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This article summarizes the state of the science on the role of the gut microbiota (GM) in diabetes from a recent international expert forum organized by Diabetes, Diabetes Care, and Diabetologia, which was held at the European Association for the Study of Diabetes 2023 Annual Meeting in Hamburg, Germany. Forum participants included clinicians and basic scientists who are leading investigators in the field of the intestinal microbiome and metabolism. Their conclusions were as follows: 1) the GM may be involved in the pathophysiology of type 2 diabetes, as microbially produced metabolites associate both positively and negatively with the disease, and mechanistic links of GM functions (e.g., genes for butyrate production) with glucose metabolism have recently emerged through the use of Mendelian randomization in humans; 2) the highly individualized nature of the GM poses a major research obstacle, and large cohorts and a deep-sequencing metagenomic approach are required for robust assessments of associations and causation; 3) because single-time point sampling misses intraindividual GM dynamics, future studies with repeated measures within individuals are needed; and 4) much future research will be required to determine the applicability of this expanding knowledge to diabetes diagnosis and treatment, and novel technologies and improved computational tools will be important to achieve this goal.

INTRODUCTION: Although poor glycemic control is associated with dementia, it is unknown if variability in glycemic control, even in those with optimal glycosylated hemoglobin A1c (HbA1c) levels, increases dementia risk. METHODS: Among 171,964 people with type 2 diabetes, we evaluated the hazard of dementia association with long-term HbA1c variability using five operationalizations, including standard deviation (SD), adjusting for demographics and comorbidities. RESULTS: The mean baseline age was 61 years (48% women). Greater HbA1c SD was associated with greater dementia hazard (adjusted hazard ratio = 1.15 [95% confidence interval: 1.12, 1.17]). In stratified analyses, higher HbA1c SD quintiles were associated with greater dementia hazard among those with a mean HbA1c

Effectively neutralizing inflammatory cytokines is crucial for managing a variety of inflammatory disorders. Current techniques that target only a subset of cytokines often fall short due to the intricate nature of redundant and compensatory cytokine networks. A promising solution to this challenge is using cell membrane-coated nanoparticles (CNPs). These nanoparticles replicate the complex interactions between cells and cytokines observed in disease pathology, providing a potential avenue for multiplex cytokine scavenging. While the development of CNPs using experimental animal models has shown great promise, their effectiveness in scavenging multiple cytokines in human diseases has yet to be demonstrated. To bridge this gap, this study selected macrophage membrane-coated CNPs (MФ-CNPs) and assessed their ability to scavenge inflammatory cytokines in serum samples from patients with COVID-19, sepsis, acute pancreatitis, or type-1 diabetes, along with synovial fluid samples from patients with rheumatoid arthritis. The results show that MФ-CNPs effectively scavenge critical inflammatory cytokines, including interleukin (IL)-6, IL-8, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α, in a dose-dependent manner. Overall, this study demonstrates MФ-CNPs as a multiplex cytokine scavenging formulation with promising applications in clinical settings to treat a range of inflammatory disorders.

Statin drugs lower blood cholesterol levels for cardiovascular disease prevention. Women are more likely than men to experience adverse statin effects, particularly new-onset diabetes (NOD) and muscle weakness. Here we find that impaired glucose homeostasis and muscle weakness in statin-treated female mice are associated with reduced levels of the omega-3 fatty acid, docosahexaenoic acid (DHA), impaired redox tone, and reduced mitochondrial respiration. Statin adverse effects are prevented in females by administering fish oil as a source of DHA, by reducing dosage of the X chromosome or the Kdm5c gene, which escapes X chromosome inactivation and is normally expressed at higher levels in females than males. As seen in female mice, we find that women experience more severe reductions than men in DHA levels after statin administration, and that DHA levels are inversely correlated with glucose levels. Furthermore, induced pluripotent stem cells from women who developed NOD exhibit impaired mitochondrial function when treated with statin, whereas cells from men do not. These studies identify X chromosome dosage as a genetic risk factor for statin adverse effects and suggest DHA supplementation as a preventive co-therapy.

BACKGROUND: Statins reduce the risk of cardiovascular events in patients with chronic kidney disease (CKD). Although diabetes mellitus (DM) is a reported side effect of statin treatment, some studies have indicated that pitavastatin does not cause DM. The present study investigated the effect of pitavastatin on the fatty acid (FA) content of erythrocyte membranes, which affects the occurrence of DM and cardiovascular diseases. In addition, changes in adiponectin and glycated hemoglobin (HbA1c) levels were evaluated after pitavastatin treatment. METHODS: A total of 45 patients were enrolled, 28 of whom completed the study. Over 24 weeks, 16 patients received 2 mg pitavastatin and 12 patients received 10 mg atorvastatin. Dosages were adjusted after 12 weeks if additional lipid control was required. There were 10 and nine patients with DM in the pitavastatin and atorvastatin groups, respectively. Erythrocyte membrane FAs and adiponectin levels were measured using gas chromatography and enzyme-linked immunosorbent assay, respectively. RESULTS: In both groups, saturated FAs, palmitic acid, trans-oleic acid, total cholesterol, and low-density lipoprotein cholesterol levels were significantly lower than those at baseline. The arachidonic acid (AA) content in the erythrocyte membrane increased significantly in the pitavastatin group, but adiponectin levels were unaffected. HbA1c levels decreased in patients treated with pitavastatin. No adverse effects were associated with statin treatment. CONCLUSION: Pitavastatin treatment in patients with CKD may improve glucose metabolism by altering erythrocyte membrane AA levels. In addition, pitavastatin did not adversely affect glucose control in patients with CKD and DM.

Cardiorespiratory fitness and mitochondrial oxidative capacity are associated with reduced walking speed in older adults, but their impact on walking speed in older adults with diabetes has not been clearly defined. We examined differences in cardiorespiratory fitness and skeletal muscle mitochondrial oxidative capacity between older adults with and without diabetes, as well as determined their relative contribution to slower walking speed in older adults with diabetes. Participants with diabetes (n = 159) had lower cardiorespiratory fitness and mitochondrial respiration in permeabilized fiber bundles compared with those without diabetes (n = 717), following adjustments for covariates including BMI, chronic comorbid health conditions, and physical activity. Four-meter and 400-m walking speeds were slower in those with diabetes. Mitochondrial oxidative capacity alone or combined with cardiorespiratory fitness mediated ∼20-70% of the difference in walking speed between older adults with and without diabetes. Additional adjustments for BMI and comorbidities further explained the group differences in walking speed. Cardiorespiratory fitness and skeletal muscle mitochondrial oxidative capacity contribute to slower walking speeds in older adults with diabetes.

OBJECTIVE: Real-time continuous glucose monitoring (CGM) is effective for diabetes management in cases of type 1 diabetes and adults with type 2 diabetes (T2D) but has not been assessed in adolescents and young adults (AYAs) with T2D. The objective of this pilot interventional study was to assess the feasibility and acceptability of real-time CGM use in AYAs with T2D. METHODS: Adolescents and young adults (13-21 years old) with T2D for six months or more and hemoglobin A1c (A1c) greater than 7%, on any Food and Drug Administration-approved treatment regimen, were included. After a blinded run-in period, participants were given access to a real-time CGM system for 12 weeks. The use and acceptability of the real-time CGM were evaluated by sensor usage, surveys, and focus group qualitative data. RESULTS: Participants (n = 9) median age was 19.1 (interquartile range [IQR] 16.8-20.5) years, 78% were female, 100% were people of color, and 67% were publicly insured. Baseline A1c was 11.9% (standard deviation ±2.8%), with median diabetes duration of 2.5 (IQR 1.4-6) years, and 67% were using insulin. Seven participants completed the study and demonstrated statistically significant improvement in diabetes-related quality of life, with the mean Pediatric Quality of Life inventory (PedsQL) diabetes score increasing from 70 to 75 after using CGM (P = .026). Focus group results supported survey results that CGM use among AYAs with T2D is feasible, can improve quality of life, and has the potential to modify behavior. CONCLUSION: Real-time CGM is feasible and acceptable for AYAs with T2D and may improve the quality of life of patients with diabetes. Larger randomized controlled trials are needed to assess the effects on glycemic control and healthy lifestyle changes.

Objectives: Fractal analysis is a numerical method that indicates the structural patterns and complexity of the trabecular bone on radiographs. The aim of this cross-sectional study was to evaluate the trabecular bone structure in systemically healthy patients and diabetes mellitus patients with periodontitis using fractal analysis. Method and materials: The study included 125 mandibular first molars of nonsmoker patients. The subjects were divided into five subgroups: diabetes mellitus patients with mild-moderate periodontitis, diabetes mellitus patients with advanced periodontitis, systemically healthy individuals with mild-moderate periodontitis, systemically healthy individuals with advanced periodontitis, and systemically healthy individuals with gingivitis (control group). Clinical periodontal parameters (pocket depth, bleeding on probing, clinical attachment loss, and bone loss) were recorded. Two specific sites located in the mesial-distal regions (n = 250) of the mandibular first molars were identified using periapical radiographs captured with a parallel technique. Fractal analysis values were calculated using the box-counting method. One-way analysis of variance (ANOVA), and Pearson correlation analysis were used forstatistical evaluation. Results: The highest fractal analysis values were observed in systemically healthy with gingivitis patients (mesial fractal analysis: 1.86 ± 0.01; distal fractal analysis: 1.85 ±0.01). Patients with periodontitis (mesial fractal analysis: 1.78 ±0.02; distal fractal analysis: 1.79 ± 0.01) exhibited lower fractal analysis values compared to the control group. There was no significant difference in mesial and distal fractal analysis values between all periodontitis groups. No correlation was found between age, sex, clinical attachment loss, bone loss, and fractal analysis (P>.05). Conclusions: Although fractal analysis values were lower in the periodontitis groups compared to the control group, fractal analysis did not demonstrate any periodontitis-associated changes of bone tra-beculationin diabetes at any stage of periodontitis. Furthermore, there was no significant association between fractal analysis values and age, sex, clinical attachment, and bone loss. [ABSTRACT FROM AUTHOR]

Aberration of the "gut-liver axis" contributes to the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we use multi-omics to analyze the gut microbiota composition and metabolic profile of patients with type-2 diabetes mellitus (T2DM). T2DM patients were screened for liver disease by blood tests, ultrasound, and liver stiffness measurements. Stool microbiota was analyzed by 16S rRNA gene sequencing; metabolomic profiling by Nuclear Magnetic Resonance spectroscopy and Ultra-High Performance-Mass Spectrometry. Microbiome and metabolic signatures were analyzed in the whole cohort and in matched subsets to identify signatures specific for steatosis (MASLD±) or fibrosis (Fibrosis±). Gut permeability was assessed in-vitro using monolayers of MDCK cells and trans-epithelial electric resistance (TEER). Cytokine profile was assessed in serum and stools.Overall, 285 patients were enrolled: 255 serum, 252 urine and 97 stool samples were analyzed. Anaeroplasma and Escherichia/Shigella ASVs were higher, while Butyricicoccus ASVs were lower in those with normal liver. In MASLD±, Butyricicoccus ASV was significantly higher in those with steatosis. In the Fibrosis±, Butyricicoccus ASV was significantly lower in those with fibrosis. Glycochenodeoxycholic acid-3-sulfate (G-UDCA-3S) appeared to be higher in MASLD with fibrosis. Fecal water from patients with MASLD and fibrosis caused the greatest drop in the TEER vs those with normal liver; this was reversed with protease inhibitors. Finally, fecal IL-13 was lower in MASLD with fibrosis. We identified microbiome signatures which were specific for steatosis and fibrosis and independent of other metabolic risk factors. Moreover, we conclude that protease-related gut permeability plays a role in those MASLD patients with fibrosis, and that disease progression is linked to a gut-liver axis which is at least partially independent of T2DM.

We previously reported two siblings with inherited PD-1 deficiency who died from autoimmune pneumonitis at 3 and 11 years of age after developing other autoimmune manifestations, including type 1 diabetes (T1D). We report here two siblings, aged 10 and 11 years, with neonatal-onset T1D (diagnosed at the ages of 1 day and 7 wk), who are homozygous for a splice-site variant of CD274 (encoding PD-L1). This variant results in the exclusive expression of an alternative, loss-of-function PD-L1 protein isoform in overexpression experiments and in the patients primary leukocytes. Surprisingly, cytometric immunophenotyping and single-cell RNA sequencing analysis on blood leukocytes showed largely normal development and transcriptional profiles across lymphoid and myeloid subsets in the PD-L1-deficient siblings, contrasting with the extensive dysregulation of both lymphoid and myeloid leukocyte compartments in PD-1 deficiency. Our findings suggest that PD-1 and PD-L1 are essential for preventing early-onset T1D but that, unlike PD-1 deficiency, PD-L1 deficiency does not lead to fatal autoimmunity with extensive leukocytic dysregulation.

Introduction: The purpose of this study was to characterize how family influences diabetes self-management in Mexican American adults. Methods: Data were analyzed from previously collected data that included 34 semi-structured interviews with Hispanic adults with diabetes and six focus groups with 37 adults with diabetes and family members. Themes related to family and diabetes management were identified and analyzed using a modified template approach. Results: Family-related facilitators to T2DM self-management were (1) provides support, (2) provides motivation, and (3) desire to protect family from diabetes. Family-related challenges were (1) lack of support, (2) family responsibilities, and (3) stress related to family. Diabetes education was shared with family members. Family member perspectives on T2DM included (1) not knowing how to help, (2) effect on emotional wellbeing, (3) diabetes affects the whole family, and (4) family provides support. Conclusion: Most participants with T2DM felt supported by family, but many desired more social support and support surrounding dietary changes from family. Many felt family did not understand what living with diabetes meant for them. Most family members wished to learn more about how to help. Future interventions should include family members and teach them supportive strategies to support beneficial diabetes self-management behaviors.

Preclinical studies indicate that diverse muscarinic receptor antagonists, acting via the M1 sub-type, promote neuritogenesis from sensory neurons in vitro and prevent and/or reverse both structural and functional indices of neuropathy in rodent models of diabetes. We sought to translate this as a potential therapeutic approach against structural and functional indices of diabetic neuropathy using oxybutynin, a muscarinic antagonist approved for clinical use against overactive bladder. Studies were performed using sensory neurons maintained in vitro, rodent models of type 1 or type 2 diabetes and human subjects with type 2 diabetes and confirmed neuropathy. Oxybutynin promoted significant neurite outgrowth in sensory neuron cultures derived from adult normal rats and STZ-diabetic mice, with maximal efficacy in the 1-100 nmol/l range. This was accompanied by a significantly enhanced mitochondrial energetic profile as reflected by increased basal and maximal respiration and spare respiratory capacity. Systemic (3-10 mg/kg/day s.c.) and topical (3% gel daily) oxybutynin reversed paw heat hypoalgesia in the STZ and db/db mouse models of diabetes and reversed paw tactile allodynia in STZ-diabetic rats. Loss of nerve profiles in the skin and cornea of db/db mice was also prevented by daily topical delivery of 3% oxybutynin for 8 weeks. A randomized, double-blind, placebo-controlled interventional trial was performed in subjects with type 2 diabetes and established peripheral neuropathy. Subjects received daily topical treatment with 3% oxybutynin gel or placebo for 6 months. The a priori designated primary endpoint, significant change in intra-epidermal nerve fibre density (IENFD) in skin biopsies taken before and after 20 weeks of treatments, was met by oxybutynin but not placebo. Secondary endpoints showing significant improvement with oxybutynin treatment included scores on clinical neuropathy, pain and quality of life scales. This proof-of-concept study indicates that muscarinic antagonists suitable for long-term use may offer a novel therapeutic opportunity for treatment of diabetic neuropathy. Trial registry number: NCT03050827.

Evaluating the quality of isolated human islets before transplantation is crucial for predicting the success in treating Type 1 diabetes. The current gold standard involves time-intensive in vivo transplantation into diabetic immunodeficient mice. Given the susceptibility of isolated islets to hypoxia, we hypothesized that hypoxia present in islets before transplantation could indicate compromised islet quality, potentially leading to unfavorable outcomes. To test this hypothesis, we analyzed expression of 39 hypoxia-related genes in human islets from 85 deceased donors. We correlated gene expression profiles with transplantation outcomes in 327 diabetic mice, each receiving 1200 islet equivalents grafted into the kidney capsule. Transplantation outcome was post-transplant glycemic control based on area under the curve of blood glucose over 4 weeks. In linear regression analysis, DDIT4 (R = 0.4971, P

Diabetes mellitus (DM) is a chronic endocrine disorder that affects more than 20 million people in the United States. DM-related complications affect multiple organ systems and are a significant cause of morbidity and mortality among people with DM. Of the numerous acute and chronic complications, atherosclerosis due to diabetic dyslipidemia is a condition that can lead to many life-threatening diseases, such as stroke, coronary artery disease, and myocardial infarction. The nuclear erythroid 2-related factor 2 (Nrf2) signaling pathway is an emerging antioxidative pathway and a promising target for the treatment of DM and its complications. This review aims to explore the Nrf2 pathways role in combating diabetic dyslipidemia. We will explore risk factors for diabetic dyslipidemia at a cellular level and aim to elucidate how the Nrf2 pathway becomes a potential therapeutic target for DM-related atherosclerosis.

BACKGROUNDPreclinical studies suggest that cholesterol accumulation leads to insulin resistance. We previously reported that alterations in a monocyte cholesterol metabolism transcriptional network (CMTN) - suggestive of cellular cholesterol accumulation - were cross-sectionally associated with obesity and type 2 diabetes (T2D). Here, we sought to determine whether the CMTN alterations independently predict incident prediabetes/T2D risk, and correlate with cellular cholesterol accumulation.METHODSMonocyte mRNA expression of 11 CMTN genes was quantified among 934 Multi-Ethnic Study of Atherosclerosis (MESA) participants free of prediabetes/T2D; cellular cholesterol was measured in a subset of 24 monocyte samples.RESULTSDuring a median 6-year follow-up, lower expression of 3 highly correlated LXR target genes - ABCG1 and ABCA1 (cholesterol efflux) and MYLIP (cholesterol uptake suppression) - and not other CMTN genes, was significantly associated with higher risk of incident prediabetes/T2D. Lower expression of the LXR target genes correlated with higher cellular cholesterol levels (e.g., 47% of variance in cellular total cholesterol explained by ABCG1 expression). Further, adding the LXR target genes to overweight/obesity and other known predictors significantly improved prediction of incident prediabetes/T2D.CONCLUSIONThese data suggest that the aberrant LXR/ABCG1-ABCA1-MYLIP pathway (LAAMP) is a major T2D risk factor and support a potential role for aberrant LAAMP and cellular cholesterol accumulation in diabetogenesis.FUNDINGThe MESA Epigenomics and Transcriptomics Studies were funded by NIH grants 1R01HL101250, 1RF1AG054474, R01HL126477, R01DK101921, and R01HL135009. This work was supported by funding from NIDDK R01DK103531 and NHLBI R01HL119962.

BACKGROUND: Diabetic cardiomyopathy (DbCM) is characterized by asymptomatic stage B heart failure (SBHF) caused by diabetes-related metabolic alterations. DbCM is associated with an increased risk of progression to overt heart failure (HF). The prevalence of DbCM in patients with type 2 diabetes (T2D) is not well established. This study aims to determine prevalence of DbCM in adult T2D patients in real-world clinical practice. METHODS: Retrospective multi-step review of electronic medical records of patients with the diagnosis of T2D who had echocardiogram at UC San Diego Medical Center (UCSD) within 2010-2019 was conducted to identify T2D patients with SBHF. We defined pure DbCM when SBHF is associated solely with T2D and mixed SBHF when other medical conditions can contribute to SBHF. Pure DbCM was diagnosed in T2D patients with echocardiographic demonstration of SBHF defined as left atrial (LA) enlargement (LAE), as evidenced by LA volume index ≥ 34 mL/m2, in the presence of left ventricular ejection fraction (LVEF) ≥ 45%, while excluding overt HF and comorbidities that can contribute to SBHF. RESULTS: Of 778,314 UCSD patients in 2010-2019, 45,600 (5.9%) had T2D diagnosis. In this group, 15,182 T2D patients (33.3%) had echocardiogram and, among them, 13,680 (90.1%) had LVEF ≥ 45%. Out of 13,680 patients, 4,790 patients had LAE. Of them, 1,070 patients were excluded due to incomplete data and/or a lack of confirmed T2D according to the American Diabetes Association recommendations. Thus, 3,720 T2D patients with LVEF ≥ 45% and LAE were identified, regardless of HF symptoms. In this group, 1,604 patients (43.1%) had overt HF and were excluded. Thus, 2,116 T2D patients (56.9% of T2D patients with LVEF ≥ 45% and LAE) with asymptomatic SBHF were identified. Out of them, 1,773 patients (83.8%) were diagnosed with mixed SBHF due to comorbidities such as hypertension (58%), coronary artery disease (36%), and valvular heart disease (17%). Finally, 343 patients met the diagnostic criteria of pure DbCM, which represents 16.2% of T2D patients with SBHF, i.e., at least 2.9% of the entire T2D population in this study. CONCLUSIONS: Our findings provide insights into prevalence of DbCM in real-world clinical practice and indicate that DbCM affects a significant portion of T2D patients.

To develop a peri-implantitis model in a Gottingen minipig and evaluate the effect of local application of salicylic acid poly(anhydride-ester) (SAPAE) on peri-implantitis progression in healthy, metabolic syndrome (MS), and type-2 diabetes mellitus (T2DM) subjects. Eighteen animals were allocated to three groups: (i) control, (ii) MS (diet for obesity induction), and (iii) T2DM (diet plus streptozotocin for T2DM induction). Maxillary and mandible premolars and first molar were extracted. After 3 months of healing, four implants per side were placed in both jaws of each animal. After 2 months, peri-implantitis was induced by plaque formation using silk ligatures. SAPAE polymer was mixed with mineral oil (3.75 mg/μL) and topically applied biweekly for up to 60 days to halt peri-implantitis progression. Periodontal probing was used to assess pocket depth over time, followed by histomorphologic analysis of harvested samples. The adopted protocol resulted in the onset of peri-implantitis, with healthy minipigs taking twice as long to reach the same level of probing depth relative to MS and T2DM subjects (∼3.0 mm), irrespective of jaw. In a qualitative analysis, SAPAE therapy revealed decreased levels of inflammation in the normoglycemic, MS, and T2DM groups. SAPAE application around implants significantly reduced the progression of peri-implantitis after ∼15 days of therapy, with ∼30% lower probing depth for all systemic conditions and similar rates of probing depth increase per week between the control and SAPAE groups. MS and T2DM conditions presented a faster progression of the peri-implant pocket depth. SAPAE treatment reduced peri-implantitis progression in healthy, MS, and T2DM groups.

BackgroundSub-optimal HbA1c control is a driver of disparities in diabetes outcomes among Hispanic patients. Differences in medication adherence may underlie racial/ethnic differences in HbA1c level.ObjectiveTo examine the relationship between medication adherence and disparities in HbA1c level among Hispanic patients, relative to other racial/ethnic groups, obtaining care in the University of California Health System (UC Health).DesignThis study used clinical, administrative, and prescription dispensing data (January-December 2021) derived from the electronic health records of 5 Academic Medical Centers in UC Health, and linear regression models (LRMs) to conduct a cross-sectional analysis of the association between medication adherence, race/ethnicity, and HbA1c level. Adjusted LRMs were run with and without the measure of medication adherence to assess this relationship.ParticipantsPatients with a UC Health primary care physician (PCP), with ≥ 1 PCP visit within the last 3 years, ages 18-75, reporting Asian, Hispanic, or White race/ethnicity, and who had ≥ 2 encounters with an ICD diagnosis of diabetes or had a prescription for a diabetes medication within the last 2 years, as of 12/31/21 (N = 27, 542; Asian = 6253, Hispanic = 7216, White = 14,073).Main measuresOur measure of medication adherence was the proportion of days covered (PDC) for diabetes medications in 2021. Our outcome was the most recent HbA1c value.Key resultsIn the LRM excluding the PDC, Hispanic ethnicity was positively associated with HbA1c level (β = 0.31, p =

CD4+ T cells recognize peptide antigens presented on class II major histocompatibility complex (MHC-II) molecules to carry out their function. The remarkable diversity of T cell receptor sequences and lack of antigen discovery approaches for MHC-II make profiling the specificities of CD4+ T cells challenging. We have expanded our platform of signaling and antigen-presenting bifunctional receptors to encode MHC-II molecules presenting covalently linked peptides (SABR-IIs) for CD4+ T cell antigen discovery. SABR-IIs can present epitopes to CD4+ T cells and induce signaling upon their recognition, allowing a readable output. Furthermore, the SABR-II design is modular in signaling and deployment to T cells and B cells. Here, we demonstrate that SABR-IIs libraries presenting endogenous and non-contiguous epitopes can be used for antigen discovery in the context of type 1 diabetes. SABR-II libraries provide a rapid, flexible, scalable and versatile approach for de novo identification of CD4+ T cell ligands from single-cell RNA sequencing data using experimental and computational approaches.

BackgroundSouth Asians are at higher risk for type 2 diabetes (T2D) than many other race/ethnic groups. Ectopic adiposity, specifically hepatic steatosis and visceral fat may partially explain this. Our objective was to derive metabolite risk scores for ectopic adiposity and assess associations with incident T2D in South Asians.MethodsWe examined 550 participants in the Mediators of Atherosclerosis in South Asians Living in America (MASALA) cohort study aged 40-84 years without known cardiovascular disease or T2D and with metabolomic data. Computed tomography scans at baseline assessed hepatic attenuation and visceral fat area, and fasting serum specimens at baseline and after 5 years assessed T2D. LC-MS-based untargeted metabolomic analysis was performed followed by targeted integration and reporting of known signals. Elastic net regularized linear regression analyses was used to derive risk scores for hepatic steatosis and visceral fat using weighted coefficients. Logistic regression models associated metabolite risk score and incident T2D, adjusting for age, gender, study site, BMI, physical activity, diet quality, energy intake and use of cholesterol-lowering medication.ResultsAverage age of participants was 55 years, 36% women with an average body mass index (BMI) of 25 kg/m2 and 6% prevalence of hepatic steatosis, with 47 cases of incident T2D at 5 years. There were 445 metabolites of known identity. Of these, 313 metabolites were included in the MET-Visc score and 267 in the MET-Liver score. In most fully adjusted models, MET-Liver (OR 2.04 [95% CI 1.38, 3.03]) and MET-Visc (OR 2.80 [1.75, 4.46]) were associated with higher odds of T2D. These associations remained significant after adjustment for measured adiposity.ConclusionsMetabolite risk scores for intrahepatic fat and visceral fat were strongly related to incident T2D independent of measured adiposity. Use of these biomarkers to target risk stratification may help capture pre-clinical metabolic abnormalities.

BACKGROUND AND HYPOTHESIS: Serious mental illness (SMI) may compromise diabetes self-management. This study assessed the association between SMI and glycemic control, and explored sociodemographic predictors and geographic clustering of this outcome among patients with and without SMI. STUDY DESIGN: We used electronic health record data for adult primary care patients with diabetes from 2 San Francisco health care delivery systems. The primary outcome was poor glycemic control (hemoglobin A1c >9.0%), which was modeled on SMI diagnosis status and sociodemographics. Geospatial analyses examined hotspots of poor glycemic control and neighborhood characteristics. STUDY RESULTS: The study included 11 694 participants with diabetes, 21% with comorbid SMI, of whom 22% had a schizophrenia spectrum or bipolar disorder. Median age was 62 years; 52% were female and 79% were Asian, Black, or Hispanic. In adjusted models, having schizophrenia spectrum disorder or bipolar disorder was associated with greater risk for poor glycemic control (vs participants without SMI, adjusted relative risk [aRR] = 1.24; 95% confidence interval, 1.02, 1.49), but having broadly defined SMI was not. People with and without SMI had similar sociodemographic correlates of poor glycemic control including younger versus older age, Hispanic versus non-Hispanic White race/ethnicity, and English versus Chinese language preference. Hotspots for poor glycemic control were found in neighborhoods with more lower-income, Hispanic, and Black residents. CONCLUSIONS: Poor diabetes control was significantly related to having a schizophrenia spectrum or bipolar disorder, and to sociodemographic factors and neighborhood. Community-based mental health clinics in hotspots could be targets for implementation of diabetes management services.

Immune checkpoint inhibitor (CPI)-induced diabetes mellitus (CPI-DM) is a rare immune-related adverse event (irAE). Patients and providers fear that continuing CPIs puts patients at risk for additional irAEs and thus may discontinue therapy. Currently, there are little data to inform this decision. Therefore, this study aims to elucidate whether discontinuing CPIs after diagnosis of CPI-DM impacts the development of future irAEs and cancer outcomes such as progression and death. Patients who developed CPI-DM during cancer treatment at UCSF from 1 July 2015 to 5 July 2023 were analyzed for cancer outcomes and irAE development. Fishers exact tests, Student t-tests, Kaplan-Meier methods, and Cox regression were used as appropriate. Of the 43 patients with CPI-DM, 20 (47%) resumed CPIs within 90 days of the irAE, 4 (9%) patients restarted after 90 days, and 19 (44%) patients never restarted. Subsequent irAEs were diagnosed in 9 of 24 (38%) who resumed CPIs and 3 of 19 (16%) who discontinued CPIs (p = 0.17). There was no significant difference in death (p = 0.74) or cancer progression (p = 0.55) between these two groups. While our single-institution study did not show worse cancer outcomes after discontinuing CPIs, many variables can impact outcomes, which our study was not adequately powered to evaluate. A nuanced approach is needed to decide whether to continue CPI treatment after a severe irAE like CPI-DM.

The Phenome-Wide Association Study (PheWAS) is increasingly used to broadly screen for potential treatment effects, e.g., IL6R variant as a proxy for IL6R antagonists. This approach offers an opportunity to address the limited power in clinical trials to study differential treatment effects across patient subgroups. However, limited methods exist to efficiently test for differences across subgroups in the thousands of multiple comparisons generated as part of a PheWAS. In this study, we developed an approach that maximizes the power to test for heterogeneous genotype-phenotype associations and applied this approach to an IL6R PheWAS among individuals of African (AFR) and European (EUR) ancestries. We identified 29 traits with differences in IL6R variant-phenotype associations, including a lower risk of type 2 diabetes in AFR (OR 0.96) vs EUR (OR 1.0, p-value for heterogeneity = 8.5 × 10-3), and higher white blood cell count (p-value for heterogeneity = 8.5 × 10-131). These data suggest a more salutary effect of IL6R blockade for T2D among individuals of AFR vs EUR ancestry and provide data to inform ongoing clinical trials targeting IL6 for an expanding number of conditions. Moreover, the method to test for heterogeneity of associations can be applied broadly to other large-scale genotype-phenotype screens in diverse populations.

Multiomics has shown promise in noninvasive risk profiling and early detection of various common diseases. In the present study, in a prospective population-based cohort with ~18 years of e-health record follow-up, we investigated the incremental and combined value of genomic and gut metagenomic risk assessment compared with conventional risk factors for predicting incident coronary artery disease (CAD), type 2 diabetes (T2D), Alzheimer disease and prostate cancer. We found that polygenic risk scores (PRSs) improved prediction over conventional risk factors for all diseases. Gut microbiome scores improved predictive capacity over baseline age for CAD, T2D and prostate cancer. Integrated risk models of PRSs, gut microbiome scores and conventional risk factors achieved the highest predictive performance for all diseases studied compared with models based on conventional risk factors alone. The present study demonstrates that integrated PRSs and gut metagenomic risk models improve the predictive value over conventional risk factors for common chronic diseases.

PURPOSE: Data are limited on sodium glucose co-transport 2 inhibitors (SGLT2-is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) among real-world cohorts of underrepresented patients. We examined these therapies and glycemic control in US adults with diabetes mellitus (DM) by atherosclerotic cardiovascular disease (ASCVD) risk and sociodemographic factors. METHODS: In the NIH Precision Medicine Initiative All of Us Research Program, we categorized DM as (1) moderate risk, (2) high risk, and (3) with ASCVD. We examined proportions on DM therapies, including SGLT2-i or GLP-1 RA, and at glycemic control by sociodemographic factors and CVD risk groups. RESULTS: Our 81,332 adults aged ≥ 18 years with DM across 340 US sites included 22.3% non-Hispanic Black, 17.2% Hispanic, and 1.8% Asian participants; 31.1%, 30.3%, and 38.6% were at moderate risk, high risk, or with ASCVD, respectively. Those with DM and ASCVD were most likely on SGLT2-i (8.6%) or GLP-1 RA (11.9%). SGLT2-i use was

Type 1 diabetes (T1D) is a prototypic T cell-mediated autoimmune disease. Because the islets of Langerhans are insulated from blood vessels by a double basement membrane and lack detectable lymphatic drainage, interactions between endocrine and circulating T cells are not permitted. Thus, we hypothesized that initiation and progression of anti-islet immunity required islet neolymphangiogenesis to allow T cell access to the islet. Combining microscopy and single cell approaches, the timing of this phenomenon in mice was situated between 5 and 8 wk of age when activated anti-insulin CD4 T cells became detectable in peripheral blood while peri-islet pathology developed. This peri-insulitis, dominated by CD4 T cells, respected the islet basement membrane and was limited on the outside by lymphatic endothelial cells that gave it the attributes of a tertiary lymphoid structure. As in most tissues, lymphangiogenesis seemed to be secondary to local segmental endothelial inflammation at the collecting postcapillary venule. In addition to classic markers of inflammation such as CD29, V-CAM, and NOS, MHC class II molecules were expressed by nonhematopoietic cells in the same location both in mouse and human islets. This CD45- MHC class II+ cell population was capable of spontaneously presenting islet Ags to CD4 T cells. Altogether, these observations favor an alternative model for the initiation of T1D, outside of the islet, in which a vascular-associated cell appears to be an important MHC class II-expressing and -presenting cell.

Insulin is an essential regulator of blood glucose homeostasis that is produced exclusively byβcells within the pancreatic islets of healthy individuals. In those affected by diabetes, immune inflammation, damage, and destruction of isletβcells leads to insulin deficiency and hyperglycemia. Current efforts to understand the mechanisms underlyingβcell damage in diabetes rely onin vitro-cultured cadaveric islets. However, isolation of these islets involves removal of crucial matrix and vasculature that supports islets in the intact pancreas. Unsurprisingly, these islets demonstrate reduced functionality over time in standard culture conditions, thereby limiting their value for understanding native islet biology. Leveraging a novel, vascularized micro-organ (VMO) approach, we have recapitulated elements of the native pancreas by incorporating isolated human islets within a three-dimensional matrix nourished by living, perfusable blood vessels. Importantly, these islets show long-term viability and maintain robust glucose-stimulated insulin responses. Furthermore, vessel-mediated delivery of immune cells to these tissues provides a model to assess islet-immune cell interactions and subsequent islet killing-key steps in type 1 diabetes pathogenesis. Together, these results establish the islet-VMO as a novel,ex vivoplatform for studying human islet biology in both health and disease.