bluuebunny/crossref_metadata_2025 huggingface dataset:
222-OR: Overcoming Islet Scarcity through In Vitro Differentiation of Human Pluripotent Stem Cells
Authors: HOGREBE NATHANIEL , ISHAHAK MATTHEW , SANCHEZ-CASTRO ENRIQUE E. , MILLMAN JEFFREY R.
Published: June 2024

The potential of cell therapy for Type 1 Diabetes (T1D) has been constrained by the scarcity of islets and the dependence on obtaining them from deceased donors. The in vitro differentiation of islets from human pluripotent stem cells (hPSCs) could overcome this limitation to provide a sustainable cell source, facilitating the broad availability of tissues for therapeutic purposes. Challenges face this approach, including large-scale biomanufacturing of high-quality stem cell-derived islets (SC-islets) and limited understanding of transitions of key cellular identities. Here we have developed a scaled differentiation process that produces over one billion cells by first generating β cells that co-express C-peptide and NKX6-1 along with other endocrine cell types on large-surface area culture flasks using combinations of growth factors and small molecules. These cells can be single-cell dispersed and cryopreserved using a controlled-rate freezer and subsequently thawed and aggregated into islet-like clusters. These clusters are glucose-responsive and able to reverse diabetes when transplanted into a streptozotocin-induced diabetes mouse model. Using single-nuclei multiomic sequencing, we have mapped the entire differentiation process epigenetically and transcriptionally. Using this data, we defined the cellular transition states and timings for the generation of β, α, and δ cells. In addition, we have identified the transcription factor LMX1A as a key determinant in the generation of a serotonin-producing enterochromaffin-like cell state. These results demonstrate larger-scale biomanufacturing of SC-islets and provide a novel epigenomic roadmap of their differentiation.

Disclosure

N. Hogrebe: Research Support; Sana Biotechnology. M. Ishahak: Stock/Shareholder; Vertex Pharmaceuticals Incorporated. E.E. Sanchez-Castro: None. J.R. Millman: Employee; Sana Biotechnology. Research Support; Sana Biotechnology. Stock/Shareholder; Sana Biotechnology.

Funding

National Institutes of Health (Human Islet Research Network Catalyst Award); JDRF (5-CDA-2017-391-A-N)
226-OR: Immunoprivileged Hydrogels Recover Normoglycemia for Extended Duration in Immunocompetent Diabetic Animals
Authors: STOVER HARALD
Published: June 2024

Introduction & Objective: The application of current islet cell transplantation is limited by the need for systemic immune suppression. Physically immuno-protective hydrogels offer a route to allogenic islet transplants. To assess the functionality of islets encapsulated in our proprietary synthetic hydrogels, we assessed in hydrogel robustness and islet function both in vitro and in immunocompetent diabetic animals, without any immunosuppression.

Methods: Rat and human donor islets were encapsulated in next generation shape-agnostic hydrogels and implanted in the peritoneal space of streptozotocin (STZ)-induced diabetic immunocompetent mice and rats to assess islet functionality over time through measurement of blood glucose, C-peptide, and HbA1c. The effect of islet loading and islet density was assessed in vitro and in vivo.

Results: Hydrogels successfully excluded IgG, maintained good islet function in vitro and showed visible blood vessels early post-implant. Encapsulated rat islets demonstrated rapid and sustained blood glucose control for 140+ days in immunocompetent mice and for 110+ days in immunocompetent rats. Our hydrogels also extended human donor islet function in mice, Yorkshire pigs and Gottingen minipigs, as indicated by reduced blood glucose and increased C-peptide and HbA1c levels. We noticed a dose-dependent effect on in vivo function, despite similar in vitro GSIS indices. When explanted from mice, rats or pigs, the encapsulated islets had indicators of good function and viability; and our hydrogels had no-to-minimal tissue response, as well as good robustness and integrity.

Conclusion: Our proprietary, retrievable hydrogels showed strong immune protection for both allogenic and xenogeneic transplantation, without any immunosuppression. We are currently scaling to therapeutic doses in large animals, in pursuit of a curative therapy based on an optimal balance of Islet protection and functionality.

Disclosure

H. Stover: None.

Funding

JDRF (2-IND-2023-1449-I-X)
228-OR: Effect of Pemvidutide, a GLP-1/Glucagon Dual Receptor Agonist, on Cardioinflammatory Lipids
Authors: SUSCHAK JOHN J. , GEORGES BERTRAND , ROBERTS M S. , SCOTT HARRIS M. , BROWNE SARAH K.
Published: June 2024

Introduction & Objective: Dysregulated lipid profiles in obesity can cause systemic inflammation and elevate cardiovascular (CV) risk. We studied the impact of pemvidutide, a dual GLP-1/glucagon receptor agonist, on lipoprotein and glycoprotein biomarkers of CV inflammation.

Methods: Subjects with overweight or obesity and without diabetes (N=34) were randomly assigned 1:1:1:1 to pemvidutide (1.2, 1.8, 2.4 mg) or placebo administered subcutaneously weekly for 12 weeks. Lipidomic and glycoprotein profiling was conducted using ultra-high performance liquid chromatography-mass spectrometry or NMR on plasma samples at Day -1, Day 43, and Day 85.

Results: Pemvidutide reduced body weight by up to 10.3% and the atherogenic lipids total cholesterol, LDL-C, and triglycerides by up to 28%, 26%, and 38%, respectively. Pemvidutide reduced pro-inflammatory lipidomic signatures such as small-dense LDL-C, short-chain, saturated diglycerides, lysophosphatidylinositols, lysophosphatidylcholines and sphingolipids. Reduction in GlycA and GlycB, biomarkers of systemic inflammation correlated with heart failure, were also observed (Table 1).    

Conclusion: Pemvidutide elicited significant weight loss and decreases in pro-inflammatory lipid species associated with atherogenesis and CV risk. These results may reflect beneficial effects of glucagon on lipoprotein and glycoprotein metabolism.

Disclosure

J.J. Suschak: Employee; Altimmune Inc. B. Georges: Employee; Altimmune. M.S. Roberts: Employee; Altimmune Inc. M. Harris: Employee; Altimmune Inc. S.K. Browne: Employee; Altimmune Inc.
23-OR: Streamlining Diabetes Device Integration into the Electronic Health Record
Authors: HUNT MELANIE , DUNCAN RAYMOND , PAYNE DANIEL , WILLIAMS STEVE , ALABI BASHAR , RENELLA JENNA , SPALDING-JACKSON JOYCE R. , MATHUR RUCHI , GIANCHANDANI ROMA
Published: June 2024

Technology has transformed diabetes management with Continuous Glucose Monitors (CGM) and Automated Insulin Delivery devices, improving A1c and reducing hypoglycemia. Multiple device usage increases download burden for clinics. To enhance this process, we integrated CGMs, pumps, smart pens and meters into the Electronic Health Record (EHR). Device data obtained via Glooko and Abbott was integrated into the EHR using HL7 v. 2.x interfaces and Single-Sign-On launches of both vendor web portals. Health care professionals (HCPs) can send orders via EHR to vendor, triggering individual enrollment and generating current data reports. Discrete data is returned as flowsheets and detailed reports load as PDF files for viewing and permanent storage. Extensive training sessions and materials were developed for HCPs and support staff. Within 6 months, over 200 patients connected devices to the EHR (Figure 1). Majority of the devices were CGMs (60%) followed by pumps. 70% of the devices were syncing remotely. AGP metrics were tracked in flowsheets. HCPs could document AGP tables and PDF reports into progress notes using dot phrases. A skilled integration team and targeted role-specific education allowed for successful integration of diabetes device data into the EHR. The efficiency for data retrieval and storage made data from people with diabetes accessible and actionable, thereby reducing retrieval and documentation burden for HCPs.

Disclosure

M. Hunt: None. R. Duncan: None. D. Payne: None. S. Williams: None. B. Alabi: None. J. Renella: None. J.R. Spalding-Jackson: None. R. Mathur: None. R. Gianchandani: None.
232-OR: Glucagon-Like Peptide-1 Receptor Agonists and Risk of Suicide/Self-Harm in U.S. Older Adults with Type 2 Diabetes—A Population-Based Cohort Study
Authors: TANG HUILIN , LU YING , DONAHOO WILLIAM T. , BIAN JIANG , GUO JINGCHUAN
Published: June 2024

Background: A major concern has recently been raised regarding the association between glucagon-like peptide-1 receptor agonists (GLP-1RAs), especially for liraglutide and semaglutide, and an increased risk of suicide or self-harm. However, the evidence supporting this association remains extremely limited.

Methods: Using 2016-2020 national Medicare Claims data, we conducted a population-based, new-user cohort study that included individuals with type 2 diabetes (T2D) who were newly prescribed a GLP-1RA or a sodium-glucose cotransporter 2 inhibitors (SGLT2i). We employed 1:1 propensity score matching to control for potential confounding at baseline and used a Cox proportional hazards regression to estimate the hazard ratio (HR) and 95% confidence intervals (CI) of the suicide/self-harm. A secondary analysis with dipeptidyl peptidase 4 inhibitor (DPP4i) as the comparator was also performed.

Results: We identified 41,894 Medicare beneficiaries with T2D who initiated either a GLP-1RA inhibitor or an SGLT2i. The incidence rate of suicide/self-harm among GLP-1RA users and SGLT2i users were 42.79 cases and 41.84 cases per 1,000 person-years, respectively. There was no significant association between GLP-1RAs and an increased risk of suicide/self-harm compared with SGLT2i (HR, 1.02; 95%CI, 0.91-1.14). In the secondary analysis, GLP-1RAs were significantly associated with a lower risk of suicide/self-harm than DPP4i (HR, 0.77; 95%CI, 0.70-0.85).

Conclusion: Among Medicare beneficiaries with T2D, GLP-1RAs were not associated with an increased risk of suicide/self-harm. Future research is needed especially in younger populations to confirm these findings.

Disclosure

H. Tang: None. Y. Lu: None. W.T. Donahoo: None. J. Bian: None. J. Guo: None.
236-OR: Short-Term Effects of Semaglutide and Tirzepatide on Body Composition in Patients with Obesity Undergoing a Low-Calorie Diet
Authors: NAKA MASAMITSU , KAMI SAORI , HAYASHI SAHO , ISHIBASHI RYOICHI
Published: June 2024

Objective: Severe caloric restriction, used for preoperative short-term weight loss, can lead to muscle loss, subsequently worsen glucose tolerance and cause weight regain. This observational study explored the short-term effects of semaglutide (SEMA) and tirzepatide (TZP) on weight loss and body composition in patients with obesity during a 13-day-low-calorie diet.

Methods: Japanese adults with a body mass index ≥ 25 kg/m2 who completed our hospital’s diet (800 kcal/day) and exercise therapy between 2019 and 2023 were included. Those who started oral or injectable SEMA or TZP upon admission, and those without a history of glucagon-like peptide-1 (GLP-1) receptor agonists or TZP use, were assigned to the GLP-1 (n = 28) and FREE groups (n = 19), respectively. Changes in body weight and body composition, measured by bioelectrical impedance analysis, before and after hospitalization were compared between the groups using Student t-test and analysis of covariance, respectively.

Results: Significant weight loss occurred in both groups, but no significant difference was observed between them (-4.34% with GLP-1 group vs. -4.63% with FREE group; estimated treatment difference, -0.28%; 95% confidence interval (CI), -1.06 to 0.49; p = 0.464). Fat mass decreased in the GLP-1 group (-10.10% with GLP-1 group vs. -1.93% with FREE group; estimated treatment difference, -8.17%; 95% CI, -1.42 to -14.92; p = 0.019), whereas fat-free mass decreased in the FREE group (0.98% with GLP-1 group vs. -4.58% with FREE group; estimated treatment difference, 5.56%; 95% CI, 0.03 to 0.75; p = 0.025). Analysis within the GLP-1 group suggested a greater body composition improvement with TZP than with SEMA.

Conclusion: A 13-day treatment with SEMA or TZP improves body composition in patients with obesity undergoing severe caloric restriction, with TZP demonstrating a more substantial effect.

Disclosure

M. Naka: None. S. Kami: None. S. Hayashi: None. R. Ishibashi: Research Support; Astellas Pharma Inc., Taiho Pharmaceutical Co. Ltd.
246-OR: Association of Erythritol and Erythronate with Cardiovascular Outcomes and Death
Authors: ABUSHAMAT LAYLA A. , SUN CAROLINE W. , YU BING , HOOGEVEEN RON C. , CHENG CHAO , HARTIG SEAN M. , HERMAN MARK A. , REUSCH JANE E.B. , SELVIN ELIZABETH , NDUMELE CHIADI E. , NAMBI VIJAY , BALLANTYNE CHRISTIE M.
Published: June 2024

Introduction & Objective: Erythritol, an endogenously produced sugar alcohol, is a commonly used artificial sweetener since 2002. However, circulating erythritol is associated with cardiovascular (CV) disease at visit 1 (1987-89) of the Atherosclerosis Risk in Communities (ARIC) study. The objective was to assess the association of erythritol and its metabolite erythronate with CV outcomes in older adults at ARIC visit 5 (2011-13).

Methods: Fasting erythritol and erythronate were measured in ARIC participants by mass spectrometry and were analyzed continuously and by tertiles. Cox proportional hazard models assessed associations with CV outcomes and death.

Results: Top tertile erythritol or erythronate levels were associated with older age, diabetes, hypertension, hyperlipidemia, higher body mass index, lower estimated glomerular filtration rate, microalbuminuria, and higher cardiac biomarkers (p<0.001). Over mean follow-up of 7.7±2 years, higher erythritol and erythronate relative concentrations were associated with CV events after adjustment for covariates (Figure). Erythronate associated more strongly than erythritol.

Conclusion: Erythritol and erythronate may serve as biomarkers of poor cardiac-kidney-metabolic syndrome (CKM) health and CV outcomes. Future studies should assess the contribution of endogenous production via the pentose phosphate pathway versus exogenous intake.

Disclosure

L.A. Abushamat: None. C.W. Sun: None. B. Yu: None. R.C. Hoogeveen: Consultant; Denka Seiken. Research Support; Denka Seiken. C. Cheng: None. S.M. Hartig: None. M.A. Herman: Research Support; Eli Lilly and Company. J.E.B. Reusch: Advisory Panel; Medtronic. E. Selvin: None. C.E. Ndumele: None. V. Nambi: Board Member; American Society of Preventive Cardiology. Stock/Shareholder; Insera. Other Relationship; American College of Cardiology. C.M. Ballantyne: Research Support; Abbott Diagnostics. Consultant; Abbott Diagnostics. Research Support; Akcea Thearpeutics, Inc., Amgen Inc. Consultant; Amgen Inc. Research Support; Arrowhead Pharmaceuticals, Inc. Consultant; Arrowhead Pharmaceuticals, Inc., AstraZeneca, Denka Seiken, Eli Lilly and Company, ESPERION Therapeutics, Inc., Genentech, Inc., Illumina. Research Support; Ionis Pharmaceuticals. Consultant; Ionis Pharmaceuticals. Research Support; Merck & Co., Inc. Consultant; Merck & Co., Inc. Research Support; New Amsterdam. Consultant; New Amsterdam. Research Support; Novartis Pharmaceuticals Corporation. Consultant; Novartis Pharmaceuticals Corporation. Research Support; Novo Nordisk. Consultant; Novo Nordisk. Research Support; Regeneron Pharmaceuticals Inc., Roche Diagnostics. Consultant; Roche Diagnostics, TenSixteen Bio, Alnylam Pharmaceuticals, Inc.
27-OR: Effect of Acute Exercise and Exercise Training on the Ability of Insulin to Clear Branched-Chain Amino Acids from Plasma in Obesity and Type 2 Diabetes
Authors: MØLLER PAULINE M. , KJØBSTED RASMUS , HOUBORG PETERSEN MARIA , WOJTASZEWSKI JØRGEN F.P. , HOJLUND KURT
Published: June 2024

Introduction & Objective: Insulin resistance in obesity and type 2 diabetes (T2D) is associated with elevated plasma branched-chain amino acid (BCAA) levels. Whether insulin action on plasma BCAA and the ability of acute exercise or exercise training to alter insulin action on plasma BCAA are intact in obesity and T2D remains to be established.

Methods: In studies (STs) of persons with T2D and glucose-tolerant, obese (OB), and lean (LE) controls examined by hyperinsulinemic-euglycemic clamps (insulin infusion 40 mU/min/m2), we studied the effect of insulin for 4-h (ST1) and insulin for 2-h before and after an acute exercise (1-h, VO2max 70%) bout (ST2) and before and after exercise training for 8 weeks (ST3) on plasma BCAA using a BCAA detection kit.

Results: Insulin-stimulated glucose disposal in T2D was 30-50% lower than in OB (ST1-3) and 40-60% lower than in LE (ST1+3), and 20% lower in OB than in LE (ST1), with p<0.05. Exercise training (ST3) increased insulin-stimulated glucose disposal by 30-40% in all groups (all p<0.01). Plasma BCAA was increased in T2D compared with OB and LE (ST1+3), and in OB compared with LE (ST1), in particular, in the insulin-stimulated state (all p<0.05). In line, the ability of insulin to reduce plasma BCAA was significantly attenuated (~30%) in T2D compared with OB and LE both before (ST1+3) and after exercise training (ST3), with p<0.05. Prior acute exercise (ST2) reduced plasma BCAA (10-15%) and attenuated (20-25%) the ability of insulin to further reduce plasma BCAA in both T2D and OB (all p<0.05).

Conclusion: An impaired ability of insulin to clear BCAA from plasma in T2D and, to a lesser extent, in OB may contribute to elevated plasma BCAA and is not improved after exercise training. An acute bout of exercise lowers plasma BCAA but does not augment insulin action on plasma BCAA in T2D or OB.

Disclosure

P.M. Møller: None. R. Kjøbsted: None. M. Houborg Petersen: None. J.F.P. Wojtaszewski: Consultant; Pfizer Inc. Stock/Shareholder; Pfizer Inc., Novo Nordisk A/S. K. Hojlund: None.
271-OR: Automated Hybrid Closed-Loop (AHCL) Systems for the Treatment of Cystic Fibrosis Related Diabetes (CFRD)
Authors: GRANCINI VALERIA , COGLIATI IRENE , GAGLIO ALESSIA , RESI VERONICA , ORSI EMANUELA
Published: June 2024

CFRD is the result of a partial to complete insulin deficiency, leading to hyperglycaemia, loss of muscle mass and catabolic state. Insulin is the only recommended therapy and continuous subcutaneous insulin infusion (CSII) systems are gaining evidence to be the best treatment, leading to a better glycemic control and an improvement in muscle mass. Today, data concerning AHCL systems in CFRD are still lacking.

Aim: to evaluate the effects of insulin therapy optimization with AHCL systems on glycemic control in people with CFRD, already insulin treated (CSII or multiple daily injections - MDI) and already trained with a structured educational program for the management of their therapy (training to MDI/CSII and carbohydrates counting)

Methods: 14 patients (7 F/7 M) agreed to participate in the study and switched to AHCL (7 from a CSII system/7 from MDI). All individuals wore a continuous glucose monitoring (CGM) at enrollment. At baseline and after 6 months patients had a blood sample for biochemistry and data were downloaded from their CGM. A mid-term evaluation of data from CGM was performed 4 weeks after baseline.

Results: We demonstrated a substantial improvement in glucose control at end of trial (HbA1c 7.1±0.9 to 6.2±0.6%, p<0.01; glucose 7.9±3.0 to 6.3±2.8 mmol/L, ns; average glucose - AG 8.7±1.7 to 8.4±1.2 mmol/L, ns; Glucose management indicator - GMI 7.5 to 0.9->6.9±0.5%, p<0.05; time in range - TIR 58.2±22.3->77.0 to 15.0%, p<0.01; coefficient of variation - CV: 35.5±8.0 to 30.3±4.8, ns). The improvement in the CGM parameters was already relevant at the mid-term analysis (AG 8.7±1.7 to 7.9±1.1 mmol/L, ns; GMI 7.5±0.9 to 6.6±0.5%, p<0.01; TIR 58.2±22.3 to 77.6±11.9%, p<0.01; CV: 35.5±8.0 to 30.4±5.2, ns).

AHCL systems lead to a significative improvement in glycemic control in CFRD and, as for type 1 DM, should be proposed as gold standard therapy, considering the pivotal role of an enhanced glycemic management in body composition and, eventually, long term outcomes in this population

Disclosure

V. Grancini: Speaker's Bureau; Vertex Pharmaceuticals Incorporated. I. Cogliati: None. A. Gaglio: Consultant; Boehringer-Ingelheim. V. Resi: None. E. Orsi: Speaker's Bureau; Sanofi, Lilly Diabetes, AstraZeneca.
287-OR: Traf6 Directs a Noncanonical Role for Innate Immune Signaling in Pancreatic ß-Cells
Authors: LEVI D ANCONA ELENA , ZHU JIE , WALKER EMILY M. , SIDARALA VAIBHAV , SOLEIMANPOUR SCOTT
Published: June 2024

Innate immune signaling links diverse intracellular pathways in eukaryotic cells, from inflammation to metabolism as well as host defense. In immune cells, mitochondria act as docking sites for innate immune signaling pathways, including those downstream of toll-like receptors (TLRs), whose activation by inflammatory signals contribute to mitochondrial damage. The importance of innate immune signaling in β-cells, however, has been vexing. Deletion of TLRs enhances β-cell mass following diet-induced obesity (DIO), while loss of downstream TLR signaling adaptors impairs β-cell function. Moreover, the regulatory relationships between innate immune signaling and mitochondrial quality control responses to mitochondrial damage are unclear. Here, we observe that the E3 ubiquitin ligase Traf6, which is central to the transmission of TLR-dependent innate immune signals to induce inflammation, surprisingly promotes glucose homeostasis following metainflammatory stress. We generated β-cell specific Traf6 knockout mice (Traf6Δβ), which were euglycemic at baseline, yet developed glucose intolerance and decreased glucose-stimulated insulin secretion following DIO. Islets from HFD-fed Traf6Δβ mice exhibit increased mitochondrial mass, abnormal mitochondrial ultrastructure, and impaired mitochondrial respiration and mitophagy flux. We also observed that Traf6 translocates to the mitochondria during metabolic stress. Interestingly, metabolic defects in Traf6Δβ mice were completely rescued by concomitant deletion of the mitophagy initiator Parkin, indicating a novel and unexpected importance for Traf6 to tune β-cell mitochondrial quality control. Thus, Traf6 links β-cell stress responses with control of mitophagy, revealing a non-canonical role for innate immune signaling in mitochondrial health.

Disclosure

E. Levi D Ancona: None. J. Zhu: None. E.M. Walker: None. V. Sidarala: None. S. Soleimanpour: Advisory Panel; Novo Nordisk. Research Support; Ono Pharmaceutical Co., Ltd.

Funding

University of Michigan Research Training in Experimental Immunology T32-AI007413 University of Michigan Career Training in the Biology of Aging T32-AG000114
305-OR: Adipose Tissue Perilipin 1 Insulin Responsiveness in Obesity
Authors: LYTLE KELLI , SONG YILIN , DAMLA KARAKAPLAN NESRIN , JENSEN MICHAEL D.
Published: June 2024

Adipose tissue (AT) lipolysis is dysregulated in obesity and type 2 diabetes, failing to respond appropriately to the lipolytic suppressive effects of insulin resulting in high free fatty acid (FFA) efflux from AT. Perilipin 1 (PLIN1) is an intracellular adipocyte protein and the primary lipid droplet coat protein. Phosphorylation of PLIN1 is purported to activate and provide access to the lipid droplet surface for lipolytic enzymes. Conversely, dephosphorylation in response to insulin protects the lipid droplet. To test the hypothesis that PLIN1 phosphorylation status is dysregulated in obesity, we recruited 8 lean and 20 volunteers with obesity who underwent a two-step hyperinsulinemic-euglycemic clamp with a [U-13C]-palmitate tracer to quantify FFA kinetics and their AT response to insulin with regards to FFA release (IC50 FFA), we performed abdominal (UBSQ) and thigh subcutaneous adipose tissue biopsies at baseline and at each clamp step. We measured adipocyte cell size, total PLIN1 protein concentrations and phospho-PLIN1-Ser522 in adipose samples. Intra-individual total PLIN1 protein content/1000 adipocytes did not change in either thigh or UBSQ at either baseline or during each clamp step. Total PLIN1/1000 cells was positively correlated with adipocyte size in UBSQ (ρ = 0.85, p <0.001) and thigh (ρ = 0.86, p <0.001). There was a step wise reduction in PLIN Phosphorylation in both depots in response to each insulin clamp step from baseline (UBSQ and thigh, baseline vs. 1st step clamp vs. 2nd step clamp, all p < 0.01) There was no difference between the ratio of phosphorylated PLIN to total PLIN (pPLIN/PLIN) between UBSQ and thigh samples. IC50 FFA was correlated Total PLIN1/1000 cells in UBSQ (ρ = 0.46, p = 0.02), but not in thigh adipose. After correcting for adipocyte size, the relationship between IC50 FFA and Total PLIN1 was no longer significant.

In conclusion, PLIN1 content or responsiveness doesn’t appear to be defective in adults with obesity that have reduced ability of insulin to suppress systemic FFA release.

Disclosure

K. Lytle: None. Y. Song: None. N. Karakaplan: None. M.D. Jensen: Advisory Panel; Biohaven.
306-OR: Diet-Induced Hyperlipidation of Adiponectin Contributes to Adiponectin Dysfunction
Authors: SMITH MAIA , HADLEY JASON , RYU JIYOON , MORALES DESIRAE , DONG LILY Q.
Published: June 2024

With the noteworthy linear rise in the prevalence of obesity in the United States, adiponectin has swiftly garnered attention as a hormone protein of interest owing to its anti-diabetic, anti-insulin-resistant, and anti-inflammatory properties. Protein S-palmitoylation is a post-translational modification that has been implicated in a wide variety of diseases including cancer, neurodegenerative disorders, and metabolic disorders, supporting its critical role in regulating protein transport, localization, and cell survivability. As serum Adiponectin exists as multimers, the distribution of which differs under disease pathology and by sex, our current study seeks to elucidate the underlying mechanism regulating adiponectin’s cellular localization, function, and stability. Utilizing acyl resin-assisted capture, our current study indicates that Adiponectin undergoes protein S-palmitoylation. Intriguingly, male mice fed a high-fat diet (HFD) exhibited an 18-fold increase in protein S-palmitoylation in their adipose tissue compared to normal chow (NC) diet-fed controls. However, no significant difference was observed in the levels of adiponectin palmitoylation between female mice on HFD compared to NC controls. Similarly, palmitoylation of adiponectin was observed in the adipose tissues of men with a BMI classified as obese and the modification was undetected in lean individuals. Collectively, our findings suggest that adiponectin undergoes protein S-palmitoylation and that this modification is associated with obesity in males. Identifying protein S-palmitoylation of adiponectin as a post-translational modification and a key regulatory mechanism in the expression and function of this beneficial hormone could unveil a novel mechanism contributing to the obesity-induced down-regulation of adiponectin - a causal factor for insulin resistance and related metabolic disorders.

Disclosure

M. Smith: None. J. Hadley: None. J. Ryu: None. D. Morales: None. L.Q. Dong: None.

Funding

National Institutes of Health (R01DK134637-01A1)
316-OR: Interoception Predicts Impaired Awareness of Hypoglycemia (IAH) in Adults with Type 1 Diabetes (T1D)
Authors: MATUS AUSTIN M. , RIEGEL BARBARA , RICKELS MICHAEL R.
Published: June 2024

Introduction: Recurrent hypoglycemia attenuates hypoglycemia symptoms, making symptom detection more challenging and leading to IAH. However, some with T1D maintain hypoglycemia awareness despite symptom attenuation. Interoception, or the ability to sense, interpret, and integrate internal somatic signals, may contribute to maintenance of hypoglycemia awareness. We sought to assess the association between interoception and IAH in adults with T1D.

Methods: Adults (n = 154, 20% Black, 64% female) with T1D (mean ±SD age: 40 ±16 years, T1D duration: 23 ±14 years) completed the Clarke questionnaire (8-items scored 0-7; ≥ 4 indicates IAH), Gold Score (1 item scored 0-7; ≥ 4 indicates IAH), HypoA-Q Impaired Awareness scale (5-items scored 0-20; ≥ 12 indicates IAH) and Multidimensional Assessment of Interoceptive Awareness Version 2 (MAIA-2; 8 scales measuring 5 dimensions of body awareness; each scale scored 0-5; higher indicates greater interoceptive awareness). IAH was defined as ≥ 2 positive IAH measures. Logistic regression was performed, and odds ratios (OR) with 95% confidence intervals (CI) were calculated to assess the association between MAIA-2 scales and IAH controlling for disease duration, age, and recurrent severe hypoglycemia.

Results: Seventeen percent of participants (n = 26) screened positive for IAH. Logistic regression revealed significant relationships between IAH and disease duration, recurrent severe hypoglycemia, and 2 MAIA-2 scales (“Attention Regulation” & “Not Worrying”). Each 1-point increase in “Attention Regulation” was associated with 72% decreased odds of IAH (OR: 0.28, CI: 0.12 - 0.66). Each 1-point increase in “Not Worrying” was associated with 87% increased odds of IAH (OR: 1.87, CI: 1.01 - 3.46).

Conclusion: Those with T1D and IAH may have reduced ability to sustain and control attention to body sensations and less worry with sensations of discomfort. Research to better understand the relationship between interoception and IAH is warranted.

Disclosure

A.M. Matus: None. B. Riegel: None. M.R. Rickels: Consultant; Vertex Pharmaceuticals Incorporated, Sernova, Corp. Research Support; Dompé.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (U01DK135120)National Institute of Nursing Research (F31NR020137)
330-OR: Narrow Variation of Glucose Inflection Points (IPs) during Progression to Type 1 Diabetes (T1D) Stratified by Demographic and Genetic Differences in Autoantibody-Positive (Ab+) Individuals
Authors: ISMAIL HEBA M. , CUTHBERTSON DAVID D. , JACOBSEN LAURA M. , NATHAN BRANDON M. , SIMS EMILY K. , REDONDO MARIA J. , SOSENKO JAY
Published: June 2024

Introduction and Objective: Evidence suggests an IP occurs 1 to 2 years before the diagnosis of T1D, after which accelerated metabolic decline occurs. We assessed whether IPs vary when stratified by age, obesity, sex, and presence of both HLA DR3 and DR4 vs. neither.

Methods: TrialNet Pathway to Prevention Ab+ participants (n=596) who had OGTTs between 0.5 years and 3 years before diagnosis were studied. Mixed-effects modeling was used to estimate AUC glucose and AUC C-peptide IPs with 95% confidence intervals (CIs), and to compare IP times before diagnosis. Since AUC C-peptide IPs had wide CIs, only AUC glucose IPs are shown.

Results: The overall AUC glucose IP was 1.39 years before diagnosis. Those older or obese had IPs significantly earlier; however, the difference by age groups was only ~0.2 years and that by obesity 0.1 year (table). The difference between those positive for both DR3 and DR4 was small while males and females did not differ. IPs were consistently within 1.3 and 1.5 years before diagnosis.

Conclusion: Older and more obese individuals have earlier AUC glucose IPs prior to diagnosis. However, the timing of the IPs differs only by a few months between populations that have demographic or genetic differences. This suggests common pathologic progression patterns to T1D despite variations in characteristics.

Disclosure

H.M. Ismail: Consultant; Sanofi, Rise Therapeutics. D.D. Cuthbertson: None. L.M. Jacobsen: Advisory Panel; Insulet Corporation. B.M. Nathan: None. E.K. Sims: Consultant; Sanofi. Board Member; American Diabetes Association. Other Relationship; American Diabetes Association, Medscape. Consultant; DRI. M.J. Redondo: None. J. Sosenko: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases
331-OR: Clinical and Immunologic Features Differ in Children at Type 1 Diabetes Onset by Ethnicity
Authors: KARAKUS KAGAN E. , FLEURY THEODORE , BASCHAL ERIN E. , MCDANIEL KRISTEN , CHOI HYELIN , LANGARICA VANESSA , YU LIPING , SIMMONS KIMBER M. , MICHELS AARON W.
Published: June 2024

Introduction & Objective: Type 1 diabetes (T1D) incidence continues to increase in children, especially among Hispanic Whites (HW). We investigated the clinical and immunologic characteristics of HW and Non-Hispanic White (NHW) children that presented at T1D diagnosis over the last two decades to the Barbara Davis Center for Diabetes.

Methods: In this single-center, observational study, children who were diagnosed with T1D (<20 years old) and tested for islet autoantibodies within 1 year of diagnosis were included and divided into two groups by ethnicity.

Results: Of 1256 children, 401 HW children presented with a younger age at T1D onset, and more DKA compared to NHW children (n=855) (Table 1). There was no difference in sex, HbA1c levels, or the number and prevalence of islet autoantibodies between the two cohorts. A subset of our cohort was HLA-DR-DQ typed as specific alleles confer strong genetic risk for T1D (e.g., HLA-DR4 and DQ8). Among 556 HLA-typed children, HW children had a significantly higher prevalence of the DR4-DQ8 haplotype compared to NHW children (75.8% vs. 59.0%, p=0.002). Moreover, DR3-DQ2 was lower in HW compared to NHW T1D children (29.8% vs. 47.1%, p=0.001).

Conclusion: Hispanic White children developing T1D have a strikingly high prevalence of HLA DR4-DQ8, which can be utilized in screening for T1D risk to lessen DKA and potentially prevent diabetes onset.

Disclosure

K.E. Karakus: None. T. Fleury: None. E.E. Baschal: None. K. McDaniel: None. H. Choi: None. V. Langarica: None. L. Yu: None. K.M. Simmons: Advisory Panel; Provention Bio, Inc. Consultant; Provention Bio, Inc. Research Support; Provention Bio, Inc., Novartis AG. Consultant; Medtronic. A.W. Michels: Stock/Shareholder; IM Therapeutics. Advisory Panel; Provention Bio, Inc.
352-OR: Selective Loss of the Spliced Form of Xbp1 Causes Early-Onset Diabetes in Male but Not Female Mice
Authors: FU LING , JANG CHELSEA , PENG YUNQIAN , XIONG QIUTANG , WANG ZHAO V. , DENG YINGFENG
Published: June 2024

Endoplasmic reticulum (ER) stress is associated with progressive deterioration in pancreatic islet beta cell function, a hallmark of type 2 diabetes. Adaptive unfolded protein response (UPR) is critical for mature beta cells to resolve ER stress due to aging and obesity. X-box binding protein 1 (Xbp1) is an essential, evolutionarily conserved transducer of the UPR. In response to ER stress, the full-length Xbp1 mRNA undergoes noncanonical splicing catalyzed by Ire1, which leads to a frame-shift and the generation of spliced Xbp1 (Xbp1s), a potent transcription factor. Recently, Xbp1 expression was shown to be increased in less mature beta cells from young individuals (<30 y) compared to beta cells from middle-aged adults (30-59 y). The physiological relevance of Xbp1s activation in the early development of the pancreas remains elusive due to the lack of a proper in vivo model; the constitutive Xbp1 KO model is embryonic lethal in rodents, whereas the Cre-loxP-mediated tissue selective Xbp1 KO model ablates both full-length and spliced-form of Xbp1. To fulfill the knowledge gap, we generated a knock-in mutant form of Xbp1 to ablate only the spliced form of Xbp1. We found that homozygous Xbp1s KO mice are born at a rate below the Mendelian ratio, indicating that selective loss of Xbp1s is not developmentally lethal in mammals despite lowering the rate of live births. Strikingly, Xbp1s ablation leads to abnormal islet architecture in both males and females, but only male mice exhibit hyperglycemia and glucose intolerance due to insulin insufficiency. The female Xbp1s KO mice maintain normoglycemia and glucose tolerance due to enhanced insulin sensitivity. Our findings suggest that Xbp1s is essential for the early development of pancreatic islets and beta cell mass, and there are sex-specific mechanisms contributing to adulthood diabetes under Xbp1s deficiency.

Disclosure

L. Fu: None. C. Jang: None. Y. Peng: None. Q. Xiong: None. Z.V. Wang: None. Y. Deng: None.

Funding

American Diabetes Association (1-19-JDF-082)
372-P: Effect of Whey Protein Consumption on Hypoglycemia Risk in Type 1 Diabetes Patients Fasting during Ramadan—A Randomized Crossover Trial
Authors: ALAMOUDI REEM , ALOTAIBI MOHAMMED N. , RADI SUHAIB , ALASSIRI MISHARY A. , ALSHARIF SARAH S. , BASULAYMAN DALIA S. , ALAHDAL LAMA , ALJUIAD FETOON M. , KHAN MUHAMMAD A. , ZARIF HAWAZEN A.
Published: June 2024

Many patients with type1 diabetes (T1DM) choose to fast during Ramadan despite the risks involved.

Objective: To examine the effectiveness of whey protein consumption with Suhoor (predawn meal) on the number of hypoglycemic events and time spent in hypoglycemia in T1DM during fasting Ramadan.

Methods: Prospective randomized cross-over design. T1DM planning to fast Ramadan recruited. Data collected using pre/post-Ramadan questionnaires, and FCGM - Freestyle Libre.

Results: 41 T1DM patients were randomized to whey protein consumption with Suhoor for a week then crossed over to Suhoor with no whey protein the second week. 33 were on MDI and 8 CSII. Mean age 24 ±4.2 years (range 18-32), DM duration 14.1 ±7.3 years, 22 (53.7%) female. Pre-Ramadan: A1c 7.6 ±1.07 (5.8-10.3). 19 (46.3 %) reported frequent hypoglycemia (≥3/week), and 3 (7.3 %) reported hypoglycemia unawareness. DaR risk score 9 ±2.4, 5 (12.2%) moderate risk and 36 (87.8%) high risk. During the whey protein vs. no whey protein week mean number of days breaking of fast with main cause being hypoglycemia was 0.73 ±1.1 vs 1.15 ±1.4, p=0.004. No severe, DKA, or hospital admission reported during either regimen. FCGM detected mean hypoglycemia events per patient per week of whey protein vs none regimen was 0.7 vs 1.1, p=0.07; for post-Suhoor (3-6am), and 0.3 vs 0.6, p=0.05 for pre-Iftar (4-6pm). AGP report: GMI 7.5 ±1.5 vs 7.4 ±1.5, p=0.7, Time in target (70-180 mg/dl) 46.4 ±17.3% vs49.4 ±17.3%, p=0.1, Time below target (<70mg/dl) 5.1 ±5.6% vs 5.9 ±5.3%, p=0.2, Time above target (>180mg/dl) 48.5 ±18.6% vs 44.7 ±18.6%, p=0.09, and Glucose variability 39.8 ±8.04% vs 40.8 ±8%, p=0.3. 51.2% of patients thought whey protein consumption with Suhoor was beneficial, and 68.4% would use it in future Ramadan.

Conclusion: Adding whey protein to Suhoor meal reduced the need to break fasting but did not affect TBR or hypoglycemic events. Larger studies needed to study effectiveness of this approach.

ClinicalTrials.gov registered

Disclosure

R. Alamoudi: None. M.N. Alotaibi: None. S. Radi: None. M.A. Alassiri: None. S.S. Alsharif: None. D.S. Basulayman: None. L. Alahdal: None. F.M. Aljuiad: None. M.A. Khan: None. H.A. Zarif: Advisory Panel; Abbott, Medtronic, Novo Nordisk.
374-P: Impact of Sulfonylurea (SU) Use on Hypoglycemia and Continuous Glucose Monitoring (CGM) Metrics after 16 Weeks of iGlarLixi in Insulin-Naïve Adults with Type 2 Diabetes (T2D) and Mean A1C >10%
Authors: RATZKI-LEEWING ALEXANDRIA , DEX TERRY A. , MENEGHINI LUIGI , RODRIGUES AMÉLIE , FRIAS JUAN P.
Published: June 2024

Introduction & Objective: In a 16-week open-label trial (NCT05114590) of insulin naïve adults (≥ 18 yrs; 70.2% Hispanic/Latino) with T2D (mean A1c >10%) suboptimally controlled on ≥2 oral antihyperglycemic drugs (OADs) ± glucagon-like peptide-1 receptor agonist (GLP-1 RA), iGlarLixi increased TIR by 26.2% (P<0.001), as measured by blinded CGM. We report a post-hoc analysis of SU users vs non-SU users.

Methods: We quantified on-treatment hypoglycemia incidence and mean changes in CGM and glucose control endpoints from baseline to Week 16 in SU vs non-SU users (Table).

Results: In total 124 participants were enrolled, 91 (73%) used a background SU (76% self-identified as Hispanic/Latino). Total hypoglycemia incidence was low and similar for SU vs non-SU users with no reported severe events. Nocturnal hypoglycemia was only reported by SU users (Table). Mean improvements in CGM (including TIR) and glucose control endpoints were numerically greater in non-SU vs SU users (Table).

Conclusion: In people with T2D suboptimally controlled on ≥2 OADs ± GLP-1 RA, iGlarLixi for 16 weeks improved glycemic control. Compared to SU users, non-SU users achieved greater improvements in glucose control without nocturnal hypoglycemia. To safely optimize T2D diabetes management, iGlarLixi may be best prescribed without a concurrent SU.

Disclosure

A. Ratzki-Leewing: Research Support; Sanofi. Advisory Panel; Dexcom, Inc. Consultant; Abbott. Advisory Panel; Sanofi-Aventis U.S. Other Relationship; American Diabetes Association. Consultant; Novo Nordisk, Eli Lilly and Company. T.A. Dex: Stock/Shareholder; Pfizer Inc. Employee; Sanofi. Stock/Shareholder; Viatris Inc., Teva Pharmaceutical Industries Ltd. L. Meneghini: Employee; Sanofi. A. Rodrigues: Consultant; Sanofi. J.P. Frias: Research Support; Akero Therapeutics, Inc. Consultant; Akero Therapeutics, Inc. Research Support; Altimmune Inc. Consultant; Altimmune Inc. Research Support; Boehringer-Ingelheim. Consultant; Boehringer-Ingelheim. Research Support; 89bio, Inc. Consultant; 89bio, Inc. Research Support; Eli Lilly and Company. Advisory Panel; Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. Research Support; Merck & Co., Inc. Consultant; Merck & Co., Inc. Research Support; Novartis Pharmaceuticals Corporation. Consultant; Novartis Pharmaceuticals Corporation, Novo Nordisk. Board Member; Novo Nordisk. Research Support; Novo Nordisk, Pfizer Inc. Consultant; Pfizer Inc. Advisory Panel; Sanofi. Speaker's Bureau; Sanofi. Research Support; Sanofi. Stock/Shareholder; Biomea Fusion, Inc. Employee; Biomea Fusion, Inc.

Funding

Sanofi US
388-P: Reproducibility of Urinary Albumin-to-Creatinine Ratio and Its Association with Prediabetes Risk in Healthy Adults with Parental Type 2 Diabetes
Authors: EVERETT MATTHEW , ASUZU PEACE , WAN JIM Y. , DAGOGO-JACK SAMUEL
Published: June 2024

Introduction & Objective: We investigated the reproducibility of consecutive uACR measurements and association with progression to prediabetes among African American (AA) and European American (EA) offspring of parents with T2D.

Methods: Normoglycemic participants in the Pathobiology of Prediabetes in a Biracial Cohort study were followed quarterly for 5.5 years (mean 2.62 years) for the primary outcome of incident prediabetes. Baseline and follow-up assessments included oral glucose tolerance test, anthropometry, uACR, and lipid profile. Baseline and annual uACR data from study participants were analyzed. We then assessed the correlation of baseline and repeated annual uACR measurements and association with incident prediabetes.

Results: Baseline uACR levels from 308 participants (167 AA, 141 EA; mean age 45.1 ± 10.3 yr; BMI 30.4 ± 7.34 kg/m2) ranged from 1-29 mg/g; were similar in AA vs. EA participants (6.40 mg/g ± 4.80 vs. 6.80 ± 5.40 mg/g, P=0.52); and higher in women than men (7.30 mg/g ± 5.30 vs. 4.60 ± 3.90 mg/g, P<0.0001). uACR levels were analyzed for the subsequent year (Year 2, N=170). Baseline uACR values were significantly correlated with Year 2 (rho=0.412, P<0.0001) and Year 3 values (rho=0.241, P=0.0023). The mean change in uACR was 2.69 + 19.49 mg/g (41.1%) (Year 2-Baseline) and 1.11 + 15.1 (17.0%) (Year 3-Baseline). During 5.5 years of follow-up, 104 participants developed prediabetes and 204 maintained normoglycemia. Baseline uACR was significantly associated with the risk of progression to prediabetes (rho=0.186, P=0.0011), as was Year 2 uACR (rho=0.247, P=0.0013).

Conclusions: In our study of normoglycemic, normoalbuminuric adults with parental diabetes, uACR in random urine specimens during three consecutive years were significantly correlated, though individual values varied by 17%-41%. Furthermore, baseline uACR and Year 2 were significantly associated with 5-year progression to prediabetes.

Disclosure

M. Everett: None. P. Asuzu: None. J.Y. Wan: None. S. Dagogo-Jack: Consultant; Merck Sharp & Dohme Corp., Medtronic, Bayer Inc. Stock/Shareholder; Aerami.
39-PUB: A Comprehensive Tool for Analyzing Continuous Glucose Monitoring Data
Authors: ZHANG XIAOHUA D. , ZHANG RENA D. , KUEI LIN YU , FISHER SIMON J.
Published: June 2024

Introduction & Objective: While existing software packages are available for Continuous Glucose Monitoring (CGM) data analysis, they lack the incorporation of novel CGM-based metrics, specifically focusing on the dynamics of health status, Shannon entropy, and fractal analysis.

Methods: We crafted R functions to execute the computation of essential parameters such as summary statistics, time within/above/below designated glucose thresholds, and glycemic variability indices. Moreover, we introduced novel metrics that capture the dynamics of health status, as well as complexity and fractality analysis. We implemented artificial intelligence methods to provide an integrated approach to diabetes care, incorporating both newly developed and existing CGM-based metrics. To facilitate widespread accessibility, we wrapped these functions into an R package, showcased its utility in analyzing CGM studies involving subjects with Type 1 diabetes and will offer it freely to the public for utilization.

Results: An R package was developed to cover a comprehensive analysis from quality control, exploratory analysis, regular statistical analysis and machine learning modeling on CGM studies. This package has more functionalities than any one of existing CGM analysis tools like GlyCulator, EasyGV (Easy Glycemic Variability), CGM-GUIDE© (Continuous Glucose Monitoring Graphical User Interface for Diabetes Evaluation), GVAP (Glycemic Variability Analyzer Program), Tidepool, CGManalyzer, cgmanalysis, GLU, CGMStatsAnalyser, iglu, rGV, and cgmquantify.

Conclusion: By addressing the limitations of current software programs and introducing advanced features, this software holds the potential to contribute significantly to the field of CGM data analysis and improve the management of diabetes.

Disclosure

X.D. Zhang: None. R.D. Zhang: None. Y. Lin: None. S.J. Fisher: None.

Funding

National Institutes of Health (UL1TR001998); National Institutes of Health (U01DK135111); National Institutes of Health (P30 DK020579); National Institutes of Health (OT2HL161847)
396-P: Consequences of Knockout of the Histone Demethylase KDM6B from Myeloid Cells Are Context-Dependent in Diabetic Kidney Disease
Authors: HONG LISA Y.Q. , KAUR HARMANDEEP , TIN TRAN DUC , LIU YOUAN , NAGARJUN BATCHU SRI , ADVANI ANDREW
Published: June 2024

Introduction & Objective: Epigenetic processes and inflammation have each emerged as key players in the development of diabetic kidney disease. Here, we compared the consequences of knockout of the epigenetic enzyme and histone demethylase, KDM6B from myeloid cells in diabetic mice and mice with obstructive uropathy.

Methods: Myeloid cell KDM6B knockout (KDM6BMyeloidKO) mice were generated by breeding Kdm6bfl/fl mice with LysMCre+mice and compared to LysMCre+ controls (KDM6BCtrl). M-CSF levels were measured by cytokine array of media conditioned by bone marrow-derived macrophages (BMDMs). Mice were studied either 12 weeks after diabetes induction with streptozotocin (STZ) or 1 week after unilateral ureteral obstruction (UUO) surgery. Kidney injury and inflammation were assessed by qRT-PCR.

Results: Basal M-CSF secretion was reduced in KDM6BMyeloidKO BMDMs in comparison to KDM6BCtrl BMDMs (KDM6BCtrl 62pg/mL, KDM6BMyeloidKO 4pg/mL, p<0.01), suggestive of a shift towards M1-like polarization. Kidney injury (as assessed by Havcr1 mRNA) was increased ~90-fold in STZ-diabetic mice and ~615-fold in UUO mice. Similarly, kidney inflammation (as assessed by Ccl2 mRNA) was increased ~9-fold in STZ-diabetic mice and ~72-fold in UUO mice. Blood glucose levels were equally elevated in STZ-diabetic KDM6BCtrl and KDM6BMyeloidKO mice. Knockout of KDM6B from myeloid cells attenuated Havcr1 and Ccl2 upregulation in UUO mice but not in STZ-diabetic mice.

Conclusion: Kidney inflammation in STZ-diabetic mice is typically mild, and myeloid cell involvement is primarily through M1-like responses that are independent of the histone demethylase KDM6B. In contrast, myeloid KDM6B contributes to the more advanced inflammation and injury associated with obstructive uropathy. These findings underscore the importance of the physiological context in determining the actions of ostensibly ‘epigenetic enzymes’ in kidney disease, including that caused by diabetes.

Disclosure

L.Y.Q. Hong: None. H. Kaur: None. D. Tran: None. Y. Liu: None. S. Batchu: None. A. Advani: None.