Onset Of Type 1 Diabetes Research Articles

A Fecal Metabolite Signature of Impaired Fasting Glucose: Results From Two Independent Population-Based Cohorts.

Prediabetes is a metabolic condition associated with gut microbiome composition, although mechanisms remain elusive. We investigated whether there is a fecal metabolite signature of impaired fasting glucose (IFG) and the possible underlying mechanisms of action. We identified a fecal metabolite signature of IFG associated with prevalent IFG in two independent cohorts and incident type 2 diabetes in a subanalysis. Although the signature consists of metabolites of nonmicrobial origin, it is strongly correlated with gut microbiome composition. Fecal metabolites enable modeling of another mechanism of gut microbiome effect on prediabetes by affecting intestinal absorption or excretion of host compounds and xenobiotics.

The role of candidate transport proteins in β-cell long-chain fatty acid uptake: Where are we now?

Type 2 diabetes (T2D) in humans is typically preceded by elevated levels of circulatory long-chain free fatty acids (LC-FFA). These excess LC-FFA are widely thought to be taken up by pancreatic β-cells, contributing to their dysfunction and death during the development of T2D; a process that has been termed lipotoxicity. Depending on their degree of saturation and carbon chain length, LC-FFA can exert different effects on pancreatic β-cells viability and function in vitro. Long-chain saturated fatty acids (LC-SFA) are thought to be toxic, whereas monounsaturated fatty acids are not and may even offer protection against the toxic effects of LC-SFAs. However, the mechanism of LC-FFA uptake into pancreatic β-cells is poorly understood, partly because it has been an understudied area of research. Determining how LC-FFA are taken up into β-cells is crucial for later formulation of therapies to prevent potential cellular overload of LC-FFA, thereby slowing the onset of T2D. In this work, we detail more than 40 years of literature investigating the role of membrane-associated transport proteins in LC-FFA uptake. By focussing on what is known in other cell types, we highlight where we can extrapolate our current understanding of protein-mediated transport to β-cells and uncover where further understanding is required.

A comparative study using insulin pump therapy and continuous glucose monitoring in newly diagnosed very young children with type 1 diabetes: it is possible to bend the curve of HbA1c.

The target of metabolic control (HbA1c < 7% or 53mmol/mol) recommended by the ADA and ISPAD is attained by 30% of children with Type 1 Diabetes (T1D). Advances in technologies for T1D aim to improve metabolic outcomes and reduce complications. This observational study assesses the long-term outcomes of advanced technologies for treatment of T1D compared to conventional approach started at onset in a group of very young children with T1D. 54 patients with less 4years old at onset of T1D were enrolled and followed for up to 9years after diagnosis. 24 subjects started continuous subcutaneous insulin (CSII) treatment and 30 subjects received MDI therapy from onset. Auxological data, HbA1c and total daily insulin dose (TDD/kg) have been collected at admission and every 4months. HbA1cAUC>6%, rates of acute complications, glycemic variability indices and glucometrics were also recorded. Patients with CSII therapy had significantly lower mean HbA1c values compared to subjects receiving MDI treatment. CSII approach also recorded lower mean HbA1cAUC>6% and TDD/kg than MDI therapy. At the last download data, the time in range (TIR) was higher in patients with CSII and hyperglycemia events were lower. Better glycemic variability indices have been described during CSII therapy, including mean glycemia, standard deviation, coefficient of variation (CV), glycemia risk index (GRI) and high blood glucose index (HBGI). There was no statistically significant difference between frequency of severe hypoglycemia and ketoacidosis episodes between groups. Early initiation of diabetes technologies is safe and able to determine a better long term glycemic control in young children with T1D. It also allows to flatten the trajectory of HbA1c, probably reducing microvascular, macrovascular and neurological complications of diabetes in this very peculiar age group.

Regulatory T cells targeting a pathogenic MHC class II: Insulin peptide epitope postpone spontaneous autoimmune diabetes.

In spontaneous type 1 diabetes (T1D) non-obese diabetic (NOD) mice, the insulin B chain peptide 9-23 (B:9-23) can bind to the MHC class II molecule (IAg7) in register 3 (R3), creating a bimolecular IAg7/InsulinB:9-23 register 3 conformational epitope (InsB:R3). Previously, we showed that the InsB:R3-specific chimeric antigen receptor (CAR), constructed using an InsB:R3-monoclonal antibody, could guide CAR-expressing CD8 T cells to migrate to the islets and pancreatic lymph nodes. Regulatory T cells (Tregs) specific for an islet antigen can broadly suppress various pathogenic immune cells in the islets and effectively halt the progression of islet destruction. Therefore, we hypothesized that InsB:R3 specific Tregs would suppress autoimmune reactivity in islets and efficiently protect against T1D. To test our hypothesis, we produced InsB:R3-Tregs and tested their disease-protective effects in spontaneous T1D NOD.CD28-/- mice. InsB:R3-CAR expressing Tregs secrete IL-10 dominated cytokines upon engagement with InsB:R3 antigens. A single infusion of InsB:R3 Tregs delayed the onset of T1D in 95% of treated mice, with 35% maintaining euglycemia for two healthy lifespans, readily home to the relevant target whereas control Tregs did not. Our data demonstrate that Tregs specific for MHC class II: Insulin peptide epitope (MHCII/Insulin) protect mice against T1D more efficiently than polyclonal Tregs lacking islet antigen specificity, suggesting that the MHC II/insulin-specific Treg approach is a promising immune therapy for safely preventing T1D.

Chromosomal deletions on 16p11.2 encompassing SH2B1 are associated with accelerated metabolic disease

New approaches are needed to treat people whose obesity and type 2 diabetes (T2D) are driven by specific mechanisms. We investigate a deletion on chromosome 16p11.2 (breakpoint 2-3 [BP2-3]) encompassing SH2B1, a mediator of leptin and insulin signaling. Phenome-wide association scans in the UK (N= 502,399) and Estonian (N= 208,360) biobanks show that deletion carriers have increased body mass index (BMI; p= 1.3×10-10) and increased rates of T2D. Compared with BMI-matched controls, deletion carriers have an earlier onset of T2D, with poorer glycemic control despite higher medication usage. Cystatin C, a biomarker of kidney function, is significantly elevated in deletion carriers, suggesting increased risk of renal impairment. In a Mendelian randomization study, decreased SH2B1 expression increases T2D risk (p= 8.1×10-6). We conclude that people with 16p11.2 BP2-3 deletions have early, complex obesity and T2D and may benefit from therapies that enhance leptin and insulin signaling.

Pericyte dysfunction and impaired vasomotion are hallmarks of islets during the pathogenesis of type 1 diabetes

Pancreatic islets are endocrine organs that depend on their microvasculature to function. Along with endothelial cells, pericytes comprise the islet microvascular network. These mural cells are crucial for microvascular stability and function, but it is not known if/how they are affected during the development of type 1 diabetes (T1D). Here, we investigate islet pericyte density, phenotype, and function using living pancreas slices from donors without diabetes, donors with a single T1D-associated autoantibody (GADA+), and recent onset T1D cases. Our data show that islet pericyte and capillary responses to vasoactive stimuli are impaired early on in T1D. Microvascular dysfunction is associated with a switch in the phenotype of islet pericytes toward myofibroblasts. Using publicly available RNA sequencing (RNA-seq) data, we further found that transcriptional alterations related to endothelin-1 signaling and vascular and extracellular matrix (ECM) remodeling are hallmarks of single autoantibody (Aab)+ donor pancreata. Our data show that microvascular dysfunction is present at early stages of islet autoimmunity.

Associations of Clinical Risk Factors and Novel Biomarkers With Age at Onset of Type 2 Diabetes.

Younger onset of type 2 diabetes (T2D) was associated with higher risks of vascular complications and mortality. To prospectively assess risk profiles for incident T2D stratified by age at onset. A total of 471 269 participants free of T2D at baseline were included from the UK Biobank. Approximately 70 clinical, lipid, lipoprotein, inflammatory, and metabolic markers, and genetic risk scores (GRSs) were analyzed. Stratified Cox proportional-hazards regression models were used to estimate hazard ratios (HRs) for T2D with age of diagnosis divided into 4 groups (≤50.0, 50.1-60.0, 60.1-70.0, and >70.0 years). During 11 years of follow-up, 15 805 incident T2D were identified. Among clinical risk factors, obesity had the highest HR at any age, ranging from 13.16 (95% CI, 9.67-17.91) for 50.0 years and younger to 4.13 (3.78-4.51) for older than 70.0 years. Other risks associated with T2D onset at age 50.0 years and younger included dyslipidemia (3.50, 2.91-4.20), hypertension (3.21, 2.71-3.80), cardiovascular disease (2.87, 2.13-3.87), parental history of diabetes (2.42, 2.04-2.86), education lower than college (1.89, 1.57-2.27), physical inactivity (1.73, 1.43-2.10), smoking (1.38, 1.13-1.68), several lipoprotein particles, inflammatory markers, liver enzymes, fatty acids, amino acids, as well as GRS. Associations of most risk factors and biomarkers were markedly attenuated with increasing age at onset (P interaction <.05), and some were not significant for onset at age older than 70.0 years, such as smoking, systolic blood pressure, and apolipoprotein B. Most risk factors or biomarkers had stronger relative risks for T2D at younger ages, which emphasizes the necessity of promoting primary prevention among younger individuals. Moreover, obesity should be prioritized.

Subtypes of Type 2 Diabetes and Incident Cardiovascular Disease Risk: UK Biobank and All of Us Cohorts

ObjectiveTo characterize and validate the subtypes of type 2 diabetes (T2D) using a novel clustering algorithm and to further assess their associations with the risk of incident cardiovascular disease (CVD) events. MethodsUnsupervised k-means clustering based on glycated hemoglobin level, age at onset of T2D, body mass index, and estimated glomerular filtration rate was conducted among participants with T2D from the UK Biobank (March 13, 2006, to October 1, 2010) and replicated in the All of Us cohort (May 30, 2017, to April 1, 2021). ResultsFive distinct T2D clusters were identified in the UK Biobank and validated in the All of Us cohort, characterizing the phenotypically heterogeneous subtypes. With a median follow-up of 11.69 years for patients with T2D in the UK Biobank, risks of incident CVD events varied considerably between the clusters after adjustment for potential confounders and multiple testing (all P<.001). With cluster 1 characterized by early onset of T2D and mild abnormalities of other variables as the reference, patients in cluster 5 characterized by poor renal function had the highest risk of CVD events (hazard ratio [95% CI], 1.72 [1.45 to 2.03], 2.41 [1.93 to 3.02], and 1.62 [1.35 to 1.94] for composite CVD event, CVD mortality, and CVD incidence, respectively; all P<.001), followed by cluster 4 characterized by poor glycemic control and cluster 3 characterized by severe obesity. No consistently significant difference was found between cluster 2 characterized by late onset of T2D and cluster 1. ConclusionOur study, using a novel clustering algorithm to identify robust subtypes of T2D, found heterogeneous associations with incident CVD risk among patients with diabetes.

Sodium Selenite Modulates Global Activation of Proinflammatory M1-like Macrophages, Necroinflammation and M1-like/M2-like Dichotomy at the Onset of Human Type 1 Diabetes.

The study aims to show that sodium selenite (Ss) would have an immunomodulatory effect on the functional activity of proinflammatory macrophages (Mφs) during their extended extracellular activation at the onset of human type 1 diabetes (T1D). Exacerbated activation of proinflammatory "M1" macrophages (Mφs) can promote chronic local pancreatic islet inflammation and T1D development. We investigated the ex vivo effects of Ss on the immune modulation of global/extended activation of human proinflammatory M1-like Mφs. Experiments were carried out on primary monocytes-derived Mφs (MDMs). The levels of IL-1β, TNF-α, H2O2 and intracellular free calcium ions (ifCa2+), and the ratios of IL-1β-to-IL-10 and TNF-α-to-IL-10 were markedly increased in T1D Mφs than in healthy control Mφs. Conversely, both IL-10 production and arginase 1 (ARG1) activity were downregulated in T1D Mφs. Additionally, Ss treatment induced a marked downregulation of respiratory burst, ifCa2+ levels, M1-like Mφ-associated inducible nitric oxide (NO) synthase (iNOS) activity, cell necrosis and related necroinflammation biomarkers, including IL-1β and TNF-α, CD14 expression, and the ratios of iNOS-to-ARG1, IL-1β-to-IL-10, and TNF-α-to-IL-10. Moreover, Ss upregulated anti-inflammatory "M2-like" Mφ activity as demonstrated by ARG1 activity and IL-10 production, as well as phagocytosis capacity. Ss exerts a potent immunomodulatory role on functional activities of human proinflammatory T1D M1-like Mφs subjected to extended activation, as well as on the M1-like/M2-like dichotomy. Additionally, the current study provides a novel therapeutic approach using Ss to promote the anti-inflammatory function of Mφs at the onset of T1D.

Early Intervention by Family Physicians to Delay Type 1 Diabetes.

Type 1 diabetes (T1D) is an autoimmune disease mediated by T cells that target and destroy insulin-producing beta cells. Individuals with genetic risk of T1D will progress at variable rates through 3 stages of immune activation and development of islet autoimmunity. Measuring pancreatic islet cell autoantibodies predicts risk for progression that can take weeks to years before the onset of T1D. Screening options available to family physicians can identify persons at risk or in the early stages of T1D, such as first- and second-degree relatives or those with a family history of autoimmune disorders, to ultimately offer proven interventions that may delay or prevent the condition. Screening can reduce emergency room visits, hospitalizations, and intensive care unit admissions for diabetic ketoacidosis, which can be fatal, and can educate and prepare individuals and families for a smoother transition to insulin therapy when necessary. Recent advances in technology and understanding of the immune pathogenesis of T1D has resulted in emerging disease-modifying therapies that are changing how family physicians approach delaying and potentially preventing or reversing the disease.

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.

Adipose Tissue-Derived Stromal/Stem Cells Transplantation with Cholecalciferol Supplementation in Recent-Onset Type 1 Diabetes Patients: Twelve Months Follow-Up.

To evaluate safety and therapeutic effect along 12 months of allogenic adipose tissue-derived stromal/stem cells (ASCs) transplantation with cholecalciferol (VITD) in patients with recent-onset type 1 diabetes (T1D). Prospective, phase II, open trial, pilot study in which patients with recent onset T1D received ASCs (1xKgx106 cells) and VITD 2000UI/day for 12 months (group 1) and were compared to controls with standard insulin therapy (group 2). Adverse events, C-peptide area under the curve (CPAUC), insulin dose, HbA1c and frequency of FoxP3+ in CD4+ or CD8+ T-cells(flow cytometry) were evaluated at baseline(T0), after 3(T3), 6(T6) and 12 months(T12). Eleven patients completed follow up (7:group 1;4:group 2). Group 1 had lower insulin requirement at T3(0.24±0.18vs0.53±0.23UI/kg,p=0.04), T6(0.24±0.15vs0.66±0.33 UI/kg,p=0.04) and T12(0.39±0.15vs0.74±0.29 UI/Kg,p=0.04).HbA1c was lower at T6 (50.57±8.56vs72.25±10.34 mmol/mol,p=0.01), without differences at T12 (57.14±11.98 in group 1 vs. 73.5±14.57 mmol/min in group 2, p=0.16). CPAUC was not significantly different between groups at T0(p=0.07), higher in group 1 at T3(p=0.04) and T6(p=0.006), but similar at T12(p=0.23). IDAA1c was significantly lower in group 1 than group 2 at T3,T6 and T12 (p=0.006, 0.006 and 0.042, respectively). IDDA1c was inversely correlated to FoxP3 expression in CD4 and CD8+ T cells at T6 (p<0.001 and p=0.01, respectively). In group 1, one patient had recurrence of a benign teratoma that was surgically removed, not associated to the intervention. ASCs with VITD without immunosuppression were safe and associated lower insulin requirements, better glycemic control, and transient better pancreatic function in recent onset T1D, but the potential benefits were not sustained.

1555-P: Novel Imaging Platform Highlights the Disconnect between ß-Cell Mass and Glucose Control in the Onset of Type 1 Diabetes

The age of onset of Type 1 Diabetes (T1D) presents considerable variation from patient to patient. Some become insulin dependent in a just few weeks, while others may take months or years. In either, immune system-β-cell interactions conspire to lead to loss of β-cells and insulin secretion. The molecular and cellular events involved have been the focus of intense research efforts, but most longitudinal studies during the onset of T1D have been limited to biomarkers (circulating autoantibodies, C-peptide⋯), without direct β-cell assessment. Despite data indicating that patients can retain functional β-cells years after the onset of the disease, one school of thought is that there is a precipitous loss of β-cells just preceding the time of clinical onset, triggering the hyperglycemia observed in T1D patients. A counter-view supported by recent studies suggests that insulin secretion is reduced even before β-cell loss. These assessments are traditionally performed through histo-morphometry. The process is time-consuming, prone to errors and costly. Using an NOD line with a SfGFP reporter attached to the C-peptide, we have designed a platform allowing the in toto imaging of β-cell mass in a model of T1D. After a 15-minute IPGTT to capture the peak of insulin secretion, pancreata were harvested and imaged on a cohort of animals at a time of early onset of T1D. A comparison of classical histo-morphometry and in toto imaging revealed a tight correlation between both approaches. Using the new platform allowed the rapid classification of large cohorts of animals based on the β-cell mass and glucose response. The results highlighted a significant disconnect between mass and function in a subset of mice: Some animals presenting near-normal mass while being glucose intolerant while others displaying a drastically reduced mass but still responding normally to a glucose challenge. These findings emphasize the role of islet dysfunction during the onset of T1D even before β-cell death. Disclosure C.Cras-méneur: None. R.J.Seeley: Board Member; Fractyl Health, Inc., Consultant; Novo Nordisk, Eli Lilly and Company, Research Support; Novo Nordisk, Fractyl Health, Inc., AstraZeneca, Eli Lilly and Company. P.Arvan: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (P30DK020572)

1309-P: Dietary Iron and Kidney Function in Youth and Young Adults with Type 1 Diabetes

The association of markers of body iron stores with kidney disease in type 1 diabetes (T1D) is complex, with both positive and inverse relationships observed. Little data are available on the relationship of dietary iron (DI) intake with markers of kidney function, prior to occult disease, in youth and young adults with T1D. We tested the association of DI with albumin-to-creatinine ratio (ACR), both measured at multiple time points over a 14-year period in youth and young adults with T1D. Study participants (n=629) were from the Colorado site of the SEARCH for Diabetes in Youth study who completed research visits at baseline and (&amp;lt;1yr diabetes duration) and at least one follow-up visit over 14 years. We applied linear mixed models (repeated measures analysis) to test the hypothesis that higher DI over time is longitudinally associated with a higher ACR, which was natural log-transformed prior to regression analysis. Results: Mean age and diabetes duration at study baseline were 10.2 (std 4.2) years and 10.4 (std 6.8) months, respectively. Older age at baseline (p=0.009), female sex (vs. male, p=0.002), and Black race (vs Non-Hispanic White, p&amp;lt;0.001) were each associated with higher ACR levels across follow-up. Contrary to our hypothesis, average DI intake was inversely associated with ACR levels in analyses adjusted for age, sex, and race (p&amp;lt;0.05). This inverse relationship persisted after further controlling for average body mass index (BMI) over time. However, controlling for average HbA1c levels over time, which were positively associated with ACR (p=0.001), attenuated the relationship between DI intake and ACR (p=0.12). In conclusion, total DI intake in children and young adults was associated with a lower ACR over 14 years, but the association was confounded by HbA1c, suggesting that DI may be a marker of total glycemic load. Whether this relationship varies by heme/non-heme content needs to be further explored. These data highlight the important role of diet in the early years after T1D onset. Disclosure R.B.Conway: None. T.L.Crume: None. W.Perng: None. D.A.Mcclain: None. D.Dabelea: None.

1401-P: Psychotropic Drug Use in Children and Adolescents with Type 1 Diabetes

Psychiatric disorders in children and adolescents with type 1 diabetes (T1D) have caught increasing attention. While psychotropic drugs offer great value in managing psychiatric symptoms, their adverse effects engender considerable controversy regarding their use in pediatric patients, let alone in those with T1D. Despite the topic’s high visibility, little evidence exists on the patterns of psychotropic drug use in pediatric T1D patients. We thus conducted this cohort study of 3,720,381 children and adolescents (13,191 [0.36%] had T1D) using several Swedish national registers. We examined the trends and patterns (prescription source and treatment duration) of psychotropic drug use and estimated the risk of initiating psychotropic drugs after T1D onset. We found that psychotropic drug use increased significantly in children and adolescents with T1D from 2006 to 2019 (Figure 1), with ADHD medications, SSRI, hypnotics and anxiolytics among the most used ones. The primary prescription source was psychiatric care, and treatment durations were mostly &amp;lt;12 months (except for ADHD medications). Children and adolescents with newly-onset T1D had a higher risk of initiating any psychotropic drug (hazard ratio 1.29, 95%CI 1.20-1.38) than their peers without T1D. Our findings highlight the need for risk/benefit studies of psychotropic drugs among young users with T1D to inform future research and guideline development. Disclosure S.Liu: None. T.Lagerberg: None. J.F.Ludvigsson: Research Support; Janssen Pharmaceuticals, Inc., MSD Life Science Foundation. M.Taylor: None. B.Donofrio: None. P.Lichtenstein: None. S.Gudbjörnsdottir: None. A.Butwicka: None. Funding Swedish Research Council (2017-00788)

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&amp;lt;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 &amp; 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.

1471-P: Metabolomic Profiling of Type 2 Diabetes Pathway-Partitioned Polygenic Risk Scores Offers Insights into Disease Etiology

Previous studies have identified type 2 diabetes (T2D) subtypes using clinical phenotypes and/or genetic information. This study aimed to identify molecular signatures associated with genetically based T2D subtypes. We analyzed data from ~100,000 unrelated European UK Biobank participants without T2D and not taking lipid-lowering medications. T2D subtypes were characterized using five polygenic scores denoting three forms of insulin resistance (lipodystrophy, obesity, and impaired lipid/hepatic metabolism) and two subtypes of insulin secretion (beta-cell dysfunction and impaired proinsulin synthesis). Nuclear magnetic resonance profiles of 249 plasma metabolites on the Nightingale platform were tested for association with T2D subtypes using linear regression adjusted for age, sex, batch, and ancestry-derived principal components; P&amp;lt;0.0002 was considered significant. Independent validation was conducted in two independent cohorts, including 720 from the ANTORCHA cohort. In general, the T2D subtypes driven by insulin resistance were characterized by alterations in lipid and lipoproteins, while the impaired insulin secretion subtypes showed aberrant plasma amino acid levels. The lipodystrophy cluster showed the most distinct molecular signature, with higher concentrations of extremely large, very large, and large VLDL particles which were enriched by triglycerides and phospholipids, and lower concentrations of HDL. The beta-cell dysfunction cluster was characterized by higher concentrations of amino acids (alanine, valine, leucine, and tyrosine). These associations were broadly consistent after adjusting for BMI, and the pattern of alterations in lipid metabolites was partially replicated in the ANTORCHA cohort. We identified specific metabolic signatures related to T2D genetic clusters before T2D onset, offering further characterization of the putative underlying pathways. Disclosure M.Sevilla: None. I.Lamiquiz-moneo: None. K.Smith: None. M.Canyelles: None. J.C.Florez: Consultant; AstraZeneca, Novo Nordisk, Other Relationship; AstraZeneca, Merck &amp; Co., Inc. A.Manning: None. F.Civeira: None. J.Merino: None. M.Udler: None. Funding American Diabetes Association (9-22-PDFPM-04 to M.S.)

1472-P: Polygenic Risk Score for Liver Fat Predicts Earlier Onset of Type 2 Diabetes in an East Asian Population

Liver, pancreas fat deposition and volume have been associated with type 2 diabetes (T2D) risk by Mendelian randomization study. However, it is unknown whether genetic variation in these traits impact on T2D onset, insulin resistance and drug use. We hypothesized that (1) genetic predisposition to smaller pancreas would be associated with earlier onset of T2D and earlier need for insulin; (2) genetic predisposition to higher pancreas and liver fat would be associated with greater insulin resistance, earlier onset of T2D and earlier need for insulin. This study utilized three Chinese cohorts of genotyped T2D patients in Hong Kong: Hong Kong Diabetes Register (HKDR, n=6011), Hong Kong Diabetes Biobank Phase 1 (HKDB-P1, n=6662) and Hong Kong Diabetes Biobank Phase 2 (HKDB-P2, n= 5899). We used lead SNPs (single nucleotide polymorphisms) associated with pancreas volume (13 SNPs), fat (7 SNPs) and liver fat (8 SNPs) from UK Biobank (n&amp;gt;32,000) to construct PRS (Polygenic risk score) in these cohorts. Linear regression models were employed to examine the associations between PRS and age of T2D onset and insulin resistance. Multivariable cox regression models were employed to examine association with time to insulin use. All models included age (except for age of T2D onset), sex and top 4 genetic principal components as covariates. To assess the confounding effects of BMI, we also performed BMI subgroup analysis by stratifying individuals into underweight, normal and overweight groups. Our analyses found that higher PRS for liver fat, but not pancreatic size or fat predicts earlier onset of T2D in HKDB-P1 (p&amp;lt;0.001, t=−3.43). The direction of association in HKDB-P2 was consistent though not significant. When stratified by BMI, higher PRS for liver fat predicts earlier onset of T2D in HKDB-P1 (p= 0.002, t=−3.14) and HKDB-P2 (p=0.029, t=−2.19) among the overweight group. Our results highlighted a PRS of liver fat as a potential biomarker for age of T2D onset, which needs further validation. Disclosure G.Yu: None. C.Huang: None. A.Luk: Research Support; Novo Nordisk, Boehringer-Ingelheim, Bayer Inc., Speaker's Bureau; Eli Lilly and Company. E.S.H.Lau: None. Hong kong diabetes biobank study group: n/a. R.C.Ma: Advisory Panel; AstraZeneca, Merck &amp; Co., Inc., Other Relationship; Bayer Inc., Boehringer-Ingelheim, Research Support; Tricida, Inc., Roche Diagnostics, Novo Nordisk. C.H.Tam: None. M.Shi: None. B.Fan: None. C.K.Lim: Stock/Shareholder; GemVCare Ltd. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer Inc., Celltrion, Boehringer Ingelheim and Eli Lilly Alliance, Sanofi, Research Support; AstraZeneca, Servier Laboratories, Viatris Inc., Hua Medicine, Merck KGaA, Applied Therapeutics Inc., Lee Powder, Pfizer Inc., Speaker's Bureau; Novartis, Stock/Shareholder; GemVCare Ltd. M.N.Weedon: None. R.A.Oram: Consultant; Janssen Research &amp; Development, LLC, Research Support; Randox R &amp; D. Funding Research Grants Council of the Hong Kong Special Administrative Region (CU-R4012-18); Croucher Foundation

1624-P: Hudev-PRE, a Combination of Plant Extracts, Improves Glucose Homeostasis in Both High-Fat Diet C57Bl/6J and Ob/Ob Mice

Despite advances in the understanding of the pathogenesis of type 2 diabetes (T2D), new therapeutic &amp; nutritional solutions are needed to delay its emergence and prevent the development of its associated complications. Here, we tested the effect of HUDEV-PRE, an original mixture of plant extracts, on glucose homeostasis in in two different mouse models of T2D. In a first experiment, 8 weeks old C57Bl/6J males were fed with high-fat diet during 8 weeks to induce insulin resistance. In a second set-up, we used 6 weeks old Ob/Ob males. In both experiments, mice received a double daily oral administration of vehicle, metformin (150mg/kg) or HUDEV-PRE for 30 days. Food intake, body weight change, random fed plasma glucose, cholesterol and triglyceride levels were measured once weekly. Finally, oral glucose tolerance tests (GTT) were performed after 7 and 21 days of treatment. In both models, HUDEV-PRE did not alter food intake and body weight. Interestingly, a rapid, sustainable and significant reduction of random fed blood glucose levels was observed in HFD fed C57Bl/6J and Ob/Ob mice receiving metformin or HUDEV-PRE administration. In HFD fed C57Bl/6J mice, GTT revealed no significant effects at day 7 but a strong improvement of glucose tolerance in mice treated for 21 days with metformin or HUDEV-PRE compared to control vehicle treated mice. In Ob/Ob mice, we observed similar results and the glucose tolerance was even improved after only 7 days of treatment. Finally, at day 21, we also measured a significant reduction of fasting plasma insulin levels and HOMA-IR in both mouse models treated with HUDEV-PRE. Together, our data demonstrate that HUDEV-PRE rapidly improve glucose homeostasis in two mouse models of T2D. Although additional studies are warranted to decipher the mechanisms of action, these findings indicate that HUDEV-PRE could represent a nutritional supplement of interest to delay the onset of insulin resistance and T2D in patients at metabolic risk. Disclosure C.Le may: None. J.Blua: None. B.Cariou: Board Member; Eli Lilly and Company, Novartis, Research Support; Sanofi, Speaker's Bureau; Abbott, AstraZeneca, Novo Nordisk, Sanofi.

1461-P: HbA1c-Independent Association between DNA Methylation (DNAm) and 28-Year Risk of Microvascular Complications in Type 1 Diabetes (T1D)

DNAm has been associated with microvascular disease but the few epigenome-wide association studies (EWAS) of complications in T1D were largely cross-sectional with limited data on glycemic exposure. We thus performed separate EWAS of 28-yr overt nephropathy (ON) and proliferative retinopathy (PR) risk to determine whether DNAm associations are independent of concurrent HbA1c or differ by long-term HbA1c trajectory in the Pittsburgh Epidemiology of Diabetes Complications study of childhood onset (&amp;lt;17 yrs) T1D (baseline mean age 29, T1D duration 21 yrs). After quality control, baseline whole blood DNAm (Illumina EPIC array) at 683,597 CpGs was analyzed in Cox models for time-to-ON (albumin excretion rate &amp;gt;200µg/min in ≥2 of 3 timed urines, n=306 free of ON at baseline) and PR (ETDRS grade≥60 or laser photocoagulation, n=265 free of PR), adjusting for T1D duration, sex, smoking pack-years, est. blood cell composition, and technical covariates. Additional EWAS further adjusted for baseline HbA1c. CpGs with false discovery rate (FDR) &amp;lt;0.20 were examined by previously derived latent HbA1c trajectory (Low: stable 7-8%, Improved: 10% decreasing to 7%, Intermediate-High: stable 9%-11%). Over 28 yrs, 65 (21.2%) developed ON; 139 (52.5%) PR. For ON, DNAm at cg19693031 (TXNIP) was associated (β per 5% DNAm=−0.43±0.09, p=2.84E-07, FDR=0.19) but attenuated in a baseline HbA1c-adjusted EWAS (β=−0.32±0.08, p=7.76E-05, FDR=0.98). For PR, 3 CpGs (cg27512687 [KIF16B]; cg04202206 [ISCA1]; cg14678509 [intergenic]) had FDR&amp;lt;0.20; only cg27512687 remained so after HbA1c adjustment (β=−2.6±0.49, p=8.46E-08, FDR=0.06). There was no interaction with baseline HbA1c (p=0.49); the magnitude of the cg27512687-PR association was similar regardless of HbA1c trajectory. Thus, further study of cg27512687 in KIF16B, a locus encoding a kinesin involved in receptor recycling/degradation, is warranted as it may make an HbA1c-independent contribution to PR risk T1D. Disclosure R.G.Miller: None. J.Mychaleckyj: None. S.Onengut-gumuscu: None. T.J.Orchard: None. T.Costacou: None. Funding American Diabetes Association (1-19-JDF-109 to R.G.M.); National Institute of Diabetes and Digestive and Kidney Diseases (R01DK034818)