Islet Cell Antibodies Represent Autoimmune Response Against Several Antigens

To study the antigens involved in the islet cell antibody (ICA) reaction we selected 30 patient serum samples (ten in each group) positive for ICA and one other additional autoantibody, such as glutamic acid decarboxylase antibodies (GADA), thyrosine phosphatase antibodies (IA-2A) or insulin autoantibodies (IAA). The serum samples were incubated with the specific antigen (GAD65, IA-2 or insulin) and the ICA analysis and the corresponding immunoprecipitation assay were performed before and after the absorption

β-cell function and metabolic control in latent autoimmune diabetes in adults with early insulin versus conventional treatment: a 3-year follow-up

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 164 239-24

IgG4 subclass glutamic acid decarboxylase antibodies (GADA) are associated with a reduced risk of developing type 1 diabetes as well as increased C-peptide levels in GADA positive gestational diabetes.

Some women with gestational diabetes (GDM) present with autoantibodies associated with type 1 diabetes. These are usually directed against glutamic acid decarboxylase (GADA) and suggested to predict development of type 1 diabetes. The primary aim of this study was to investigate if GADA IgG subclasses at onset of GDM could assist in predicting postpartum development. Of 1225 women diagnosed with first-time GDM only 51 were GADA-positive. Total GADA was determined using ELISA. GADA subclasses were determined with radioimmunoassay. Approximately 25% of GADA-positive women developed type 1 diabetes postpartum. Titers of total GADA were higher in women that developed type 1 diabetes (142.1 vs 74.2u/mL; p=0.04) and they also had lower titers of GADA IgG4 (index=0.01 vs 0.04; p=0.03). In conclusion we found that that women with high titers of total GADA but low titers of GADA IgG4 were more prone to develop type 1 diabetes postpartum

Primary triage nurses do not divert patients away from the emergency department at times of high in-hospital bed occupancy - a retrospective cohort study

Background: Emergency department (ED) overcrowding is frequently described in terms of input- throughput and output. In order to reduce ED input, a concept called primary triage has been introduced in several Swedish EDs. In short, primary triage means that a nurse separately evaluates patients who present in the Emergency Department (ED) and either refers them to primary care or discharges them home, if their complaints are perceived as being of low acuity. The aim of the present study is to elucidate whether high levels of in-hospital bed occupancy are associated with decreased permeability in primary triage. The appropriateness of discharges from primary triage is assessed by 72-h revisits to the ED. Methods: The study is a retrospective cohort study on administrative data from the ED at a 420-bed hospital in southern Sweden from 2011-2012. In addition to crude comparisons of proportions experiencing each outcome across strata of in-hospital bed occupancy, multivariate models are constructed in order to adjust for age, sex and other factors. Results: A total of 37,129 visits to primary triage were included in the study. 53.4 % of these were admitted to the ED. Among the cases referred to another level of care, 8.8 % made an unplanned revisit to the ED within 72 h. The permeability of primary triage was not decreased at higher levels of in-hospital bed occupancy. Rather, the permeability was slightly higher at occupancy of 100-105 % compared to <95 % (OR 1.09 95 % CI 1.02-1.16). No significant association between in-hospital bed occupancy and the probability of 72-h revisits was observed. Conclusions: The absence of a decreased permeability of primary triage at times of high in-hospital bed occupancy is reassuring, as the opposite would have implied that patients might be denied entry not only to the hospital, but also to the ED, when in-hospital beds are scarce

Genetic prediction of postpartum diabetes in women with gestational diabetes mellitus

Aims: To examine whether genetic variants that predispose individuals to type 2 diabetes (T2D) could predict the development of diabetes after gestational diabetes mellitus (GDM). Methods: 13 SNPs (FTO rs8050136, CDKAL1 rs7754840 and rs7756992, CDKN2A/2B rs10811661, HHEX rs1111875, IGF2BP2 rs1470579 and rs4402960, SLC30A8 rs13266634, TCF7L2 rs7903146, PPARG rs1801282, GCK rs1799884, HNF1A rs1169288, and KCNJ11 rs5219) were genotyped in 793 women with GDM after a median follow-up of 57 months. Results: After adjustment for age and ethnicity, the TCF7L2 rs7903146 and the FTO rs8050136 variants significantly predicted postpartum diabetes; hazard ratio (95% confidence interval 1.29 (1.01-1.66) and 1.36 (1.06-1.74), respectively (additive model) versus 1.45 (1.01-2.08) and 1.56 (1.06-2.29) (dominant model)). Adjusting for BMI attenuated the effect of the FTO variant, suggesting that the effect was mediated through its effect on BMI. Combining all risk alleles to a weighted risk score was significantly associated with the risk of postpartum diabetes (hazard ratio 1.11, 95% confidence interval 1.05-1.18, p = 0.00016 after adjustment for age and ethnicity). Conclusions: The TCF7L2 rs7903146 and FTO rs8050136 polymorphisms, and particularly a weighted risk score of T2D risk alleles, predict diabetes after GDM. Further studies in other populations are needed to confirm our results. (C) 2012 Elsevier Ireland Ltd. All rights reserved

Insulin detemir offers improved glycemic control compared with NPH insulin in people with type 1 diabetes - A randomized clinical trial

OBJECTIVE—Insulin detemir is a soluble long-acting basal insulin analog designed to overcome the limitations of conventional basal insulin formulations. Accordingly, insulin detemir has been compared with NPH insulin with respect to glycemic control (HbA1c, prebreakfast glucose levels and variability, and hypoglycemia) and timing of administration. RESEARCH DESIGN AND METHODS—People with type 1 diabetes (n = 408) were randomized in an open-label, parallel-group trial of 16-week treatment duration using either insulin detemir or NPH insulin. Insulin detemir was administered twice daily using two different regimens, either before breakfast and at bedtime (IDetmorn+bed) or at a 12-h interval (IDet12h). NPH insulin was administered before breakfast and at bedtime. Mealtime insulin was given as the rapid-acting insulin analog insulin aspart. RESULTS—With both insulin detemir groups, clinic fasting plasma glucose was lower than with NPH insulin (IDet12h vs. NPH, −1.5 mmol/l [95% CI −2.51 to −0.48], P = 0.004; IDetmorn+bed vs. NPH, −2.3 mmol/l (−3.32 to −1.29), P < 0.001), as was self-measured prebreakfast plasma glucose (P = 0.006 and P = 0.004, respectively). The risk of minor hypoglycemia was lower in both insulin detemir groups (25%, P = 0.046; 32%, P = 0.002; respectively) compared with NPH insulin in the last 12 weeks of treatment, this being mainly attributable to a 53% reduction in nocturnal hypoglycemia in the IDetmorn+bed group (P < 0.001). Although HbA1c for each insulin detemir group was not different from the NPH group, HbA1c for the pooled insulin detemir groups was significantly lower than for the NPH group (mean difference −0.18% [−0.34 to −0.02], P = 0.027). Within-person between-day variation in self-measured prebreakfast plasma glucose was lower for both detemir groups (both P < 0.001). The NPH group gained weight during the study, but there was no change in weight in either of the insulin detemir groups (IDet12h vs. NPH, −0.8 kg [−1.44 to −0.24], P = 0.006; IDetmorn+bed vs. NPH, −0.6 kg [−1.23 to −0.03], P = 0.040). CONCLUSIONS—Overall glycemic control with insulin detemir was improved compared with NPH insulin. The data provide a basis for tailoring the timing of administration of insulin detemir to the individual person’s needs

Antibodies to the Mr 64,000 (64K) protein in islet cell antibody positive non-diabetic individuals indicate high risk for impaired Beta-cell function

A prospective study of a normal childhood population identified 44 islet cell antibody positive individuals. These subjects were typed for HLA DR and DQ alleles and investigated for the presence of antibodies to the Mr 64,000 (64K) islet cell antigen, complement-fixing islet cell antibodies and radiobinding insulin autoantibodies to determine their potency in detecting subjects with impaired Beta-cell function. At initial testing 64K antibodies were found in six of 44 islet cell antibody positive subjects (13.6%). The same sera were also positive for complement-fixing islet cell antibodies and five of them had insulin autoantibodies. During the follow-up at 18 months, islet cell antibodies remained detectable in 50% of the subjects studied. In all six cases who were originally positive, 64K antibodies were persistently detectable, whereas complement-fixing islet cell antibodies became negative in two of six and insulin autoantibodies in one of five individuals. HLA DR4 (p < 0.005) and absence of asparic acid (Asp) at position 57 of the HLA DQ chain (p < 0.05) were significantly increased in subjects with 64K antibodies compared with control subjects. Of 40 individuals tested in the intravenous glucose tolerance test, three had a first phase insulin response below the first percentile of normal control subjects. Two children developed Type 1 (insulin-dependent) diabetes mellitus after 18 and 26 months, respectively. Each of these subjects was non-Asp homozygous and had persistent islet cell and 64K antibodies. We conclude that 64K antibodies, complement-fixing islet cell antibodies and insulin autoantibodies represent sensitive serological markers in assessing high risk for a progression to Type 1 diabetes in islet cell antibody positive non-diabetic individuals

Variability in the CIITA gene interacts with HLA in multiple sclerosis

The human leukocyte antigen (HLA) is the main genetic determinant of multiple sclerosis (MS) risk. Within the HLA, the class II HLA-DRB1*15:01 allele exerts a disease-promoting effect, whereas the class I HLA-A*02 allele is protective. The CIITA gene is crucial for expression of class II HLA molecules and has previously been found to associate with several autoimmune diseases, including MS and type 1 diabetes. We here performed association analyses with CIITA in 2000 MS cases and up to 6900 controls as well as interaction analysis with HLA. We find that the previously investigated single-nucleotide polymorphism rs4774 is associated with MS risk in cases carrying the HLA-DRB1*15 allele (P=0.01, odds ratio (OR): 1.21, 95% confidence interval (CI): 1.04-1.40) or the HLA-A*02 allele (P=0.01, OR: 1.33, 95% CI: 1.07-1.64) and that these associations are independent of the adjacent confirmed MS susceptibility gene CLEC16A. We also confirm interaction between rs4774 and HLA-DRB1*15:01 such that individuals carrying the risk allele for rs4774 and HLA-DRB1*15:01 have a higher than expected risk for MS. In conclusion, our findings support previous data that variability in the CIITA gene affects MS risk, but also that the effect is modulated by MS-associated HLA haplotypes. These findings further underscore the biological importance of HLA for MS risk.This work was supported by grants from the Juvenile Diabetes Research Foundation International (2-2000-570 and 1-2001-873), the Swedish Research Council, Swedish Diabetes Foundation, Swedish Child Diabetes Foundation, The Swedish association of persons with neurological disabilities (Neurologiskt Handikappades Riksforbund, NHR), Novo Nordisk Foundation, Magnus Bergvalls Foundation, Neuropromise (LSHM-CT-2005-018637) and the International Multiple Sclerosis Genetics Consortium (IMSGC)Publishe