 361-369
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Tidskriftsartikel (refereegranskat)abstract
- The splice variant INS-IGF2 entails the preproinsulin signal peptide, the insulin B-chain, eight amino acids of the C-peptide and 138 unique amino acids from an ORF in the IGF2 gene. The aim of this study was to determine whether levels of specific INS-IGF2 autoantibodies (INS-IGF2A) were related to age at diagnosis, islet autoantibodies, HLA-DQ or both, in patients and controls with newly diagnosed type 1 diabetes. Patients (n = 676), 0-18 years of age, diagnosed with type 1 diabetes in 1996-2005 and controls (n = 363) were analysed for specific INS-IGF2A after displacement with both cold insulin and INS-IGF2 to correct for non-specific binding and identify double reactive sera. GADA, IA-2A, IAA, ICA, ZnT8RA, ZnT8WA, ZnT8QA and HLA-DQ genotypes were also determined. The median level of specific INS-IGF2A was higher in patients than in controls (P < 0.001). Irrespective of age at diagnosis, 19% (126/676) of the patients had INS-IGF2A when the cut-off was the 95th percentile of the controls (P < 0.001). The risk of INS-IGF2A was increased among HLA-DQ2/8 (OR = 1.509; 95th CI 1.011, 2.252; P = 0.045) but not in 2/2, 2/X, 8/8, 8/X or X/X (X is neither 2 nor 8) patients. The association with HLA-DQ2/8 suggests that this autoantigen may be presented on HLA-DQ trans-heterodimers, rather than cis-heterodimers. Autoantibodies reactive with both insulin and INS-IGF2A at diagnosis support the notion that INS-IGF2 autoimmunity contributes to type 1 diabetes.
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| 3. |
- Larsson, Helena, et al.
(författare)
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Diabetes-associated HLA genotypes affect birthweight in the general population.
- 2005
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 48:Jul 1, s. 1484-1491
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesisThe aim of our study was to test the hypothesis that HLA genotypes conferring risk of diabetes, cord blood autoantibodies, or both are associated with increased birthweight. Methods: HLA genotypes were determined in dried blood spots of cord blood from a total of 16,709 children born to healthy mothers in the Diabetes Prediction in Skane (DiPiS) study, a population-based observational clinical investigation of newborn children. Children born to mothers with diabetes or gestational diabetes were excluded. Autoantibodies to glutamic acid decarboxylase (GAD65Ab) and insulinoma-associated protein 2 were determined in standard radioligand binding assays. Birthweight was adjusted for gestational age and divided into quartiles. The upper quartile was defined as high relative birthweight (HrBW) and the lower quartile as low relative birthweight (LrBW). Results: Genotypes conferring risk of type 1 diabetes were strongly associated with relative birthweight (rBW) (p=0.01). The high-risk HLA-DQ2/8, DQ8/0604 and DQ8/X genotypes were associated with HrBW (odds ratio [OR] [95% CI]=1.20 [1.08-1.33], p=0.0006). The HLA-DQB1*0603 allele, which is negatively associated with type 1 diabetes, was also associated with HrBW (p=0.025), confirming a previous report on DQB1*0603-linked HLA-DR13. GAD65Ab were negatively associated with HrBW (OR [95% CI]=0.72 [0.56-0.93], p=0.01). Regression analysis showed that the HLA-associated increase in rBW was independent of confounding factors. Conclusions/Interpreation: HLA genotypes may be associated with intrauterine growth independent of type 1 diabetes risk. The epidemiological observation that high birthweight is a risk factor for type 1 diabetes could possibly result from a moderating effect on intrauterine growth of HLA genotypes conferring a high risk of diabetes.
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| 4. |
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| 5. |
- Christie, M., et al.
(författare)
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Antibodies to a Mr-64000 islet cell protein in Swedish children with newly diagnosed Type 1 (insulin-dependent) diabetes
- 1988
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Ingår i: Diabetologia. - 0012-186X. ; 31:8, s. 597-602
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Tidskriftsartikel (refereegranskat)abstract
- Sera from 40 Swedish children diagnosed as having Type 1 (insulin-dependent) diabetes mellitus during a one year period along with 40 age and geographically matched control subjects were tested for antibodies to a Mr-64000 islet protein by immunoprecipitation of 35S-methionine-labelled rat islet amphiphilic proteins. Of the 40 diabetic patients, 29 (73%) were found to be positive whereas all 40 control subjects were negative. Samples were also tested for titres of islet cell cytoplasmic antibodies by indirect immunofluorescence on frozen sections of human pancreas. In the diabetic group, 30 of the 40 patients (75%) were positive for islet cell cytoplasmic antibodies compared with 2 of the 40 control subjects (5%). A comparison of levels of antibodies to the Mr-64000 protein with islet cell cytoplasmic antibodies revealed a weak (rs=0.46), but significant (p<0.01) correlation between the two tests. There was no effect of age or sex on levels of antibodies to the Mr-64000 protein. These results in population-based diabetic children and control subjects demonstrate a high frequency of antibodies to the Mr-64000 protein at the time of clinical onset.
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| 6. |
- ERINGSMARK REGNÉLL, SIMON, et al.
(författare)
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Pancreas volume and fat fraction in children with Type 1 diabetes
- 2016
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Ingår i: Diabetic Medicine. - : Wiley. - 1464-5491 .- 0742-3071. ; 33:10, s. 1374-1379
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: People with Type 1 diabetes have smaller pancreases than healthy individuals. Several diseases causing pancreatic atrophy are associated with pancreatic steatosis, but pancreatic fat in Type 1 diabetes has not been measured. This cross-sectional study aimed to compare pancreas size and fat fraction in children with Type 1 diabetes and controls.METHODS: The volume and fat fraction of the pancreases of 22 children with Type 1 diabetes and 29 controls were determined using magnetic resonance imaging.RESULTS: Pancreas volume was 27% smaller in children with diabetes (median 34.9 cm(3) ) than in controls (47.8 cm(3) ; P < 0.001). Pancreas volume correlated positively with age in controls (P = 0.033), but not in children with diabetes (P = 0.649). Pancreas volume did not correlate with diabetes duration, but it did correlate positively with units of insulin/kg body weight/day (P = 0.048). A linear model of pancreas volume as influenced by age, body surface area and insulin units/kg body weight/day found that insulin dosage correlated with pancreas volume after controlling for both age and body surface area (P = 0.009). Pancreatic fat fraction was not significantly different between the two groups (1.34% vs. 1.57%; P = 0.891).CONCLUSIONS: Our findings do not indicate that pancreatic atrophy in Type 1 diabetes is associated with an increased pancreatic fat fraction, unlike some other diseases featuring reduced pancreatic volume. We speculate that our results may support the hypotheses that much of pancreatic atrophy in Type 1 diabetes occurs before the clinical onset of the disease and that exogenous insulin administration decelerates pancreatic atrophy after diabetes onset. This article is protected by copyright. All rights reserved.
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| 7. |
- Ferrat, L.A., et al.
(författare)
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A combined risk score enhances prediction of type 1 diabetes among susceptible children
- 2020
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 26:8, s. 1247-1255
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Tidskriftsartikel (refereegranskat)abstract
- Type 1 diabetes (T1D)-an autoimmune disease that destroys the pancreatic islets, resulting in insulin deficiency-often begins early in life when islet autoantibody appearance signals high risk1. However, clinical diabetes can follow in weeks or only after decades, and is very difficult to predict. Ketoacidosis at onset remains common2,3 and is most severe in the very young4,5, in whom it can be life threatening and difficult to treat6-9. Autoantibody surveillance programs effectively prevent most ketoacidosis10-12 but require frequent evaluations whose expense limits public health adoption13. Prevention therapies applied before onset, when greater islet mass remains, have rarely been feasible14 because individuals at greatest risk of impending T1D are difficult to identify. To remedy this, we sought accurate, cost-effective estimation of future T1D risk by developing a combined risk score incorporating both fixed and variable factors (genetic, clinical and immunological) in 7,798 high-risk children followed closely from birth for 9.3 years. Compared with autoantibodies alone, the combined model dramatically improves T1D prediction at ≥2 years of age over horizons up to 8 years of age (area under the receiver operating characteristic curve ≥ 0.9), doubles the estimated efficiency of population-based newborn screening to prevent ketoacidosis, and enables individualized risk estimates for better prevention trial selection.
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| 8. |
- Gottsäter, A., et al.
(författare)
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Glutamate decarboxylase antibody levels predict rate of β-cell decline in adult-onset diabetes
- 1995
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Ingår i: Diabetes Research and Clinical Practice. - 0168-8227. ; 27:2, s. 133-140
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Tidskriftsartikel (refereegranskat)abstract
- Glutamate decarboxylase autoantibodies (GAD65Ab) and β-cell function were evaluated at and 3 years after diabetes onset in consecutive subjects over 15 years of age. At onset, 21 32 (66%) insulin-treated patients (mean age 43, range 16-79 years) had GAD65Ab; all GAD65Ab persisted 3 years later. At onset, 20 82 (24%) non-insulin-treated patients (mean age 56, range 20-79 years) had GAD65Ab. Of those with persistent GAD65Ab, 8 non-insulin-treated and 11 insulin-treated patients consented to follow-up glucose and glucagon stimulation tests. For non-insulin-treated patients, quantitative GAD65Ab index at onset correlated inversely with 1+3 min C-peptide response to glucose (r = -0.68, P < 0.05) and to glucagon (r = -0.79, P < 0.05) 3 years later. Those with high (> 0.50) initial GAD65Ab index had lower C-peptide (fasting, 1+3 min after glucose and after glucagon) 3 years later, versus those with low (<0.50) initial GAD65Ab index (P < 0.05). In conclusion, not only did GAD65Ab presence predict future insulin dependence, but higher GAD65Ab levels may mark more rapid decline in β-cell function in apparent non-insulin-dependent diabetes.
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| 9. |
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| 10. |
- Gottsäter, A., et al.
(författare)
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Islet cell antibodies are associated with β-cell failure also in obese adult onset diabetic patients
- 1994
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Ingår i: Acta Diabetologica. - 0940-5429. ; 31:4, s. 226-231
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Tidskriftsartikel (refereegranskat)abstract
- To clarify the utility of islet cell antibodies (ICA) to correctly classify and predict insulin treatment in newly diagnosed diabetic subjects, ICA, body mass index (BMI), glycated hemoglobin (HbA1c), and fasting plasma C-peptide values were evaluated at and 3 years after diagnosis in 233 new, consecutively diagnosed, adult diabetic patients classified as obese or nonobese (National Diabetes Data Group, NDDG criteria). Among the 233 patients, 31 were nonobese ICA-positive (mean age at diagnosis 43±3 years), 55 nonobese ICA-negative (mean age at diagnosis 58±2 years), 7 obese ICA-positive (mean age at diagnosis 57±5 years), and 139 obese ICA-negative (mean age at diagnosis 58±1 years). Fasting C-peptide decreased (P<0.05) in nonobese ICA-positive patients who after 3 years showed lower BMI (22.6±0.6 versus 24.5±0.4;P<0.05), lower fasting C-peptide (0.14±0.06 nmol/l versus 0.71±0.07 nmol/l;P<0.001), and higher frequency of insulin treatment [28/31 (90%) versus 6/45 (13%);P<0.001] than nonobese ICA-negative patients. In obese ICA-positive patients, fasting C-peptide also decreased (Δ C-peptide 0.17±0.04 nmol/l;P<0.05) after diagnosis, and 3 years after diagnosis, obese ICA-positive patients showed lower BMI (25.7±1.2 versus 29.8±0.4;P<0.01) and fasting C-peptide (0.08±0.04 nmol/l versus 1.06±0.05 nmol/l;P<0.001) and higher HbA1c values (9.92%±0.68% versus 7.39%±0.21%;P<0.01) and a higher frequency of insulin treatment [7/7 (100%) versus 5/121 (4%);P<0.001] than obese ICA-negative patients. Therefore, ICA detected at diagnosis of diabetes in both obese and nonobese adult patients indicate β-cell dysfunction, high HbA1c levels, and progression to insulin dependency.
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