Prevention Of Type 1 Diabetes Research Articles

Dietary Components in the Pathogenesis and Prevention of Type 1 Diabetes in Children.

Type 1 diabetes (T1D) is a disease closely linked to nutrition and modifications in various dietary components have been part of the effort to prevent or slow the progression of the disease even before the discovery of insulin. The scientific focus in the prevention or progression modification of T1D is mostly centered on four dietary compounds and their modifications - gluten and its omission, vitamin D supplementation, omega-3 fatty acids supplementation, and decreasing of the amount of ingested carbohydrates. The aim of this narrative review was to provide an overview of nutritional interventions studied in children either as preventive methods or as modifiers in the early stages of T1D from autoantibody positive individuals to persons with newly diagnosed T1D. Our review shows that dietary modifications in various dietary components might be useful but none of them seems to provide universal effects in T1D prevention or progression modification. More research is therefore needed with focus on promising modes of action of individual dietary components.

Immunopeptidome mining reveals a novel ERS-induced target in T1D.

Autoreactive CD8+ T cells play a key role in type 1 diabetes (T1D), but the antigen spectrum that activates autoreactive CD8+ T cells remains unclear. Endoplasmic reticulum stress (ERS) has been implicated in β-cell autoantigen generation. Here, we analyzed the major histocompatibility complex class I (MHC-I)-associated immunopeptidome (MIP) of islet β-cells under steady and ERS conditions and found that ERS reshaped the MIP of β-cells and promoted the MHC-I presentation of a panel of conventional self-peptides. Among them, OTUB258-66 showed immunodominance, and the corresponding autoreactive CD8+ T cells were diabetogenic in nonobese diabetic (NOD) mice. High glucose intake upregulated pancreatic OTUB2 expression and amplified the OTUB258-66-specific CD8+ T-cell response in NOD mice. Repeated OTUB258-66 administration significantly reduced the incidence of T1D in NOD mice. Interestingly, peripheral blood mononuclear cells (PBMCs) from patients with T1D, but not from healthy controls, showed a positive IFN-γ response to human OTUB2 peptides. This study provides not only a new explanation for the role of ERS in promoting β-cell-targeted autoimmunity but also a potential target for the prevention and treatment of T1D. The data are available via ProteomeXchange with the identifier PXD041227.

An antigen-specific immunotherapeutic, AKS-107, deletes insulin-specific B cells and prevents murine autoimmune diabetes.

The antigen-presenting cell function of insulin-reactive B cells promotes type 1 diabetes (T1D) in non-obese diabetic (NOD) mice by stimulating pathogenic T cells leading to destruction of insulin-producing β-cells of pancreatic islets. To target insulin-reactive B cells, AKS-107, a human IgG1 Fc molecule fused with human insulin A and B chains, was engineered to retain conformational insulin epitopes that bound mouse and human B cell receptors but prevented binding to the insulin metabolic receptor. AKS-107 Fc-mediated deletion of insulin-reactive B cells was demonstrated via ex vivo and in vivo experiments with insulin-reactive B cell receptor transgenic mouse strains, VH125Tg/NOD and Tg125(H+L)/NOD. As an additional immune tolerance feature, the Y16A mutation of the insulin B(9-23) dominant T cell epitope was engineered into AKS-107 to suppress activation of insulin-specific T cells. In mice and non-human primates, AKS-107 was well-tolerated, non-immunogenic, did not cause hypoglycemia even at high doses, and showed an expectedly protracted pharmacokinetic profile. AKS-107 reproducibly prevented spontaneous diabetes from developing in NOD and VH125Tg/NOD mice that persisted for months after cessation of treatment, demonstrating durable immune tolerance. These preclinical outcomes position AKS-107 for clinical development in T1D prevention settings.

An orally available cancer drug AZD6738 prevents type 1 diabetes.

Type 1 diabetes (T1D) affects three million Americans, with 80 new people diagnosed each day. T1D is currently uncurable and there is an urgent need to develop additional drug candidates to achieve the prevention of T1D. We propose AZD6738 (ATRi), an orally available drug currently in phases I and II of clinical trials for various cancers, as a novel candidate to prevent T1D. Based on previously reported findings of ATRi inducing cell death in rapidly proliferating T cells, we hypothesized that this drug would specifically affect self-antigen activated diabetogenic T cells. These cells, if left unchecked, could otherwise lead to the destruction of pancreatic β cells, contributing to the development of T1D. This work demonstrates that increasing the duration of ATRi treatment provides extended protection against T1D onset. Remarkably, 5-week ATRi treatment prevented T1D in a robust adoptive transfer mouse model. Furthermore, the splenocytes of animals that received 5-week ATRi treatment did not transfer immune-mediated diabetes, while the splenocytes from control animal transferred the disease in 10 days. This work shows that ATRi prevents T1D by specifically inducing cell death in self-antigen activated, highly proliferative diabetogenic T cells through the induction of DNA damage, resulting in the inhibition of IFNγ production and proliferation. These findings support the consideration of repurposing ATRi for T1D prevention.

Pleconaril and ribavirin in new-onset type 1 diabetes: a phase 2 randomized trial

Previous studies showed a low-grade enterovirus infection in the pancreatic islets of patients with newly diagnosed type 1 diabetes (T1D). In the Diabetes Virus Detection (DiViD) Intervention, a phase 2, placebo-controlled, randomized, parallel group, double-blind trial, 96 children and adolescents (aged 6–15 years) with new-onset T1D received antiviral treatment with pleconaril and ribavirin (n = 47) or placebo (n = 49) for 6 months, with the aim of preserving β cell function. The primary endpoint was the mean stimulated C-peptide area under the curve (AUC) 12 months after the initiation of treatment (less than 3 weeks after diagnosis) using a mixed linear model. The model used longitudinal log-transformed serum C-peptide AUCs at baseline, at 3 months, 6 months and 1 year. The primary endpoint was met with the serum C-peptide AUC being higher in the pleconaril and ribavirin treatment group compared to the placebo group at 12 months (average marginal effect = 0.057 in the linear mixed model; 95% confidence interval = 0.004–0.11, P = 0.037). The treatment was well tolerated. The results show that antiviral treatment may preserve residual insulin production in children and adolescent with new-onset T1D. This provides a rationale for further evaluating antiviral strategies in the prevention and treatment of T1D. European Union Drug Regulating Authorities Clinical Trials identifier: 2015-003350-41.

T1dCteGui: A User-Friendly Clinical Trial Enrichment Tool to Optimize T1D Prevention Studies by Leveraging AI/ML Based Synthetic Patient Population.

Whereas islet autoantibodies (AAs) are well-established risk factors for developing type 1 diabetes (T1D), there is a lack of biomarkers endorsed by regulators to enrich clinical trial populations for those at risk of developing T1D. As such, the development of therapies that delay or prevent the onset of T1D remains challenging. To address this drug development need, the Critical Path Institute's T1D Consortium (T1DC) acquired patient-level data from multiple observational studies and used a model-based approach to evaluate the utility of islet AAs as enrichment biomarkers in clinical trials. An accelerated failure time model was developed, discussed in our previous publication, which provided the underlying evidence required to receive a qualification opinion for islet AAs as enrichment biomarkers from the European Medicines Agency (EMA) in March 2022. To further democratize the use of the model for scientists and clinicians, we developed a Clinical Trial Enrichment Graphical User Interface. The interactive tool allows users to specify trial participant characteristics, including the percentage of participants with a specific AA combination. Users can specify ranges for participant baseline age, sex, blood glucose measurement from the 120-minute timepoints of an oral glucose tolerance test, and HbA1c. The tool then applies the model to predict the mean probability of a T1D diagnosis for that trial population and renders the results to the user. To ensure adequate data privacy and to make the tool open-source, a deep learning-based generative model was used to generate a cohort of synthetic subjects that underpins the tool.

1442-P: Composite Scores Using Fasting and Stimulated C-Peptide Are Equivalent and Can Track Beta-Cell Function in New-Onset Type 1 Diabetes

Composite scores using fasting samples have been developed to routinely monitor beta cell mass after islet transplantation in type 1 diabetes (T1D). They may also have utility in new onset or T1D prevention trials as an alternative to mixed meal tolerance tests measuring AUC C-peptide. We examined if a composite score using stimulated C-peptide was equivalent to fasting C-peptide in estimating beta cell mass in new onset T1D and reflected changes in AUC C-peptide over time. BETA-2 (fasting C-peptide, glucose, insulin dose, HbA1c) and BETA-2stim (using C-peptide AUC) were calculated in 1312 individuals from the TOMI dataset (median (IQR) age 16y (12, 24); 42% F). The dataset comprises 3200 participants within 100 days of diagnosis across 22 studies. Studies meeting their primary end point were deemed positive. BETA-2 and BETA-2stim were strongly correlated (R2=0.96, p<0.0001) and showed good agreement using Bland-Altman plots. Both BETA-2 and BETA-2stim showed changes over time which mirrored those for AUC C-peptide, but both composite scores showed differences between active and control participants in positive studies by 3 months while differences in AUC C-peptide were not seen until 6 months (Fig1). Composite scores using fasting C-peptide may provide a simple, sensitive and practical tool to monitor beta cell mass without complex stimulation tests in new onset diabetes. Disclosure A.Carr: None. K.S.Collins: None. S.Karpen: None. E.Atabakhsh: None. A.Lam: None. P.Taylor: None. C.Dayan: Advisory Panel; AstraZeneca, Consultant; Provention Bio, Sanofi, Avotres Inc., Other Relationship; Dompé, Merck & Co., Inc. P.A.Senior: Advisory Panel; Novo Nordisk Canada Inc., Consultant; Novo Nordisk Canada Inc., Bayer Inc., Viatris Inc., Vertex Pharmaceuticals Incorporated, ViaCyte, Inc., Insulet Corporation.

300-OR: Stage Transitions in Preclinical Type 1 Diabetes—Protective Effect of IA2 Variant Autoantibody Positivity

We previously demonstrated that the IA2 variant (IA2var) autoantibody (AA) is associated with enhanced prediction of type 1 diabetes (T1D) in at-risk individuals but its effect on progression through preclinical T1D stages is unknown. We aimed to assess the influence of IA2var AA on rates and risks of transitions from Stage 1 (multiple AA positive, no dysglycemia) to Stage 2 (multiple AA positive, dysglycemia) and to Stage 3 (clinical T1D). Participants in the Diabetes Prevention Trial (DPT-1) with Stage 1 or Stage 2 T1D at baseline and having ≥2 glucose tolerance tests during follow-up were selected (N=175). Standard AA (GAD65, ICA, ICA512 and insulin AA) were considered as biomarkers in addition to IA2var. Data analysis used Markov transition models. The estimated 12-month probability of transition from Stage 1 to 3 (N=89) was 13.8% (95% CI: 9.7%, 18.8%) and from Stage 2 to 3 (N=86) it was 41.3% (30.6%, 52.6%). IA2var AA, sex, age and were statistically significant risk factors for the Stage 2 to 3 transition (Table 1, B). Importantly, IA2var AA (the only significantly influential AA) was associated with a reduction in the risk of transition from Stage 2 to 3. In sum, male sex, older age and positive IA2var AA significantly decreased the risk of transition from Stage 2 to Stage 3 T1D. This information has important implications for the selection of candidates for T1D prevention in clinical and research practices. Disclosure C.Beam: None. S.Pietropaolo: None. M.J.Acevedo-calado: None. M.A.Herman: Research Support; Eli Lilly and Company. M.J.Redondo: None. M.Pietropaolo: None. Funding National Institutes of Health (2R01DK053456-19A1); Robert and Janice McNair Foundation

226-LB: Repurposing a Cancer Drug, AZD6738 (ATRi), for the Prevention of Type 1 Diabetes

Type 1 diabetes (T1D) is a chronic, incurable autoimmune disorder caused by the destruction of pancreatic β cells by diabetogenic T cells, leading to insulin deficiency and hyperglycemia. It affects 3 million Americans and 80 new people are diagnosed daily. Despite treatment with insulin, patients have a significantly reduced life expectancy. This study proposes a new approach to prevent T1D by specifically targeting diabetogenic T cells undergoing the Warburg effect, a metabolic process similar to cancer cells, with a cancer drug approved by the FDA. The use of FDA-approved drugs accelerates the development of new therapies as these agents have already undergone initial efficacy and toxicity tests in humans. One promising drug for this purpose is AZD6738 (ATRi), a cancer drug that is currently in clinical trials. ATRi is a small molecule inhibitor that targets ATR, a central DNA damage response kinase, whose inhibition blocks DNA replication. We demonstrate that ATRi treatment significantly delays T1D onset in an adoptive transfer mouse model by reducing the survival of diabetogenic CD4+ T cells by inhibiting their proliferation. Furthermore, an FDA-approved glycolysis inhibitor PFK158 potentiates inhibition of diabetogenic CD4+ T cells by ATRi. These agents target different properties of the Warburg effect. While ATRi inhibits rapid proliferation, PFK158 blocks glycolysis. Combination therapy allows for increased efficacy while reducing potential toxicity by allowing the use of lower doses of each agent. These data show promise in the rapid establishment of novel T1D prevention methods by repurposing FDA-approved cancer drugs. Disclosure N. Sugitani: None. H. R. Mason: None. S. Roy: None. J. D. Piganelli: None. Funding National Institutes of Health (R01DK132583); JDRF (2-SRA2020-910-S-B)

Preventing rheumatoid arthritis: Lessons from that of type 1 diabetes

Preventing rheumatoid arthritis: Lessons from that of type 1 diabetes

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

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

Barriers to Screening: An Analysis of Factors Impacting Screening for Type 1 Diabetes Prevention Trials.

Participants with stage 1 or 2 type 1 diabetes (T1D) qualify for prevention trials, but factors involved in screening for such trials are largely unknown. To identify factors associated with screening for T1D prevention trials. This study included TrialNet Pathway to Prevention participants who were eligible for a prevention trial: oral insulin (TN-07, TN-20), teplizumab (TN-10), abatacept (TN-18), and oral hydroxychloroquine (TN-22). Univariate and multivariate logistic regression models were used to examine participant, site, and study factors at the time of prevention trial accrual. Screening rates for trials were: 50% for TN-07 (584 screened/1172 eligible), 9% for TN-10 (106/1249), 24% for TN-18 (313/1285), 17% for TN-20 (113/667), and 28% for TN-22 (371/1336). Younger age and male sex were associated with higher screening rates for prevention trials overall and for oral therapies. Participants with an offspring with T1D showed lower rates of screening for all trials and oral drug trials compared with participants with other first-degree relatives as probands. Site factors, including larger monitoring volume and US site vs international site, were associated with higher prevention trial screening rates. Clear differences exist between participants who screen for prevention trials and those who do not screen and between the research sites involved in prevention trial screening. Participant age, sex, and relationship to proband are significantly associated with prevention trial screening in addition to key site factors. Identifying these factors can facilitate strategic recruitment planning to support rapid and successful enrollment into prevention trials.

Prevention of Type 1 Diabetes: Current Perspective.

People living with type 1 Diabetes (T1D) and their families have poor perception of health related quality of life. Therapies for T1D are becoming better with time, but they still involve a lot of effort. Prevention of T1D, if successful, has potential to change lives of millions of families across the globe. Type 1 diabetes is an autoimmune disease with underlying genetic predisposition for autoimmunity against beta cell antigens upon exposure to an environmental trigger. Identifying underlying primary antigen responsible for initiating autoimmune cascade, avoiding environmental trigger and modifying immunity has all been used as strategies for preventing or delaying onset of type 1 diabetes. Primary prevention for type 1 diabetes is hindered by difficulty in identifying at-risk population and also due to lack of effective preventive strategy. Secondary prevention, in children with presence of autoimmunity, has recently received a boost with approval of Teplizumab, an immunity modifying drug by its Anti-CD3 action. Application of preventive strategies would also change based on country specific incidence, prevalence and availability of health resources. In current review, an update on preventive strategies for type 1 diabetes is being discussed as well as their applicability in Indian context.

Type 1 diabetes - What's new in prevention and therapeutic strategies?

Type 1 diabetes (T1D) is an autoimmune disorder, and insulin deficiency is the result of b-cell dysfunction. Treatment of type 1 diabetes requires constant parenteral insulin administration, which can be very burdensome for the patient. Meticulous use of insulin therapy does not protect the patient against complications. Hence, the search for other methods of treatment as well as ways of preventing the onset of diabetes has been ongoing for along time. The main obstacle in the implementation of the prevention task is the need to identify people at risk of developing diabetes before the start of autoimmunity. It seems that primary prevention is still unrealistic at the moment, because we do not know all the factors leading to the activation of autoimmunity processes. Research on the use of late secondary prevention in people who develop glucose tolerance disorders or in the early period after the onset of type1 diabetes are at the most advanced stage. Gene therapy is another attempt at an alternative treatment and prevention of type1 diabetes and still requires further research. Recent years have brought alot of information about the nature of type 1 diabetes and the mechanisms leading to its development. However, it has not yet been established what factors decide about the initiation of autoimmunity and what determines the dynamics of these processes.

Coxsackievirus B infection and pathogenesis of type1 diabetes

Epidemiological and experimental studies suggest that enteroviruses (EV) and particularly coxsackievirusesB (CVB) are likely to trigger or accelerate the onset of islet autoimmunity and the development of type1 diabetes (T1D) in genetically susceptible individuals. Several mutually non-exclusive mechanisms have been proposed to explain the involvement of CVB in the pathogenesis of T1D. CVB can infect and persist in the intestine, thymic cells, monocytes/macrophages, ductal cells and pancreatic β-cells, which leads to structural or functional alterations of these cells. A chronic inflammatory response and disruption of tolerance towards β-cells due to CVB infections are able to promote the recruitment and activation of pre-existing autoreactive T-cells and the destruction of β-cells. Vaccine or therapeutic strategies to control EV infections have been developed and open perspectives for the prevention or treatment of T1D.

Insights on the role of anti-inflammatory and immunosuppressive agents in the amelioration of diabetes.

Diabetes is a major health problem worldwide. It is a chronic metabolic disorder that produces overt hyperglycemic condition that occurs either when the pancreas does not produce enough insulin due to excessive destruction of pancreatic β-cells (type 1 diabetes) or due to development of insulin resistance (type 2 diabetes). An autoimmune condition known as type 1 diabetes (T1D) results in the targeted immune death of β-cells that produce insulin. The only available treatment for T1D at the moment is the lifelong use of insulin. Multiple islet autoantibody positivity is used to diagnose T1D. There are four standard autoantibodies observed whose presence shows the development of T1D: antibodies against insulin, glutamic acid decarboxylase (GAD65), zinc T8 transporter (ZnT8), and tyrosine phosphatase-like protein (ICA512). In type 2 diabetes (T2D), an inflammatory response precipitates as a consequence of the immune response to high blood glucose level along with the presence of inflammation mediators produced by macrophages and adipocytes in fat tissue. The slow and chronic inflammatory condition of adipose tissue produces insulin resistance leading to increased stress on pancreatic β-cells to produce more insulin to compensate for the insulin resistance. Thus, this stress condition exacerbates the apoptosis of β-cells leading to insufficient production of insulin, resulting in hyperglycemia which signifies late stage T2D. Therefore, the therapeutic utilization of immunosuppressive agents may be a better alternative over the use of insulin and oral hypoglycemic agents for the treatment of T1D and T2D, respectively. This review enlightens the immune intervention for the prevention and amelioration of T1D and T2D in humans with main focus on the antigen-specific immune suppressive therapy.

Advanced Glycation End Products and Inflammation in Type 1 Diabetes Development.

Type 1 diabetes (T1D) is an autoimmune disease in which the β-cells of the pancreas are attacked by the host's immune system, ultimately resulting in hyperglycemia. It is a complex multifactorial disease postulated to result from a combination of genetic and environmental factors. In parallel with increasing prevalence of T1D in genetically stable populations, highlighting an environmental component, consumption of advanced glycation end products (AGEs) commonly found in in Western diets has increased significantly over the past decades. AGEs can bind to cell surface receptors including the receptor for advanced glycation end products (RAGE). RAGE has proinflammatory roles including in host-pathogen defense, thereby influencing immune cell behavior and can activate and cause proliferation of immune cells such as islet infiltrating CD8+ and CD4+ T cells and suppress the activity of T regulatory cells, contributing to β-cell injury and hyperglycemia. Insights from studies of individuals at risk of T1D have demonstrated that progression to symptomatic onset and diagnosis can vary, ranging from months to years, providing a window of opportunity for prevention strategies. Interaction between AGEs and RAGE is believed to be a major environmental risk factor for T1D and targeting the AGE-RAGE axis may act as a potential therapeutic strategy for T1D prevention.

LBSUN309 The Effect Of Prebiotics In Newly Diagnosed Youth With Type 1 Diabetes (T1D)

Abstract Acetylated and butyrylated high amylose starch (HAMS-AB) is a prebiotic that is effective in T1D prevention in mouse models. It alters the gut microbiome profile towards bacterial fermenters with increases short chain fatty acids (SCFA) production which improves glycemia, insulin sensitivity and secretion. The objective of this pilot study is to assess the effect of oral HAMS-AB for 4 weeks on glycemia, microbial metabolite and SCFA production in newly diagnosed (<2 years of diagnosis) youth with T1D. Thus far, we have enrolled 7 subjects with 1 early drop out due to nausea secondary to the prebiotic. The mean±SD age in the remaining 6 was 14.4±1.8 yrs, diabetes duration 18.6±6.3 months, 4/6 were female and White, all with BMI of <85th%. The prebiotic was safe and well-tolerated in all 6 who remained in the study. We assessed glycemia changes pre and post-intervention and the percent time in range (TIR) from continuous glucose monitoring data over a 4 week period increased significantly: 61. 0% vs. 71.8%, X2 18.2, p=0. 001. Stool SCFA levels were measured in 4 subjects, and butyrate levels increased post-prebiotic (8.1±9.8 vs 22.6± 6.4mmol SCFA/kg fecal material, p=0. 047). Serum and plasma Hippurate levels (a microbial metabolite associated with increased gut bacterial diversity and improved glycemia) increased significantly after 4 weeks of prebiotic consumption compared to before in all 6 individuals (p=0. 028 for serum and p=0. 033 for plasma, respectively). In summary, the prebiotic HAMS-AB was safe in adolescents with T1D. It significantly increased the percent TIR, serum and plasma Hippurate levels and stool butyrate levels. Enrollment continues as collection of samples from more participants should allow for a more conclusive analysis. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Triple drug therapy with GABA, sitagliptin, and omeprazole prevents type 1 diabetes onset and promotes its reversal in non-obese diabetic mice.

Previous studies have reported that dual drug combinations consisting of γ-aminobutyric acid (GABA) together with a dipeptidyl-peptidase-4 inhibitor (DPP-4i), also a DPP-4i with a proton pump inhibitor (PPI), could improve pancreatic β-cell function and ameliorate diabetes in diabetic mice. In this study, we sought to determine if a triple drug combination of GABA, a DPP-4i and a PPI might have superior therapeutic effects compared with double drug therapies in the prevention and reversal of diabetes in the non-obese diabetic (NOD) mouse model of human type 1 diabetes (T1D). In a diabetes prevention arm of the study, the triple drug combination of GABA, a DPP-4i, and a PPI exhibited superior therapeutic effects in preventing the onset of diabetes compared with all the double drug combinations and placebo. Also, the triple drug combination significantly increased circulating C-peptide and serum insulin levels in the mice. In a diabetes reversal arm of the study, the triple drug combination was superior to all of the double drug combinations in reducing hyperglycemia in the mice. In addition, the triple drug combination was the most effective in increasing circulating levels of C-peptide and serum insulin, thereby significantly reducing exogenous insulin needs. The combination of GABA, a DPP-4i and a PPI appears to be a promising and easily scalable therapy for the treatment and prevention of T1D.

Ultrasound Imaging of Pancreatic Perfusion Dynamics Predicts Therapeutic Prevention of Diabetes in Preclinical Models of Type 1 Diabetes.

In type 1 diabetes (T1D), immune-cell infiltration into islets of Langerhans (insulitis) and β-cell decline occur years before diabetes presents. There is a lack of validated clinical approaches for detecting insulitis and β-cell decline, to diagnose eventual diabetes and monitor the efficacy of therapeutic interventions. We previously determined that contrast-enhanced ultrasound measurements of pancreas perfusion dynamics predict disease progression in T1D pre-clinical models. Here, we test whether these measurements predict therapeutic prevention of T1D. We performed destruction-reperfusion measurements with size-isolated microbubbles in non-obese diabetic (NOD)-severe combined immunodeficiency (SCID) mice receiving an adoptive transfer of diabetogenic splenocytes. Mice received vehicle control or the following treatments: (i) anti-CD3 to block T-cell activation; (ii) anti-CD4 to deplete CD4+ T cells; (iii) verapamil to reduce β-cell apoptosis; or (iv) tauroursodeoxycholic acid (TUDCA) to reduce β-cell endoplasmic reticulum stress. We compared measurements of pancreas perfusion dynamics with subsequent progression to diabetes. Anti-CD3, anti-CD4, and verapamil delayed diabetes development. Blood flow dynamics was significantly altered in treated mice with delayed/absent diabetes development compared with untreated mice. Conversely, blood flow dynamics in treated mice with unchanged diabetes development was similar to that in untreated mice. Thus, measurement of pancreas perfusion dynamics predicts the successful prevention of diabetes. This strategy may provide a clinically deployable predictive marker for therapeutic prevention in asymptomatic T1D.