| 1. |
- Agardh, Carl-David, et al.
(författare)
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Clinical evidence for the safety of GAD65 immunomodulation in adult-onset autoimmune diabetes.
- 2005
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Ingår i: Journal of Diabetes and its Complications. - : Elsevier BV. - 1873-460X .- 1056-8727. ; 19:4, s. 238-246
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this Phase II study was to evaluate if alum-formulated human recombinant GAD65 is safe and does not compromise beta cell function. The study was conducted as a randomized, double blind, placebo-controlled, dose-escalation clinical trial in a total of 47 Latent Autoimmune Diabetes in Adults (LADA) patients who received either placebo or 4, 20, 100, or 500 μg Diamyd subcutaneously at Weeks 1 and 4. Safety evaluations, including neurology, beta cell function tests, diabetes status assessment, hematology, biochemistry, and cellular and humoral immunological markers, were repeatedly assessed over 24 weeks. None of the patients had significant study-related adverse events (AE). Fasting c-peptide levels at 24 weeks were increased compared with placebo (P=.0015) in the 20 μg but not in the other dose groups. In addition, both fasting (P=.0081) and stimulated (P=.0236) c-peptide levels increased from baseline to 24 weeks in the 20 μg dose group. GADA log levels clearly increased (P=.0002) in response to 500 μg Diamyd. The CD4+CD25+/CD4+CD25− cell ratio increased (P=.0128) at 24 weeks in the 20 μg group. No sudden increase in HbA1c or plasma glucose or decrease in beta cell function was observed in any of the dose groups. These positive findings for clinical safety further support the clinical development of Diamyd as a therapeutic to prevent autoimmune diabetes.
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| 2. |
- Bekris, L. M., et al.
(författare)
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GAD65 autoantibody epitopes in adult patients with latent autoimmune diabetes following GAD65 vaccination
- 2007
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Ingår i: Diabetic Medicine. - : Wiley. - 1464-5491 .- 0742-3071. ; 24:5, s. 521-526
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Tidskriftsartikel (refereegranskat)abstract
- Aims Subcutaneous injection of recombinant human GAD65 (rhGAD65) in patients with latent autoimmune diabetes in adults (LADA) correlates with an increase in C-peptide levels. In this study we analysed the effect of rhGAD65 administration on the GAD65-specific autoimmune response. Methods Longitudinal serum samples obtained from LADA patients (n = 47) who received 4, 20, 100 or 500 mu g alum-formulated rhGAD65 or placebo by subcutaneous injection twice (4 weeks apart) were analysed for their epitope recognition using GAD65-specific recombinant Fab and GAD65/67 fusion proteins. Results Overall, minor changes in the epitope pattern were observed using either approach. Only in the 500-mu g dosage group was an increase in GAD65Ab level associated with a significant increase in the binding to a conformational epitope located at the middle part of GAD65. Conclusions Our data suggest that the apparent beneficial effects of 20 mu g alum-formulated recombinant human GAD65 is not explained by changes in the GAD65Ab epitope pattern.
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| 3. |
- Burman, Pia, et al.
(författare)
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Dual bronchial carcinoids and Cushing's syndrome with a paradoxical response to dexamethasone and a false positive outcome of inferior petrosal sinus sampling
- 2008
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Ingår i: European Journal of Endocrinology. - 0804-4643 .- 1479-683X. ; 159:4, s. 483-8
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Establishing the cause of Cushing's syndrome (CS) can be a considerable challenge, in particular in ectopic adrenocorticotropic hormone (ACTH) syndrome, and often requires a combination of biochemical tests and imaging procedures. SUBJECT: A 27-year-old man presented with signs of CS. P-ACTH levels were three times above the upper limit of normal (ULN) and free urinary cortisol around 2000 nmol/24 h. The work-up showed remarkable results. RESULTS: A 2-day low-dose dexamethasone suppression test demonstrated paradoxical increases in cortisol. Sampling from the bilateral inferior petrosal sinus sampling (BIPSS) showed a central to peripheral ACTH ratio of 4.7 after corticotrophin-releasing hormone (CRH) stimulation, i.e. indicated pituitary disease, but magnetic resonance imaging of the pituitary was normal. Computed tomography (CT) scan of the lungs showed two oval-shaped masses, 1.3 x 1.8 and 1.3 x 2 cm, in the middle lobe. Both were positive at somatostatin receptor scintigraphy, compatible with tumors or inflammatory lesions. Subsequently, (11)C-5-hydroxytryptophan-PET showed distinct uptake in the tumors but not elsewhere. Two carcinoids situated 3 cm apart, both staining for ACTH, were removed at surgery. CONCLUSION: This unique case with dual bronchial carcinoids inducing hypercortisolism illustrates the problems with identifying the source of ACTH in CS. Possibly, an abnormal regulation of ACTH production in response to dexamethasone, or steroid-induced tumor necrosis, explains the paradoxical outcome at dexamethasone suppression, and the false positive result at BIPSS reflects an unusual sensitivity of the pituitary corticotrophs to CRH in this patient. The work-up illustrates the great value of (11)C-5-hydroxytryptophan-PET as a diagnostic procedure when other investigations have produced ambiguous results.
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| 4. |
- Lethagen, ÅsaLinda
(författare)
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Clinical, Genetic and Metabolic Characterisation of LADA (Latent Autoimmune Diabetes in Adults)
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Latent autoimmune diabetes in adults (LADA) comprises about 10% of patients initially diagnosed with type 2 diabetes but who are positive for pancreatic islet antibodies, especially to glutamic acid decarboxylase (GADabs). The present studies focused on clinical, genetic and metabolic characterisation of patients with LADA. In LADA, the frequency of the type 1 diabetes susceptibility genotype HLA-DQB1*0201/*0302 and genotypes including the 0302 allele was higher than in type 2 diabetes but lower than in type 1 diabetes. No difference was seen between LADA and type 2 diabetic or control subjects regarding the frequency of the insulin gene alleles associated with the risk of type 1 diabetes, whereas the frequency of these alleles was high in type 1 diabetic patients. In the LADA subjects, beta-cell function was significantly impaired at diagnosis compared with type 2 diabetic patients, but was markedly better preserved compared with age-matched adult type 1 diabetic patients. GADab positivity was linked with decreased insulin secretion in non-diabetic subjects, suggesting that GADabs are markers of beta-cell autoimmunity, although this does not always lead to overt diabetes. Features of the metabolic syndrome in LADA were fewer than in type 2 diabetes but more common than in type 1 diabetes. The results show that although LADA shares characteristics with both type 1 and type 2 diabetes it can be clinically, genetically, and metabolically distinguished from both types. The distinction is of clinical importance for identifying LADA and to achieve proper care of these patients.
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| 5. |
- Lethagen, ÅsaLinda, et al.
(författare)
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Glutamic acid decarboxylase antibody positivity is associated with an impaired insulin response to glucose and arginine in nondiabetic patients with autoimmune thyroiditis
- 2002
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - 1945-7197. ; 87:3, s. 1177-1183
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Tidskriftsartikel (refereegranskat)abstract
- To study whether antibodies to glutamic acid decarboxylase (GADab) are associated with subclinical beta-cell damage and impaired insulin secretion, we screened 441 nondiabetic patients with autoimmune thyroiditis (AT) for GADab, and 15 (3.4%) were found positive. Antibodies to IA-2 were found in two GADab+ and one GADab- patients. We matched 11 GADab+ and 13 GADab- AT patients who were euthyroid on thyroxin supplementation, and 13 control subjects for sex, age, and body mass index and measured insulin, C-peptide, and glucagon response to glucose and arginine at three blood glucose concentrations (fasting, 14 mmol/liter, >25 mmol/liter). In the fasting state, all groups had similar blood glucose concentration and HbA1c level, but the serum insulin concentration was higher in the AT patients compared with the control subjects (P < 0.04). The acute insulin response to arginine was lower in GADab+ than in GADab- thyroiditis subjects at glucose concentration of 14 and >25 mmol/liter (AIR,4: 76.8 +/- 52.0 vs. 158.2 +/- 118.2 mU/liter, P = 0.040; AIR(>25): 84.3 +/- 64.4 vs. 167.9 +/- 101.5 mU/liter, P = 0.035). In conclusion, GADab were associated with a decreased insulin secretion capacity in nondiabetic subjects with thyroiditis, which suggests that GADab positivity could be a marker of subclinical insulitis.
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| 6. |
- Lyssenko, Valeriya, et al.
(författare)
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Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes.
- 2007
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Ingår i: Journal of Clinical Investigation. - 0021-9738. ; 117:8, s. 2155-2163
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Tidskriftsartikel (refereegranskat)abstract
- Genetic variants in the gene encoding for transcription factor-7-like 2 (TCF7L2) have been associated with type 2 diabetes (T2D) and impaired beta cell function, but the mechanisms have remained unknown. We therefore studied prospectively the ability of common variants in TCF7L2 to predict future T2D and explored the mechanisms by which they would do this. Scandinavian subjects followed for up to 22 years were genotyped for 3 SNPs (rs7903146, rs12255372, and rs10885406) in TCF7L2, and a subset of them underwent extensive metabolic studies. Expression of TCF7L2 was related to genotype and metabolic parameters in human islets. The CT/TT genotypes of SNP rs7903146 strongly predicted future T2D in 2 independent cohorts (Swedish and Finnish). The risk T allele was associated with impaired insulin secretion, incretin effects, and enhanced rate of hepatic glucose production. TCF7L2 expression in human islets was increased 5-fold in T2D, particularly in carriers of the TT genotype. Overexpression of TCF7L2 in human islets reduced glucose-stimulated insulin secretion. In conclusion, the increased risk of T2D conferred by variants in TCF7L2 involves the enteroinsular axis, enhanced expression of the gene in islets, and impaired insulin secretion.
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| 7. |
- Ortqvist, E, et al.
(författare)
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Changes in GAD65Ab-Specific Antiidiotypic Antibody Levels Correlate with Changes in C-Peptide Levels and Progression to Islet Cell Autoimmunity.
- 2010
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 95, s. 310-318
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Tidskriftsartikel (refereegranskat)abstract
- Context: The previously reported absence of 65-kDa glutamate decarboxylase antibody (GAD65Ab)-specific antiidiotypic antibodies (anti-Id) in type 1 diabetes (T1D) patients at clinical onset could be due to an inability to mount an antibody response to GAD65Ab or a longitudinal decline in anti-Id levels. Objective and Design: We investigated anti-Id levels in longitudinal samples obtained from T1D patients (n = 41) (clinical diagnosis - 12 months), and latent autoimmune diabetes in adults (LADA) patients (n = 32) who received alum-formulated human recombinant GAD65 (baseline - 12 months). We also determined anti-Id levels in a small cohort of Type 2 diabetes patients during their development of autoimmune T cell responses. Results: At clinical onset T1D patients presented no or low anti-Id levels. However, 22/41 T1D patients showed >/=50% increase in GAD65Ab-specific anti-Id levels during follow-up; peaking at 3 (n = 1), 6 (n = 10), 9 (n = 10), or 12 (n = 1) months. Increasing anti-Id levels marked patients who experienced a temporary increase in C-peptide levels. Anti-Id levels correlated significantly with glycated hemoglobin and C-peptide levels at 6 and 9 months (P values ranged from <0.001 to <0.05). In LADA patients receiving placebo, anti-Id levels declined in seven of nine patients, whereas four of five patients receiving 20 mug alum-formulated human recombinant GAD65 showed increasing anti-Id levels. Changes in anti-Id and C-peptide levels closely correlated (P < 0.0001). The significant decline in anti-Id levels (P = 0.03) in T2D patients developing T cell autoimmune responses supports our hypothesis that declining anti-Id levels are associated with developing islet autoimmunity. Conclusions: The close association between GAD65Ab-specific anti-Id levels and beta-cell function may provide a novel marker for the progression of autoimmune diabetes.
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| 8. |
- Vaziri Sani, Fariba, et al.
(författare)
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ZnT8 autoantibody titers in type 1 diabetes patients decline rapidly after clinical onset.
- 2010
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Ingår i: Autoimmunity. - : Informa UK Limited. - 0891-6934 .- 1607-842X. ; Apr 7, s. 598-606
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Tidskriftsartikel (refereegranskat)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.
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