HLA-DQ-conferred risk for type 1 diabetes does not alter neutralizing antibody response to a widely used enterovirus vaccine, the poliovirus vaccine.

This study investigated whether children with HLA-DQ-conferred risk for type 1 diabetes (T1D) have an altered immune response to the widely-used enterovirus vaccine, namely poliovirus vaccine, and whether initiation of autoimmunity to pancreatic islets modulates this response. Neutralizing antibodies induced by the inactivated poliovirus vaccine against poliovirus type 1 (Salk) were analysed as a marker of protective immunity at the age of 18 months in a prospective birth cohort. No differences were observed in antibody titers between children with and without genetic risk for T1D (odds ratio [OR] = 0.90 [0.83, 1.06], p = 0.30). In the presence of the genetic risk, no difference was observed between children with and without islet autoimmunity (OR = 1.00 [0.78, 1.28], p = 1.00). This did not change when only children with the autoimmunity before 18 months of age were included in the analyses (OR = 1.00 [0.85, 1.18], p = 1.00). No effect was observed when groups were stratified based on autoantigen specificity of the first-appearing autoantibody (IAA or GADA). The children in each comparison group were matched for sex, calendar year and month of birth, and municipality. Accordingly, we found no indication that children who are at risk to develop islet autoimmunity would have a compromised humoral immune response which could have increased their susceptibility for enterovirus infections. In addition, the proper immune response supports the idea of testing novel enterovirus vaccines for the prevention of T1D among these individuals.

Anti-glutamic Acid Decarboxylase Antibody-Positive Gestational Diabetes Mellitus with Autoimmune Type 1 Diabetes Mellitus in the Early Postpartum Period: A Case Report and Literature Review.

Gestational diabetes mellitus (GDM) is a state of pre-diabetic impaired glucose tolerance initially occurring during pregnancy. Although abnormalities in glucose metabolism normally resolve rapidly after delivery, women with GDM have a higher lifetime risk of developing diabetes mellitus than those without GDM; thus, postpartum healthcare is essential. Of all GDM patients, 5%-10% test positive for diabetes-related autoantibodies, which increase the risk of developing type 1 diabetes mellitus (T1DM). Autoantibody measurement in GDM screening remains debatable; however, it may be useful for the postnatal follow-up of GDM patients at high risk of developing T1DM. We treated a 29-year-old woman who was GDM positive for anti-glutamic acid decarboxylase antibody (GADA) requiring high-dose insulin therapy during pregnancy. As the patient tested positive for GADA, she received judicious postpartum management, allowing for early diagnosis of T1DM and resumption of treatment. Her insulin secretory capacity was preserved at 1 year after parturition, suggesting either slowly progressive insulin-dependent T1DM or latent autoimmune diabetes in adults. This was a rare case of slowly progressive insulin-dependent T1DM or latent autoimmune diabetes in adults in the early postpartum period, but the fact that GADA was positive during pregnancy enabled early treatment without overlooking it. Measuring diabetes-related autoantibodies in patients considered to be at a high risk for T1DM, such as those who are of slim build, young, or suffering from autoimmune thyroid disorders, may be important for appropriate individualized follow-up.

Time-dependent effects on circulating cytokines in patients with LADA: A decrease in IL1-ra and IL-1 beta is associated with progressive disease.

BACKGROUND: Cytokines and chemokines participate in autoimmune processes at cellular targets which include insulin-producing beta cells. To which extent such participation is reflected in the circulation has not been conclusively resolved. AIM: We compared the time course of cytokines/chemokines in Latent Autoimmune Diabetes in Adults (LADA) patients heterogeneous for high or low autoimmune activity as determined by levels of antibodies against glutamic acid decarboxylase (GADA). METHODS: Serum samples to be measured were from a two-armed randomized controlled trial (RCT) in 68 LADA patients. The study encompassed 21 months with C-peptide as primary endpoint. We measured 27 immune mediators at baseline, at 9 and at 21 months (end of study). Results of measurements were analyzed by multiple linear regression. RESULTS: At baseline, a high body mass index (BMI) (>26 kg/m2) was associated with elevated levels of the interleukins (IL) IL-1 beta, IL-1ra, IL-2, IL-5, IL-6 and IL-13. Treatment during RCT (sitagliptin vs. insulin) did not affect the time course (21 months) of levels of cytokines/chemokines (by univariate analyses). However, levels of the cytokines IL-1ra and IL-1 beta decreased significantly (p < 0.04 or less) in patients with high vs. low GADA when adjusted for BMI, age, gender (male/female), treatment (insulin/sitagliptin) and study site (Norwegian/Swedish). CONCLUSIONS: In LADA, high levels of GADA, a proxy for high autoimmune activity and linked to a decline in C-peptide, was associated with a decrease of selected cytokines over time. This implies that the decline of IL-1ra and IL-1 beta in the circulation reflects autoimmune activity and beta cell demise in LADA.

HbA1c as a time predictive biomarker for an additional islet autoantibody and type 1 diabetes in seroconverted TEDDY children.

OBJECTIVE: Increased level of glycated hemoglobin (HbA1c) is associated with type 1 diabetes onset that in turn is preceded by one to several autoantibodies against the pancreatic islet beta cell autoantigens; insulin (IA), glutamic acid decarboxylase (GAD), islet antigen-2 (IA-2) and zinc transporter 8 (ZnT8). The risk for type 1 diabetes diagnosis increases by autoantibody number. Biomarkers predicting the development of a second or a subsequent autoantibody and type 1 diabetes are needed to predict disease stages and improve secondary prevention trials. This study aimed to investigate whether HbA1c possibly predicts the progression from first to a subsequent autoantibody or type 1 diabetes in healthy children participating in the Environmental Determinants of Diabetes in the Young (TEDDY) study. RESEARCH DESIGN AND METHODS: A joint model was designed to assess the association of longitudinal HbA1c levels with the development of first (insulin or GAD autoantibodies) to a second, second to third, third to fourth autoantibody or type 1 diabetes in healthy children prospectively followed from birth until 15 years of age. RESULTS: It was found that increased levels of HbA1c were associated with a higher risk of type 1 diabetes (HR 1.82, 95% CI [1.57-2.10], p < 0.001) regardless of first appearing autoantibody, autoantibody number or type. A decrease in HbA1c levels was associated with the development of IA-2A as a second autoantibody following GADA (HR 0.85, 95% CI [0.75, 0.97], p = 0.017) and a fourth autoantibody following GADA, IAA and ZnT8A (HR 0.90, 95% CI [0.82, 0.99], p = 0.036). HbA1c trajectory analyses showed a significant increase of HbA1c over time (p < 0.001) and that the increase is more rapid as the number of autoantibodies increased from one to three (p < 0.001). CONCLUSION: In conclusion, increased HbA1c is a reliable time predictive marker for type 1 diabetes onset. The increased rate of increase of HbA1c from first to third autoantibody and the decrease in HbA1c predicting the development of IA-2A are novel findings proving the link between HbA1c and the appearance of autoantibodies.

Latent Autoimmune Diabetes in Adults: A Review of Clinically Relevant Issues.

Latent autoimmune diabetes in adults (LADA) is still a poorly characterized entity. However, its prevalence may be higher than that of classical type 1 diabetes. Patients with LADA are often misclassified as type 2 diabetes. The underlying autoimmune process against ß-cell has important consequences for the prognosis, comorbidities, treatment choices and even patient-reported outcomes with this diabetes subtype. However, there is still an important gap of knowledge in many areas of clinical relevance. We are herein focusing on the state of knowledge of relevant clinical issues than may help in the diagnosis and management of subjects with LADA.

Current view of diagnosis and treatment of latent autoimmune diabetes in adults.

Latent Autoimmune Diabetes in Adults (LADA) is an autoimmune disease arising at adulthood. LADA is characterized by a less intensive autoimmune process, slower progression and a mild metabolic decompensation at onset compared with young-onset type 1 diabetes mellitus. The onset of LADA is usually in non-obese patients over 30, without prominent features of metabolic syndrome and insulin resistance. Nevertheless it may be falsely classified as type 2 diabetes, especially, when diagnosed in older age and for the possibility of non-insulin treatment for at least 6 months after diagnosis. LADA is treated early with insulin and combined with metformin in patients with a higher level of insulin resistance. Clinical studies suggested also effectivity of other oral antidiabetics enabling preservation of residual β-cell function, such as particularly incretines.

Adding vitamin D3 to the dipeptidyl peptidase-4 inhibitor saxagliptin has the potential to protect ß-cell function in LADA patients: A 1-year pilot study.

AIMS: This trial was conducted to explore the protective effect on ß-cell function of adding vitamin D3 to DPP-4 inhibitors to treat patients with latent autoimmune diabetes in adults (LADA). METHODS: 60 LADA patients were randomized to group A (n = 21) - conventional therapy with metformin (1-1.7 g/day) and/or insulin treatment; group B (n = 20) - saxagliptin (5 mg/day) plus conventional therapy; and group C (n = 19) - vitamin D3 (2000 IU/day) plus saxagliptin and conventional therapy for 12 months. Fasting and 2-hour postprandial blood samples were collected to measure blood glucose, glycosylated hemoglobin and C-peptide levels at baseline and after 3, 6 and 12 months of treatment. RESULTS: During the 12 months of follow-up, the levels of fasting C-peptide (FCP), 2-hour postprandial C-peptide (PCP) and the C-peptide index (CPI, serum C-peptide-to-plasma glucose level ratio) were maintained in group C. In contrast to those in group A and group B, FCP levels decreased significantly in group B, and CPI levels declined significantly in group A during the 1-year treatment (P < .05). Additionally, the levels of GADA titers in group C significantly decreased compared with those at baseline (P < .05), but no significant differences in GADA titers levels were detected in group A and group B. No significant differences were found among the three groups in the levels of FCP, PCP, the CPI or GADA titers. CONCLUSIONS: The data suggested that adding 2000 IU/day vitamin D3 to saxagliptin might preserve ß-cell function in patients with LADA.

Coxsackievirus B1 infections are associated with the initiation of insulin-driven autoimmunity that progresses to type 1 diabetes.

AIMS/HYPOTHESIS: Islet autoimmunity usually starts with the appearance of autoantibodies against either insulin (IAA) or GAD65 (GADA). This categorises children with preclinical type 1 diabetes into two immune phenotypes, which differ in their genetic background and may have different aetiology. The aim was to study whether Coxsackievirus group B (CVB) infections, which have been linked to the initiation of islet autoimmunity, are associated with either of these two phenotypes in children with HLA-conferred susceptibility to type 1 diabetes. METHODS: All samples were from children in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study. Individuals are recruited to the DIPP study from the general population of new-born infants who carry defined HLA genotypes associated with susceptibility to type 1 diabetes. Our study cohort included 91 children who developed IAA and 78 children who developed GADA as their first appearing single autoantibody and remained persistently seropositive for islet autoantibodies, along with 181 and 151 individually matched autoantibody negative control children, respectively. Seroconversion to positivity for neutralising antibodies was detected as the surrogate marker of CVB infections in serial follow-up serum samples collected before and at the appearance of islet autoantibodies in each individual. RESULTS: CVB1 infections were associated with the appearance of IAA as the first autoantibody (OR 2.4 [95% CI 1.4, 4.2], corrected p = 0.018). CVB5 infection also tended to be associated with the appearance of IAA, however, this did not reach statistical significance (OR 2.3, [0.7, 7.5], p = 0.163); no other CVB types were associated with increased risk of IAA. Children who had signs of a CVB1 infection either alone or prior to infections by other CVBs were at the highest risk for developing IAA (OR 5.3 [95% CI 2.4, 11.7], p < 0.001). None of the CVBs were associated with the appearance of GADA. CONCLUSIONS/INTERPRETATION: CVB1 infections may contribute to the initiation of islet autoimmunity being particularly important in the insulin-driven autoimmune process.

Biofuel production with a stress-resistant and growth phase-independent promoter: mechanism revealed by in vitro transcription assays.

The carbon and energy needed for bioconversion processes face trade-offs between cell reproduction and chemical synthesis. In most processes, microbial cells containing overexpressed pathway enzymes were accumulated in exponential phase before the productions of value-added chemicals dominate the carbon and energy fluxes in stationary phase. The pathway enzymes need to be continuously supplied to compensate their degradation, but the promoters driving their overexpressions are downregulated under stationary phase or stressed conditions. In this study, the gadA promoter enabled stress-resistant and growth phase-independent isobutanol production up to 10-28 g l-1. To investigate the activation mechanism of gadA promoter and its potential in metabolic engineering, an in vitro transcription system was established. Results showed that gadA promoter could be transcribed efficiently under environments that inhibit the transcription of ribosomal promoters, while under moderate to rapid growth conditions, the large majority of new cellular transcripts are ribosomal. This differential transcription relies on the accumulation of environmental glutamate and/or the loss of supercoiling. These results implied that the gadA promoter could be functional or even dominate the cellular transcription under an exceedingly wide range of physiological conditions. Therefore, the gadA promoter is a novel candidate for driving pathway enzyme overexpressions under not only exponential phase but also stationary phase and stressed conditions, which is important for achieving efficient biofuel production.

Presence of diabetes-specific autoimmunity in women with gestational diabetes mellitus (GDM) predicts impaired glucose regulation at follow-up.

PURPOSE: Gestational diabetes mellitus (GDM) is the most frequent complication of pregnancy; around 10% of GDM cases may be determined by autoimmunity, and our aims were to establish the role of autoimmunity in a population of Sardinian women affected by GDM, to find predictive factors for autoimmune GDM, and to determine type 1 diabetes (T1D) auto-antibodies (Aabs) together with glucose tolerance after a mean 21.2 months of follow-up. METHODS: We consecutively recruited 143 women affected by GDM and 60 without GDM; clinical data and pregnancy outcomes were obtained by outpatient visit or phone recall. T1D auto-antibodies GADA, IA2-A, IAA, ZnT8-A were measured in the whole population at baseline, and in the Aab-positive women at follow-up. RESULTS: The overall prevalence of autoimmunity was 6.4% (13/203). No significant difference was found in the prevalence of auto-antibodies between GDM (5.6%) and control (8.3%) women, neither in antibody titres. Highest titres for GADA and ZnT8-A were observed in the control group; no phenotypic factors were predictive for autoimmune GDM. Diabetes-related autoantibodies were still present in all the GDM women at follow-up, and their presence was associated with a 2.65 (p < 0.0016) relative risk (RR) of glucose impairment. CONCLUSION: We observed a low prevalence (5.6%) of diabetes-related autoimmunity in our GDM cohort, consistent with the prevalence reported in previous studies. It was not possible to uncover features predictive of autoimmune GDM. However, given the significant risk of a persistent impaired glycemic regulation at follow-up, it is advisable to control for glucose tolerance in GDM women with diabetes-related autoimmunity.

GADA and anti-ZnT8 complicate the outcome of phenotypic type 2 diabetes of adults.

BACKGROUND: A proportion of phenotypic type 2 diabetes (T2D) patients produce pancreatic autoantibodies and a majority of T2D patients develop serious life-disabling complications over time despite the implementation of adequate clinical interventions. This study determined whether the presence of pancreatic autoantibodies (GADA, IA-2A, anti-ZnT8, or ICA) was associated with serious complications or concomitant diseases of adult patients diagnosed with T2D (N = 305). MAIN RESULTS: In the study population, 22.3% (N = 68) of subjects were positive for at least 1 of the 4 of the markers associated with autoimmune diabetes (presence of pancreatic autoantibody - pAb), followed by GADA (14.1%, N = 43), ICA (8.9%, N = 27), anti-ZnT8 (5.6%, N = 17) and IA-2A (2.0%, N = 6). Logistic regression analysis adjusted for patient's age, gender and duration of T2D revealed that (i) pAb was associated with higher prevalence of adiposity (odds ratio of adjusted regression model (adOR) 2.51, P = 0.032); (ii) pAb, GADA and anti-ZnT8 were associated with autoimmune thyroid disease (adORs 3.07, P = 0.012; 6.29, P < 0.001 and 3.52, P = 0.052, respectively); (iii) pAb and GADA, in particular, were risk factors for neurological complications (adORs 2.10, P = 0.036; 2.76, P = 0.009, respectively) and polyneuropathy in particular (adORs 2.60, P = 0.012; 3.10, P = 0.007, respectively); and (iv) anti-ZnT8 was a risk factor for developing nephropathy (adOR 4.61, P = 0.022). In addition, adiposity was associated with 5.3-year earlier onset of disease (adjusted linear regression model, P = 0.006). CONCLUSIONS: These results suggest that GADA and anti-ZnT8 are associated with progression of serious T2D complications, including polyneuropathy and nephropathy. In addition, adiposity represents a significant risk for autoimmunity development in T2D patients.

Analysis of the autoimmune regulator gene in patients with autoimmune non-APECED polyendocrinopathies.

The pathogenesis of autoimmunity was derived from a complex interaction of genetic and environmental factors. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy is a rare autosomal recessive disease caused by mutations in the autoimmune regulator (AIRE) gene. AIRE gene variants and, in particular, heterozygous loss-of-function mutations were also discovered in organ-specific autoimmune disorders, possibly contributing to their etiopathogenesis. It was suggested that even predisposition to develop certain autoimmune conditions may be derived from AIRE gene polymorphisms including S278R and intronic IVS9+6 G>A. In this study we unravel the hypothesis on whether AIRE gene variants may predispose individuals to associated autoimmune conditions in 41 Italian patients affected by non-APECED autoimmune polyendocrinopathies. We could not detect any heterozygous mutations of the AIRE gene. Although a trend of association was observed, heterozygous polymorphisms S278R and IVS9+6 G>A were detected in patients without statistically significant prevalence than in controls. Their putative contribution to autoimmune polyendocrinopathies and their predictive value in clinical strategies of disease development could be unravelled by analysing a larger sample of diseased patients and healthy individuals.

Improved HbA1c and body weight in GADA-positive individuals treated with tirzepatide: A post hoc analysis of SURPASS.

CONTEXT: People with clinically diagnosed type 2 diabetes (T2D) but positive anti-glutamic acid decarboxylase autoantibodies (GADA), referred to here as latent autoimmune diabetes in adults (LADA), may experience more rapid glycemic deterioration than those with T2D and may benefit from effective diabetes treatment with additional metabolic benefits. OBJECTIVE: Assess glycated hemoglobin (HbA1c) and body weight (BW) changes associated with tirzepatide in GADA-positive versus GADA-negative participants with clinical T2D diagnosis. DESIGN: Post hoc analyses based on pooled data from SURPASS 2-5, using mixed-model repeated measures from the efficacy analysis set, adjusting for study and baseline covariates including age, sex, baseline values, body mass index (BMI), and GADA status. SETTING: N/A. PATIENTS: N = 3791. INTERVENTION: Tirzepatide (5, 10, 15 mg). MAIN OUTCOME MEASURE(S): Change from baseline in HbA1c at Weeks 40 (SURPASS-2, -3, -5) and 42 (SURPASS-4)by GADA status. RESULTS: In participants with confirmed GADA status, 3671 (96.8%) were GADA-negative and 120 (3.2%) were GADA-positive (76 [63.3%] with low and 44 [36.7%] with high GADA levels). Baseline characteristics were similar between groups, except for slightly lower BMI in GADA-positive versus GADA-negative participants (mean [SD] BMI 32.2 [6.1] versus 33.6 [6.3] kg/m2). At Week 40/42, both groups achieved robust reductions in HbA1c (-2.11% versus -2.32%) and BW (9.2 kg versus -9.6 kg) (p < 0.001, both groups). HbA1c reductions were greater in GADA-negative participants (estimated difference [95% CI]: 0.21% [0.03, 0.39]; p = 0.024) and BW reductions did not differ between groups (0.38 kg [-0.99, 1.75]; p = 0.588). CONCLUSIONS: In this post hoc analysis, tirzepatide was associated with substantial reductions in HbA1c and BW irrespective of GADA status in adults diagnosed with T2D, suggesting that tirzepatide may improve glycemic control in individuals with LADA.

Impact of Thyroid Autoimmunity on the Clinical and Biochemical Characteristics of Type 1 Diabetes Mellitus Patients.

INTRODUCTION: Type 1 diabetes mellitus (T1DM) is frequently associated with other autoimmune disorders that are characterized by the presence of organ-specific autoantibodies. Autoimmune thyroid disease (AIT) is the most frequent autoimmune disorder associated with T1DM. Thyroid peroxidase antibodies (TPOAb) serve as a marker for diagnosing AIT. Prior research indicates that thyroid dysfunction can negatively impact linear growth and glycemic control in subjects with T1DM. The present study was done to determine the impact of thyroid autoimmunity on the clinical and biochemical characteristics of patients with newly diagnosed T1DM. METHODS: In this single-center, hospital-based, observational cross-sectional study, we enrolled 70 patients with newly diagnosed T1DM ≤18 years of age. Type 1 diabetes mellitus was diagnosed based on the acute onset of osmotic symptoms with or without diabetic ketoacidosis (DKA), severe hyperglycemia (blood glucose >13.9 mmol/l (>250 mg/dl)), and insulin requirement from the onset of diabetes. Secondary diabetes, pancreatic diabetes (Type 3c), and maturity-onset diabetes of the young (MODY) were excluded. Participants were screened for AIT disease using TPOAb testing. Based on the presence or absence of TPOAb, the participants were categorized into two groups: Group A comprised individuals with T1DM who tested positive for TPOAb, while Group B consisted of those who tested negative for TPOAb. RESULTS: Out of 70 patients, 41.4% were girls and 58.6% were boys, with a mean age of 9.8±4.4 years. The prevalence of TPOAb among the cohort was 18.6%. A significant majority of patients (71.4%), presented with DKA. Group A showed significantly lower mean height standard deviation scores (SDS) compared to Group B (-0.3±0.6 vs. -0.8±0.5, p = 0.004), but no differences in weight SDS or BMI SDS. Hemoglobin A1C (HbA1c) levels, C-peptide levels, and frequency of DKA did not differ between groups. Group A had higher mean thyroid-stimulating hormone (TSH) levels (4.8±3.7 µU/ml vs. 2.6±1.5 µU/ml, p = 0.001) and a greater proportion of patients with TSH levels above the upper limit of normal compared to Group B (38.4% vs. 7.1%, p = 0.008). Additionally, Group A exhibited a higher frequency of glutamic acid decarboxylase antibody (GADA) positivity compared to Group B (46.1% vs. 17.5%, p = 0.04). CONCLUSION: Patients positive for TPOAb exhibited significantly lower height SDS compared to TPOAb-negative patients. Additionally, T1DM patients with TPOAb positivity showed an increased frequency of GADA compared to those without TPOAb. However, no significant differences were found in HbA1c levels, C-peptide levels, or hematological parameters between TPOAb-positive and TPOAb-negative patients. These findings emphasize the impact of TPOAb on growth parameters in T1DM and advocate for routine screening of TPOAb in all T1DM patients, starting at the time of diabetes diagnosis.

High glutamic acid decarboxylase antibody titers may be associated with a decline in ß-cell function over time and future insulin deficiency in latent autoimmune diabetes in adults.

AIMS: Latent autoimmune diabetes in adults (LADA) is characterized by positive islet-associated autoantibodies including glutamic acid decarboxylase antibody (GADA), and gradual decline in insulin secretion, progressing to insulin dependency. This cross-sectional study aimed to determine whether GADA by enzyme-linked immunosorbent assay (GADA-ELISA) titer of ≥180 U/mL could be associated with decline in ß-cell function in participants with LADA. METHODS: Sixty-three participants with LADA were recruited and an association between insulin secretion capacity and disease duration was investigated. Insulin peptide-specific inflammatory immunoreactivity was investigated to determine the disease's activity. RESULTS: There was a significant inverse correlation between disease duration and C-peptide index in participants with GADA-ELISA titer of ≥180 U/mL (Spearman's r (rs) = -0.516, p < 0.01). The positivity rate of insulin peptide-specific inflammatory immunoreactivity was significantly higher in those with ≥180 U/mL than in those with <180 U/mL (p < 0.05). In participants with human leukocyte antigen (HLA)-DRB1*04:05, a significant inverse correlation was observed between disease duration and C-peptide index in those with ≥180 U/mL (rs = -0.751, p < 0.01). CONCLUSIONS: GADA-ELISA titer of ≥180 U/mL, especially with HLA-DRB1*04:05, might reflect higher disease activity and may be associated with decline in ß-cell function over time and future insulin dependency in LADA.

Electricity demand analysis and forecasting: The case of GADA special economic zone.

Ethiopia is a country in East Africa experiencing significant economic growth in recent years, with an increasing electricity demand. Ensuring sustainable and efficient energy for newly developed industries and economic zones is crucial. In this study, a 15-year electric power demand forecast for the new economic zone under construction is conducted. The electrical power demand forecast is done for the year 2025-2040 by using bottom-up forecasting approach for three different scenarios. Long-range Energy Alternatives Planning (LEAP) system software is used to analyze residential, industrial, and general business sector electric power demand. The analysis of the assessed scenario shows that the economic zone's electric power demand increases by 52.2 % from the base year 2025-2040 for the baseline scenario, due to anticipated rapid urbanization, growth in population, economic expansion, and anticipated political stability. Compared to the baseline scenario, the total power demand shows a growth of 68 % from the forecast year (2025) to 2040 for the aggressive scenario, which ensures sustainable and efficient energy options that can draw businesses from both domestic and international baselines. In contrast, the total power demand in the conservative scenario shows a growth of 30.3 % from the base year (2025) to 2040. This reduction in demand compared to the two scenarios indicates a reflection of how much electricity power demand could be if certain development conditions failed to be realized in the economy. In general, both results show a rapid increase in power demand compared to the base year. To address this increasing demand, a supply-side demand analysis can be done for reference and aggressive scenarios. The analysis result indicated that by 2040, supply-side demand from the national grid will increase by 93.5 % and 175.9 % for reference and aggressive scenarios, respectively, compared to the base year 2025 demand. Due to the huge gap between the supply and demand in the country, onsite off-grid generation can be considered to cover 25 % of the demand in the economic zone. Hence, with the support of off-grid generation, the demand from the national grid was reduced to 45 % and 107 % for reference and aggressive scenarios with the support of onsite generation. Hence, this research clearly shows that there is a serious need for large scale electricity generation and distribution planning and preparation to meet the continually increasing electric power demand in a sustainable manner to accommodate the growth and change required to develop the modern economic zones in the country.

The prevalence of diabetes and thyroid related autoantibodies in Sri Lankan children with type 1 diabetes and their unaffected siblings - The utility of a new screening assay.

Background: There is limited information about diabetes and thyroid related autoantibodies in children with type 1 diabetes (T1D) or their siblings in Sri Lanka. Objectives: To assess in T1D children and their unaffected siblings the prevalence of autoantibodies to (1) glutamic acid decarboxylase (GADA), insulinoma associated antigen-2 (IA-2A) and zinc transporter 8 (ZnT8A) using 3 Screen ICA™ (3-Screen) and individual ELISA assays; (2) insulin (IAA); and (3) thyroid peroxidase (TPOA), thyroglobulin (TgA) and the TSH receptor (TSHRA). Methods: We selected - (a) consecutive T1D children, and (b) their unaffected siblings of both sexes, from the T1D Registry at Lady Ridgeway Hospital, Colombo. Results: The median age (IQR) of 235 T1D children and 252 unaffected siblings was 11 (8.4, 13.2) and 9 (5.4, 14.9) years respectively, and the duration of T1D was 23 (7, 54) months. (1) T1D children (a) 79.1% were 3-Screen positive; (b) all 3-Screen positives were individual antibody positive (GADA in 74%; IA-2A 31.1%; ZnT8A 38.7%); (c) and were younger (p=0.01 vs 3-Screen negatives); (d) multiple autoantibodies were present in 45.1%; (e) IA-2A (p=0.002) and ZnT8A (p=0.006) prevalence decreased with T1D duration. (f) TPOA and TgA prevalence was higher in T1D children compared to unaffected siblings (28%, p=0.001 and 31%, p=0.004, respectively). (2) Unaffected siblings (a) 6.3% were 3-Screen positive (p=0.001 vs T1D), and 2.4% were positive for IAA; (b) four subjects had two diabetes related autoantibodies, one of whom developed dysglycaemia during follow-up. Conclusions: The 3-Screen assay, used for the first time in Sri Lankan T1D children and their siblings as a screening tool, shows a high prevalence of T1D related Abs with a high correlation with individual assays, and is also a helpful tool in screening unaffected siblings for future T1D risk. The higher prevalence of thyroid autoantibodies in T1D children is consistent with polyglandular autoimmunity.

Associations between glutamic acid decarboxylase antibodies, oxidative stress markers, and cognitive capacity in adolescents who stutter.

In this study, we amid to evaluate the correlation between the change in the expressed levels of anti-GAD antibodies titers, oxidative stress markers, cytokines markers, and cognitive capacity in adolescents with mild stuttering. Eighty participants (60 male/20 female) with the age range of 10-18 years with moderate stutteringparticipated in this study. To assess the stuttering and cognitive function, stutteringseverity instrument (SSI-4; 4th edit.)and the LOTCA-7 scores assessment were applied respectively in all subjects. In addition, serum GAD antibodies, cytokines like TNF-α, CRP,and IL-6 withtotal antioxidant capacity and nitric oxide as oxidative stress markers were estimated using calorimetry and immunoassay techniques.The results showed that good cognitive capacity was reported in about 56.25 % of the study population (n = 45) with a 117.52 ± 6.3 mean LOTCA-7 score. However, abnormal cognitive function was identified in 43.75 % of the study population (n = 35); they were categorized into moderate (score 62-92, n = 35), and poor (score 31-62; n = 10). There were significant associations between cognitive capacity reported and all biomarkers. The expression of GAD antibodies is significantly associated with the degree of cognitive capacity among students with stuttering. Significant association with the reduction (P = 0.01) in LOTCA-7 score domains, particularly orientation, thinking operations, attention, and concentration among students with variable cognitive capacity compared to controls. In addition, the expressed higher GAD antibodies in students with moderate and poor cognitive capacity showed to be significantly correlated with both elevated concentrations of cytokines; TNF-α, CRP, and IL-6, and the reduction of TAC and nitric oxide (NO) respectively. This study concludes that abnormality of cognitive capacity showed to be associated with higher expression of GAD antibodies, cytokines, and oxidative stress in school students with moderate stuttering.

A comparison in women with newly diagnosed diabetes between those with and without a history of gestational diabetes: a new perspective.

AIMS: Previous gestational diabetes mellitus (GDM) entails increased risk of future diabetes. We describe the characteristics of women with previous GDM and compare with no previous GDM from the cohort Diabetes in Kalmar and Kronoberg (DKK) of 1248 adults, 40% women, with new diabetes, and factors affecting age and C-peptide levels at diagnosis of diabetes. METHODS: Age-at-diagnosis of diabetes, BMI, hypertension, hyperlipidemia, smoking, physical activity, and pre-existing myocardial infarction, stroke, or peripheral arterial insufficiency were registered at ordinary care visits close to diagnosis of diabetes, for the 43 women (9.4% of 456 from DKK with complete data for this analysis) with self-reported previous GDM (yes/no) and 86 controls without it, matched for date of diagnosis of diabetes. Blood samples were centrally analyzed for GADA and C-peptide for classification of diabetes. RESULTS: Women with previous GDM had lower mean age-at-diagnosis of diabetes, 53.4 vs 65.0 years, lower systolic blood pressure (SBP), 131.2 vs 137.5 mmHg, and fewer had pre-existing hypertension than without previous GDM (p < 0.001-0.05). Among antibody negative women with previous GDM, BMI (p = 0.024), hypertension (p = 0.023) and hyperlipidemia (p < 0.001) were associated with higher levels of C-peptide, while physical activity was inversely associated (p = 0.035), and SBP (p = 0.02) and hypertension (p = 0.016) were associated with age-at-diagnosis of diabetes. CONCLUSIONS: Women with previous GDM were a decade younger and had lower prevalence of hypertension at diagnosis of diabetes; C-peptide levels were associated with BMI, hypertension, and hyperlipidemia and showed a tendency to be lower, possibly indicating a phenotype with higher risk of overt cardiovascular disease later in life.

Prevalence of Organ-Specific Autoimmunity in Patients With Type 1 Diabetes Mellitus.

INTRODUCTION: Type 1 diabetes mellitus (T1DM) is associated with other autoimmune disorders that are characterized by presence of organ-specific autoantibodies. The present study was undertaken to assess the prevalence of organ-specific autoantibodies among newly diagnosed T1DM subjects of India and to study its relationship with glutamic acid decarboxylase antibody (GADA). We also compared the clinical and biochemical parameters in GADA-positive and -negative T1DM subjects. METHODS: In a hospital-based cross-sectional study, we studied 61 patients with newly diagnosed T1DM ≤ 30 years of age. T1DM was diagnosed on the basis of acute onset of osmotic symptoms with or without ketoacidosis, severe hyperglycaemia [blood glucose > 13.9 mmol/l (>250 mg/dl)] and insulin requirement from the onset of diabetes. Subjects were screened for autoimmune thyroid disease (thyroid peroxidase antibody [TPOAb]), celiac disease (tissue transglutaminase antibody [tTGAb]), and gastric autoimmunity (parietal cell antibody [PCA]). RESULTS: Of the 61 subjects, more than one-third (38%) had at least one positive organ-specific autoantibody. In particular, 13 (21.3%) were found to be positive for TPOAb, nine (14.8%) were positive for tTGAb and 11 (18%) were positive for PCA. GADA was positive in 15 (25%) subjects. The frequency of TPOAb tended to be higher in patients who had GADA positivity compared with those with no circulating GADA (40% vs. 15.2%; p=0.07). Subjects positive for GADA were also more likely to be PCA positive compared with those who were GADA negative (40 vs.10.9%, p=0.02). There were no differences in frequency of diabetic ketoacidosis, body mass index, hemoglobin A1C (HbA1c), insulin requirement or fasting C-peptide in GADA-positive and -negative patients. CONCLUSION: We support the recommendation for regular screening of organ-specific autoantibodies, in particular TPOAb, tTGAb and PCA in all patients with T1DM. Detection of these autoantibodies at onset may prevent complications associated with delayed diagnosis of these disorders. We also conclude that there is higher frequency of TPOAb and PCA in GADA-positive T1DM patients as compared to negative ones. However, patients with positive GADA had similar clinical and biochemical parameters compared to GADA-negative subjects. Lastly, low GADA positivity in our study cohort as compared to Western populations suggests the heterogenous nature of T1DM in the Indian population.