American diabetes association - http://www.diabetes.org
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Journal Article↗
Biomedical subjects
A Lernmark
Publications and source records attributed to A Lernmark.
Type 1 diabetes.
Type 1 (insulin-dependent) diabetes occurs worldwide and can appear at any age. The genetic susceptibility is strongly associated with HLA-DQ and DR on chromosome 6, but genetic factors on other chromosomes such as the insulin gene on chromosome 11 and the cytotoxic T-lymphocyte antigen gene on chromosome 2 may modulate disease risk. Numerous studies further support the view that environmental factors are important. Gestational infections may contribute to initiation, whereas later infections may accelerate islet beta-cell autoimmunity. The pathogenesis is strongly related to autoimmunity against the islet beta cells. Markers of autoimmunity include autoantibodies against glutamic acid decarboxylase, insulin, and islet cell antigen-2, a tyrosine phosphatase-like protein. Molecular techniques are used to establish reproducible and precise autoantibody assays, which have been subject to worldwide standardization. The diagnostic sensitivity (40-80%) and specificity (99%) of all three autoantibodies for type 1 diabetes are high, and double or triple positivity among first-degree relatives predicts disease. Combined genetic and antibody testing improved prediction in the general population despite the transient nature of these autoantibodies. Classification of diabetes has also been improved by autoantibody testing and may be used in type 2 diabetes to predict secondary failure and insulin requirement. Islet autoantibodies do not seem to be related to late complications but rather to metabolic control, perhaps because the presence of islet cell autoantibodies marks different residual beta-cell function. Combined genetic and autoantibody screening permit rational approaches to identify subjects for secondary and tertiary intervention trials.
Clinical Laboratory Techniques↗
A simple and rapid microSepharose assay for GAD65 and ICA512 autoantibodies in diabetes. Diabetes Incidence Study in Sweden (DISS).
GAD65Ab and ICA512Ab are strongly associated with insulin-dependent (Type 1) diabetes mellitus. A novel, simple radio-antigen binding assay with microSepharose conjugated with monoclonal antibodies specific for human immunoglobulin light chains was developed to provide diagnostic sensitivity and specificity of GAD65Ab and ICA512Ab for Type 1 diabetes. The Receiver Operating Characteristic (ROC) curve was used to determine the upper level of Normal in 583 new onset Type 1 diabetic patients and in 829 matched controls. The sensitivity of GAD65Ab and ICA512Ab was 66% (384/583) and 41% (211/520), respectively, and the diagnostic specificity was 96% for both autoantibodies. Levels, but not frequency, of GAD65Ab were higher among female Type 1 diabetes patients, whereas ICA512Ab levels did not differ between males and females. Positivity for GAD65Ab. ICA512Ab or both showed a sensitivity of 74% and a specificity of 92% for Type 1 diabetes. This simple, one-step centrifugation, high-capacity radio-antigen binding assay has a high precision and reproducibility to accurately detect both GAD65Ab and ICA512Ab. This assay should also prove useful in other autoantibody assays against conformation-sensitive autoantigens.
Adolescent↗
Immunology in diabetes: an update.
Type 1 (insulin-dependent) diabetes mellitus is strongly associated with autoimmune phenomena connected to the loss of beta-cells in the pancreatic islets. Despite considerable progress in our understanding of genetic susceptibility factors and islet autoimmunity preceding the clinical onset of Type 1 diabetes there are considerable gaps in our knowledge. First, the etiology is unclear. It is speculated that multiple etiological factors may initiate a common pathogenic pathway which results in immune-mediated beta-cell destruction. In 1998 we will need to learn more about the possible importance of gestational infections, as well as isolation of viral DNA or RNA from the blood of new-onset patients or marker-positive individuals. The scan of the whole genome has provided a smorgasbord of genetic regions which confer diabetes risk either alone or in combination. HLA remains the major genetic risk factor, and while HLA peptide binding information is considerable, we understand less of autoantigen processing and presentation. Cloned autoantigens and their use in standardized autoantibody assays have improved our ability to identify individuals at risk for diabetes. The diagnostic sensitivity and specificity of autoantibody markers for Type 1 diabetes are high as are their predictive values. We need methods to combine autoantibodies with genetic risk factors. The identification of individuals in different stages of their pathogenesis, including patients with so-called slowly progressive Type 1 diabetes (SPIDDM, LADA etc.), allow approaches to novel therapeutic interventions. Insulin is currently the therapeutic agent of choice and although spontaneous insulin-dependent diabetes in the NOD mouse and the BB rat can be prevented by immune suppression or modulation, this has not yet been possible in humans. The 1998 research on the interaction between environmental factors and susceptibility genes to initiate beta-cell specific autoreactivity should allow the development of therapies for prevention, and perhaps a cure, of insulin-dependent (Type 1) diabetes.
Allergy and Immunology↗
Genetic isolation of iddm 1 on chromosome 4 in the biobreeding (BB) rat.
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Animals↗
Inverse relationship between GAD65 antibody levels and severe retinopathy in younger type 1 diabetic patients.
Several risk factors for severe non-proliferative and proliferative retinopathy in type 1 diabetes mellitus have been proposed without explaining the rapid progression of retinopathy in some patients. Since GAD65 autoantibodies (GAD65Abs) are detected against glutamic acid decarboxylase (GAD), which is mainly expressed in islets and nervous tissue in type 1 diabetic patients, the aim of the present investigation was to test the hypothesis whether GAD65Abs are associated with rapidly progressing severe retinopathy. Patients with severe non-proliferative or proliferative retinopathy (n = 27) were compared with another group, which in spite of long diabetes duration had no or only mild signs of retinopathy (n = 28). GAD65Abs were analysed in a radioimmunoassay using in vitro translated human GAD65, and the levels were expressed as an index in relation to positive and negative reference samples. Using a cut-off level representing the 99th percentile of normals, 6/27 (22%) with and 9/28 (32%) without severe retinopathy were considered GAD65Ab positive. Although there was no difference in the number of GAD65Ab positive patients, the GAD65Ab levels were lower in patients with (0.30; 0.11-0.64) than without (0.68; 0.34-1.12) severe retinopathy (P = 0.03). The patients were also subjected to HLA-DR and DQ typing by PCR and hybridization with oligospecific probes. DQ2/8 was more common in patients with (56%) than without (29%) severe retinopathy (P = 0.05), but DQ2/8 could not account for the lower GAD65Ab levels in patients with severe retinopathy. It is concluded that GAD65Ab levels are inversely correlated with severe retinopathy in young type 1 diabetic patients.
Adult↗
Severe insulin resistance in a patient with type 1 diabetes and stiff-man syndrome treated with insulin lispro.
We describe a patient with type 1 diabetes with recurrent diabetic ketoacidosis and severe insulin resistance. Extensive evaluation of the etiology of the insulin resistance did not reveal an etiology, and well over 1000 U of daily insulin did not prevent the ketoacidosis. Her blood glucose and insulin requirements were improved with glucocorticoids and octreotide, but the effects of both of these agents were short-lived. She was given a trial of insulin lispro with immediate and dramatic effects, lowering her HbA1c from 14.6 to 5.1% in 7 months with a decrease in insulin requirements of 1600-100 U per day. Besides her diabetes, she had a history of pain and stiffness affecting numerous muscle groups, and hospitalization was required for pain control. The diagnosis of stiff-man syndrome (SMS) was confirmed with high titers of glutamic acid decarboxylase 65 antibodies in both serum and cerebral spinal fluid. In summary, we describe the first patient with type 1 diabetes, SMS, and severe insulin resistance. Although the etiology of the insulin resistance is unknown, due to the efficacious response to insulin lispro, hydrocortisone, and perhaps octreotide, we propose an immune-mediated etiology. Although rare, this syndrome needs to be considered as an etiology of insulin resistance.
Adult↗
Sometimes it's hot, sometimes it's not.
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Diabetes Mellitus, Type 1↗
Association between autoantibody markers and subtypes of DR4 and DR4-DQ in Swedish children with insulin-dependent diabetes reveals closer association of tyrosine pyrophosphatase autoimmunity with DR4 than DQ8.
HLA DQA1*0301-DQB1*0302 (DQ8) and DQA1*0501-DQB1*0201 (DQ2) are positively and DQA1*0102-DQB1*0602 (DQ6) negatively associated with IDDM. In DQA1*0301-DQB1*0302 (DQ8)-positive patients, susceptibility is also mediated by DRB1*0401. The aim of the study was to determine the association between HLA-DR4 and DQ and the presence of GAD65, ICA512, and insulin autoantibodies as well as ICA in 425 Swedish children with IDDM and 367 controls in the age group of 0-15 years. We found that ICA512 autoantibodies were associated primarily with DRB1*0401 and not with DQA1*0301-DQB1*0302 (DQ8). No such hierarchy could be demonstrated for insulin autoantibodies, which were associated with both DQA1*0301-DQB1*0302 (DQ8) and DRB1*0401. GAD65 autoantibodies, known to be closely associated with DQA1*0501-DQB1*0201 (DQ2)-DRB1*0301 haplotype, also showed no preferential association with DQA1*0301-DQB1*0302 (DQ8) versus DRB1*04. These results suggest that the immune response to different beta-cell autoantigens may be mediated via HLA class II molecules from different loci. Design of the antigen-specific immuno-intervention trials should take into account these HLA-DR and DQ subtype associations.
Adolescent↗
Etiological diagnosis of primary adrenal insufficiency using an original flowchart of immune and biochemical markers.
Approximately 70-80% of cases of primary adrenal insufficiency are classified as idiopathic. An effective protocol for the etiological diagnosis of primary adrenal insufficiency is needed to ensure correct patient management. With the aim of developing an algorithm for the etiological diagnosis of primary adrenal insufficiency, we studied 56 Italian patients with nonsurgical primary adrenal insufficiency and 24 French patients with X-linked adrenoleukodystrophy (ALD) for serum levels of adrenal cortex, steroid-21-hydroxylase (21OHAb), islet cell (ICA), glutamate decarboxylase (GAD65Ab), IA2/ICA512 (ICA512Ab), thyroid peroxidase (TPOAb) autoantibodies, and plasmatic concentrations of very long chain fatty acids (VLCFA). High levels of 21OH and adrenal cortex antibodies were found in 35/42 (83%) and 17/42 (40%) Italian patients with idiopathic adrenal insufficiency, respectively. Levels of adrenal autoantibodies correlated inversely with disease duration (P < 0.0001). Elevated VLCFA were found in 4/42 (10%) idiopathic patients. A total of 34/35 (97%) idiopathic patients with a disease duration of less than 20 yr was positive for either 21OHSAb or elevated levels of VLCFA. None of 14 patients with posttuberculosis adrenal insufficiency had elevated levels of either adrenal antibodies or VLCFA. ICA, GAD65Ab, ICA512Ab, and TPOAb were found in 6/56 (11%), 8/56 (14%), 4/56 (7%), and 23/56 (41%) patients, respectively. None of 24 French ALD patients with adrenal insufficiency was positive for organ-specific autoantibodies. The measuring of 21OH antibodies and plasma VLCFA levels enabled a correct diagnosis of autoimmune (89%) and ALD (8%) in 97% of patients with idiopathic primary adrenal insufficiency of less than 20 yr of duration. The results of our study have important therapeutic and prognostic implications.
Adolescent↗
Pituitary autoantibodies in patients with hypopituitarism and their relatives.
Autoantibodies to human pituitary cytosol proteins were determined by immunoblotting in sera from patients with hypopituitarism and their relatives. Reactivity to an M(r) 49,000 protein was significantly more frequent in patients (6/21 (28%) P < 0.05) as well as in relatives (10/35 (28%) P < 0.02) compared with controls (3/44 (6.8%)). Autoantibodies to this particular protein have previously been detected in sera from 70% of patients with biopsy-proven lymphocytic hypophysitis. Unlike patients with biopsy-proven lymphocytic hypophysitis, none of the patients in this study presented with a suspected pituitary adenoma or showed an enlarged sella turcica. Cisternal herniation was seen in 6/21 patients and this may very well represent the end stage of lymphocytic hypophysitis. Since organ specific autoantibodies are frequent in patients with autoimmune endocrine disease as well as in their unaffected relatives, autoantibodies to this M(r) 49,000 pituitary cytosolic protein may represent markers for an immunological process affecting the pituitary gland.
Aged↗
Autoantibodies to the GM2-1 islet ganglioside and to GAD-65 at type 1 diabetes onset.
The GM2-1 islet ganglioside has been sequenced, found to be a novel ganglioside structure with a sialic acid moiety in the terminal position and two residues of non-acetylated galactosamine and also shown to be a target of autoantibodies in a subset of ICA+ relatives of type 1 diabetic patients who subsequently progressed to the overt disease. In the present study we determined whether antibodies to GM2-1 or to other pancreatic gangliosides (a) are also expressed at disease onset and (b) are correlated with other diabetes-associated autoantibodies. Pancreatic gangliosides were extracted from human pancreas and purified by thin layer chromatography (TLC). Anti-ganglioside autoantibodies were determined using an indirect immunoperoxidase technique performed directly on TLC plates in the following groups of patients: (a) newly diagnosed type 1 diabetic subjects before insulin therapy (n = 45); all were tested for GAD65 autoantibodies in a fluid-phase RIA using 35S-methionine-labelled recombinant human GAD65. Of these patients, 24 were also tested for insulin autoantibodies (IAA) by a competitive fluid phase radioimmunoassay and 21 were tested for GAD67 reactivity. (b) Forty-two age- and sex-matched normal control subjects. Autoantibodies to GM2-1, but not to other pancreatic gangliosides (GM3, GD3, GD1a), were expressed in 31 of 45 new-onset type 1 diabetic subjects and in one of 42 normal controls (P < 0.01), while anti-GAD65, IAA and anti-GAD67 were found in 31 of 45, 12 of 24 and three of 21 patients respectively, but not in the control group of subjects. Interestingly, occurrence of GM2-1 autoantibodies was significantly correlated (P < 0.005) with positivity for GAD65 autoantibodies, but not for IAA or GAD67 autoantibodies. It is of note that both GAD and gangliosides are mainly expressed in islets and in neuronal tissues and, therefore, type 1 diabetes may be regarded as a neuroendocrine autoimmune disease.
Adolescent↗
The lymphopenia (lyp) gene controls the intrathymic cytokine ratio in congenic BioBreeding rats.
The lymphopenia gene (lyp) on rat chromosome 4 is closely linked to autoimmune diabetes in the BioBreeding (BB) rat. Lyp controls the number of peripheral lymphocytes by reducing T cells of the RT6+ phenotype by almost 90%. Following nine cycle of marker-assisted cross-intercross breeding we have developed congenic lyp/lyp, lyp/+ and +/+ (wildtype) rats on the background of DR rats. Prediabetic and insulitis free lyp/lyp, lyp/+ and +/+ rats were used to determine the effect of lyp on cytokine expression in the thymus. In situ hybridization of thymus cryosections showed that the interferon gamma (IFN gamma) mRNA expression was highest in lyp/lyp rats and the hybridization signal was restricted to the medullary compartment. The frequency of IFN gamma and interleukin (IL)-10 mRNA expressing cells in isolated thymocytes determined by quantitative image analysis, demonstrated an increased IFN gamma: IL-10 ratio in thymocytes from lyp/lyp homozygotes compared to lyp/+ and +/+ rats. This confirmed a lyp gene dose-dependent segregation of the IFN gamma high phenotype. Recombinant human glutamic acid decarboxylase (GAD65) increased the number of IFN gamma and IL-10 mRNA expressing thymocytes after in vitro culture. We conclude that the quantitative ratio of cytokine producing thymocytes is associated with the lyp genotype. These potentially autoreactive thymocytes may explain the establishment of beta-cell directed autoimmunity in the BB rat despite peripheral lymphopenia.
Animals↗
The beta cell glucokinase promoter variant is an unlikely risk factor for diabetes mellitus. Diabetes Incidence Study in Sweden (DISS).
Glucokinase plays an important role in the regulation of insulin secretion and is therefore an attractive candidate gene for both insulin dependent (IDDM) and non-insulin-dependent (NIDDM) diabetes mellitus. A single G-A nucleotide polymorphism at the -30 position of the beta-cell specific promoter region of the glucokinase gene was previously associated with reduced beta-cell function. In the present study we analysed 268 consecutive newly diagnosed Swedish patients classified with either IDDM (n = 205), NIDDM (n = 31) or unclassifiable (n = 32) diabetes between the ages of 15 and 35 years along with a group of 158 age- and sex-matched control subjects. The beta-cell promoter region was amplified by the polymerase chain reaction and the G-A variant identified by single strand conformational polymorphism. There was no significant difference in allele frequencies of G and A between any of the subject groups and likewise, no significant difference in the frequencies of the G/G, G/A, or A/A genotypes. Eight subjects were homozygous for the less common A allele, five had IDDM and three were control subjects. Our results suggest that the -30 beta-cell glucokinase promoter variant is not associated with IDDM.
Adolescent↗
Family cell lines available for research--an endangered resource?
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Biological Specimen Banks↗
Regulation of islet growth: reports from the Second Seattle Islet Symposium.
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Animals↗
Analysis of critical residues of HLA-DQ6 molecules in insulin-dependent diabetes mellitus.
Among DQ6 molecules, DQA1*0102-DQB1*0602 is negatively associated with insulin-dependent diabetes mellitus (IDDM), but DQA1*0102-DQB1*0604 shows a neutral to positive association in Swedish children with IDDM. The aim of this study was to identify critical DQB1 residues that may account for the differences in IDDM association observed for these two DQ6 molecules. HLA-DQ genotyping in 425 IDDM patients and 367 matched controls showed DQ6 (B1*0602) in 1% of patients and 25% of controls (odds ratio (OR) 0.02). DQ6 (B1*0604) alone was neutral (9% of patients and 10% of controls) but in combination with DQ8, was positively associated (5% of patients, 1% of controls, OR 9.49). In both these DQ6 molecules the alpha-chain is the same but the beta-chain differs at positions 9, 30, 57, 70, 86 and 87. DQB1*0602 has F9, Y30, D57, G70, A86 and F87, whereas DQB1*0604 has Y9, H30, V57, R70, G86 and Y87. Three-dimensional models of the two DQ6 molecules, based on crystal coordinates of the homologous DR1 molecule, suggest that residue 57 beta will likely play a critical role in peptide-binding selectivity, whereas residue 70 beta is probably is major contact site for the T-cell receptor. The effects of these specific polymorphic substitutions in DQ molecules on peptide binding and T-cell receptor recognition may be significant in IDDM susceptibility.
Adolescent↗