Prevention Of T1D Research Articles

Review on Monoclonal Antibodies (mAbs) as a Therapeutic Approach for Type 1 Diabetes.

Monoclonal antibodies have been successfully utilized in a variety of animal models to treat auto-immune illnesses for a long time. Immune system responses will either be less active or more active depending on how the immune system is operating abnormally. Immune system hypoactivity reduces the body's capacity to fight off various invading pathogens, whereas immune system hyperactivity causes the body to attack and kill its own tissues and cells. For maximal patient compliance, we will concentrate on a variety of antibody therapies in this study to treat Type 1 diabetes (an autoimmune condition). T-cells are responsible for the auto-immune condition known as T1D, which causes irregularities in the function of β-cells in the pancreas. As a result, for the treatment and prevention of T1D, immunotherapies that selectively restore continuous beta cellspecific self-tolerance are needed. Utilizing monoclonal antibodies is one way to specifically target immune cell populations responsible for the auto-immune-driven disease (mAb). Numerous mAbs have demonstrated clinical safety and varied degrees of success in modulating autoimmunity, including T1D. A targeted cell population is exhausted by mAb treatments, regardless of antigenic specificity. One drawback of this treatment is the loss of obtained protective immunity. Immune effector cell function is regulated by nondepleting monoclonal antibodies (mAb). The antigenfocused new drug delivery system is made possible by the adaptability of mAbs. For the treatment of T1D and T-cell-mediated autoimmunity, different existing and potential mAb therapy methods are described in this article.

Disease-modifying therapies and features linked to treatment response in type 1 diabetes prevention: a systematic review

BackgroundType 1 diabetes (T1D) results from immune-mediated destruction of insulin-producing beta cells. Prevention efforts have focused on immune modulation and supporting beta cell health before or around diagnosis; however, heterogeneity in disease progression and therapy response has limited translation to clinical practice, highlighting the need for precision medicine approaches to T1D disease modification.MethodsTo understand the state of knowledge in this area, we performed a systematic review of randomized-controlled trials with ge50 participants cataloged in PubMed or Embase from the past 25 years testing T1D disease-modifying therapies and/or identifying features linked to treatment response, analyzing bias using a Cochrane-risk-of-bias instrument.ResultsWe identify and summarize 75 manuscripts, 15 describing 11 prevention trials for individuals with increased risk for T1D, and 60 describing treatments aimed at preventing beta cell loss at disease onset. Seventeen interventions, mostly immunotherapies, show benefit compared to placebo (only two prior to T1D onset). Fifty-seven studies employ precision analyses to assess features linked to treatment response. Age, beta cell function measures, and immune phenotypes are most frequently tested. However, analyses are typically not prespecified, with inconsistent methods of reporting, and tend to report positive findings.ConclusionsWhile the quality of prevention and intervention trials is overall high, the low quality of precision analyses makes it difficult to draw meaningful conclusions that inform clinical practice. To facilitate precision medicine approaches to T1D prevention, considerations for future precision studies include the incorporation of uniform outcome measures, reproducible biomarkers, and prespecified, fully powered precision analyses into future trial design.

328.6: Alginate-based (G) microcapsules (MC): a versatile tool for the experimental cell therapy and prevention of T1D

328.6: Alginate-based (G) microcapsules (MC): a versatile tool for the experimental cell therapy and prevention of T1D

Secondary Prevention of Diabetes Type 1 with Oral Calcitriol and Analogs, the PRECAL Study.

Screening for Type 1 Diabetes (T1D, incidence 1:300) with T1D autoantibodies (T1Ab) at ages 2 and 6, while sensitive, lacks a preventive strategy. Cholecalciferol 2000 IU daily since birth reduced T1D by 80% at 1 year. T1D-associated T1Ab negativized within 0.6 years with oral calcitriol in 12 children. To further investigate secondary prevention of T1D with calcitriol and its less calcemic analog, paricalcitol, we initiated a prospective interventional non-randomized clinical trial, the PRECAL study (ISRCTN17354692). In total, 50 high-risk children were included: 44 were positive for T1Ab, and 6 had predisposing for T1D HLA genotypes. Nine T1Ab+ patients had variable impaired glucose tolerance (IGT), four had pre-T1D (3 T1Ab+, 1 HLA+), nine had T1Ab+ new-onset T1D not requiring insulin at diagnosis. T1Ab, thyroid/anti-transglutaminase Abs, glucose/calcium metabolism were determined prior and q3-6 months on calcitriol, 0.05 mcg/Kg/day, or paricalcitol 1-4 mcg × 1-3 times/day p.o. while on cholecalciferol repletion. Available data on 42 (7 dropouts, 1 follow-up < 3 months) patients included: all 26 without pre-T1D/T1D followed for 3.06 (0.5-10) years negativized T1Ab (15 +IAA, 3 IA2, 4 ICA, 2 +GAD, 1 +IAA/+GAD, 1 +ICA/+GAD) within 0.57 (0.32-1.3) years or did not develop to T1D (5 +HLA, follow-up 3 (1-4) years). From four pre-T1D cases, one negativized T1Ab (follow-up 1 year), one +HLA did not progress to T1D (follow-up 3.3 years) and two +T1Ab patients developed T1D in 6 months/3 years. Three out of nine T1D cases progressed immediately to overt disease, six underwent complete remission for 1 year (1 month-2 years). Five +T1Ab patients relapsed and negativized again after resuming therapy. Four (aged <3 years) negativized anti-TPO/TG, and two anti-transglutaminase-IgA. Eight presented mild hypercalciuria/hypercalcemia, resolving with dose titration/discontinuation. Secondary prevention of T1D with calcitriol and paricalcitol seems possible and reasonably safe, if started soon enough after seroconversion.

Bacille Calmette Guerin (BCG) and prevention of types 1 and 2 diabetes: Results of two observational studies.

Diabetes is a common disease marked by high blood sugars. An earlier clinical trial in type 1 diabetic subjects (T1Ds) found that repeat BCG vaccinations succeeded in lowering HbA1c values over a multi-year course. Here we seek to determine whether BCG therapy for bladder cancer may improve blood sugar levels in patients with comorbid T1D and type 2 diabetes (T2D). We also investigate whether BCG exposure may reduce onset of T1D and T2D by examining country-by-country impact of BCG childhood vaccination policies in relation to disease incidence. We first analyzed three large US patient datasets (Optum Labs data [N = 45 million], Massachusetts General Brigham [N = 6.5 million], and Quest Diagnostics [N = 263 million adults]), by sorting out subjects with documented T1D (N = 19) or T2D (N = 106) undergoing BCG therapy for bladder cancer, and then by retrospectively assessing BCG's subsequent year-by-year impact on blood sugar trends. Additionally, we performed an ecological analysis of global data to assess the country-by-country associations between mandatory neonatal BCG vaccination programs and T1D and T2D incidence. Multi-dose BCG therapy in adults with comorbid diabetes and bladder cancer was associated with multi-year and stable lowering of HbA1c in T1Ds, but not in T2Ds. The lack of a similar benefit in T2D may be due to concurrent administration of the diabetes drug metformin, which inhibits BCG's beneficial effect on glycolysis pathways. Countries with mandatory neonatal BCG vaccination policies had a lower incidence of T1D in two international databases and a lower incidence of T2D in one of the databases. The epidemiological evidence analyzed here suggests that BCG may play a role in the prevention of T1D. It does not support prevention of T2D, most likely because of interference by metformin. Our ecological analysis of global data suggests a role for neonatal BCG in the prevention of T1D and, to a lesser extent, T2D. Randomized clinical trials are needed to confirm these findings.

Potential risk factors for diabetes mellitus type 1

Diabetes mellitus type 1 (T1D) develops as a result of the interaction of genetic and environmental factors. Genetic predisposition to T1D turns into clinical reality only in half of hereditary cases, which indirectly indicates the importance of external factors, the significance of which is periodically reviewed. Retrospective and prospective clinical foreign and national studies were included. PubMed, Medline and eLibrary were searched. Modern ideas about the possible impact of the main prenatal and postnatal environmental factors on the development of autoimmune response against insulin-producing islet cells and T1D were discussed. The risk of developing type 1 diabetes is determined by the complex interaction of environmental factors and genetic predisposition. The mechanisms of their influence remain rather unknown. Further research is needed to determine strategies of primary and secondary prevention of T1D.

Prevention of type 1 diabetes: where we are and where we are going.

T1D (T1D) is one of the most frequent chronic disease in children and is associated to the risk of severe acute and chronic complications. There are about 550,000 children with T1D in the world; and about 86,000 children are diagnosed with T1D every year and its incidence is ever increasing. In this narrative review we will discuss current and future perspectives in T1D prevention strategies as well as their pitfalls. It is important to remember that for the first time one drug, in particular teplizumab (antibody anti-CD3) is going to be accepted for treatment in stage 2 of type 1 diabetes mellitus. This represent the onset of a new era.

Use of glycosylated hemoglobin and C-peptide levels in the diagnosis and prevention of type 1 diabetes mellitus as an immune-related adverse event secondary to treatment with immunotherapy in solid tumors.

97 Background: Type 1 diabetes mellitus (T1D) as an immune-related adverse event (irAE) is found in 0.5-5% of all patients treated with immunotherapy (IT) and it is associated with life-threatening complications. However, there are no official guidelines that suggest methods for the prevention and monitoring of T1D during treatment with IT. The algorithms described in the literature only assess the fasting blood sugar levels for prevention and monitoring. The objective of this review is to find factors that establish a relationship with the appearance of T1D as an irAE and to put forward a new algorithm for prevention and monitoring based on those findings. Methods: We carried out a clinical review of the cases published in the literature on T1D secondary to IT between 2012 and 2019. Through a statistical analysis, the relevant clinical characteristics will be determined, together with the factors related to the appearance of T1D, which will make it possible to put forward a new algorithm for the prevention and monitoring of T1D during treatment with IT for solid tumors. Results: Eighty one cases were reported. Of the reported cases, 90% were associated with Nivolumab or Pembrolizumab. The median age was 67 years (23-84 years), and the patients were predominantly men. The average number of administered doses was 5.3 with a lapse of 14.6 weeks from the administration of the first dose until diagnosis. In 48 cases (59%) the levels of C-peptide were low or undetectable, and the glycosylated hemoglobin (HbA1c) levels were elevated by an average of 8.8% (73 mmol/mol). Anti-β-cell antibodies were found in less than half of the patients (44). Diabetic ketoacidosis was observed at diagnosis in 61 patients (75%). Conclusions: Based on the results of our review, we propose including the levels of C-peptide and HbA1C in the usual protocol for the management of adverse events related to IT. Our algorithm suggests that the levels must be determined prior to the IT, after the first 2 cycles, and then every 2 months. This algorithm will enable the prevention, early diagnosis and monitoring of T1D during treatment with IT.

Individuals with Single Islet Autoantibody Positivity (SA+) at Type 1 Diabetes (T1D) Diagnosis Have Distinct Characteristics

Multiple autoantibody positivity (MA+) usually precedes clinical T1D. However, a subset of patients who develop T1D have SA+. We hypothesized that individuals who at T1D diagnosis express SA+ compared with MA+ have different demographic, metabolic, immunologic and genetic characteristics. We studied 620 TrialNet participants who developed clinical T1D (median age=12.3 years [range=1.4-58.6], 47.5% male, 88% white). Using multivariable modeling and adjusting for potential confounders, we investigated differences between participants with SA+ vs. MA+ (of autoantibodies to GAD65 [GADA], insulin [mIAA], IA2, ZnT8 and ICA) at T1D diagnosis. We found 95 participants who had SA+ (70% GADA+) and 525 participants with MA+. In univariate analyses, individuals with SA+ vs. MA+ were older at T1D diagnosis (median 16.4 vs. 11.7 years, p&amp;lt;0.0001) and had higher fasting C-peptide (1.87 vs. 1.47 nmol/L, p=0.007), higher 30-0 minute C-peptide difference (1.42 vs. 1.18, p=0.009) and lower Index60 (composite measure of fasting C-peptide, 60-min glucose and 60-min C-peptide) (2.31 vs. 2.68, p=0.0005). Gender, race, ethnicity, BMI-Z-score, presence of HLA DR3-DQ2 and/or DR4-DQ8, fasting glucose, AUC glucose and AUC C-peptide were not significantly different. By multivariable analyses, SA+ at onset corresponded with older age (OR=1.05, p&amp;lt;0.0001), lower Index60 (OR=0.77, p=0.008), and lower likelihood of mIAA+ (OR=0.27, p&amp;lt;0.0001) and GADA+ (OR=0.25, p&amp;lt;0.0001); gender, HLA, BMI-Z-score and other autoantibody types were not significantly different. Independent factors of being SA+ differed between DR3/DR4-DQ8 heterozygous participants (older age and not having mIAA+ or GADA+) (p&amp;lt;0.01) and those not DR3/DR4-DQ8 (lower Index60 and not having GADA+) (p&amp;lt;0.01). In conclusion, the number of islet autoantibodies at T1D diagnosis is associated with distinct characteristics, which may suggest heterogeneous pathogenesis with relevance for T1D prevention and treatment. Disclosure M.J. Redondo: None. J. Sosenko: None. I. Libman: Consultant; Self; Novo Nordisk A/S. J.J. McVean: Speaker's Bureau; Self; Medtronic MiniMed, Inc. M.A. Atkinson: Other Relationship; Self; Patent Issued. D.J. Becker: None. S. Geyer: None.

Index60 Is More Strongly Associated with the Highest Type 1 Diabetes (T1D) Risk HLA DR3-DQ2/DR4-DQ8 (DQ2/DQ8) Genotype than Glucose Measures

Dysglycemia (i.e., fasting glucose=110-125 mg/dl; 30, 60, or 90-minutes glucose ≥200 mg/dl; and/or 2-h glucose=140-199 mg/dl, from oral glucose tolerance test [OGTT]) is used both as a predictive marker and pre-diagnostic endpoint in T1D prevention trials. However, recent evidence suggests that Index60 (based on fasting C-peptide, 60-minutes glucose and 60-minutes C-peptide, from OGTT) at a 1.00 threshold may be superior to dysglycemia. We thus hypothesized that Index60 is more strongly associated with T1D-linked genetic factors than glucose measures alone. We compared autoantibody-positive TrialNet Pathway to Prevention Study participants (n=1,098) with or without DQ2/DQ8 for associations with Index60, fasting glucose, 2-h glucose and dysglycemia. Participants with DQ2/DQ8 (n=159) compared to those without it (n=912) had higher Index60 values (median [interquartile range, IQR]=0.6 [-5.6 to 2.6] vs. 0.25 (-4.4 to 2.9]; p=0.001). In contrast, neither fasting glucose (p=0.51) nor 2-hour glucose p=0.07) were significantly different between the groups. The percentage with Index60≥1.00 was significantly higher in participants with (37.6%) than without (22.8%) DQ2/DQ8 (p=0.0001), whereas the percentages with dysglycemia were not significantly different (32.7% vs. 26.1%; p=0.11). Among those with normal OGTTs, Index60≥1.00 was more frequent among participants with DQ2/DQ8 (23.8%) than without it (12.0%; p=0.001), while among participants with Index60&amp;lt;1.00, the frequency of dysglycemia was similar in those with and without DQ2/DQ8 (17.5% vs. 16.0%; p=0.70). In conclusion, Index60, a metabolic marker based on glucose and C-peptide, is more strongly associated with the highest T1D risk HLA DQ2/DQ8 genotype than glucose measures, including dysglycemia. This suggests that Index60 has higher pathogenic specificity for T1D than glucose measures and should be considered for use in T1D prevention trials. Disclosure M.J. Redondo: None. S. Geyer: None. H.M. Ismail: None. K.C. Herold: None. A. Pugliese: None. J.P. Palmer: None. J. Sosenko: None.

GUT MICROBIOTA AND DIABETES MELLITUS - AN INTERLINKAGE

In recent years, the curiosity to investigate the relationship between gut microbiota and diabetes development has increased. Evidence from previous studies suggests that gut microbiota manipulation may assure to prevent diabetes development in future, primarily in susceptible individuals. Here, we reviewed special gut microbiota types proposing development of Type 1 (T1D) and Type 2 diabetes (T2D) in humans and laboratory animals. The available data we found are still inconclusive and required more attention in discriminating specific groups of gut microbiomes strongly indicating T1D and T2D development or prevention. Further, we suggested for the first time to study the gut microbiota in different ways to find the root cause of diabetes development.

GUT MICROBIOTA AND DIABETES MELLITUS - AN INTERLINKAGE

In recent years, the curiosity to investigate the relationship between gut microbiota and diabetes development has increased. Evidence from previous studies suggests that gut microbiota manipulation may assure to prevent diabetes development in future, primarily in susceptible individuals. Here, we reviewed special gut microbiota types proposing development of Type 1 (T1D) and Type 2 diabetes (T2D) in humans and laboratory animals. The available data we found are still inconclusive and required more attention in discriminating specific groups of gut microbiomes strongly indicating T1D and T2D development or prevention. Further, we suggested for the first time to study the gut microbiota in different ways to find the root cause of diabetes development.

Anonna muricata L. (soursop) seed oil improves type 1 diabetes parameters in vivo and in vitro

Annona muricata have many properties reported as antidiabetic, antitumor and antioxidant effects. However, studies on the use of fruit seeds are limited. In this study, we identified the immunomodulatory potential of A. muricata seed oil (AmSO) in streptozotocin (STZ)-induced in vivo and in vitro experimental model of T1D and whole blood cell culture from diabetic patients. AmSO cytotoxicity was evaluated by MTT-tetrazolium and resazurin. AmSO was orally administered to BALB/c mice for 48days and were divided into groups: control, STZ (diabetic), STZ–AmSO (diabetic, treated with 1.0mg/kg AmSO), and AmSO groups (nondiabetic, treated with 1.0mg/kg AmSO). T1D was induced with intraperitoneal administration of STZ (3×100mg/kg). Biochemistry and histopathological analysis and area of pancreatic islets were evaluated. IL-10, IL-4, IL-17 production in spleen cell culture from diabetic mice exposed to AmSO and IFN-γ and IL-10 levels in whole blood cell culture from diabetic patients exposed to AmSO was determined by ELISA. AmSO showed antihyperglycemic effect, preserved the area of ​​pancreatic islets, preserved liver tissue, increased IL-4 and IL-10 levels in spleen cell culture, and decreased IFN-γ level in whole blood cell culture. AmSO demonstrated immunomodulatory effect and therapeutic potential for the treatment and/or prevention of clinical T1D.

In vivo biodistribution of antihyperglycemic biopolymer-based nanoparticles for the treatment of type 1 and type 2 diabetes

This study aimed to assess the biodistribution of antihyperglycemic insulin-loaded alginate/dextran sulfate-based nanoparticles dual coated with chitosan and technetium-99m-albumin (99mTc-BSA) after oral administration.The oral administration of 50IU/kg insulin-loaded nanoparticles to type 1 diabetic rats showed prolonged antihyperglycemic effects up to 12h and relative pharmacological availability of 5.04% comparing to the subcutaneous administration. The oral antihyperglycemic effect was further compared between type 1 and type 2 diabetic models by the intraperitoneal glucose tolerance test, revealing that the effect lasted longer in the type 1 diabetic model. 99mTc-BSA revealed to be a good nanoparticles’ tracer since there was no systemic absorption and 99mTc-BSA-nanoparticles were capable of increasing their residence time in the intestinal epithelium of balb-c mice when compared with 99mTc-BSA biodistribution. Thus, this biopolymeric-based delivery nanoparticulate system is a promising tool for the therapy of type 1 and type 2 diabetic individuals and prevention of T1D.

Cholinergic Stimulation Prevents the Development of Autoimmune Diabetes: Evidence for the Modulation of Th17 Effector Cells via an IFNγ-Dependent Mechanism.

Type I diabetes (T1D) results from T cell-mediated damage of pancreatic β-cells and loss of insulin production. The cholinergic anti-inflammatory pathway represents a physiological link connecting the central nervous and immune systems via vagus nerve, and functions to control the release of proinflammatory cytokines. Using the multiple low-dose streptozotocin (MLD-STZ) model to induce experimental autoimmune diabetes, we investigated the potential of regulating the development of hyperglycemia through administration of paraoxon, a highly specific acetylcholinesterase inhibitor (AChEI). We demonstrate that pretreatment with paraoxon prevented hyperglycemia in STZ-treated C57BL/6 mice. This correlated with a reduction in T cell infiltration into pancreatic islets and preservation of the structure and functionality of β-cells. Gene expression analysis of pancreatic tissue revealed that increased peripheral cholinergic activity prevented STZ-mediated loss of insulin production, this being associated with a reduction in IL-1β, IL-6, and IL-17 proinflammatory cytokines. Intracellular cytokine analysis in splenic T cells demonstrated that inhibition of AChE led to a shift in STZ-induced immune response from a predominantly disease-causing IL-17-expressing Th17 cells to IFNγ-positive Th1 cells. Consistent with this conclusion, inhibition of AChE failed to prevent STZ-induced hyperglycemia in IFNγ-deficient mice. Our results provide mechanistic evidence for the prevention of murine T1D by inhibition of AChE and suggest a promising strategy for modulating disease severity.

Elevated anthranilic acid plasma concentrations in type 1 but not type 2 diabetes mellitus.

Experimental data suggested involvement of tryptophan (Trp) - kynurenine (Kyn) pathway (TKP) in mechanisms of autoimmune, type 1 (T1D), and metabolic, type 2 (T2D), diabetes. However, clinical evaluations of TKP metabolites were limited to T2D. We assessed Trp, Kyn and TKP metabolites: anthranilic (AA), kynurenic (KYNA) and xanthurenic (XA) acids, in plasma samples of fifteen T1D, thirty T2D patients and twenty eight non-diabetic subjects by HPLC-mass spectrometry. Trp concentrations were higher in T1D than in T2D and controls while Kyn concentrations were not changed suggesting down-regulation of indoleamine-2,3-dioxygenase (IDO), a rate-limiting enzyme of TKP, in T1D. AA concentrations were 2.3-fold higher in T1D than in T2D and in controls. KYNA and XA concentrations were higher in T1D than in controls, and in previously reported T2D. AA elevation might be a specific feature of T1D. TKP shift towards AA formation in T1D may result from riboflavin deficiency, that increases AA in rats and baboons, and is highly associated with T1D but not T2D. AA augments autoimmune-induced apoptosis of pancreatic cells (PC) by increasing formation of antibodies to PC auto-antigen. Marked increase of AA was reported in rheumatoid arthritis, another autoimmune disorder. Trp, an essential amino acid for humans, is synthesized from AA by diabetogenic intestinal microbiome. AA down-regulates IDO by inhibition of Trp entry into cells. Resulting elevation of Trp attenuates Trp depletion-induced protection of PC against autoimmunity. Further studies of TKP might offer new tools for prevention and treatment of T1D and other autoimmune disorders.

Predictive, preventive and personalized medicine (PPPM) as a strategic avenue and global tool for advancing T1D-related care: Fundamental, Applied and Affiliated Issues

Type one diabetes (T1D: (juvenile onset) whilst being a chronic disease, the defining feature of which is the destruction of the insulin-secreting beta-cells and subsequent dependence on exogenous insulin, is possessing with hallmark characteristics of the complex T cellmediated autoimmunity superimposed on genetic susceptibility. Both genetic and environmental factors combine to precipitate disease, and the outcome of the pathological process is dependent on multiple interrelated factors. The annual global incidence of T1D is increasing by 3-5% per year. Both HLA-genes and immune markers (autoantibodies/autoAbs) have been validated as predictive biomarkers of the subsequent development of the disease in higher-risk relatives and the lower-risk general population. Over the last three decades, using a combination of genomic, proteomic, and metabolomic biomarkers, clinicians are now able to quantify an individual’s disease risk from 1 in 100,000 to more than 1 in 2. The HLA genes are reported to account for approximately 40-50% of the familial aggregation of T1D. Current approaches for the prediction of T1D in screening studies take advantage of genotyping HLA-DR and HLA-DQ loci, which is then combined with family history and screening for autoAbs directed against isletcell Ags. Inclusion of additional moderate HLA risk haplotypes may help identify the majority of children withT1D before the onset of the disease. Fine mapping and functional studies are gradually revealing the complex mechanisms whereby immune self-tolerance is lost, involving adaptive immunity. Genetic prediction of T1D risks is showing promise of use for preventive strategies. And understanding of the genetics, environmental factors, and natural history of T1D has resulted in greater understanding of the etiology and epidemiology of the disease. The clinical care of patients with T1D has greatly improved over the past few decades; however, it remains impossible to completely normalize blood sugar utilizing currently available tools. Meanwhile, subclinical and predictive diagnostic armamentarium is still far from being unique, and innovative algorithms that significantly differ from the clinical approaches should become the major bricks to be laid into the basis of a subclinical diagnosis of pre-T1D. Generally, there are three levels desirable for an optimal pre-T1D and T1D-related healthcare, namely, (i) 1 level: prediction of the familial predisposition, targeted prevention of pre-T1D early in childhood; (ii) 2 level: prediction of early/premature aging and targeted prevention of T1D-related pre-stages; (iii) 3 level: prediction of secondary complications in the cohort of T1D-patients and creation of personalized treatment modes tailored to the patient to prevent postT1D complications frequently developed. Accurate prediction is vital for T1D prevention so that preventive treatment can be given to those individuals who are most likely to develop the disease. Predictive medicine is intended more so for healthy individuals, its purpose being to determine whether susceptibility to a * Correspondence: ssuchkov57@gmail.com I.M.Sechenov First Moscow State Medical University, Moscow, Russia Full list of author information is available at the end of the article Suchkov et al. EPMA Journal 2014, 5(Suppl 1):A69 http://www.epmajournal.com/content/5/S1/A69

Is Autoimmunity or Insulin Resistance the Primary Driver of Type 1 Diabetes?

Diabetes is usually classified as autoimmune or metabolic but, as difficulties have arisen with the taxonomy of diabetes, it may help to forego the conventional classification for a more inclusive model. Thus, all diabetes can be ascribed to beta cell insufficiency-hyperglycemia occurs only when the insulin supply fails to meet demand. Humans enter the world with a reserve of beta cells, which is eroded variably by apoptosis over the course of a lifetime. For most, the loss is slow and inconsequential but, for others fast enough to be critical within a lifetime. The challenge now is to define the factors that vary the tempo of beta cell loss, because tempo, not type, seems likely to determine whether diabetes occurs at all, in adulthood or in childhood. Insulin resistance is generally believed to underpin T2D, but has been a feature of insulin-dependent diabetes as well for nearly 80years, though largely ignored until immunotherapy trials to test the autoimmunity hypothesis persistently failed to bring patient benefit. It seems possible that insulin resistance accelerates beta cell loss generally, its impact modulated by an immune response (autoimmunity) to the beta-cell stress whose intensity varies with immunogenotype. If so, the target for prevention of T1D might more logically lie with insulin sensitivity than with immunoregulation.

Effects of combination therapy with dipeptidyl peptidase-IV and histone deacetylase inhibitors in the non-obese diabetic mouse model of type 1 diabetes

Type 1 diabetes (T1D) results from T helper type 1 (Th1)-mediated autoimmune destruction of insulin-producing β cells. Novel experimental therapies for T1D target immunomodulation, β cell survival and inflammation. We examined combination therapy with the dipeptidyl peptidase-IV inhibitor MK-626 and the histone deacetylase inhibitor vorinostat in the non-obese diabetic (NOD) mouse model of T1D. We hypothesized that combination therapy would ameliorate T1D by providing protection from β cell inflammatory destruction while simultaneously shifting the immune response towards immune-tolerizing regulatory T cells (T(regs)). Although neither mono- nor combination therapies with MK-626 and vorinostat caused disease remission in diabetic NOD mice, the combination of MK-626 and vorinostat increased β cell area and reduced the mean insulitis score compared to diabetic control mice. In prediabetic NOD mice, MK-626 monotherapy resulted in improved glucose tolerance, a reduction in mean insulitis score and an increase in pancreatic lymph node T(reg) percentage, and combination therapy with MK-626 and vorinostat increased pancreatic lymph node T(reg) percentage. We conclude that neither single nor combination therapies using MK-626 and vorinostat induce diabetes remission in NOD mice, but combination therapy appears to have beneficial effects on β cell area, insulitis and T(reg) populations. Combinations of vorinostat and MK-626 may serve as beneficial adjunctive therapy in clinical trials for T1D prevention or remission.

Orally efficacious novel small molecule 6-chloro-6-deoxy-1,2,3,4-tetra-O-galloyl-α-d-glucopyranose selectively and potently stimulates insulin receptor and alleviates diabetes

Type 2 diabetes (T2D) has become an epidemic worldwide while T1D remains a great medical challenge. Insulin receptor (IR) signaling activators could alleviate hyperglycemia, reduce the burden on the pancreas, and contribute to prevention and treatment of both types of diabetes. Previously, we reported the synthesis and identification of a natural antidiabetic compound α-penta-galloyl-glucose (α-PGG). Subsequent studies led to the identification of an α-P6GG derivative, 6-chloro-6-deoxy-1,2,3,4-tetra-O-galloyl-α-D-glucopyranose (6Cl-TGQ). Here, we report that 6Cl-TGQ not only induced rapid and long-lasting glucose uptake comparable to insulin in adipocytes but also reduced high blood glucose levels to near normal and significantly decreased plasma insulin levels and improved glucose tolerance performance in high-fat diet-induced T2D mice when administered orally at 5 mg/kg once every other day. Moreover, a single gavage of 6Cl-TGQ at 10 mg/kg induced rapid and sharp decline of blood glucose in streptozotocin-induced T1D mice. Our studies further indicated that 6Cl-TGQ activated IR signaling in cell models and insulin-responsive tissues of mice. 6Cl-TGQ-induced Akt phosphorylation was completely blocked by IR and PI3K inhibitors, while the induced glucose uptake was blocked by the same compounds and a Glut4 inhibitor. Receptor binding studies indicated that 6Cl-TGQ bound to IR with a higher affinity than α-PGG. Importantly, 6Cl-TGQ, unlike insulin, selectively induced phosphorylation of IR without activating IGF1R or its signaling and did not increase cancer cell proliferation. These results indicate that 6Cl-TGQ is a potent orally efficacious compound with low carcinogenic potential and may contribute to the prevention and treatment of T1D and T2D.