Glutamic Acid Decarboxylase Autoantibodies Research Articles

Prevalence of diabetes-associated autoantibodies among patients presenting with type 2 diabetes and related metabolic differences

BackgroundTo explores the prevalence of autoantibodies (zinc transporter 8 autoantibodies (ZnT8A), antibodies to insulin (IAAs), glutamic acid decarboxylase autoantibody (GAD65)), the relation of the type of positive autoantibody and the number of positive autoantibodies with the glycemic and lipid profile of the patients with LADA (Latent Autoimmune Diabetes in Adults) and compares it to the metabolic profile of patients presenting with type 2 diabetes (T2DM). Methods263 patients with T2DM were recruited for this cross-sectional study in Tehran, Iran. Data from patients included complete medical history, GAD65, ZnT8A, IAA and routine metabolic laboratory workup. Assay for autoantibodies were conducted using ELISA kits. The association between autoantibodies and glycemic and lipid profile of patients with diabetes was assessed using univariate and multivariate regression analysis. ResultsOur study revealed that among 263 patients with T2DM, 29 (11%) cases were positive for IAAs, 9 (3.4%) for ZnT8A, and 12 (4.6%) for GAD65. Six (2.3%) of the patients had triple positive antibodies. Patients with positive results were younger, had lower body mass index (BMI), c-peptide, triglyceride, low-density lipoprotein (LDL), and higher high-density lipoprotein (HDL), HbA1c and fasting blood glucose (FBG) levels. Triple antibody positivity was significantly associated with lower levels of C-Peptide, Triglycerides, FBG, and HbA1c compared to triple negative antibodies. ConclusionPatients with LADA positive for either of the autoantibodies (GAD65, ZnT8 and IAA) presented with worse glycemic control. Measurement of these autoantibodies can assist in discrimination of these patients and help with earlier control of glycemic profile.

Islet cell and glutamic acid decarboxylase-65 autoantibodies in young diabetic patients attending in a General Hospital in Dhaka City

Background: Immune mediated destruction of pancreatic beta cell in type-I diabetes is well established but its’ role in young type-2 diabetic patients is still not conclusive. These young diabetic patients pass through several stages where they do not need insulin but found to have serum autoantibody against islets cell and even become dependent on insulin for survival in course of time. This study aims to find the presence of islets cell auto-antibodies (ICA) and autoantibody to glutamic acid decarboxylase-65 (GAD-65) in non-insulin requiring young diabetic patients of Bangladesh.
 Objective: To evaluate the presence of ICA and GAD-65 between the non-insulin requiring young type-2 diabetic patients and compare with the non-diabetic control group.
 Method: This case control study was carried out at the Department of Immunology, BIRDEM General Hospital, Dhaka for a period of one year from July 2013, A total of 120 non-insulin requiring (≥12 months) young type-2 diabetic patients and 60 age, sex matched non-diabetic were enrolled as control subjects following inclusion and exclusion criteria. ICA and GAD-65 tests were performed by enzyme linked immune-sorbent assay (ELISA) method by using kits from DRG Inc. International, USA.
 Results: In this study statistically significant difference found between non insulin requiring young diabetic patients and non diabetic control in respect of positive ICA result (p=0.015). The moderately strong negative association was found between different age of onset of diabetes mellitus and value of ICA level (r=-0.45). Only 20-24 years age group showed statistically significant difference between patient and control (p=0.013). Statistically significant difference was not found in GAD-65 values of non insulin requiring young diabetic patients and non diabetic controls (p=0.441).
 Conclusion: This study revealed that there is significant difference present in respect of ICA among non-insulin requiring young diabetic patients and non-diabetic controls. Therefore, autoimmune pathogenesis of beta cell killing by producing ICA against islets cell take place in young type-2 diabetic patients.
 Bangladesh Med Res Counc Bull 2020; 46(2): 104-108

A non-coding RNASEH1 gene variant associates with type 1 diabetes and interacts with HLA tagSNPs in families from Colombia.

RNASEH1 gene has recently been associated with type 1 diabetes (T1D) in Colombia. The purpose of this study was to fine mapping the putative functional variant in RNASEH1 and testing its interaction with HLA tagSNPs. Two-hundred nuclear families with T1D were included in this study. Probands were tested for GAD65 and IA-2 autoantibodies. Genotyping was performed using 20 coding tagSNPs uncovered through Sanger sequencing (N = 96), in addition to 23 tagSNPs chosen from 1000genomes to cover the extent of the gene region. Also, 45 tagSNPs for classic HLA alleles associated with T1D were also genotyped. The transmission disequilibrium test (TDT) was used to test for association and a multiple testing correction was made using permutation. Interaction between RNASEH1 variants and HLA was evaluated by means of the M-TDT test. We identified 20 variants (15 were novel) in the 96 patients sequenced. None of these variants were in linkage disequilibrium. In total, 43 RNASEH1 variants were genotyped in the 200 families. Association between T1D and rs7607888 was identified (P = .002). Haplotype analysis involving rs7607888 variant revealed even stronger association with T1D (most significative P = .0003). HLA tagSNPs displayed stronger associations (OR = 6.39, 95% CI = 4.33-9.44, P-value = 9.74E-28). Finally, we found several statistically significant interactions of HLA variants with rs7607888 (P-value ranged from 8.77E-04 to 5.33E-12). Our results verify the association of rs7607888 in RNASEH1 gene with T1D. It is also shown in the interaction between RNASEH1 and HLA for conveying risk to T1D in Northwest Colombia. Work is underway aiming to identify the actual classic HLA alleles associated with the tagSNPs tested here.

Rapid onset type 1 diabetes with anti-PD-1 directed therapy.

Type 1 diabetes is a rare immune-related adverse event (irAE) caused by checkpoint inhibitors with serious risk for diabetic ketoacidosis (DKA). Using our electronic medical record, we identified 1327 adult patients who received PD-(L)1 or CTLA-4 inhibitors from 2013 to 2018. Of the patients who received immunotherapy, 5 (0.38%) patients were found to have type 1 diabetes, all of whom presented with DKA requiring insulin at 20 to 972 days from their first anti-PD-(L)1 dose. All patients were treated with anti-PD-1 therapy (nivolumab or pembrolizumab). Four patients had new onset diabetes with mean HbA1c of 9.1% on DKA presentation and persistent elevations over time. Two patients who tested positive for glutamic acid decarboxylase (GAD) antibodies presented with DKA at 20 and 106 days from first anti-PD-1 administration whereas patients who were autoantibody negative had DKA more than a year later. Type 1 diabetes occurs within a wide time frame after anti-PD-1 initiation and commences with an abrupt course. Our case series suggests that monitoring glycemia in patients on PD-1 inhibitors is not predictive for diabetes occurrence. GAD autoantibodies could portend earlier onset for diabetes, although further prospective studies are needed to elucidate their diagnostic utility and contribution in therapeutic interception.

Characterization of patients with diabetes who were incidentally found to be glutamic acid decarboxylase autoantibody-positive by bridging-type enzyme-linked immunosorbent assay.

This study aimed to characterize diabetic patients incidentally found to be positive for glutamic acid decarboxylase autoantibodies (GADA) in general practice. Using bridging‐type enzyme‐linked immunosorbent assay, we screened 1,040 patients with phenotypic type 2 diabetes for GADA, finding 25 (2.4%) to be positive. However, on retesting, with a median interval of 19 days, 44% of GADA‐positive patients turned negative (Disappearing Group). The mean age at diabetes onset was significantly higher (P < 0.05) and GADA titers at first determination were significantly lower (P < 0.001) in the Disappearing Group compared with the Persistent Positive Group. On initial screening, all patients in the Disappearing Group had GADA titers of <6.5 U/mL. The current study showed that a portion of phenotypic type 2 diabetic patients incidentally identified as GADA‐positive were falsely positive, and that to avoid the misclassification, remeasurement of GADA is essential in cases showing very low titers.

Decline Pattern of Beta Cell Function in LADA: Relationship to GAD Autoantibodies.

Decline Pattern of Beta Cell Function in LADA: Relationship to GAD Autoantibodies.

1679-P: Islet Autoimmunity in Adults with Impaired Glucose Tolerance (IGT) and Newly Diagnosed, Treatment-Naïve Type 2 Diabetes (NDX T2D) in the Restoring Insulin Secretion (RISE) Study

In obesity, immune cells establish a systemic inflammatory state associated with development of insulin resistance and T2D. Previous studies have shown that peripheral blood mononuclear cell (PBMC) responses to islet proteins (IPs) in adults with established T2D on glucose-lowering therapies identify those patients with more severe β-cell dysfunction. Moreover, attenuation of PBMC responses to IPs in adults with established T2D improves β-cell function. However, the presence of IP reactive PBMCs, glutamic acid decarboxylase autoantibodies (GADA), and their relationship to insulin sensitivity and β-cell function has never been evaluated in IGT or Ndx T2D. We measured at baseline and after 12 months of RISE medication interventions (12 months with either metformin or liraglutide plus metformin or for 3 months with insulin glargine followed by 9 months of metformin), PBMC responses to IPs, GADA, insulin sensitivity, and β-cell function in 258 RISE participants (mean ± SD) 53.3 ± 9.2 years of age, BMI 35.1 ± 5.4 kg/m2, with IGT (n=180) or Ndx T2D (&amp;lt;12 months duration, n=78). At baseline, IP reactive PBMCs were present in 46% of participants with IGT and 40% of participants with Ndx T2D. However, 97% of IGT and 98% of Ndx T2D were GADA negative. There were no significant relationships between the presence of PBMC reactivity to IPs, GADA positivity and insulin sensitivity or β-cell function. RISE treatments did not alter PBMC responses to IPs, GADA, or the relationship between IP reactive PBMCs or GADA with glycemic responses. In summary, IP reactive PBMCs are present in a large percentage of adults with very early dysglycemia, However, the presence of IP reactive PBMCs did not correlate with insulin sensitivity or early β-cell dysfunction. Further studies are needed to unravel the pathogenesis of IP reactive PBMCs and GADA and their effects on β-cell function during progression of T2D. Disclosure B. Brooks-Worrell: None. A.H. Tjaden: None. S. Edelstein: None. B.M. Palomino: None. K. Utzschneider: Other Relationship; Self; Medtronic. S.A. Arslanian: Research Support; Self; National Institutes of Health. Other Relationship; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc. K.J. Mather: Research Support; Self; Abbott, Merck &amp; Co., Inc., Novo Nordisk Inc., Sanofi. T.A. Buchanan: None. K.J. Nadeau: None. K.M. Atkinson: None. E. Barengolts: None. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Janssen Scientific Affairs, LLC., Merck &amp; Co., Inc., Novo Nordisk A/S, Pfizer Inc. J.P. Palmer: None. Funding National Institutes of Health (R01DK107560)

1482-P: Effect of Age on Diabetes-Specific Autoantibodies in a Large Laboratory-Based Cohort

Type 1 diabetes mellitus (T1DM) can occur at any age, the presence of diabetes related autoantibodies predicts increased risk of disease and supports an autoimmune etiology for T1DM. Since 2017, Mayo Clinic Laboratories has been offering a comprehensive type 1 diabetes autoantibody evaluation (DM1Eval) which includes testing for 4 autoantibodies targeting glutamic acid decarboxylase autoantibodies (GAD), protein tyrosine phosphatase-like islet antigen 2 (IA-2), insulin (IAA), and zinc transporter 8 protein (ZnT8). The aim of this study was to determine the frequency of individual antibodies and antibody clusters (2, 3 or 4) stratified into 4 ages groups (children 0-17, young adult 18-35, middle aged 36-55 and older &amp;gt;55 years). Over a 30 month period (June 2017-Nov 2019) the DM1Eval was performed on 6,446 samples. At least 1 autoantibody was found in 3596 (56%) of all samples: 68% of children, 49% of young adults, 40% of middle aged and 41% of older adults. In patients with at least 1 antibody positive, GAD 65 antibodies were the most common in all age groups followed by ZnT8 in those &amp;lt;36 years or IAA antibody in those 36 and older older (Figure). The frequencies of IA2 and ZnT8 antibodies dropped significantly with increasing age strata. Autoantibody clusters of 3 or 4 antibodies were more frequently encountered in younger patients (41% of pediatric and 27% of young adult patients in contrast to just 12% in middle and older age groups). Disclosure A.R. Dahl: None. S. Pittock: None. A. McKeon: None. J. Foster: None. J. Mills: None.

100-OR: High-Affinity Islet Autoantibodies Predict Progression to Diabetes in Those Who Seroconvert after Age 10

The objective of this study was to determine if islet autoantibodies (IA) can develop de novo in youth ≥10 y. We also explored the risk of progression to T1D in youth seroconverting to IA after 10 y. From the prospective DAISY birth cohort (n=2547), we excluded those who were ever previously IA positive, disenrolled prior to age 10, or had &amp;gt;24 month gap in annual IA testing, leaving 917 for analysis. Seroconversion was defined as IA+ by radiobinding assays for insulin, GAD, IA-2 or ZnT8 autoantibodies, confirmed within 3-6 months. The same autoantibodies were also measured by electrochemiluminescence (ECL) assays, to identify high-affinity IA. IA developed after age 10 at a higher rate (p=0.049) in first-degree relatives than in general population youth with increased-risk HLA (Figure 1); there was no difference by sex or race/ethnicity. Of the 35 IA+ seroconverters, 6 progressed to T1D, during a median follow-up of 5.04 years (IQR: 3.56-8.45). This included 2 of 5 individuals who were multiple IA+ at seroconversion, with at least one IA confirmed as high-affinity by ECL. Among those with a single persistent IA+ at seroconversion, 4/9 youth with high-affinity IA (ECL+) progressed to T1D, compared to 0/21 of the youth with low-affinity IA (ECL-). In conclusion, seroconversion continues after age 10. In our genetically at-risk cohort, all who progress to T1D had high-affinity IA confirmed by ECL. Disclosure B.I. Frohnert: None. F. Dong: None. K. Waugh: None. A. Steck: None. J.M. Norris: None. L. Yu: None. M. Rewers: None. Funding JDRF (5-ECR-2017-388-A-N); National Institutes of Health (R01DK32493)

Type 1 diabetes and epilepsy in childhood and adolescence: Do glutamic acid decarboxylase autoantibodies play a role? Data from the German/Austrian/Swiss/Luxembourgian DPV Registry.

We aimed to analyze the relationship between epilepsy and glutamic acid decarboxylase autoantibodies (GADA) in patients with type 1 diabetes mellitus (T1DM) and the impact of GADA on demographic, clinical, and metabolic data in T1DM patients with epilepsy. We searched for patients with T1DM ≤20 years and GADA measurements, and within this group for patients with epilepsy. We formed groups: T1DM + Epilepsy + GADA positive; T1DM + Epilepsy + GADA negative; T1DM + GADA positive; T1DM + GADA negative. We used logistic regression to analyze the relationship between epilepsy and GADA with odds ratio adjusted for sex, duration of diabetes (DOD), and age at diabetes onset (ADO). We used logistic regression with odds ratio adjusted for DOD and ADO onset using epilepsy as a dependent variable and GADA, HbA1c, ketoacidosis, severe hypoglycemia (SH), sex, celiac disease, and autoimmune thyroiditis as independent variables. We conducted regression analyses adjusted for sex, DOD, and ADO to analyze differences in clinical/metabolic parameters between the groups. Epilepsy was not more frequent in GADA-positive patients (GPP). Logistic regression including all patients with GADA measurements showed that hypoglycemia with coma (HC) correlated with epilepsy when compared to no SH. We found no differences in clinical and metabolic data between GPP and GADA-negative patients (GNP) with epilepsy. SH occurred more often in GPP with epilepsy in comparison to GPP without epilepsy. GNP with epilepsy had a higher rate of HC than GPP without epilepsy. We found no relationship between epilepsy and GADA. A relationship between T1DM and epilepsy might be explainable by SH.

Impaired vibrotactile sense showed no association with insulinoma associated protein 2 and glutamic acid decarboxylase autoantibodies in paediatric type 1 diabetes.

Diabetic peripheral neuropathy (DPN) is a well-known complication of type 1 diabetes in children and adults and may present early after diagnosis. It is frequently asymptomatic in young patients, but can be confirmed using screening tools, such as monofilaments, tuning forks or a biothesiometer. Electrophysiology is the gold standard examination for detecting DPN, but is seldom used due to lack of resources and because it is time consuming, expensive and possibly unpleasant for subjects (1). Multi-frequency vibrometry can also determine impaired vibrotactile sense, a sign of large nerve fibre pathology (2). We previously studied this tool in 72 asymptomatic children and adolescents aged 8-18 with type 1 diabetes and 13 had impaired vibrotactile sense (2).

Zinc transporter8 autoantibodies complement glutamic acid decarboxylase and insulinoma-associated antigen-2 autoantibodies in the identification and characterization of Japanese type1 diabetes.

Aims/IntroductionThis study aimed to investigate the significance of zinc transporter 8 autoantibody (ZnT8A) in identifying and characterizing autoimmune‐mediated type 1 diabetes in Japanese individuals.MethodsZnT8A were determined in 324 patients with type 1 diabetes, 191 phenotypic type 2 diabetes and 288 healthy control individuals using bridging‐type enzyme‐linked immunosorbent assay in addition to autoantibodies to glutamic acid decarboxylase and insulinoma‐associated antigen‐2.ResultsWe set a cut‐off value of 10.0 U/mL, and 25% of the type 1 diabetic patients had ZnT8A levels exceeding this level. The prevalence of ZnT8A was significantly higher in patients with acute‐onset type 1 diabetes than in those with slowly progressive and fulminant type 1 diabetes (P < 0.05). ZnT8A were more frequent in patients aged ≤10 years, but less frequent in patients with duration ≥5 years (P < 0.05). ZnT8A were detected in 5.2% of phenotypic type 2 diabetic patients, with 90% of these being ZnT8A‐single‐positive. Furthermore, the ZnT8A levels in the phenotypic type 2 diabetes cohort (143.8 ± 194.9 U/mL) were significantly higher than those in the type 1 diabetes cohort (22.9 ± 8.3 U/mL, P < 0.05). In the acute‐onset and slowly progressive type 1 diabetic patients with duration ≤5 years, additional measurement of glutamic acid decarboxylase autoantibodies significantly increased the disease sensitivity in patients aged ≤10 years, but not in patients aged ≥11 years (11.7 vs 3.6%, P < 0.05). Multivariate analysis showed that ZnT8A positivity was independently associated with age at sampling and insulinoma‐associated antigen‐2 autoantibody positivity.ConclusionsThese results suggest that the bridging‐type ZnT8A enzyme‐linked immunosorbent assay might provide a valuable additional marker for Japanese patients with type 1 diabetes, which could, in turn, allow for an increase in the number of identifiable cases and differentiate clinical phenotypes.

Decline Pattern of Beta-cell Function in Adult-onset Latent Autoimmune Diabetes: an 8-year Prospective Study.

To explore the decline pattern and possible determinants of beta-cell function progression in patients with latent-onset autoimmune diabetes in adults (LADA). In this 8-year prospective study, 106 LADA individuals underwent annual follow-up and their pattern of beta-cell function progression was assessed. Beta-cell function failure was defined by fasting C-peptide (FCP) < 75 pmol/L. Other clinical characteristics, including age of onset, body mass index (BMI), and glutamic acid decarboxylase autoantibody (GADA) titer, were analyzed to find out possible determinants of beta-cell function progression. The dropout rate was 4.7%. During the 8-year follow-up period, 29 (28.7%) of the 101 subjects developed beta-cell function failure. The decline pattern of C-peptide in LADA was biphasic, showing an initial rapid linear progression and then followed by a stable mode. The declination speed of FCP was 55.19 pmol/L/year (95% CI, -62.54 to -47.84, P < 0.001) during the first 5 years and 4.62 pmol/L/year (95% CI, -69.83 to 60.60, P = 0.790) thereafter. Further analysis showed that GADA titer was the most valuable discriminatory parameter related to a higher risk of development of beta-cell function failure (GADA titer of 173.5 WHO units/mL; area under the curve [AUC], 0.824). Beta-cell function failure occurred in 71.3% of high-GADA titer patients while only 6.2% of low-titer patients. The decline pattern of C-peptide was a fast-followed-by-slow biphasic mode, with about a quarter of LADA patients developing beta-cell function failure during the first 8 years. GADA titer less than 173.5 WHO units /mL was propitious for the preservation of beta-cell function.

Motifs of Three HLA-DQ Amino Acid Residues (α44, β57, β135) Capture Full Association With the Risk of Type 1 Diabetes in DQ2 and DQ8 Children.

HLA-DQA1 and -DQB1 are strongly associated with type 1 diabetes (T1D), and DQ8.1 and DQ2.5 are major risk haplotypes. Next-generation targeted sequencing of HLA-DQA1 and -DQB1 in Swedish newly diagnosed 1- to 18 year-old patients (n = 962) and control subjects (n = 636) was used to construct abbreviated DQ haplotypes, converted into amino acid (AA) residues, and assessed for their associations with T1D. A hierarchically organized haplotype (HOH) association analysis allowed 45 unique DQ haplotypes to be categorized into seven clusters. The DQ8/9 cluster included two DQ8.1 risk and the DQ9 resistant haplotypes, and the DQ2 cluster included the DQ2.5 risk and DQ2.2 resistant haplotypes. Within each cluster, HOH found residues α44Q (odds ratio [OR] 3.29, P = 2.38 * 10−85) and β57A (OR 3.44, P = 3.80 * 10−84) to be associated with T1D in the DQ8/9 cluster representing all ten residues (α22, α23, α44, α49, α51, α53, α54, α73, α184, β57) due to complete linkage disequilibrium (LD) of α44 with eight such residues. Within the DQ2 cluster and due to LD, HOH analysis found α44C and β135D to share the risk for T1D (OR 2.10, P = 1.96 * 10−20). The motif “QAD” of α44, β57, and β135 captured the T1D risk association of DQ8.1 (OR 3.44, P = 3.80 * 10−84), and the corresponding motif “CAD” captured the risk association of DQ2.5 (OR 2.10, P = 1.96 * 10−20). Two risk associations were related to GAD65 autoantibody (GADA) and IA-2 autoantibody (IA-2A) but in opposite directions. CAD was positively associated with GADA (OR 1.56, P = 6.35 * 10−8) but negatively with IA-2A (OR 0.59, P = 6.55 * 10−11). QAD was negatively associated with GADA (OR 0.88; P = 3.70 * 10−3) but positively with IA-2A (OR 1.64; P = 2.40 * 10−14), despite a single difference at α44. The residues are found in and around anchor pockets 1 and 9, as potential T-cell receptor contacts, in the areas for CD4 binding and putative homodimer formation. The identification of three HLA-DQ AAs (α44, β57, β135) conferring T1D risk should sharpen functional and translational studies.

Impact of Pancreatic Autoantibodies in Pancreas Graft Survival After Pancreas-Kidney Transplantation

BackgroundIn simultaneous pancreas-kidney transplantation (SPKT), persistence or recurrence of pancreatic autoantibodies (PAs) has been associated with pancreas graft (PG) autoimmune-driven injury. Our aim was to analyze the impact of PAs on PG survival. MethodsBetween January 1, 2000, and December 31, 2017, we studied 139 patients with post-SPKT anti–glutamic acid decarboxylase (GAD) autoantibody. Alloimmune (ALI) events were defined as PG rejection and/or de novo donor-specific antibodies (DSA). Hence, 3 groups were defined: patients without ALI events or anti-GAD (n = 42), those with ALI events (n = 14), or those only with autoimmune events (positive for anti-GAD and no ALI events; n = 83). ResultsMale sex was predominant (n = 72, 52%). Median age was 35 years (interquartile range: 31-39) and median follow-up was 6-7 years (interquartile range: 4.1-9.2). Regarding anti-GAD positivity post-SPKT (n = 90, 65%), no differences were observed concerning age, sex, anti-HLA antibodies, HLA mismatch number and de novo DSA. ALI events were present in 10% (n = 14). PG survival 15 years post-SPKT was better in patients without immune events (96%) followed by those with ALI (69%) and autoimmune events (63%) (P = .025). Anti-GAD was associated to higher annualized mean Hb1AC (P = .006) and lower mean C-peptide (P = .013). According to pre- and post-SPKT anti-GAD status, conversion from negative to positive was associated to worse (63%) 10-year PG survival (P = .044), compared to persistence of negative (100%) or positive anti-GAD (88%). Anti-islet cell and anti-insulin autoantibodies had no impact. ConclusionAnti-GAD presence post-SPKT was associated to higher pancreas disfunction and lower PG survival. De novo anti-GAD seems to offer a particular risk of PG failure.

Study of the difficult glycemic control in relation to autoantibodies present among patients of Type 1 Diabetes mellitus (Glutamic acid decarboxylase autoantibodies GADA- Islet cells cytoplasmic autoantibodies ICA- Insulin autoantibodies IAA)

Abstract Background Type 1 DM is sub-divided into type 1A (immune-mediated) and type 1B (other forms of type 1 DM that include virus-triggered autoimmune response, genetic factors and idiopathic). It is widely recognized that the presence of two or more auto-antibodies has a high sensitivity and specificity for rapid progression to insulin dependency within 5 years. It is hypothesized that the difficult glycemic control among some type 1 diabetic patients is attributed to the presence of diabetes-autoantibodies. Aim This study was designed to assess the relationship between the presence of diabetes autoantibodies and the poor glycemic control developed by patients who receive more than 100 insulin units per day and yet they are not controlled i.e. HbA1c &amp;gt; 7%, elevated plasma glucose level on frequent monitoring although they are non-obese and strictly stuck to healthy diet and exercise, and whether the number of positive autoantibodies affect the glycemic control or not. Methods This study was conducted on 60 patients 30 males and 30 females, they were all subjected to full history taking, anthropometric measurements, clinical examination and laboratory assessment in the form of C-peptide, fasting blood glucose, 2 hours post-prandial blood glucose, HbA1c level, serum GADA level, serum ICA level and serum IAA level. The patients were classified according to presence of diabetes autoantibodies into two groups; Group I consisted of 6 patients (10%) with negative auto-antibodies and Group II consisted of 54 patients (90%) with positive auto-antibodies, Group II was further classified according to the number of positive diabetes autoantibodies into 3 sub-groups, Group II a: Formed of 9 patients with 1 positive autoantibody (16.7% of the study population). Group II b: Formed of 12 patients with 2 positive autoantibodies (22.2% of the study population) and Group II c: Formed of 33 patients with 3 positive autoantibodies (61.1% of the study population). Results HbA1c level was significantly higher in group II than group I (11.85 ± 1.61% vs. 8.52 ± 0.41%, p = 0.000). Similarly it was higher in group IIc than group IIb than group IIa (12.25 ± 1.48% vs. 11.57 ± 1.59% vs. 10.78 ± 1.73%, p = 0.038).Moreover HbA1c was significantly higher in patients with positive GADA, patients with positive ICA and those with positive IAA than those with negative GADA, negative ICA and negative IAA (p = 0.000, p = 0.000, p = 0.012 respectively). The total number of insulin units per day was significantly higher in group II than group I (109.83 ± 7.77 U/day vs. 100.83 ± 1.83 U/day, p = 0.007). The duration of diabetes mellitus was significantly higher in group I than group II (10.17 ± 1.94 years vs. 8.11 ± 2.20 years, p = 0.033). By doing the multivariate regression analyses we found that HbA1c level, total number of insulin units per day and the duration of developing diabetes mellitus were significant predictive factors for the presence of diabetes autoantibodies (p = 0.007, p = 0.033 and p = 0.043 respectively). Conclusion The presence of diabetes autoantibodies affect the glycemic control represented by HbA1c level; also it affects the total number of insulin units per day used by the patients; the more the presence of diabetes autoantibodies, the higher the HbA1c level, the more insulin units required by patients to control their glycemic state.

Distinct Growth Phases in Early Life Associated With the Risk of Type 1 Diabetes: The TEDDY Study.

This study investigates two-phase growth patterns in early life and their association with development of islet autoimmunity (IA) and type 1 diabetes (T1D). The Environmental Determinants of Diabetes in the Young (TEDDY) study followed 7,522 genetically high-risk children in Sweden, Finland, Germany, and the U.S. from birth for a median of 9.0 years (interquartile range 5.7-10.6) with available growth data. Of these, 761 (10.1%) children developed IA and 290 (3.9%) children were diagnosed with T1D. Bayesian two-phase piecewise linear mixed models with a random change point were used to estimate children's individual growth trajectories. Cox proportional hazards models were used to assess the effects of associated growth parameters on the risks of IA and progression to T1D. A higher rate of weight gain in infancy was associated with increased IA risk (hazard ratio [HR] 1.09 [95% CI 1.02, 1.17] per 1 kg/year). A height growth pattern with a lower rate in infancy (HR 0.79 [95% CI 0.70, 0.90] per 1 cm/year), higher rate in early childhood (HR 1.48 [95% CI 1.22, 1.79] per 1 cm/year), and younger age at the phase transition (HR 0.76 [95% CI 0.58, 0.99] per 1 month) was associated with increased risk of progression from IA to T1D. A higher rate of weight gain in early childhood was associated with increased risk of progression from IA to T1D (HR 2.57 [95% CI 1.34, 4.91] per 1 kg/year) in children with first-appearing GAD autoantibody only. Growth patterns in early life better clarify how specific growth phases are associated with the development of T1D.

Identification of a subgroup of black South Africans with type 1 diabetes who are older at diagnosis but have lower levels of glutamic acid decarboxylase and islet antigen 2 autoantibodies.

To compare the age at diagnosis and prevalence of islet autoantibody [glutamic acid decarboxylase (65kDa) 65 and islet antigen 2] positivity in black and white participants with type 1 diabetes in South Africa, and to analyse the relationship between age at diagnosis and the presence of autoantibodies. Participants were recruited from diabetes outpatient departments and autoantibodies to glutamic acid decarboxylase (65kDa) and islet antigen 2 were measured by enzyme-linked immunosorbent assay. We recruited 472 (353 black and 119 white) participants with type 1 diabetes. Age at diagnosis of diabetes was later in black (19.7±10.5) than in white participants (12.7±10.8years; P<0.001) with a median (interquartile range) disease duration of 5.0 (2.0-10.0) and 8.5 (4.0-20.0) years (P<0.001), respectively. An older age at diagnosis (≥21years) was more frequent in black (152 of 340, 45%) than in white participants (24 of 116, 21%; P<0.001). The prevalence of islet antigen 2 autoantibodies was 19% (66/352) in black and 41% in white participants (48/118; P<0.001). There was no significant difference in glutamic acid decarboxylase (65kDa) autoantibody positivity between black (212/353, 60%) and white participants (77/117, 66%; P=0.269). In black, but not white, participants the prevalence of both glutamic acid decarboxylase (65kDa) and islet antigen 2 autoantibody positivity was significantly lower in participants diagnosed at age≥21years (P<0.001 for both comparisons). The older age at diagnosis, lower prevalence of islet antigen 2 autoantibodies and a distinct subgroup of participants with type 1 diabetes with age at diagnosis of >20years in the black compared to white population suggest a difference in the immunological aetiology of type 1 diabetes in these two population groups.

The risk of progression to type 1 diabetes is highly variable in individuals with multiple autoantibodies following screening.

Young children who develop multiple autoantibodies (mAbs) are at very high risk for type 1 diabetes. We assessed whether a population with mAbs detected by screening is also at very high risk, and how risk varies according to age, type of autoantibodies and metabolic status. Type 1 Diabetes TrialNet Pathway to Prevention participants with mAbs (n = 1815; age, 12.35 ± 9.39years; range, 1-49years) were analysed. Type 1 diabetes risk was assessed according to age, autoantibody type/number (insulin autoantibodies [IAA], glutamic acid decarboxylase autoantibodies [GADA], insulinoma-associated antigen-2 autoantibodies [IA-2A] or zinc transporter 8 autoantibodies [ZnT8A]) and Index60 (composite measure of fasting C-peptide, 60min glucose and 60min C-peptide). Cox regression and cumulative incidence curves were utilised in this cohort study. Age was inversely related to type 1 diabetes risk in those with mAbs (HR 0.97 [95% CI 0.96, 0.99]). Among participants with 2 autoantibodies, those with GADA had less risk (HR 0.35 [95% CI 0.22, 0.57]) and those with IA-2A had higher risk (HR 2.82 [95% CI 1.76, 4.51]) of type 1 diabetes. Those with IAA and GADA had only a 17% 5year risk of type 1 diabetes. The risk was significantly lower for those with Index60 <1.0 (HR 0.23 [95% CI 0.19, 0.30]) vs those with Index60 values ≥1.0. Among the 12% (225/1815) ≥12.0years of age with GADA positivity, IA-2A negativity and Index60 <1.0, the 5year risk of type 1 diabetes was 8%. Type 1 diabetes risk varies substantially according to age, autoantibody type and metabolic status in individuals screened for mAbs. An appreciable proportion of older children and adults with mAbs appear to have a low risk of progressing to type 1 diabetes at 5years. With this knowledge, clinical trials of type 1 diabetes prevention can better target those most likely to progress.

Type 1 diabetes loci display a variety of native American and African ancestries in diseased individuals from Northwest Colombia.

BACKGROUNDType 1 diabetes (T1D) is a complex disease with a higher incidence in Europeans than other populations. The Colombians Living in Medellin (CLM) is admixed with ancestry contributions from Europeans, Native Americans (NAT) and Africans (AFR).AIMOur aim was to analyze the genetic admixture component at candidate T1D loci in Colombian individuals with the disease.METHODSSeventy-four ancestry informative markers (AIMs), which tagged 41 T1D candidate loci/genes, were tested by studying a cohort of 200 Northwest Colombia diseased individuals. T1D status was classified by testing for glutamic acid decarboxylase (GAD-65 kDa) and protein tyrosine-like antigen-2 auto-antibodies in serum samples. Candidate loci/genes included HLA, INS, PTPN22, CTLA4, IL2RA, SUMO4, CLEC16A, IFIH1, EFR3B, IL7R, NRP1 and RNASEH1, amongst others. The 1,000 genome database was used to analyze data from 94 individuals corresponding to the reference CLM. As the data did not comply with a normal distribution, medians were compared between groups using the Mann-Whitney U-test.RESULTSBoth T1D patients and individuals from CLM displayed mainly European ancestry (61.58 vs 62.06) followed by Native American (27.34 vs 27.46) and to a lesser extent the AFR ancestry (10.28 vs 10.65) components. However, compared to CLM, ancestry of T1D patients displayed a decrease of NAT ancestry at gene EFR3B (24.30 vs 37.10) and an increase at genes IFIH1 (32.07 vs 14.99) and IL7R (52.18 vs 39.18). Also, for gene NRP1 (36.67 vs 0.003), we observed a non-AFR contribution (attributed to NAT). Autoimmune patients (positive for any of two auto-antibodies) displayed lower NAT ancestry than idiopathic patients at the MHC region (20.36 vs 31.88). Also, late onset patients presented with greater AFR ancestry than early onset patients at gene IL7R (19.96 vs 6.17). An association analysis showed that, even after adjusting for admixture, an association exists for at least seven such AIMs, with the strongest findings on chromosomes 5 and 10 (gene IL7R, P = 5.56 × 10-6 and gene NRP1, P = 8.70 × 10-19, respectively).CONCLUSIONAlthough Colombian T1D patients have globally presented with higher European admixture, specific T1D loci have displayed varying levels of Native American and AFR ancestries in diseased individuals.