Autoimmune Type 1 Diabetes Mellitus Research Articles

Increased Severity of Presentation Signs in Children with Newly Diagnosed Type 1 Diabetes during the COVID-19 Pandemic: A Tertiary Center Experience

Introduction: Diabetic ketoacidosis (DKA) is an important complication of type 1 diabetes mellitus (T1DM) which is worsened when the diagnosis of T1DM is delayed. The aim of this study was to evaluate the presentation patterns, severity, autoantibody status, and seasonal variability of newly diagnosed T1DM patients during the pandemic period of 2 years compared to those in the pre-pandemic period. Methods: In this single tertiary center retrospective cohort study, newly diagnosed T1DM patients were grouped as pre-pandemic and pandemic period. Age, gender, the month of diagnosis, hemoglobin A1c, venous blood gas parameters, duration of symptoms, glutamic-acid-decarboxylase-antibody (anti-GAD), islet-cell antibody (ICA), and insulin autoantibody levels were recorded. The data obtained were compared between the groups. Results: Number of patients presenting with DKA was significantly higher during the pandemic period (92 [65.7%] vs. 62 [40.8%] patients, p < 0.001). In terms of clinical severity of DKA, pH, and HCO3 levels were lower during the pandemic period (p < 0.001), while the number of patients presenting with severe DKA was significantly higher during the pandemic period (41 [44.6%] vs. 17 [27.4%] patients, p = 0.031). ICA positivity was significantly higher in patients admitted during the pandemic period (47 [36.4%] vs. 21 patients [16.9%], p < 0.001), especially in the second year of the pandemic (p < 0.001). Anti-GAD-ICA co-positivity was significantly higher in patients admitted during the pandemic period and also in second year of the pandemic (p < 0.001). Conclusion: DKA rates increased in newly diagnosed T1DM cases during the pandemic. Despite the relaxation of bans, the second year of the pandemic also saw increased rates of DKA and severe DKA compared to the pre-pandemic period. The significantly increased ICA positivity in the pandemic may support the effects of COVID-19 on autoimmune T1DM.

Predictors of the clinical severity of T1DM presentation at diagnosis in children and adolescents with type 1 diabetes mellitus (T1DM).

We aimed to assess factors associated with the presence and severity of ketoacidosis (DKA) at pediatric type 1 diabetes (T1DM) diagnosis, in relation to pancreatic, associated and familial autoimmunity. Antibodies against pancreatic beta-cells, organ specific autoantibodies (thyroid, celiac, and parietal) and family history of autoimmunity were retrospectively evaluated in 116 T1DM patients aged 11.9 ± 4.6 (mean ± SD) years, with disease duration 7.62 ± 3.67years (mean ± SD). Most patients (67.2%) presented with DKA at diagnosis. Younger children (< 2years) had tenfold risk of DKA, compared to older children (12.1-15years) (OR = 10.8, 95% CI: 1.0-116.9, P = 0.05). Fasting c-peptide levels were lower in the DKA group (OR = 0.26, 95% CI = 0.07-0.89, P = 0.033). The number of anti-pancreatic antibodies at disease onset did not show any significant correlations with the presence (p = 0.889) or severity of DKA (p = 0.863). All patients with multiple autoimmunity (> 2 autoimmune diseases plus T1DM) presented with DKA. Familial autoimmunity acted protectively against DKA manifestation (OR = 0.40, 95% CI = 0.16-1.0, P = 0.051). Among newly diagnosed T1DM patients, 67.2% presented with DKA. Younger age, lower c-peptide and the presence of associated autoimmunity were predictive factors of the presence and severity of DKA at diagnosis. High degree of suspicion, due to family history, may prevent DKA development and severity.

Autoimmune diseases and their prevalence in Saudi Arabian patients with type 1 diabetes mellitus.

To evaluate the prevalence of autoimmune disorders among young and adult populations diagnosed with type 1 diabetes mellitus (T1DM) in Al-Madinah Al-Munawarah, Saudi Arabia, and assess the potential impact of these conditions on other comorbidities. A retrospective, descriptive study examined autoimmune disorders in T1DM youth and adults. A total of 2258 verified T1DMs were tested. Analyzed hospital and laboratory data. Autoimmune T1DM was investigated clinically and laboratory. A total of 2258 T1DM adults, adolescents, and children were investigated; 500 (22.2%) were under 12, 540 (23.9%) were 13-17, and 1218 (53.9%) were 18 plus. Autoimmune with T1DM was 67.4%. Gender and age affect prevalence. 25.7% of adult females had autoimmune thyroiditis. Children and adolescents have greater rates of celiac disease than adults of both genders. Adrenal insufficiency was more frequent in adults. Adult males had 28.5% polyglandular autoimmune diseases, and women had 19.7%. Type 1 DM and other autoimmune illnesses increase the risk of nephropathy, CVD, and hypoglycemia. Bloodstream biomarkers linked to these disorders corroborate this. Autoimmune diseases in Saudi patients with T1DM exhibited specificity with respect to gender and age. Al-Madinah Al-Munawwarah have a heightened prevalence of autoimmune diseases among young individuals diagnosed with T1DM, such as celiac disease and autoimmune thyroiditis. Conversely, older individuals in the region have been observed to exhibit a greater incidence of adrenal failure and polyglandular autoimmune disorders. Autoimmune diseases that result in nephropathy, CVD, and hypoglycemia are highly prevalent based on biomarker levels.

Engineered Extracellular Vesicles in Treatment of Type 1 Diabetes Mellitus: A Prospective Review.

Insulin replacement is an available treatment for autoimmune type 1 diabetes mellitus (T1DM). There are multiple limitations in the treatment of autoimmune diseases such as T1DM by immunosuppression using drugs and chemicals. The advent of extracellular vesicle (EV)-based therapies for the treatment of various diseases has attracted much attention to the field of bio-nanomedicine. Tolerogenic nanoparticles can induce immune tolerance, especially in autoimmune diseases. EVs can deliver cargo to specific cells without restrictions. Accordingly, EVs can be used to deliver tolerogenic nanoparticles, including iron oxide-peptide-major histocompatibility complex, polyethylene glycol-silver-2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester, and carboxylated poly (lactic-co-glycolic acid) nanoparticles coupled with or encapsulating an antigen, to effectively treat autoimmune T1DM. The present work highlights the advances in exosome-based delivery of tolerogenic nanoparticles for the treatment of autoimmune T1DM.

Fecal microbiota transplantation treatment of autoimmune-mediated type 1 diabetes mellitus.

Type 1 diabetes mellitus (T1DM) is an autoimmune-mediated disease characterized by a reduced or absolute lack of insulin secretion and often associated with a range of vascular and neurological complications for which there is a lack of effective treatment other than lifestyle interventions and pharmacological treatments such as insulin injections. Studies have shown that the gut microbiota is involved in mediating the onset and development of many fecal and extrafecal diseases, including autoimmune T1DM. In recent years, many cases of gut microbiota transplantation for diseases of the bowel and beyond have been reported worldwide, and this approach has been shown to be safe and effective. Here, we conducted an experimental treatment study in two adolescent patients diagnosed with autoimmune T1DM for one year. Patients received one to three rounds of normal fecal microbiota transplants (FMT) and were followed for up to 30 weeks. Clinical outcomes were measured, including biochemical indices, medication regimen, and dosage adjustment. Fecal microbiota metagenomic sequencing after transplantation provides a reference for more reasonable and effective microbiota transplantation protocols to treat autoimmune T1DM. Our results suggest that FMT is an effective treatment for autoimmune T1DM.Clinical Trial Registration http://www.chictr.org.cn, identifier ChiCTR2100045789.

The relation between residual β-cell function and autoimmune status in long-term type 1 diabetes patients

Objective: We aimed to investigate the autoimmune status of long-term type 1 diabetes mellitus (T1DM) patients with residual β-cell function. Methods: The residual β-cell function of long-term (disease duration≥10 years) autoimmune T1DM patients from the T1DM Integrated Management Clinic of the Second Xiangya Hospital was assessed by serum C-peptide levels. Patients with fasting or 2-hour postprandial C-peptide levels over the lower sensitivity limit of detection (16.7 pmol/L) were grouped as C-peptide-positive, and others were grouped as C-peptide-negative. We screened and enrolled all the C-peptide-positive patients (n=19). C-peptide-negative patients with matched sex, age, duration, BMI (n=19) and healthy controls (n=19) were recruited at the same time. The frequencies of CD4+T cell (Th1/Th2/Th17/Treg) and B cell (MZB/FoB/B10) subsets, the expression of PD-1/PD-L1 on T and B lymphocytes, and the levels of T1DM related cytokines including IFN-γ, TNF-α, IL-1β, IL-1RA, IL-4, IL-6, IL-10, IL-12p40, IL-12p70, IL-23 and IP-10 were tested. We compared these parameters in patients with different levels of β-cell function. Results: In healthy controls, C-peptide-negative and C-peptide-positive patients, the frequencies M (Q1, Q3) of Th1 cells were 9.93% (7.45%, 15.20%), 14.90% (11.70%, 18.00%) and 10.20% (6.93%, 15.80%) (P=0.015), and the frequencies M (Q1, Q3) of Treg cells were 3.52% (2.92%, 5.68%),2.88% (1.64%, 3.22%) and 3.12% (2.81%, 4.81%) (P=0.005), and the frequencies M(Q1,Q3) of PD-1+B cells were 4.69% (2.64%, 6.37%), 2.11% (1.45%, 3.63%) and 4.20% (2.53%, 6.01%) (P=0.003), respectively. The levels of IL-6 M(Q1,Q3)were 26.43(18.06, 33.35) ng/L, 42.97 (25.52, 66.30) ng/L, and 22.07 (14.85, 34.45) ng/L (P=0.006), and the levels of IP-10 M(Q1,Q3) were 107.39 (76.19, 126.07) ng/L, 188.82 (131.27, 348.18) ng/L and 128.26 (114.31, 136.50) ng/L (P<0.001) in healthy controls, C-peptide-negative and C-peptide-positive patients, respectively. Compared with C-peptide-positive patients, the frequency of Th1 cells and the levels of IL-6 and IP-10 cytokines were higher, while the frequencies of Treg cells and PD-1+B cells were lower in C-peptide-negative patients (all P<0.05). Conclusions: Long-term T1DM patients with residual β-cell function had lower frequency of Th1 cells, lower levels of IL-6, IP-10 cytokines, and higher frequencies of Treg and PD-1+B cells, which indicated a pronounced autoimmune tolerance.

Gut microbiota composition change in type 1 diabetes brazilian patients

Rationale: Gut Microbiota (GM) profile may change in autoimmune diseases such as Type 1 Diabetes mellitus (T1DM), although there is heterogeneity across studies. Our aim was to evaluate changes in the GM of Brazilian patients with autoimmune T1DM.

Study of Autoantibodies and DQ Antigens in Patient with Celiac Disease

Introduction: Celiac Disease (CD) is a chronic autoimmune mediated disorder triggered by the ingestion of gluten. It is seen in genetically predisposed person and results in small intestine injury. Its aetiopathogenesis is not clear. Simple histopathology is not able to diagnose the disease many times. Aim: Aim of present study was to assess the prevalence of HLA DQ alleles and autoantibodies in diagnosis of the disease and association of DQ antigens with Type 1 Diabetes mellitus (T1DM) and autoimmune hypothyroidism in CD patients. Materials and Methods: Total 100 cases of CD and 31 healthy controls were studied, within a period of January 2015 to Febuary 2016. Autoantibodies like ANA, anti-tTg, anti-TPO and anti-scl 70 were done by ELISA kits. HLA DQ typing was done in 44 cases of CD, 20 cases of CD with T1DM, 22 cases of CD with autoimmune thyroid disease and 31 healthy controls. HLA DQ typing was done by SSO hybridisation method by Mr. SPOT machine. Results: About 70% patients were children between 6 months to 20 years of age and female formed the maximum number of cases (60%). Anti-tTg ab was positive in all cases (100%), anti-Scl 70 Ab was positive in 25%, anti-TPO ab was found in 22% and ANA was positive in only 10% cases. Most frequent DQβ1 haplotype in CD were DQβ1*02:01 (45.5%, p&lt;0.001) and DQβ1*02:02 (20.5%, p=0.007) while DQ*06:01 was significantly more common in controls suggesting its protective role. Among DQα1 typing DQα1*05:01 (45.5%, p&lt;0.001) and DQα1*05:05 (40.9%, p&lt;0.001) which were significantly more in CD than controls. Contrary to this DQα1*01:01, DQα1*01:03 and DQα1*01:04 were significantly reduced in CD patients. CD patients associated with T1DM and autoimmune thyroid disease had significantly more DQβ1 02:01, DQβ1*02:02, DQα1*05:01 and DQα1*05:05. Conclusion: CD is an autoimmune disease, DQ typing should be kept in diagnostic criteria of CD. Association of autoimmune thyroid diseases and T1DM in CD is due to common sharing of these DQ antigens suggesting its role in predisposing autoimmune diseases.

PEMBROLIZUMAB-INDUCED TYPE 1 DIABETES PRESENTING AS DIABETIC KETOACIDOSIS

SESSION TITLE: Wednesday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/23/2019 09:45 AM - 10:45 AM INTRODUCTION: Pembrolizumab is an immune checkpoint inhibitor, a humanized monoclonal IgG4 antibody against programed death 1 (PD-1). It is approved for treatment of malignancies including but not limited to, metastatic melanoma, non-small cell lung, renal cell, squamous cell, gastric, colon, cervical and urothelial carcinomas as well as classic Hodgkin lymphoma.[1] Immune check point inhibitors are rarely associated with immune adverse events. Endocrinopathies such as hypo and hyperthyroidism are more common compared to hypophysitis, type 1 diabetes mellitus (T1DM) and adrenal insufficiency.[2] We present a case of pembrolizumab induced severe DKA. CASE PRESENTATION: A 67-year-old female with history of recurrent esophageal squamous cell cancer despite concurrent chemoradiation and esophagectomy, previously treated with carboplatin paclitaxel and FOLFOX, now on immunotherapy with pembrolizumab (second cycle given two weeks prior), presented to a community hospital with malaise, nausea and emesis. Investigations revealed blood glucose of 595 with anion gap of 30. Urinalysis showed 3+ glucose and 2+ ketones, beta hydroxybutyrate 6.1, pH of 7.19 with base deficit 16.4. Patient was admitted to the intensive care unit with the diagnosis of moderate diabetic ketoacidosis (DKA) without evidence of infection. Patient was treated with institutional DKA protocol and later transitioned to basal-bolus insulin regimen. Studies during hospitalization revealed hemoglobin A1c (HbA1c) of 7.9%. Glutamic acid decarboxylase 65 antibody was elevated at 0.81 and C peptide was low at 0.1. In the absence of preexisting diabetes, these findings were consistent with pembrolizumab-induced autoimmune-mediated T1DM precipitating DKA. DISCUSSION: Pembrolizumab is associated with endocrinopathies with hyperglycemia reported around 45%, grade 3-4 hyperglycemia in 3-6% and T1DM or DKA only in 0.1 % individuals.[3] With increasing reports about pembrolizumab associated DKA, we suggest that the patients on pembrolizumab need to be educated about possible symptoms of diabetes and DKA. Other than autoimmune T1DM development, common side effects of treatment including decreased appetite, diarrhea and nausea may also contribute to starvation ketosis. Baseline HbA1c and interval blood glucose measurements may help in timely identification of individuals at risk of development of T1DM and prevention of DKA, which is a common initial presentation. European society for medical oncology (ESMO) recommends regular glucose monitoring in immune checkpoint inhibitors.[2] CONCLUSIONS: Endocrinopathies including life-threatening DKA may result with pembrolizumab use. Measurement of baseline HbA1c and regular monitoring of blood glucose in these patients may help identify patients at risk for pembrolizumab associated T1DM and DKA. Reference #1: Joshi, S.S., S.B. Maron, and D.V. Catenacci, Pembrolizumab for treatment of advanced gastric and gastroesophageal junction adenocarcinoma. Future Oncol, 2018. 14(5): p. 417-430. Reference #2: Hakami, O.A., et al., A case of pembrolizumab-induced severe DKA and hypothyroidism in a patient with metastatic melanoma. Endocrinol Diabetes Metab Case Rep, 2019. 2019. Reference #3: Hwangbo, Y. and E.K. Lee, Acute Hyperglycemia Associated with Anti-Cancer Medication. Endocrinol Metab (Seoul), 2017. 32(1): p. 23-29. DISCLOSURES: No relevant relationships by Allisa ALpert, source=Web Response No relevant relationships by Christine Blaski, source=Web Response No relevant relationships by Adam Matos, source=Web Response No relevant relationships by Jose Mena, source=Web Response No relevant relationships by Ian Nagus, source=Web Response No relevant relationships by Tatyana Sycheva, source=Admin input No relevant relationships by Usama Talib, source=Web Response

Thyroid Dysfunction in Type 1 Diabetes Mellitus in an Iranian Elderly Woman

Objective: Type 1 Diabetes mellitus (T1DM) and thyroid dysfunction consider as main metabolic and endocrine disorders. In previous studies, individuals with T1DM were susceptible to Thyroid disorders. The prevalence of clinical and subclinical Thyroid dysfunction have noticeable importance especially regarding women and their related stigma. Methods: The presented survey, a case-control study evaluated the thyroid dysfunction among T1DM elderly women referred to diabetes clinic of Tohid Hospital in Sanandaj city. The whole blood samples were attained from all individuals and then the following tests were done: fasting blood-sugar (FBS), Serum TSH, anti-Thyroperoxidase (Anti-TPO) and Free T4.Results: The prevalence of Thyroid disorder in examined patients was 17 percent and autoimmune Thyroid dysfunction disorder, that examined by positive test-result of Anti-TPO showed up in 10.2 percent of patients. Prevalence of sub-clinical Hypothyroidism was 13.2 percent; the clinical Hypothyroidism were 7.3 percent. Based on our data 2.9 percent of T1DM have subclinical Hyperthyroidism and 1.4 percent have clinical Hyperthyroidism. In our study, increased TSH level and existence of Anti-TPO in TIDM patients might be regarded as an additional TIDM problem in studied disease.Conclusion: This study confirmed the association between autoimmune Thyroid dysfunction (based on positive Serum-test of Anti-TPO) and T1DM.

Immunomodulatory effects of mesenchymal stem cell-derived exosomes on experimental type-1 autoimmune diabetes.

Exosomes derived from adipose tissue-derived mesenchymal stem cells (AD-MSCs) have immunomodulatory effects of T-cell inflammatory response and reduction of clinical symptoms on streptozotocin-induced of the type-1 diabetes mellitus (T1DM). Beside control group and untreated T1DM mice, a group of T1DM mice was treated with intraperitoneal injections of characterized exosomes derived from autologous AD-MSCs. Body weight and blood glucose levels were measured during the procedure. Histopathology and immunohistochemistry were used for evaluation of pancreatic islets using hemotoxylin and eosin (H&E) staining and anti-insulin antibody. Isolated splenic mononuclear cells (MNCs) were subjected to splenocytes proliferation assay using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, immunophenotyping of regulatory T cells and cytokines. A significant increase in the levels of interleukin-4 (IL-4), IL-10, and transforming growth factor-β, and a decrease in the levels of IL-17 and interferon-γ in concordance with the significant increase in the Treg cell ratio in splenic MNCs (P < 0.05) was shown in T1DM mice treated with AD-MSC's exosomes as compared to T1DM untreated mice. This amelioration of autoimmune reaction after treatment of T1DM mice with the AD-MSC exosomes was confirmed with a significant increase in islets using H&E staining and Immunohistochemistry analyses. As expected, body weight, blood glucose levels in a survival of T1DM mice treated with AD-MSC's exosomes were maintained stable in comparison to untreated T1DM mice. It can be concluded that AD-MSC's exosomes exert ameliorative effects on autoimmune T1DM through increasing regulatory T-cell population and their products without a change in the proliferation index of lymphocytes, which makes them more effective and practical candidates.

Unexplained fever and arthritis in a teenager with Type 1 diabetes

Brucellosis is a relatively prevalent zoonotic infection in the Mediterranean region and the Arabian Peninsula. Due to the multi-system involvement and nonspecific nature of the complaints, making a diagnosis can sometimes be particularly challenging. We present the case of a Libyan-American adolescent with type 1 diabetes mellitus (T1DM) residing in the United Arab Emirates who presented with fever, flu-like symptoms, and arthritis. When his initial septic workup did not reveal a focus of infection, and he continued to be febrile with the development of multiple painful and swollen joints, a diagnosis of autoimmune arthritis was entertained given his background history of autoimmune T1DM. However, on further probing, we ascertained a history of raw camel cheese ingestion. This redirected us to look for and subsequently confirm the diagnosis of brucellosis. Appropriate antibiotic treatment led to rapid recovery of the patient.

Higher cardiometabolic risk in idiopathic versus autoimmune type 1 diabetes: a retrospective analysis

BackgroundIdiopathic type 1 diabetes mellitus (IDM) is characterized by an onset with insulinopenia and ketoacidosis with negative β-cell autoimmunity markers and lack of association with HLA. The aim of the study is to compare the clinical and metabolic parameters, the macro and microvascular complications, the adipose tissue dysfunction and the insulin secretion and sensitivity indexes in patients with IDM and autoimmune type 1 diabetes mellitus (ADM) at clinical onset.MethodsThirty patients with IDM and 30 with ADM, matched for age and gender, were retrospectively analyzed. BMI, waist circumference, lipids, glycemia, HbA1c, insulin requirement, glutamic oxaloacetic and glutamic pyruvic transaminases (GOT and GPT), glucagon stimulated c-peptide (GSC-pep) test levels, M value during hyperinsulinemic euglycemic clamp and Visceral Adiposity Index (VAI) were obtained from our database.ResultsPatients with IDM showed a significantly higher BMI (p 0.012), WC (p 0.07), VAI (p 0.004), LDL-cholesterol (p 0.027), GOT (p 0.005), GPT (p 0.001), M value (p 0.006) and GSC-pep peak (p 0.036), with concomitant lower HDL-cholesterol (p < 0.001), than patients with ADM. In addition, patients with IDM showed a more marked familial history for diabetes (p 0.005) and a higher percentage of hepatic steatosis (p 0.001), visceral obesity (p 0.032) and hypercholesterolemia (p 0.007) compared to patients with ADM.ConclusionsPatients with IDM show many metabolic complications at onset, such as visceral obesity, hepatic steatosis and hypercholesterolemia and a higher cardiometabolic risk, than patients with ADM, similarly to patients with type 2 diabetes at onset.

Determination the IL-10 serum level for the T1DM al-diwanyah patients

The autoimmune disease T1DM (Type 1 diabetes mellitus) consider as important endocrine disorder described by the damage of beta cells of pancreatic islets. There is confirmation the IL-10 is a significant player on both immunity arms: innate and adaptive immunity. This study aimed to determined the essential role of IL-10 serum in the T1DM al-diwanyah patients as a vital immune factor for prevention and treatment of T1DM.

Chinese medicine Ginseng and Astragalus granules ameliorate autoimmune diabetes by upregulating both CD4+FoxP3+ and CD8+CD122+PD1+ regulatory T cells.

Type 1 diabetes mellitus (T1DM) is an autoimmune disease mainly mediated by effector T cells that are activated by autoantigen, thereby resulting in the destruction of pancreatic islets and deficiency of insulin. Cyclosporine is widely used as an immunosuppressant that suppresses autoimmunity in clinic. However, continuous treatments with conventional immunosuppressive drugs may cause severe side effects. Therefore it is important to seek alternative medicine. Chinese medicine Ginseng and Astragalus granule (GAG) was used to successfully treat type 2 diabetes mellitus in clinic in China. Here we found that GAG ameliorated T1DM in autoimmune NOD mice by increasing the level of insulin and reducing the level of blood glucose. Treatments with both GAG and CsA further decreased the blood glucose level. Moreover, GAG increased both CD4+FoxP3+ and CD8+CD122+PD-1+ Treg numbers in both spleens and lymph nodes of NOD mice. In particular, GAG could reverse a decline in CD4+FoxP3+ Tregs resulted from CsA treatments. The percentage of effector/memory CD8+ T cells (CD44highCD62Llow) was significantly reduced by GAG, especially in the presence of low-doses of CsA. Histopathology also showed that GAG attenuated cellular infiltration and lowered CD3+ T cell numbers around and in islets. Thus, we demonstrated that GAG ameliorated autoimmune T1DM by upregulating both CD4+FoxP3+ and CD8+CD122+PD-1+ Tregs while GAG synergized with CsA to further suppress autoimmunity and T1DM by reversing the decline in CD4+FoxP3+ Tregs resulted from CsA treatments. This study may have important clinical implications for the treatment of T1DM using traditional Chinese medicine.

Polymorphisms in genes encoding miR-155 and miR-146a are associated with protection to type 1 diabetes mellitus.

Type 1 diabetes mellitus (T1DM) is characterized by severe autoimmune destruction of pancreatic beta-cells. The triggering of autoimmunity against beta-cells is probably caused by a combination of environmental and genetic risk factors. Even though much is known about the genetic of T1DM, more information is needed to completely unravel this tangled disease. MicroRNAs (miRNAs) are a class of small noncoding RNAs molecules that negatively regulate gene expression by inducing target mRNA cleavage or by inhibiting protein translation. Abnormal miRNA expressions have been described in autoimmune diseases and T1DM. Polymorphisms in genes codifying miRNAs may alter the expression of the corresponding miRNA and, thus, confer susceptibility for a given disease. Therefore, the aim of this study was to investigate whether polymorphisms in genes encoding miR-155, miR-146a, and miR-375 are associated with T1DM. Frequencies of the miRNA-146a rs2910164, miRNA-155 rs767649 and miRNA-375 rs6715345 polymorphisms were analyzed in 490 T1DM patients and in 469 nondiabetic subjects. The miR-146a rs2910164 and miR-155 rs767649 polymorphisms were associated with protection for T1DM, and the strongest association was observed for the dominant model [odds ratio (OR)=0.557 95% CI 0.355-0.874 and OR=0.508, 95% CI 0.265-0.973, respectively, after adjustment for age, ethnicity, and risk HLA loci]. However, miR-375 rs6715345 frequencies did not differ between cases and controls. MiR-146a rs2910164 and miR-155 rs767649 polymorphisms were associated with protection for T1DM.

Metformin Use in Overweight/Obese Adolescents with Type 1 Diabetes

A growing proportion of adolescents with type 1 diabetes mellitus (T1DM) are overweight or obese. Metformin appears to have some benefit in overweight/obese adults with T1DM, but data for adolescents are lacking. Investigators from 26 sites randomized 140 adolescents (mean age, 15.3 years; age range, 12–19.6 years; 66% female; 74% white) with presumed autoimmune T1DM (age <10 years at diagnosis or presence …

Antiaging Gene Klotho Attenuates Pancreatic β-Cell Apoptosis in Type 1 Diabetes.

Apoptosis is the major cause of death of insulin-producing β-cells in type 1 diabetes mellitus (T1DM). Klotho is a recently discovered antiaging gene. We found that the Klotho gene is expressed in pancreatic β-cells. Interestingly, halplodeficiency of Klotho (KL+/−) exacerbated streptozotocin (STZ)-induced diabetes (a model of T1DM), including hyperglycemia, glucose intolerance, diminished islet insulin storage, and increased apoptotic β-cells. Conversely, in vivo β-cell–specific expression of mouse Klotho gene (mKL) attenuated β-cell apoptosis and prevented STZ-induced diabetes. mKL promoted cell adhesion to collagen IV, increased FAK and Akt phosphorylation, and inhibited caspase 3 cleavage in cultured MIN6 β-cells. mKL abolished STZ- and TNFα-induced inhibition of FAK and Akt phosphorylation, caspase 3 cleavage, and β-cell apoptosis. These promoting effects of Klotho can be abolished by blocking integrin β1. Therefore, these cell-based studies indicated that Klotho protected β-cells by inhibiting β-cell apoptosis through activation of the integrin β1-FAK/Akt pathway, leading to inhibition of caspase 3 cleavage. In an autoimmune T1DM model (NOD), we showed that in vivo β-cell–specific expression of mKL improved glucose tolerance, attenuated β-cell apoptosis, enhanced insulin storage in β-cells, and increased plasma insulin levels. The beneficial effect of Klotho gene delivery is likely due to attenuation of T-cell infiltration in pancreatic islets in NOD mice. Overall, our results demonstrate for the first time that Klotho protected β-cells in T1DM via attenuating apoptosis.

Preserved C-peptide levels in overweight or obese compared with underweight children upon diagnosis of type 1 diabetes mellitus.

PurposeWe hypothesized that overweight or obese children might develop type 1 diabetes mellitus (T1DM) early despite residual beta-cell function. Factors independently associated with preservation of C-peptide level were analyzed.MethodsWe retrospectively reviewed the medical data of 135 children aged 2.1-16.5 years with autoimmune T1DM. Body mass index (BMI), pubertal stage, and glycosylated hemoglobin (HbA1c) and C-peptide levels were evaluated. Patients were assigned to underweight (22.2%), normal weight (63.7%), and overweight or obese (14.1%) groups according to their BMI.ResultsPreservation of serum C-peptide levels (≥0.6 ng/mL) was found in 43.0% of subjects. With increasing BMI, the proportions of children with preserved C-peptide levels increased from 33.3% to 41.9% to 63.2%, with marginal significance (P=0.051). Interaction analysis indicated no effect of BMI score on age at onset associated with serum C-peptide levels. The lower the C-peptide level, the younger the age of onset (P<0.001), after adjustment for BMI z-score and HbA1c level. However, no significant relationship between BMI z-score or category and onset age was evident. Upon multivariate-adjusted modeling, the odds that the C-peptide level was preserved increased by 1.2 fold (P=0.001) per year of life, by 3.1 folds (P=0.015) in children presenting without (compared to with) ketoacidosis, and by 5.0 folds (P=0.042) in overweight or obese (compared to underweight) children.ConclusionOverweight or obese children had slightly more residual beta-cell function than did underweight children. However, we found no evidence that obesity temporally accelerates T1DM presentation.

Toll-like receptor 3 is critical for coxsackievirus B4-induced type 1 diabetes in female NOD mice.

Group B coxsackieviruses (CVBs) are involved in triggering some cases of type 1 diabetes mellitus (T1DM). However, the molecular mechanism(s) responsible for this remain elusive. Toll-like receptor 3 (TLR3), a receptor that recognizes viral double-stranded RNA, is hypothesized to play a role in virus-induced T1DM, although this hypothesis is yet to be substantiated. The objective of this study was to directly investigate the role of TLR3 in CVB-triggered T1DM in nonobese diabetic (NOD) mice, a mouse model of human T1DM that is widely used to study both spontaneous autoimmune and viral-induced T1DM. As such, we infected female wild-type (TLR3(+/+)) and TLR3 knockout (TLR3(-/-)) NOD mice with CVB4 and compared the incidence of diabetes in CVB4-infected mice with that of uninfected counterparts. We also evaluated the islets of uninfected and CVB4-infected wild-type and TLR3 knockout NOD mice by immunohistochemistry and insulitis scoring. TLR3 knockout mice were markedly protected from CVB4-induced diabetes compared with CVB4-infected wild-type mice. CVB4-induced T-lymphocyte-mediated insulitis was also significantly less severe in TLR3 knockout mice compared with wild-type mice. No differences in insulitis were observed between uninfected animals, either wild-type or TLR3 knockout mice. These data demonstrate for the first time that TLR3 is 1) critical for CVB4-induced T1DM, and 2) modulates CVB4-induced insulitis in genetically prone NOD mice.