Autoantibodies against IA-2, GAD, and topoisomerase II in type 1 diabetic patients

Prevalence of autoantibodies against IA-2 (IA-2A), glutamic acid decarboxylase (GADA), and type II DNA topoisomerase (TopIIA) of Taiwanese type 1 diabetes mellitus (T1DM) patients was investigated. Correlations of these autoantibodies with patients' clinical manifestations were also analyzed. Prevalence of IA-2A, GADA, and TopIIA in our patients was 23.6%, 47.1%, and 55.2%, respectively. Eighty percent of the IA-2A recognized the carboxyl terminus of the IA-2 protein tyrosine phosphatase-like domain. Average disease duration of IA-2A+ patients was significantly shorter than that of IA-2A- patients [3.76+/-0.42 vs. 4.98+/-0.34 years, p = 0.028]. Presence of GADA was correlated with the mean age of onset [10.82+/-0.76 vs. 8.38+/-0.77 years for GADA+ and GADA- patients, p = 0.026]. Patients with adolescent onset have higher GADA prevalence and better residual beta-cell functions. TopIIA and GADA are suggested to be better markers for Taiwanese T1DM patients because of their higher prevalence and persistence.     

Radioimmunologic determination of pituitary autoantibodies in patients with Addison's disease]

The occurrence of pituitary autoantibodies was investigated in 34 patients, 25 females and 9 males, with Addison's disease of autoimmune origin and in 10 patients with tuberculous etiology of the disease. In both groups adrenal autoantibodies were also determined. Autoantibodies were determined by radioimmunoassay using solid phase technique in tubes coated with proteins of human adrenal and pituitary microsomal fractions. Pituitary autoantibodies were detected in 28 of 34 patients (20 females and 8 males) with autoimmune Addison's disease but only in 3 patients (2 females and one male) with nonimmune etiology of the disease. Both antipituitary and antiadrenal antibodies remain present in the circulation for many years as they were detected in autoimmune Addison's disease even after 10 or more years after the onset of the disease. There was a close relationship between the occurrence of pituitary antibodies and adrenal autoantibodies: they both appeared in the same patients and high titres of pituitary autoantibodies were associated with high titres of adrenal autoantibodies. This suggests a close similarity or identity of pituitary and adrenal autoantigens.     

Anti-GAD-positive patients with type 1 diabetes mellitus have higher prevalence of autoimmune thyroiditis than anti-GAD-negative patients with type 1 and type 2 diabetes mellitus

The aim of our study was to evaluate antibodies against thyroglobulin (anti-TG) and thyroid peroxidase (anti-TPO) - markers of autoimmune thyroiditis - in several groups of adult patients with type 1 and type 2 diabetes mellitus (DM). We were particularly interested whether the presence of thyroid antibodies is related to the positivity of glutamic acid decarboxylase antibodies (anti-GAD). We found elevated anti-GAD in 46 % (97/210) patients with type 1 DM. All patients with type 2 diabetes were anti-GAD-negative. At least one thyroid antibody (anti-TG and/or anti-TPO) was found in 30 % (62/210) patients with type 1 DM and 27 % (22/83) type 2 diabetes patients. The patients with type 1 DM were further grouped according to their anti-GAD status. The anti-GAD-positive patients had a higher prevalence of anti-TG antibodies than the anti-GAD-negative patients (25 % vs. 12 %, p=0.03) as well as anti-TPO antibodies (32 % vs. 12 %, p<0.001). At least one thyroid antibody was detected in 39 % (38/97) of anti-GAD-positive but only in 21 % (24/113) of anti-GAD-negative patients with type 1 DM (p=0.006). No significant difference in the frequency of thyroid antibodies was found between anti-GAD-negative patients with type 1 and type 2 DM (21 % vs. 27 %, p=0.4). The groups with or without thyroid antibodies in both type 1 and type 2 diabetic patients did not differ in actual age, the age at diabetes onset, duration of diabetes, body mass index or HbA1c level. Patients with elevated thyroid antibodies had significantly higher levels of TSH than those without thyroid antibodies (1.86 vs. 3.22 mIU/l, p=0.04 in type 1 DM; 2.06 vs. 4.89 mIU/l, p=0.003 in type 2 DM). We conclude that there is a higher frequency of thyroid-specific antibodies in anti-GAD-positive adult patients with type 1 DM than in anti-GAD-negative patients or in patients with type 2 DM. Patients with or without thyroid antibodies do not differ in age, DM onset and duration, BMI or HbA1c. Thyroid antibodies-positive patients have higher levels of thyroid stimulating hormone (TSH).     

Early and quantal (by litter) expression of insulin autoantibodies in the nonobese diabetic mice predict early diabetes onset

Aiming to study the early stages of type 1 diabetes phenotype, before insulitis appears, we measured insulin autoantibodies (IAA) between 3 and 5 wk of age in the NOD mouse (early-IAA (E-IAA)). We report that IAA are found as early as at 3 wk of age, at weaning, and their expression is a quantal phenotype. Maternal autoantibody status influences this early phenotype, because animals of litters issued from IAA-positive ante partum mothers develop E-IAA with a significantly higher incidence than animals issued from IAA-negative mothers. These E-IAA represent synthesized rather than transplacental autoantibodies, as evidenced by higher levels in many offspring compared with maternal IAA, and negative as well as positive offspring in the same litters and it correlates with early diabetes onset, defining the first autoimmune window in diabetes pathogenesis. Therefore, autoimmune processes leading to type 1 diabetes initiate early in life, are influenced by maternal autoantibody status, and can be revealed by the presence of IAA. Our data suggest that the mechanisms responsible for the breakdown of self-tolerance are subjected not only to genetic predisposition, but also to the physiological status of the mother. Pathological progression to autoimmunity is marked by the presence of immunological windows relating early steps with final disease onset.     

Polymorphism of INS VNTR is associated with glutamic acid decarboxylase antibodies and postprandial C-peptide in patients with onset of diabetes after 35 years of age

Variability in the number of tandem repeats of the insulin gene (INS VNTR) is probably involved in the genetic regulation of insulin secretion. The aim of this study was to investigate the association of INS VNTR polymorphism with the presence of glutamic acid decarboxylase antibodies (GADA) and C-peptide levels in patients with the onset of diabetes after 35 years of age. We investigated 117 patients, median of age 63 (range 40-83) years, median of diabetes duration 8 (range 1-30) years; 31 GADA-positive and 86 GADA-negative subjects. INS VNTR polymorphism was typed indirectly using - 23HphI (T/A) polymorphism, which is in complete linkage disequilibrium with INS VNTR. The I/I, I/III and III/III genotypes were found in 22 (71 %), 8 (26 %), 1 (3 %) GADA-positive individuals and in 39 (45 %), 35 (41 %), 12 (14 %) GADA-negative individuals, respectively. The Class I allele and the genotype I/I were significantly associated with the presence of GADA (OR=2.72, CI 95 %=1.29-5.73 and OR=2.95, CI 95 %=1.22-7.13). The presence of Class III allele was significantly associated with a higher level of postprandial C-peptide in GADA-positive subjects, even when regarding the duration of diabetes. Our results of INS VNTR polymorphism in patients with the onset of diabetes after 35 years of age confirm the association of Class I INS VNTR with autoimmune diabetes and the protective effect of Class III INS VNTR on the insulin secretion in GADA-positive subjects.     

High frequency of diabetes-specific autoantibodies in parents of children with type 1 diabetes. DENIS study group.

Strategies to identify subjects at risk for type 1 diabetes are largely based on the detection of autoantibodies directed to various beta cell autoantigens. Most previous studies only comprise siblings and children of patients with type 1 diabetes; only scare data are available on the antibody profile in older relatives. In this study, we examined the prevalence of cytoplasmic islet cell antibodies (ICA), antibodies to glutamic acid decarboxylase (GADA), antibodies to the protein tyrosine phosphatase IA-2 (IA-2A) and IA-2beta (IA-2betaA) in 531 unaffected parents of patients with type 1 diabetes, and compared the results with antibody frequencies in 2425 siblings. The frequency of ICA, GADA and IA-2A was substantially higher among siblings as compared to parents of patients with type 1 diabetes (8.0% vs. 4.5%, 8.0% vs. 4.3%, and 4.5% vs. 1.9%, respectively; p<0.01). However, subdividing the probands according to age revealed a high prevalence of ICA (5.5 %), GADA (5.9 %), and IA-2A (3.1%) among parents aged 31 -40 years which was similar to that observed in siblings above 20 years of age (6.4%, 6.4%, and 3.1%). In both cohorts, GADA and IA-2A were significantly associated with the presence of ICA. The combined screening for GADA and IA-2A identified 100% of parents and 91.9% of siblings at high risk for type 1 diabetes (>10 JDF-U). Furthermore, the analysis of antibody combinations revealed that among antibody positive individuals the percentage of subjects with two or three antibodies was even higher in parents (69.0%) than in siblings (58.2%). The present study shows a high frequency of single and multiple autoantibodies in unaffected parents of patients with type 1 diabetes. Our data indicate that GAD and IA-2 not only represent the major target of autoantibodies in young siblings but also in adult relatives. These findings may be important for the design of future intervention studies.     

IAA、ICA及GADA联合检测对糖尿病分型的诊断价值

目的:探讨胰岛素自身抗体(IAA)、胰岛细胞抗体(ICA)及谷氨酸脱羧酶抗体(GADA)联合检测对糖尿病分型的诊断价值。方法:选择2015年6月~2016年6月在我院进行诊治的1型糖尿病患者30例为A组,2型糖尿病患者60例为B组,同期在我院进行体检健康者50例为C组,采用酶联免疫吸附法(ELISA)检测三组的IAA、ICA及GADA,比较三组的阳性检出率。结果:A组空腹血糖为(10.12±3.68)mmol/L,B组空腹血糖为(11.23±3.26)mmol/L,A组和B组的空腹血糖均明显高于C组(4.35±1.42mmol/L)(P0.05),但A组和B组的空腹血糖相比无明显差异(P0.05);A组和B组的IAA、ICA及GADA单独和联合检测的阳性率均明显高于C组(P0.05),且A组的IAA、ICA及GADA单独和联合检测的阳性率明显高于B组(P0.05);IAA、ICA及GADA联合检测对1型和2型糖尿病的敏感性和特异性均明显高于单独检测(P0.05)。结论:IAA、ICA及GADA联合检测对糖尿病分型具有较高的临床诊断价值。     

Premature chromosome condensation is not essential for nuclear reprogramming in bovine somatic cell nuclear transfer

Premature chromosome condensation (PCC) was believed to promote nuclear reprogramming and to facilitate cloning by somatic cell nuclear transfer (NT) in mammalian species. However, it is still uncertain whether PCC is necessary for the successful reprogramming of an introduced donor nucleus in cattle. In the present study, fused NT embryos were subjected to immediate activation (IA, simultaneous fusion and activation), delayed activation (DA, activation applied 4 h postfusion), and IA with aged oocytes (IAA, activation at the same oocyte age as group DA). The morphologic changes, such as nuclear swelling, the occurrence of PCC, and microtubule/aster formation, were analyzed in detail by laser-scanning confocal microscopy. When embryos were subjected to IA in both IA and IAA groups, the introduced nucleus gradually became swollen, and a pronuclear-like structure formed within the oocyte, but PCC was not observed. In contrast, delaying embryo activation resulted in 46.5%-91.2% of NT embryos exhibiting PCC. This PCC was observed beginning at 4 h postcell fusion and was shown as one, two, or multiple chromosomal complexes. Subsequently, a diversity of pronuclear-like structures existed in NT embryos, characterized as single, double, and multiple nuclei. In the oocytes exhibiting PCC, the assembled spindle structure was observed to be an interactive mass, closely associated with condensed chromosomes, but no aster had formed. Regardless of whether they were subjected to IA, IAA, or DA treatments, if the oocytes contained pronuclear-like structures, either one or two asters were observed in proximity to the nuclei. A significantly higher rate of development to blastocysts was achieved in embryos that were immediately activated (IA, 59.1%; IAA, 40.7%) than in those for which activation was delayed (14.2%). The development rate was higher in group IA than in group IAA, but it was not significant (P = 0.089). Following embryo transfer, there was no statistically significant difference in the pregnancy rates (Day 70) between two of the groups (group IA, 11.7%, n = 94 vs. group DA, 12.3%, n = 130; P > 0.05) or live term development (group IA, 4.3% vs. group DA, 4.6%; P > 0.05). Our study has demonstrated that the IA of bovine NT embryos results in embryos with increased competence for preimplantational development. Moreover, PCC was shown to be unnecessary for the reprogramming of a transplanted somatic genome in a cattle oocyte.     

Clinical characteristics, and time course of pancreatic beta-cell function and glutamic acid decarboxylase antibodies in Thai patients with adult-onset Type 1 diabetes: distinction between patients of rapid- and slow-onset.

In order to study the clinical characteristics, time course of beta cell function and glutamic acid decarboxylase antibodies (GAD65Ab) in Thai patients with adult-onset Type 1 diabetes and to examine the distinctive features between patients with rapid-and slow-onset, 61 Thai patients with Type 1 diabetes who had age of disease onset at or after 20 years were studied. All patients were treated with insulin at the time of study and had fasting C-peptide levels +/-0.33 nmol/l. Twenty-six (42.6%) were in rapid-onset and 35 (57.4%) were in slow-onset groups. Fourty-four of 61 (70.5%) were male. About three-fourths had body mass index (BMI) < 19 kg/m2 at the time of insulin therapy. Only 7 of 61 (11.5%) patients had ketoacidosis at first presentation. Five patients had associated autoimmune thyroid disease and 10 (16.7%) patients had family history of diabetes in first-degree relatives. GAD65Ab was positive in 31 patients (50.8%); 10 (38.5%) were in rapid-onset and 21 (60.0%) were in slow-onset groups. GAD65Ab particularly of high levels were persistently elevated during 3-4 years follow-up period. The persistence of GAD65Ab were not associated with changes in fasting C-peptide levels. At the time of insulin dependency, there were no distinctive clinical features between rapid- and slow-onset patients except higher fasting C-peptide (0.08+/-0.08 vs. 0.14+/-0.10 nmol/l; p = 0.023) and GAD65Ab levels (19.6+/-17.4 vs. 46.1+/-49.7 U/ml; p = 0.036) in slow-onset patients. Fasting C-peptide levels of patients in the latter group were also demonstrated to be higher after 3-4 years of follow-up. In conclusion, most Thai patients with adult-onset Type 1 diabetes in this study were male and had significant degree of weight loss and lean BMI prior to insulin therapy. The presence of GAD65Ab did not predict clinical features or rate of beta cell loss. Patients in rapid-onset group had lower fasting C-peptide and GAD65Ab levels than those of slow-onset group which confirms the slower process of beta cell failure in the latter.     

Quantifying Cancer Absolute Risk and Cancer Mortality in the Presence of Competing Events after a Myotonic Dystrophy Diagnosis

Recent studies show that patients with myotonic dystrophy (DM) have an increased risk of specific malignancies, but estimates of absolute cancer risk accounting for competing events are lacking. Using the Swedish Patient Registry, we identified 1,081 patients with an inpatient and/or outpatient diagnosis of DM between 1987 and 2007. Date and cause of death and date of cancer diagnosis were extracted from the Swedish Cause of Death and Cancer Registries. We calculated non-parametric estimates of absolute cancer risk and cancer mortality accounting for the high non-cancer competing mortality associated with DM. Absolute cancer risk after DM diagnosis was 1.6% (95% CI=0.4-4%), 5% (95% CI=3-9%) and 9% (95% CI=6-13%) at ages 40, 50 and 60 years, respectively. Females had a higher absolute risk of all cancers combined than males: 9% (95% CI=4-14), and 13% (95% CI=9-20) vs. 2% (95%CI= 0.7-6) and 4% (95%CI=2-8) by ages 50 and 60 years, respectively) and developed cancer at younger ages (median age =51 years, range=22-74 vs. 57, range=43-84, respectively, p=0.02). Cancer deaths accounted for 10% of all deaths, with an absolute cancer mortality risk of 2% (95%CI=1-4.5%), 4% (95%CI=2-6%), and 6% (95%CI=4-9%) by ages 50, 60, and 70 years, respectively. No gender difference in cancer-specific mortality was observed (p=0.6). In conclusion, cancer significantly contributes to morbidity and mortality in DM patients, even after accounting for high competing DM mortality from non-neoplastic causes. It is important to apply population-appropriate, validated cancer screening strategies in DM patients.     

Anti-MJ/NXP-2 autoantibody specificity in a cohort of adult Italian patients with polymyositis/dermatomyositis

Introduction

Autoantibodies in patients with polymyositis/dermatomyositis (PM/DM) are associated with unique subsets, clinical course and outcome. Anti-MJ antibodies, which recognize the nuclear protein NXP-2/MORC3, are reported in ~25% of juvenile DM. Prevalence and clinical significance of anti-MJ antibodies in adult Italian PM/DM patients were studied.

Methods

Sera from 58 consecutive adult Italian PM/DM patients were analyzed by immunoprecipitation of ³⁵S-labeled K562 cells extract, ELISA (anti-MJ, Jo-1), Western blot and indirect immunofluorescence. Clinical associations were analyzed using information from medical charts.

Results

Anti-MJ antibodies were the most prevalent specificity (17%) found mainly in DM (30%, 8 cases) vs 8% of PM (2 cases, P = 0.02). Comparing 10 anti-MJ (+) vs 48 anti-MJ (-) cases, DM was more common (P = 0.03), and age at onset was younger in anti-MJ (+) (P = 0.0006). In anti-MJ (+), heliotrope rash (P = 0.01) and calcinosis (P = 0.09) were more frequent. None of them had heart or lung involvement, or malignancy. Myopathy in anti-MJ (+) patients responded well to therapy and none of them had elevated CPK at last visit (0% vs 25% in anti-MJ (-)). Only 60% of anti-MJ (+) showed immunofluorescent nuclear dots staining, despite PML localization of NXP-2/MORC3.

Conclusions

Anti-MJ antibodies are the most frequent specificity in our cohort of adult Italian PM/DM. Anti-MJ (+) were associated with young onset DM, calcinosis, no internal organ involvement and good response of myopathy to therapy. Anti-MJ reported in juvenile DM is also found in adult PM/DM, and could be a new useful biomarker.     

Immunity to tetanus: tetanus antitoxin and anti-BIIb in human sera

Immunity to tetanus was investigated in 157 individuals aged between 1 and 77 years using, for the evaluation of both tetanus antitoxin and antibody to fragment BIIb (anti-BIIb), an easily performed ELISA that gave reproducible results. Among these people 72% were protected against tetanus (tetanus antitoxin titres greater than 0.06 IU ml-1). Anti-BIIb titres greater than 0.15 U ml-1 were found in 75% of the males vs 57% of the females (P less than 0.02) with marked variations according to age. Furthermore, 13 out of 41 individuals with antitoxin titres less than 0.06 IU ml-1 (not protected against tetanus) were found to have anti-BIIb titres greater than 0.15 U ml-1. These data raise questions as to the significance and protective effect of anti-BIIb against tetanus.     

Impact of type 2 diabetes mellitus on short- and long-term mortality after coronary artery bypass surgery

Background

Type 2 diabetes mellitus (DM) is a frequent co-morbidity among patients undergoing coronary artery bypass grafting (CABG) surgery. The aim of this study was to evaluate the impact of DM on the early- and long-term outcomes of patients who underwent isolated CABG.

Methods

We performed an observational cohort study in a large tertiary medical center over a period of 11 years. All data from patients who had undergone isolated CABG surgery between 2004 and 2014 were obtained from our departmental database. The study population included 2766 patients who were divided into two groups: Group I (1553 non-diabetic patients), and Group II (1213 patients suffering from type 2 DM). Group II patients were then divided into two subgroups: subgroup IIA (981 patients treated with oral antihyperglycemic medications) and subgroup IIB (232 insulin-treated patients with or without additional oral antihyperglycemic drugs). In-hospital, 1-, 3-, 5- and 10-year mortality outcome variables were evaluated. Mean follow-up was 97?±?41 months.

Results

In-hospital mortality was similar between Group I and Group II patients (1.87% vs. 2.31%, p?=?0.422) and between the subgroups IIA and IIB (2.14% vs. 3.02%, p?=?0.464). Long-term mortality (1, 3, 5 and 10 years) was higher in Group II (DM type 2) compared with Group I (non-diabetic patients) (5.3% vs. 3.6%, p?=?0.038; 9.3% vs. 5.6%, p?<?0.001; 15.3% vs. 9.3%, p?<?0.001 and 47.3% vs. 29.6% p?<?0.001). Kaplan–Meier analysis demonstrated that all-cause mortality was higher in Group II compared with Group I (p?<?0.001) and in subgroup IIB compared with subgroup IIA (p?=?0.001). Multivariable analysis showed that DM increased the mortality hazard by twofold, and among diabetic patients, insulin treatment increased the mortality hazard by twofold.

Conclusions

Diabetic and non-diabetic patients have similar in-hospital mortality rates. Survival rates of diabetic patients start to deteriorate 3 year after surgery. Type 2 DM is an independent predictor for long-term mortality after isolated CABG surgery. Mortality is even higher when the diabetes treatment strategy included insulin.

     

Phenotypic and genotypic characteristics of mastocytosis according to the age of onset

Adult's mastocytosis is usually associated with persistent systemic involvement and c-kit 816 mutation, while pediatrics disease is mostly limited to the skin and often resolves spontaneously. We prospectively included 142 adult patients with histologically proven mastocytosis. We compared phenotypic and genotypic features of adults patients whose disease started during childhood (Group 1, n = 28) with those of patients whose disease started at adult's age (Group 2, n = 114). Genotypic analysis was performed on skin biopsy by sequencing of c-kit exons 17 and 8 to 13. According to WHO classification, the percentage of systemic disease was similar (75 vs. 73%) in 2 groups. C-kit 816 mutation was found in 42% and 77% of patients in groups 1 and 2, respectively (p<0.001). 816 c-kit mutation was associated with systemic mastocytosis in group 2 (87% of patients with systemic mastocytosis vs. 45% with cutaneous mastocytosis, p = 0.0001). Other c-kit activating mutations were found in 23% of patients with mastocytosis' onset before the age of 5, 0% between 6 and 15 years and 2% at adults' age (p<0.001). In conclusion, pathogenesis of mastocytosis significantly differs according to the age of disease's onset. Our data may have major therapeutic relevance when considering c-kit-targeted therapy.     

Glycolytic buffering affects cardiac bioenergetic signaling and contractile reserve similar to creatine kinase

Creatine kinase (CK) and glycolysis represent important energy-buffering processes in the cardiac myocyte. Although the role of compartmentalized CK in energy transfer has been investigated intensely, similar duties for intracellular glycolysis have not been demonstrated. By measuring the response time of mitochondrial oxygen consumption to dynamic workload jumps (tmito) in isolated rabbit hearts, we studied the effect of inhibiting energetic systems (CK and/or glycolysis) on transcytosolic signal transduction that couples cytosolic ATP hydrolysis to activation of oxidative phosphorylation. Tyrode-perfused hearts were exposed to 15 min of the following: 1) 0.4 mM iodoacetamide (IA; n = 6) to block CK (CK activity <3% vs. control), 2) 0.3 mM iodoacetic acid (IAA; n = 5) to inhibit glycolysis (GAPDH activity <3% vs. control), or 3) vehicle (control, n = 7) at 37 degrees C. Pretreatment tmito was similar across groups at 4.3 +/- 0.3 s (means +/- SE). No change in tmito was observed in control hearts; however, in IAA- and IA-treated hearts, tmito decreased by 15 +/- 3% and 40 +/- 5%, respectively (P < 0.05 vs. control), indicating quicker energy supply-demand signaling in the absence of ADP/ATP buffering by CK or glycolysis. The faster response times in IAA and IA groups were independent of the size of the workload jump, and the increase in myocardial oxygen consumption during workload steps was unaffected by CK or glycolysis blockade. Contractile function was compromised by IAA and IA treatment versus control, with contractile reserve (defined as increase in rate-pressure product during a standard heart rate jump) reduced to 80 +/- 8% and 80 +/- 10% of baseline, respectively (P < 0.05 vs. control), and significant elevations in end-diastolic pressure, suggesting raised ADP concentration. These results demonstrate that buffering of phosphate metabolites by glycolysis in the cytosol contributes appreciably to slower mitochondrial activation and may enhance contractile efficiency during increased cardiac workloads. Glycolysis may therefore play a role similar to CK in heart muscle.     

Disease-Specific Mortality and Secondary Primary Cancer in Well-Differentiated Thyroid Cancer with Type 2 Diabetes Mellitus

Background

Increased body mass index is related to the incidence of thyroid cancer. However, the presentation and therapeutic outcomes of different thyroid cancers and type 2 diabetes mellitus (DM) have not been studied. This study investigated the effect of type 2 DM on the clinical presentations and therapeutic outcome of well-differentiated thyroid cancer.

Methods and Findings

A retrospective analysis of adult thyroid cancer patients with or without type 2 DM admitted between January 2001 and December 2010 was performed at an institution. A total of 1,687 well-differentiated thyroid cancer patients with different histological patterns were enrolled. Among these subjects, 122 were type 2 DM patients. Patients with thyroid cancer and type 2 DM were significantly older than non-DM patients. After a mean follow-up period of 5.6±0.1 years, patients with thyroid cancer and type 2 DM showed a higher percentage of disease progression than non-DM patients (24.6% vs. 17.4%). In addition, disease-specific mortality was higher in the type 2 DM group (10.7% vs. 3.8%). Thyroid cancer patients with type 2 DM showed a higher percentage of secondary primary cancers than those without DM (10.7% vs. 4.9%). Thyroid cancer-specific survival rates in the type 2 DM and non-DM groups were 82.2% and 94.9% at 5 years, 72.9% and 91.4% at 10 years, and 36.5% and 61.3% at 20 years, respectively. Multivariate analysis showed that type 2 DM was independent of thyroid cancer-specific mortality.

Conclusion

Patients with type 2 DM and well-differentiated thyroid cancer had an advanced tumor-node-metastasis stage at the time of diagnosis and an increased disease-specific mortality. Aggressive surgical procedures and close follow-up for well-differentiated thyroid cancer patients with type 2 DM are therefore necessary.     

Latent Autoimmune Diabetes in Adults in the United Arab Emirates: Clinical Features and Factors Related to Insulin-Requirement

Aims

To describe and to characterize clinical features of latent autoimmune diabetes in adults (LADA) compared to type 1 and type 2 diabetes in the UAE.

Methods

In this cross-sectional study a dataset including 18,101 subjects with adult-onset (>30 years) diabetes was accessed. 17,072 subjects fulfilled the inclusion/exclusion criteria. Data about anthropometrics, demographics, autoantibodies to Glutamic Acid Decarboxylase (GADA) and to Islet Antigen 2 (anti-IA2), HbA1c, cholesterol and blood pressure were extracted. LADA was diagnosed according to GADA and/or anti-IA2 positivity and time to insulin therapy.

Results

437 (2.6%) patients were identified as LADA and 34 (0.2%) as classical type 1 diabetes in adults. Mean age at diagnosis, BMI, waist circumference, systolic blood pressure and HbA1c significantly differed between, LADA, type 2 and type 1 diabetes, LADA showing halfway features between type 2 and type 1 diabetes. A decreasing trend for age at diagnosis and waist circumference was found among LADA subjects when subdivided by positivity for anti-IA2, GADA or for both antibodies (p=0.013 and p=0.011 for trend, respectively). There was a gradual downward trend in autoantibody titre in LADA subjects requiring insulin within the first year from diagnosis to subjects not requiring insulin after 10 years of follow-up (p<0.001).

Conclusions

This is the first study describing the clinical features of LADA in the UAE, which appear to be different from both type 1 and type 2 diabetes. Furthermore, we showed that the clinical phenotype of LADA is dependent on different patterns of antibody positivity, influencing the time to insulin requirement.     

HLA genes, islet autoantibodies and residual C-peptide at the clinical onset of type 1 diabetes mellitus and the risk of retinopathy 15 years later

Aims/Hypothesis

HLA genes, islet autoantibodies and residual C-peptide were studied to determine the independent association of each exposure with diabetic retinopathy (DR), 15 years after the clinical onset of type 1 diabetes in 15–34 year old individuals.

Methods

The cohort was identified in 1992 and 1993 by the Diabetes Incidence Study in Sweden (DISS), which investigates incident cases of diabetes for patients between 15 and 34 years of age. Blood samples at diagnosis were analyzed to determine HLA genotype, islet autoantibodies and serum C-peptide. In 2009, fundus photographs were obtained from patient records. Study measures were supplemented with data from the Swedish National Diabetes Registry.

Results

The prevalence of DR was 60.2% (148/246). Autoantibodies against the 65 kD isoform of glutamate decarboxylase (GADA) at the onset of clinical diabetes increased the risk of DR 15 years later, relative risk 1.12 for each 100 WHO units/ml, [95% CI 1.02 to 1.23]. This equates to risk estimates of 1.27, [95% CI 1.04 to 1.62] and 1.43, [95% CI 1.06 to 1.94] for participants in the highest 25^th (GADA>233 WHO units/ml) and 5^th percentile (GADA>319 WHO units/ml) of GADA, respectively. These were adjusted for duration of diabetes, HbA_1c, treated hypertension, sex, age at diagnosis, HLA and C-peptide. Islet cell autoantibodies, insulinoma-antigen 2 autoantibodies, residual C-peptide and the type 1 diabetes associated haplotypes DQ2, DQ8 and DQ6 were not associated with DR.

Conclusions

Increased levels of GADA at the onset of type 1 diabetes were associated with DR 15 years later. These results, if confirmed, could provide additional insights into the pathogenesis of the most common microvascular complication of diabetes and lead to better risk stratification for both patient screenings and DR treatment trials.     

Seroprotection against serogroup C meningococcal disease in adolescents in the United Kingdom: observational study

Objective To determine the persistence of bactericidal antibody titres following immunisation with serogroup C meningococcal glycoconjugate vaccine at age 6-15 years in order to examine changes in persistence of antibodies with age.Design Observational study.Setting Secondary and tertiary educational institutions in the United Kingdom.Participants Healthy adolescents aged 11-20 years previously immunised between 6 and 15 years of age with one of the three serogroup C meningococcal vaccines.Intervention Serum obtained by venepuncture.Main outcome measures Percentage of participants with (rabbit complement) serum bactericidal antibody titres of at least 1:8; geometric mean titres of serogroup C meningococcal serum bactericidal antibody.Results Five years after immunisation, 84.1% (95% confidence interval 81.6% to 86.3%) of 987 participants had a bactericidal antibody titre of at least 1:8. Geometric mean titres of bactericidal antibody were significantly lower in 11-13 year olds (147, 95% confidence interval 115 to 188) than in 14-16 year olds (300, 237 to 380) and 17-20 year olds (360, 252 to 515) (P<0.0001 for both comparisons). Within these age bands, no significant difference in geometric mean titres of bactericidal antibody between recipients of the different serogroup C meningococcal vaccines was seen. More than 70% of participants had received a vaccine from one manufacturer; in this cohort, geometric mean titres were higher in those immunised at aged 10 years or above than in those immunised before the age of 10.Conclusions Higher concentrations of bactericidal antibody are seen five years after immunisation with serogroup C meningococcal vaccine at age 10 years or above than in younger age groups, possibly owing to immunological maturation. This provides support for adolescent immunisation programmes to generate sustained protection against serogroup C meningococcal disease not only for the vaccine recipients but also, through the maintenance of herd immunity, for younger children.     

TRH test in patients with diabetes mellitus type 1 and/or autoimmune thyroiditis. Changes in the pituitary-thyroid axis, reverse T3, prolactin and growth hormone levels

The response of the pituitary- thyroid axis, reverse triiodothyronine (rT3), prolactin, and growth hormone (GH) levels following TRH stimulus (Relefact TRH 200 microg 2 amp. i.v.) was examined in patients with autoimmune diabetes type 1 (DM1, n=30), with autoimmune thyroiditis (AT, n=25), and with concurrent DM1 and AT (n=22) to evaluate the influence of DM1 and AT of autoimmune pathogenesis on the above-mentioned hormonal parameters. Statistical analysis (ANOVA) showed that: a) the response of TSH did not differ from control groups (C); b) free triiodothyronine (fT3), free thyroxine (fT4) and their ratio in DM1, DM1+AT and C rose in 120 and 180 min, while a similar increase was not seen in AT (p<0.000001); c) rT3 was not present in any group, with rT3 levels higher in AT (p<0.00002) and lower in DM1 (p<0.02); d) the response of GH had a paradoxical character in some patients in all groups, most often in DM1 (52 %, DM1 vs C, p <0.01). The characteristic response difference was not in the peak GH level, but the delayed return to basal levels in DM1 (p<0.0001) and an abrupt one in AT (p<0.0001). The major findings in DM1 were the differences in GH response, while significant impairment of pituitary-thyroid axis and PRL response to TRH was absent. AT was associated with impairment of TRH stimulated fT3, fT4, fT3/fT4 response and changes in rT3 levels, in spite of preserved TRH-stimulated TSH secretion. GH response in AT patients was also altered.