Type 1 Diabetes Mellitus Progression Research Articles

The protective roles of allicin on type 1 diabetes mellitus through AMPK/mTOR mediated autophagy pathway.

Background: Type 1 diabetes mellitus (T1DM) is one of the most common endocrine and metabolic diseases in children. Pancreatic β cells are thought to be critical cells involved in the progression of T1DM, and their injury would directly lead to impaired insulin secretion. Purpose: To investigate the protective effects of allicin on pancreatic β cell injury and elucidate the underlying mechanism. Methods: The streptozotocin (STZ)-induced mouse T1DM model in vivo and STZ-induced pancreatic β cell Min6 model in vitro were used to explore the effects of allicin on T1DM. The experiments include fasting blood glucose test, oral glucose tolerance detection, HE staining, immunohistochemistry, immunofluorescence, TUNEL staining, western blot, real-time quantitative PCR (RT-qPCR), and flow cytometry. Results: Allicin could significantly decrease blood glucose level, improve islet structure and insulin expression, and inhibit apoptosis to reduce STZ-induced pancreatic β cell injury and loss through activating AMPK/mTOR mediated autophagy pathway. Conclusion: Allicin treatment significantly reduced STZ-induced T1DM progression, suggesting that allicin may be a potential therapy option for T1DM patients.

Immunological predictors of type 1 diabetes mellitus (literature review)

Background: Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease characterized by insulin deficiency due β-cell destruction and following hyperglycaemia. Specific markers of T1DM are pancreatic islet-targeting autoantibodies that are found months to years before symptom onset, and can be used to identify individuals who are at risk of developing T1DM.Aim: The study is aimed at the review of current knowledge of diabetes-related autoantibodies as biomarkers of T1DM.Materials and methods: Foreign and national clinical studies on this topic were included. PubMed, Medline and ­eLibrary were searched.Results: Modern ideas about known diabetes-specific autoantibodies as markers of autoimmune inflammation of β-cells of the pancreas were discussed. The analysis of their independent diagnostic value in predicting the occurrence of T1DM were carried out.Conclusion: There is no unified concept in the literature on this issue. Current data on autoantibodies in T1DM show a ­significant individual variability in the timing, dynamic changes and autoantibody composition in T1DM progression.

Прогностические иммунологические маркеры риска развития сахарного диабета 1 типа

Background: Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease characterized by insulin deficiency due β-cell destruction and following hyperglycaemia. Specific markers of T1DM are pancreatic islet-targeting autoantibodies that are found months to years before symptom onset, and can be used to identify individuals who are at risk of developing T1DM. Aim: The study is aimed at the review of current knowledge of diabetes-related autoantibodies as biomarkers of T1DM. Materials and methods : Foreign and national clinical studies on this topic were included. PubMed, Medline and ­eLibrary were searched. Results: Modern ideas about known diabetes-specific autoantibodies as markers of autoimmune inflammation of β-cells of the pancreas were discussed. The analysis of their independent diagnostic value in predicting the occurrence of T1DM were carried out. Conclusion: There is no unified concept in the literature on this issue. Current data on autoantibodies in T1DM show a ­significant individual variability in the timing, dynamic changes and autoantibody composition in T1DM progression.

Histone Deacetylase 3 Aggravates Type 1 Diabetes Mellitus by Inhibiting Lymphocyte Apoptosis Through the microRNA-296-5p/Bcl-xl Axis.

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease characterized by immune-mediated destruction of pancreatic beta-cells. Multiple microRNAs (miRNAs) have been implicated in T1DM pathogenesis. Although histone deacetylase 3 (HDAC3) has been reported to be involved in T1DM, the underlying mechanisms remain to be further elucidated. This study was designed to investigate the potential regulatory role of Hdac3 on T1DM progression. The expression of miR-296-5p and B-cell leukemia-XL (BCL-XL) was determined using RT-qPCR and Western blot assay in peripheral blood mononuclear cells (PBMCs) of patients with T1DM, tumor necrosis factor-α (TNF-α)- and cycloheximide (CHX)-induced cell model, and streptozotocin (STZ)-induced rat model. The binding affinity between miR-296-5p and Bcl-xl was verified by using dual-luciferase reporter gene assay, and the binding between Hdac3 and the promoter region of miR-296-5p was validated using chromatin immunoprecipitation assay. Western blot analysis and flow cytometry were conducted to assess the apoptotic events of lymphocytes. miR-296-5p expression was downregulated while BCL-XL expression was upregulated in PBMCs of patients with T1DM. An adverse correlation was identified between miR-296-5p and Bcl-xl in mouse TE15 B lymphocytes. Bcl-xl was further validated to be targeted and negatively regulated by miR-296-5p in 293 T cells. Hdac3 inhibited miR-296-5p expression by binding to its promoter region. The effects of overexpressed Hdac3 on lymphocyte apoptosis was counterweighed via downregulation of Bcl-xl or upregulation of miR-296-5p, the mechanism of which was further validated in a rat model of DM. Taken together, the Hdac3-mediated upregulation of Bcl-xl via inhibiting miR-296-5p promoter activity enhanced the anti-apoptotic capacity of lymphocytes to accelerate the occurrence of T1DM.

Genetic aspects of type 1 diabetes.

Type 1 diabetes mellitus (T1DM) is characterized by autoimmune destruction of pancreatic beta-cells in genetically predisposed individuals, eventually resulting in severe insulin deficiency. It is the most common form of diabetes in children and adolescents. Genetic susceptibility plays a crucial role in development of T1DM. The human leukocyte antigen complex plays a key role in the pathogenesis of T1DM. Furthermore, genome-wide association studies and linkage analysis have recently made a significant contribution to current knowledge relative to the impact of genetics on T1DM development and progression. This review focuses on current knowledge of genetics as a pathogenesis for T1DM. It also discusses mechanisms by which genes influence the risk of developing T1DM as well as the clinical and research applications of genetic risk scores in T1DM.

Effect of gamma aminobutyric acid (GABA) or GABA with glutamic acid decarboxylase (GAD) on the progression of type 1 diabetes mellitus in children: Trial design and methodology

BackgroundEvidence suggests that GABA may reduce pancreatic inflammation, protect β-cells from autoimmune destruction, and potentiate the regeneration of new β-cells in the setting of type 1 diabetes mellitus (T1DM). The enzyme GAD, also expressed in human pancreatic β-cells, is an antigenic target of reactive T cells. We hypothesized that treatment of children with recent onset T1DM with GABA or combination GABA with GAD will preserve β-cell function and ameliorate autoimmune dysregulation. MethodsThis is a one-year, prospective, randomized, double-blind, placebo-controlled trial. Ninety-nine patients aged 4–18 years with newly diagnosed T1DM are randomized into three treatment groups: 1) oral GABA twice daily in addition to two injections of recombinant GAD enzyme, 2) oral GABA plus placebo GAD injections, or 3) placebo GABA and placebo GAD. Patients are evaluated at baseline and months 1, 5, 8 and 12. Mixed meal tolerance testing is performed at all but the 8-month visit. Laboratory studies will assess indices of beta and alpha cell function, glycemic control, immunophenotyping, and diabetes-related autoantibodies. ResultsThe primary outcome is the effect on pancreatic β-cell function as measured by meal-stimulated c-peptide secretion compared between the treatment groups before and after one year of treatment. Secondary outcomes include: 1) fasting and meal stimulated glucagon and proinsulin levels, 2) response in insulin usage by participants, 3) indices of immune cell function, and 4) effect on autoantibodies GAD65, ICA512, and ZnT8.Conclusions: This trial will determine the safety and efficacy of GABA and combination GABA/GAD therapy to delay T1DM progression in children.

1739-P: Checking the Checkpoints: A Case of Type 1 Diabetes following PD-1 Inhibition in a Patient with HIV

Introduction: Type 1 diabetes mellitus (T1DM) is a known immune related adverse event (irAE) following treatment with Programmed Death 1 (PD-1) immune checkpoint inhibitors with reported 0.9% incidence. Little is known about such irAEs in individuals with HIV treated with PD-1 inhibitors. Case: A 48-year-old man with HIV on HAART, diagnosed with Hodgkin’s lymphoma, initiated PD-1 inhibitor nivolumab. After 6 months, he reported polydipsia and polyuria. Labs revealed glucose 764 mg/dl and A1c 7.1%. Low C-peptide and elevated GAD-65 antibody levels confirmed T1DM, and he started insulin therapy. Nivolumab continued for 12 more months. Despite discontinuation of nivolumab, he remains on insulin therapy. Discussion: While A1c may reflect average glycemia, it alone cannot distinguish T2DM from T1DM progression. C-peptide and autoantibodies for T1DM must be included when screening patients on PD-1 inhibitors. Patients with HIV have higher autoantibody titers in active disease states or following HAART initiation, as seen in immune reconstitution. Moreover, in vitro PD-1 inhibition elevates HIV cell proliferation and immune hyperactivity. The challenge in patients with HIV on HAART and PD-1 inhibitors is unraveling whether autoantibody generation resulting in T1DM is potentiated by pre-existing HIV on HAART and/or provoked by immune response to PD-1 inhibition. Conclusion: Clinicians treating patients with immune checkpoint inhibitors should maintain a high index of suspicion for development of autoimmune disorders. Literature on the use of PD-1 inhibitors in HIV patients is limited and warrants further investigation. To our knowledge, this is the first reported case of T1DM following PD-1 inhibition in a patient with HIV on HAART therapy. Such patients are predisposed to immune reconstitution, and response to PD-1 inhibition may potentiate risk for autoimmune complications. Therefore, higher clinical suspicion for irAEs is merited in patients with HIV on PD-1 inhibitors. Disclosure M.S. Hughes: None. S. Bedrose: None. M. Vasudevan: None. M. Marcelli: None.

Risk of allergic conjunctivitis in patients with type 1 diabetes mellitus: a population-based retrospective cohort study

ObjectiveIn accordance with the dichotomy between T helper type 1(Th1) and T helper type 2 (Th2) responses, the occurrence of allergic conjunctivitis (AC) and type 1 diabetes mellitus (T1DM) is,...

The Prime Diabetes Model: Novel Methods for Estimating Long-Term Clinical and Cost Outcomes in Type 1 Diabetes Mellitus.

Recent publications describing long-term follow-up from landmark trials and diabetes registries represent an opportunity to revisit modeling options in type 1 diabetes mellitus (T1DM). To develop a new product-independent model capable of predicting long-term clinical and cost outcomes. After a systematic literature review to identify clinical trial and registry data, a model was developed (the PRIME Diabetes Model) to simulate T1DM progression and complication onset. The model runs as a patient-level simulation, making use of covariance matrices for cohort generation and risk factor progression, and simulating myocardial infarction, stroke, angina, heart failure, nephropathy, retinopathy, macular edema, neuropathy, amputation, hypoglycemia, ketoacidosis, mortality, and risk factor evolution. Several approaches novel to T1DM modeling were used, including patient characteristics and risk factor covariance, a glycated hemoglobin progression model derived from patient-level data, and model averaging approaches to evaluate complication risk. Validation analyses comparing modeled outcomes with published studies demonstrated that the PRIME Diabetes Model projects long-term patient outcomes consistent with those reported for a number of long-term studies. Macrovascular end points were reliably reproduced across five different populations and microvascular complication risk was accurately predicted on the basis of comparisons with landmark studies and published registry data. The PRIME Diabetes Model is product-independent, available online, and has been developed in line with good practice guidelines. Validation has indicated that outcomes from long-term studies can be reliably reproduced. The model offers new approaches to long-standing challenges in diabetes modeling and may become a valuable tool for informing health care policy.

Therapeutic window of globular adiponectin against cerebral ischemia in diabetic mice: the role of dynamic alteration of adiponectin/adiponectin receptor expression.

Recent studies have demonstrated that adiponectin (APN) attenuates cerebral ischemic/reperfusion via globular adiponectin (gAD). However, the therapeutic role of gAD in cerebral ischemic injury in type 1 diabetes mellitus (T1DM) remains unclear. Our results showed that gAD improved neurological scores and reduced the infarct volumes in the 8-week T1DM (T1DM-8W) mice, but not in the 2-week T1DM (T1DM-2W) mice. Moreover, the ischemic penumbra APN levels increased and peaked in T1DM-2W mice, and reduced to normal in T1DM-8W mice, while the APN receptor 1 (AdipoR1) expression change was the opposite. Administration of rosiglitazone in T1DM-2W mice up-regulated the expression of AdipoR1 and restored the neuroprotection of gAD, while intracerebroventricular injection of AdipoR1 small interfering RNA (siRNA) in T1DM-8W mice reversed it. Furthermore, the expression of p-PERK, p-IRE1 and GRP78 were increased whereas the expressions of CHOP and cleaved caspase-12 as well as the number of apoptotic neurons were decreased after gAD treatment in T1DM-8W mice. These beneficial effects of gAD were reversed by pretreatment with AdipoR1 siRNA. These results demonstrated a dynamic dysfunction of APN/AdipoR1 accompanying T1DM progression. Interventions bolstering AdipoR1 expression during early stages and gAD supplementation during advanced stages may potentially reduce the cerebral ischemic injury in diabetic patients.

Prediction and prevention of type 1 diabetes: update on success of prediction and struggles at prevention.

Type 1 diabetes mellitus (T1DM) is the archetypal example of a T cell-mediated autoimmune disease characterized by selective destruction of pancreatic β cells. The pathogenic equation for T1DM presents a complex interrelation of genetic and environmental factors, most of which have yet to be identified. On the basis of observed familial aggregation of T1DM, it is certain that there is a decided heritable genetic susceptibility for developing T1DM. The well-known association of T1DM with certain human histocompatibility leukocyte antigen (HLA) alleles of the major histocompatibility complex (MHC) was a major step toward understanding the role of inheritance in T1DM. Type 1 diabetes is a polygenic disease with a small number of genes having large effects (e.g., HLA) and a large number of genes having small effects. Risk of T1DM progression is conferred by specific HLA DR/DQ alleles [e.g., DRB1*03-DQB1*0201 (DR3/DQ2) or DRB1*04-DQB1*0302 (DR4/DQ8)]. In addition, the HLA allele DQB1*0602 is associated with dominant protection from T1DM in multiple populations. A concordance rate lower than 100% between monozygotic twins indicates a potential involvement of environmental factors on disease development. The detection of at least two islet autoantibodies in the blood is virtually pre-diagnostic for T1DM. The majority of children who carry these biomarkers, regardless of whether they have an a priori family history of the disease, will develop insulin-requiring diabetes. Facilitating pre-diagnosis is the timing of seroconversion which is most pronounced in the first 2 yr of life. Unfortunately the significant progress in improving prediction of T1DM has not yet been paralleled by safe and efficacious intervention strategies aimed at preventing the disease. Herein we summarize the chequered history of prediction and prevention of T1DM, describing successes and failures alike, and thereafter examine future trends in the exciting, partially explored field of T1DM prevention.

Deciphering early development of complex diseases by progressive module network

There is no effective cure nowadays for many complex diseases, and thus it is crucial to detect and further treat diseases in earlier stages. Generally, the development and progression of complex diseases include three stages: normal stage, pre-disease stage, and disease stage. For diagnosis and treatment, it is necessary to reveal dynamical organizations of molecular modules during the early development of the disease from the pre-disease stage to the disease stage. Thus, we develop a new framework, i.e. we identify the modules presenting at the pre-disease stage (pre-disease module) based on dynamical network biomarkers (DNBs), detect the modules observed at the advanced stage (disease-responsive module) by cross-tissue gene expression analysis, and finally find the modules related to early development (progressive module) by progressive module network (PMN). As an application example, we used this new method to analyze the gene expression data for NOD mouse model of Type 1 diabetes mellitus (T1DM). After the comprehensive comparison with the previously reported milestone molecules, we found by PMN: (1) the critical transition point was identified and confirmed by the tissue-specific modules or DNBs relevant to the pre-disease stage, which is considered as an earlier event during disease development and progression; (2) several key tissues-common modules related to the disease stage were significantly enriched on known T1DM associated genes with the rewired association networks, which are marks of later events during T1DM development and progression; (3) the tissue-specific modules associated with early development revealed several common essential progressive genes, and a few of pathways representing the effect of environmental factors during the early T1DM development. Totally, we developed a new method to detect the critical stage and the key modules during the disease occurrence and progression, and show that the pre-disease modules can serve as warning signals for the pre-disease state (e.g. T1DM early diagnosis) whereas the progressive modules can be used as the therapy targets for the disease state (e.g. advanced T1DM), which were also validated by experimental data.

Proteomic Analysis of Hearts from Akita Mice Suggests That Increases in Soluble Epoxide Hydrolase and Antioxidative Programming Are Key Changes in Early Stages of Diabetic Cardiomyopathy

Cardiovascular disease is the leading cause of diabetic morbidity with more than 10% of type 1 diabetes mellitus (T1DM) patients dying before they are 40 years old. This study utilized Akita mice, a murine model with T1DM progression analogous to that of humans. Diabetic cardiomyopathy in Akita mice presents as cardiac atrophy and diastolic impairment at 3 months of age, but we observed cardiac atrophy in hearts from recently diabetic mice (5 weeks old). Hearts from 5 week old mice were analyzed with a rigorous label-free quantitative proteomic approach to identify proteins that may play a critical role in the early pathophysiology of diabetic cardiomyopathy. Eleven proteins were differentially expressed in diabetic hearts: products of GANC, PLEKHN1, COL1A1, GSTK1, ATP1A3, RAP1A, ACADS, EEF1A1, HRC, EPHX2, and PKP2 (gene names). These proteins are active in cellular defense, metabolism, insulin signaling, and calcium handling. Further analysis of Akita hearts using biochemical assays showed that the cellular defenses against oxidative stress were increased, including antioxidant capacity (2-3-fold) and glutathione levels (20%). Immunoblots of five and twelve week old Akita heart homogenates showed 30% and 145% increases in expression of soluble epoxide hydrolase (sEH (gene name EPHX2)), respectively, and an approximate 100% increase in sEH was seen in gastrocnemius tissue of 12 week old Akita mice. In contrast, 12 week old Akita livers showed no change in sEH expression. Our results suggest that increases in sEH and antioxidative programming are key factors in the development of type 1 diabetic cardiomyopathy in Akita mice and reveal several other proteins whose expression may be important in this complex pathophysiology.

Exercise in An Islet-Transplanted Amateur Marathon Runner: Effects on Training, Autoimmunity and Metabolic Profile

Introduction: Type 1 diabetes mellitus (T1DM) is a chronically progressive autoimmune disease in which the adverse immune response is induced and promoted by the interaction of genetic and environmental factors. Recent studies have suggested that physical exercise may interfere with immune system function even at low intensity and duration. Methods: An islet-transplanted T1DM patient (M, 44yrs) has been longitudinally monitored for autoimmunity markers, metabolic profile and physical performance, being himself an amateur marathon runner, over a 7-year period since he received an islet allograft. Given his irregular history of training (because of injuries, medical issues etc), we identified 4 phases throughout this period, lasting 2 years each, alternating between phases of rest and training. Results: An ad hoc regime of training (supervised interval training) resulted in an improvement in HbA1c (-9.2%, p< 0.05), C-reactive protein (-16.6%, p< 0.05) and a decrease of exogenous insulin (from 4-8 to 4-6 U/day) during the 2nd phase compared to the 1st phase of rest (recovery after allograft). In the 3rd phase (post-injury resting), Hb1Ac increased by 13.3% (p< 0.05 vs 2nd phase), as did the insulin dose (6-8 U/day). In the 4th phase, exercise training was accompanied by an amelioration of Hb1Ac of 22% compared to the 3rd phase, and the number of required insulin units diminished dramatically vs the 1st phase (2-3 U twice a week), as did the levels of autoimmunity markers (antiGAD and antiINS ab, from 0.5 to 0.0 and from 6.6 to 1.6 AU, respectively). Race time during competition improved by 10.5% vs the 2nd phase of training (p< 0 .05). Also in the 4th phase, aerobic, anaerobic thresholds and heart rates were significantly higher than in the previous phases (p< 0.05). Conclusions: Altogether, these data suggest an association between the alterations in detrimental metabolic and autoimmunity profiles and the successive training/resting periods, evoking a potential role for exercise in the positive immunomodulation against T1DM progression and inflammation.

Dynamic alteration of adiponectin/adiponectin receptor expression and its impact on myocardial ischemia/reperfusion in type 1 diabetic mice

The present study determined the dynamic change of adiponectin (APN, a cardioprotective adipokine), its receptor expression, and their impact upon myocardial ischemia/reperfusion (MI/R) injury during type 1 diabetes mellitus (T1DM) progression, and involved underlying mechanisms. Diabetic state was induced in mice via multiple intraperitoneal injections of low-dose streptozotocin. The dynamic change of plasma APN concentration and cardiac APN receptor-1 and -2 (AdipoR1/2) expression were assessed immediately after diabetes onset (0 wk) and 1, 3, 5, and 7 wk thereafter. Indicators of MI/R injury (infarct size, apoptosis, and LDH release) were determined at 0, 1, and 7 wk of DM duration. The effect of APN on MI/R injury was determined in mice subjected to different diabetic durations. Plasma APN levels (total and HMW form) increased, whereas cardiac AdipoR1 expression decreased early after T1DM onset. With T1DM progression, APN levels were reduced and cardiac AdipoR1 expression increased. MI/R injury was exacerbated with T1DM progression in a time-dependent manner. Administration of globular APN (gAD) failed to attenuate MI/R injury in 1-wk T1DM mice, while an AMP-activated protein kinase (AMPK) activator (AICAR) reduced MI/R injury. However, administration of gAD (and AICAR) reduced infarct size and cardiomyocyte apoptosis in 7-wk T1DM mice. In conclusion, our results demonstrate a dynamic dysfunction of APN/AdipoR1 during T1DM progression. Reduced cardiac AdipoR1 expression and APN concentration may be responsible for increased I/R injury susceptibility at early and late T1DM stages, respectively. Interventions bolstering AdipoR1 expression during early T1DM stages and APN supplementation during advanced T1DM stages may potentially reduce the myocardial ischemic injury in diabetic patients.

Cytoplasmic islet cell antibodies remain valuable in defining risk of progression to type 1 diabetes in subjects with other islet autoantibodies

The discovery of islet cell antibodies (ICAs) was the prelude to the understanding that type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease. The issue regarding whether or not the measurement of ICAs should be completely replaced by biochemical markers detecting islet autoantibodies (AAs) for the prediction of T1DM has been the subject of endless international debates. In light of this controversy, we assessed the current role of ICAs as a predictive marker for T1DM progression. We examined a cohort of 1484 first-degree relatives (FDRs) of T1DM probands from the Children's Hospital of Pittsburgh Registry. These relatives were consecutively enrolled between 1979 through 1984 and followed up to 22 yr. Serum obtained at the time of enrollment was assayed for ICAs, glutamic acid decarboxylase (GAD)65, insulin A (IA)-2 AA, and insulin AAs (IAAs). In FDRs who had ICAs in addition to GAD65 and IA-2 AAs, the cumulative risk of developing insulin-requiring diabetes was 80% at 6.7 yr of follow-up, whereas this risk in those with GAD65 and IA-2 AAs without ICAs was only 14% at 10 yr of follow-up (log rank: P < 0.00001). Cox regression analysis showed that diabetes risk was significantly associated with the presence of ICAs in both subjects with low titer and high titer GAD65 and IA-2 AAs. The addition of IAAs in GAD65 and IA-2 AA-positive relatives did not increase the cumulative risk for conversion to insulin-treated diabetes. We provide evidence that a subgroup of ICAs predicts a more rapid progression to insulin-requiring diabetes in GAD65 and IA-2 AA-positive relatives and should remain part of the assessment of T1DM risk for intervention trials. In addition, these findings provide impetus for efforts to identify a novel islet autoantigen(s) reactive with this ICA subset.