bluuebunny/crossref_metadata_2025 huggingface dataset:
218-LB: Younger Veterans with Adult-Onset Diabetes Who Have High Type 1 Diabetes (T1D) Genetic Risk Are Disproportionately of Minority Ancestry and Have Features Typical of T1D but Are Often Unrecognized—A Health Disparity
Authors: YANG PETER K. , SUN YAN , RAGHAVAN SRIDHARAN , LITKOWSKI ELIZABETH M. , LEGVOLD BRIAN T. , RHEE MARY K. , VUJKOVIC MARIJANA , REAVEN PETER , LEONG AARON , PHILLIPS LAWRENCE S.
Published: June 2023

Diabetes in Veterans is usually presumed to be T2D because T1D precludes enlistment, but T1D may present in adults; how T1D genetic risk impacts different racial/ethnic groups is unknown. To assess the contributions of T1D genetic risk, we examined 109,954 Veterans in the VA's Million Veteran Program (MVP), using a 30 SNP T1D genetic risk score (GRS) for those with European, Hispanic, and Asian ancestry, and a separate 7-SNP GRS for those of African ancestry. High T1D genetic risk (GRS ≥90th percentile) was characterized according to age at diabetes onset (20-39, 40-59, and 60+ years). High T1D genetic risk was more common with the earliest onset group (13.2%, 10.0% and 9.0%, respectively), and that group had the highest proportion of minority ancestry (47%, 37%, and 25%), all p<0.001. The three high T1D risk groups had similar follow-up (13, 12, and 11 years), GAD antibodies if tested (39%, 41%, and 40%), and low C-peptide levels if measured (36%, 23%, and 33%). However, typical T1D features were more common with earlier onset: use of insulin (80%, 63%, and 43%), time to insulin (0.2, 2.4, and 1.4 yr), diabetic ketoacidosis (11%, 3%, and 0.8%), and severe hypoglycemia prompting an ED visit (10%, 5%, and 3%), all p<0.001. While earlier age of onset groups had more use of T1D ICD codes (50%, 25% and 13%), testing for GAD antibodies (18%, 4%, and 2%), and testing for C-peptide (24%, 9%, and 3%), respectively, all p<0.001, less than half of any group had diagnostic testing for T1D. Conclusions: Increased T1D genetic risk is associated with earlier age of diabetes onset in adults and increased prevalence of typical T1D characteristics, but similar GAD antibodies and C-peptide levels. Since individuals with high T1D risk and early diabetes onset are disproportionately of minority ancestry, health policies aimed to improve T1D recognition and management are needed to remedy this health disparity.

Disclosure

P. K. Yang: None. L. S. Phillips: Other Relationship; Diasyst Inc., Research Support; Abbott Diabetes, Janssen Pharmaceuticals, Inc., Pfizer Inc., Kowa Pharmaceuticals America, Inc., GlaxoSmithKline plc. Y. Sun: None. S. Raghavan: None. E. M. Litkowski: None. B. T. Legvold: None. M. K. Rhee: Research Support; Kowa Research Institute, Inc. M. Vujkovic: None. P. Reaven: Research Support; Dexcom, Inc. A. Leong: Other Relationship; Merck & Co., Inc.

Funding

National Institutes of Health (U01DK098245, P30DK111024, AI156161, DK127083); U.S. Department of Veterans Affairs (I01-CX001025, I01-BX005831, I01-BX003340, CX001899, I01CX001737)
220-OR: First-in-Human Study of a Pharmacological Duodenal Exclusion Therapy Mimics a Roux-en-Y Gastric Bypass Biomarker Signature
Authors: FINEMAN MARK , BRYANT CHRISTINE , COLBERT KEVIN , JOZEFIAK THOMAS H. , PETERSEN JOHN S. , VORA JITEN , RAYNER CHRISTOPHER K. , NIMGAONKAR ASHISH
Published: June 2023

To address the need for non-invasive alternatives to metabolic surgery or duodenal exclusion devices for the management of type 2 diabetes (T2D) and obesity, we designed an orally administered therapeutic polymer, GLY-200, that binds to and enhances the barrier function of mucus in the gastrointestinal tract.

Methods: A Phase 1, randomized, double-blind, placebo (PBO)-controlled, multiple ascending dose study was conducted in healthy volunteers. Four cohorts (N=32, 19-61 yrs, BMI 26.2 ± 3.20 kg/m2) received 5 days of BID or TID dosing (total daily dose between 2.0 g and 6.0 g GLY-200 or PBO). Assessments included safety and tolerability (primary) and exploratory pharmacodynamics (PD), including serum glucose, insulin, bile acids, and gut hormones.

Results: No safety signals were observed; tolerability signals were limited to mild to moderate dose-dependent gastrointestinal events. On Day 5, reductions in glucose and insulin and increases in bile acids, GLP-1, PYY, and glicentin were observed following a non-standardized meal in subjects receiving 2.0 g BID GLY-200 (N=9) vs PBO (N=8).

Conclusions: GLY-200 is safe and generally well tolerated. PD results mimic the biomarker signature observed following RYGB and duodenal exclusion devices, indicating a pharmacological effect in the proximal small intestine.

Disclosure

M.Fineman: Employee; Glyscend Inc., Stock/Shareholder; Glyscend Inc. C.Bryant: Employee; Glyscend Inc. K.Colbert: Consultant; LifeSprout, Employee; Glyscend Inc. T.H.Jozefiak: Employee; Glyscend Inc., Stock/Shareholder; Glycologix, LLC. J.S.Petersen: None. J.Vora: Other Relationship; Avotres Inc., Glyscend Inc. C.K.Rayner: Advisory Panel; Glyscend Inc. A.Nimgaonkar: Employee; Glyscend Inc.
221-LB: Identification of PAM as Novel Monogenic Diabetes Gene
Authors: FEINER JAMES , PERROT NICOLAS , CHONG MICHAEL , LALI RICKY , MORTON ROBERT , MOHAMMADI-SHEMIRANI PEDRUM , YUSUF SALIM , GERSTEIN HERTZEL C. , PARE GUILLAUME , PIGEYRE MARIE
Published: June 2023

Background/Objectives: Various biological mechanisms involved in type 2 diabetes (T2D) have been unveiled through converging evidence in common variants from Genome wide association studies (GWAS) and rare or low frequency variants (RV/LFV) from Exome wide association studies (EXWAS). We hypothesized that a two-pronged approach interrogating both RV/LFV and common variants could yield identification of new pathways involved in T2D.

Methods: Protein-altering RV/LFV burden was tested for T2D association in an EXWAS of 11,731 cases and 149,613 controls in the UKBiobank. Significant encoded proteins were then investigated using 2-sample Mendelian randomization for causal association with T2D and related variables. Protein quantitative trait loci were estimated in the Prospective Urban and Rural Epidemiological study (N=11,020) and tested against GWAS-summary statistics of T2D and related traits from 10 consortia.

Results: At the EXWAS significance threshold (P=0.05/19,589=2.55×10-6), we identified loss-of-function RV/LFV in GCK and PAM, which encode the proteins glucokinase and peptidylgycine α-amidating monooxygenase respectively, to be associated with T2D risk. Deleterious mutations in the PAM gene were associated with an 29% increase in T2D risk (OR per RV/LFV=1.29; 95%CI=1.17-1.43; P=7.17×10-7). This association was driven by a low frequency variant, rs78408340-G present in 2.6% of T2D cases and only in 1.8% of controls. MR analyses confirmed that 1 SD decrease in PAM circulating levels was consistently associated with increased T2D risk (OR=1.16; 95%CI=1.14-1.19; P=9.54×10-52) and HbA1c (%) (β=0.0047; 95%CI= 0.00051-0.0090; P=0.028), and decreased post-prandial insulin (mU/L) secretion (β=-0.060; 95% CI=-0.083(-)-0.036; P=8.32×10-7).

Conclusion: We identified PAM variants as a novel cause of monogenic diabetes and demonstrated a strong causal effect of circulating PAM levels on T2D risk and post-prandial insulin secretion. This supports further investigation of PAM as a therapeutic T2D target.

Disclosure

J. Feiner: None. N. Perrot: None. M. Chong: Research Support; Bayer Inc. R. Lali: None. R. Morton: None. P. Mohammadi-Shemirani: None. S. Yusuf: None. H. C. Gerstein: Advisory Panel; Abbott Diagnostics, Eli Lilly and Company, Sanofi. Research Support; Novo Nordisk. Advisory Panel; Novo Nordisk. Research Support; Eli Lilly and Company, Sanofi. Advisory Panel; Kowa Company, Ltd., Hanmi Pharm. Co., Ltd. Other Relationship; Zuellig Pharma Holdings Pte. Ltd., DKSH, AstraZeneca. G. Pare: Research Support; Bayer Inc. Advisory Panel; Bayer Inc., Amgen Inc., Novartis AG. M. Pigeyre: None.

Funding

Bayer; Canadian Institutes of Health Research
223-OR: Identification of Novel Therapies for Monogenic Diabetes Using Connectivity Map (CMap)
Authors: KREIENKAMP RAYMOND J. , BRYAN CHRISTOPHER , FLOREZ JOSE C. , UDLER MIRIAM
Published: June 2023

Monogenic diabetes is an underdiagnosed form of diabetes that is caused by DNA variation of strong effect in a single gene. While it is an exciting area for targeted drug development, as some forms of monogenic diabetes can be treated with gene-specific therapies, there are currently few targeted therapies available. Additionally, existing treatments are not able to cure or modify the underlying disease. Therefore, to identify novel therapies, we leveraged CMap, a data resource developed at the Broad Institute that contains over one million gene expression signatures from treatment of cell types with perturbagens including drugs, bioactive small molecules, gene overexpression, and gene knockdown reagents. We analyzed connectivity, or the similarity between two gene expression signatures, to search for perturbagen gene expression signatures opposing gene expression changes associated with monogenic diabetes. We were able to identify 15 classes of medications with significantly enriched connectivity with HNF1A-knockdown by Mann-Whitney U-test (BH-adjusted P< 0.05). Included in these classes were sulfonylureas, which are known to have preferential therapeutic benefit for this specific condition, supporting this method for drug discovery. Other medications included HDAC inhibitors, tyrosine kinase inhibitors, and riboflavin. We also surveyed other genes causing monogenic syndromes that include diabetes, such as PPARG, where CMap indicated high connectivity with thiazolidinediones (BH-adjusted P=0.015), a type 2 diabetes drug class with known mechanism targeting PPARγ, opposing PPARγ-knockdown and beneficial for treating patients with PPARγ-driven familial partial lipodystrophy. Our findings support the use of expression signature mapping as a novel approach for identifying therapies for monogenic diabetes. Further exploration of databases like CMap and validation of identified medication classes could lead to new pharmacological treatments for diabetes.

Disclosure

R.J.Kreienkamp: None. C.Bryan: None. J.C.Florez: Consultant; AstraZeneca, Novo Nordisk, Other Relationship; AstraZeneca, Merck & Co., Inc. M.Udler: None.

Funding

National Institutes of Health (T32GM774844, K24HL157960, K23DK114551); Pediatric Endocrine Society
225-LB: Reciprocal Regulatory Interactions of Adipocytes and B Lymphocytes
Authors: BREWER JOSEPH W. , ALLMAN MARY K. , CARROLL STEVEN R. , GRANGER SARAH , HALL ALEXANDER , POWNALL KEELEY , QUINTANA JOSHUA , ARELLANO RANGEL NANCY , THOMAS JADE , JUDD ROBERT L.
Published: June 2023

Obesity, a global health problem, leads to chronic inflammation of adipose tissue (AT), an immune-mediated process linked to metabolic dysfunction and disease, including type II diabetes mellitus. Adipocytes, the most abundant cellular constituent of AT, store lipids and secrete adipokines, a group of hormone-like molecules such as adiponectin and adipsin that regulate metabolism and immune cell functions. In mouse models of diet-induced obesity, distinct subsets of B lymphocytes have been implicated in both exacerbating and mitigating AT inflammation and insulin resistance, but the immunoregulatory mechanisms underlying these effects are incompletely understood. Similarly, whether B lymphocytes and adipocytes engage in regulatory interactions with each other is not known. To investigate this question, we performed in vitro co-culture studies using murine 3T3-L1 adipocytes and I.29µ+ B cells, a murine B cell lymphoma that initiates robust secretion of IgM antibodies and the anti-inflammatory cytokine interleukin (IL)-10 upon activation by lipopolysaccharide (LPS). The induction of IgM and IL-10 secretion was markedly attenuated when I.29µ+ B cells were stimulated with LPS while co-cultured in direct contact with 3T3-L1 adipocytes. This inhibitory effect was also observed, albeit to a lesser degree, when the two cell types were co-cultured but separated by a semipermeable membrane. Conversely, secretion of adiponectin and adipsin by 3T3-L1 adipocytes was reduced when the adipocytes were co-cultured with I.29µ+ B cells, both in direct contact and when separated by a semipermeable membrane. This reduction of adipokine output was observed in both the absence and presence of LPS to activate the B cells. These data support the hypothesis that B lymphocytes and adipocytes can engage in reciprocal interactions that modulate the functions of these two secretory cell types and, in turn, may influence AT homeostasis and inflammation in healthy and obese states.

Disclosure

J. W. Brewer: None. R. L. Judd: None. M. K. Allman: None. S. R. Carroll: None. S. Granger: None. A. Hall: None. K. Pownall: None. J. Quintana: None. N. Arellano rangel: None. J. Thomas: None.

Funding

Edward Via College of Osteopathic Medicine Center for One Health
225-OR: The Effect of Tirzepatide vs. Insulin Degludec on Post-meal Glucose Control in Patients with Type 2 Diabetes (SURPASS-3 CGM)
Authors: BATTELINO TADEJ , JOHNSON JENNAL , KATZ MICHELLE , BRAY ROSS , XUE JIE , BROWN KATELYN
Published: June 2023

Tirzepatide (TZP) is a GIP/GLP-1 receptor agonist approved for treatment of patients with type 2 diabetes (T2D). This post-hoc analysis evaluated the impact of TZP vs insulin degludec (IDeg) on post-meal glucose control. In this sub-study of the 52-week open label, parallel arm, Phase 3, SURPASS-3 trial, 243 insulin naive adults with T2D (mean age 57 years; T2D duration 8.8 years, HbA1c 8.15%), were randomised (1:1:1:1 to receive weekly TZP 5, 10, 15 mg or titrated IDeg daily). Interstitial glucose values were collected by continuous glucose monitor (CGM) for approx. 7-10 days at baseline and 52 weeks. The 5-hour post-prandial period (PPP) was defined after meals detected via a validated algorithm. The impact of TZP 5, 10, and 15mg vs IDeg on interstitial glucose post meal from area under the curve (AUC) and peak post prandial glucose (PPG) at 52 weeks were assessed. PPG excursions were decreased with all doses of TZP as seen by less AUC >140 mg/dL and >180 mg/dL vs IDeg (Fig). All TZP doses spent significantly less time > 140mg/dL during the PPP 0-5 hrs (135, 96, and 99 mins for TZP 5, 10, and 15mg) vs IDeg (171 mins; p=0.051, p<0.001, p<0.001 respectively). All TZP doses had significantly lower peak PPG at 52 weeks vs IDeg (180.4 ± 4.45 mg/dL, 163.2 ± 4.97 mg/dL, 168.5 ±4.38 mg/dL vs 198.6± 4.98mg/dL respectively, p<0.001). All 3 doses of TZP led to improved AUC and reduced peak PPG vs IDeg as assessed by CGM.

Disclosure

T.Battelino: Advisory Panel; Eli Lilly and Company, Novo Nordisk, Sanofi, Medtronic, Abbott Diabetes, Consultant; Indigo Diabetes, Research Support; Novo Nordisk, Sanofi, Medtronic, Novartis, Speaker's Bureau; Eli Lilly and Company, Novo Nordisk, Sanofi, Medtronic, Abbott Diabetes, Dexcom, Inc. J.Johnson: Employee; Eli Lilly and Company. M.Katz: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. R.Bray: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. J.Xue: Employee; Eli Lilly and Company. K.Brown: Employee; Eli Lilly and Company.

Funding

Eli Lilly and Company
228-OR: Accuracy and Reliability of Real-Time Continuous Glucose Monitoring in the Intensive Care Unit after Major Abdominal Surgery
Authors: HAGERF (VOGLOVÁ) BARBORA , PROTUS MAREK , NEMETOVA LENKA , MRAZ MILOS , HALUZIK MARTIN , GIRMAN PETER , FRANEKOVA JANKA , SVIRLOCHOVA VERONIKA , JABOR ANTONIN
Published: June 2023

Introduction: Blood glucose control in patients requiring intensive care remains a therapeutic challenge; however, recent advancements in glucose sensing technologies have sparked interest in the potential use of real-time continuous glucose monitoring in the subcutaneous compartment (rtCGM) also in the intensive care unit (ICU) setting. We performed a clinical trial assessing the accuracy and reliability of rtCGM in postoperative ICU patients after major abdominal surgery.

Methods: Patients undergoing pancreatic surgery, liver transplantation, pancreas (or pancreatic islets) and kidney transplantation were enrolled in the trial. Dexcom G6 (Dexcom, Inc., San Diego, USA) was used for rtCGM. Arterial blood glucose measured by the amperometric principle (ABL 800, Radiometer, Copenhagen, Denmark) served as reference and to calibrate the Dexcom G6 (every 6 hours on day 1, once daily day 2 and 3). Sensor accuracy was assessed by computing mean absolute relative difference (MARD), bias, modified Bland-Altman plot and surveillance error grid for paired samples of glucose values from CGM and ABL.

Results: Sixty-one patients after major abdominal surgery staying in ICU post-operatively were included into this analysis. Median monitoring length was 7 days with a 97.1 ± 6.5% proportion of active CGM use. Overall, 1566 paired glucose values measured with CGM and ABL were obtained. MARD for CGM compared with ABL-measured glucose was 9.7% with a bias of 0.9% and coefficient of variation of 14%. In the surveillance error grid analysis, 90.9% of pairs were in the 0 risk zone and 7.9% in the risk zone 1 (out of 7). Throughout the study 3 sensors needed to be replaced due to technical problems.

Conclusion: Our results show a clinically applicable accuracy and reliability of the Dexcom G6 continuous glucose monitoring system in postoperative ICU. This opens up new possibilities in intensifying ICU glucose control, lowering hypoglycaemia risk and reducing nursing staff workload.

Disclosure

B.Hagerf (voglová): None. M.Protus: None. L.Nemetova: None. M.Mraz: None. M.Haluzik: Advisory Panel; Novo Nordisk, Lilly Diabetes, Boehringer-Ingelheim, Research Support; Sanofi, Speaker's Bureau; Abbott, AstraZeneca. P.Girman: None. J.Franekova: None. V.Svirlochova: None. A.Jabor: None.

Funding

Charles University; Czech Ministry of Health; Institute for Clinical and Experimental Medicine (IKEM, IN00023001); National Institute for Research of Metabolic and Cardiovascular Diseases (EXCELES, LX22NPO5104)
235-OR: Myc Activity Is Required for Mitochondrial Function and Glucose-Stimulated Insulin Secretion (GSIS) in Pancreatic ß-Cells
Authors: LU GEMING , KANG RANDY , DIAZ-POZO PEDRO , LEE JUNGEUN , LI MINGPEI , VICTOR VICTOR M. , SCOTT DONALD , GARCIA-OCANA ADOLFO
Published: June 2023

Glucose enhances mitochondrial function, insulin secretion and Myc expression in β-cells. β-cell-specific Myc knockout mice show glucose intolerance, hypoinsulinemia and lack of adaptive β-cell mass expansion following high-fat diet feeding. However, whether Myc regulates GSIS and mitochondrial function in β-cells is unknown. Here, we tested the effects of the Myc activity inhibitor 10058-F4 (1RH) in GSIS, mitochondrial function and metabolism in islets using islet perifusion, Seahorse and metabolomics/transcriptomics approaches. Mouse and human islets incubated 6h with 40µM 1RH displayed impaired phase 1 and phase 2 insulin secretion induced by 11mM glucose. Insulin secretion was not affected in the presence of 25mM KCl suggesting that Myc is required for glucose- but not membrane depolarization-induced insulin secretion. Since adequate mitochondrial function is essential for GSIS, we measured oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) to analyze mitochondrial respiration and glycolytic flux in these islets. 1RH significantly reduced OCR, ECAR and glucose-induced ATP production. Conversely, the Myc inducer harmine (10µM), increased basal OCR, ATP production, and ECAR and partially reversed 1RH effects on mitochondrial function. RNAseq of mouse islets treated with 1RH in 11mM glucose revealed reduced expression of both oxidative phosphorylation and β-cell signature genes but enhanced gene expression of glycolysis, ROS, fatty acid metabolism and autophagy/mitophagy pathways. Metabolomics analysis of mouse islets treated with 1RH in 11mM glucose confirmed the reduction in ATP and highlighted the accumulation of L-palmitoylcarnitine and palmitic acid suggesting inefficient β-oxidation. In conclusion, Myc is required for GSIS and mitochondrial function in β-cells. Impaired Myc action can lead to unbalanced metabolism and autophagy/mytophagy leading to β-cell dysfunction.

Disclosure

G.Lu: None. R.Kang: None. P.Diaz-pozo: None. J.Lee: None. M.Li: None. V.M.Victor: None. D.Scott: None. A.Garcia-ocana: Consultant; Sun Pharmaceutical Industries Ltd.

Funding

National Institutes of Health (R01DK126450)
237-LB: Regulation of Brown Adipose Tissue Neurovasculature by Slit3 Fragments
Authors: NETO FELIPPE M. , CERVANTES HEIDI E. , DUARTE AFONSO SERDAN TAMIRES , SHAMSI FARNAZ
Published: June 2023

The ability of brown adipocytes to dissipate chemical energy as heat counteracts weight gain and has gained considerable attention as a target against obesity. Chronic cold exposure increases brown adipose tissue (BAT) mass by de novo recruitment of brown adipocytes, as well as expanding the number of blood vessels and sympathetic nerves in the tissue. This coordinated expansion of the BAT neurovasculature is essential for enhanced thermogenesis. However, how these distinct processes are coordinated remains unclear. We have recently identified Slit guidance ligand 3 (Slit3) as a new niche factor that mediates crosstalk between preadipocytes, sympathetic neurons, and endothelial cells. We showed that Slit3 is essential for cold-induced angiogenesis and sympathetic innervation in BAT and that loss of Slit3 impairs cold-induced BAT thermogenesis in vivo. However, how Slit3 regulates the expansion of angiogenesis and sympathetic innervation is not known. Members of the Slit family are proteolytically cleaved into a large N-terminal fragment and a shorter C-terminal fragment. We observed that Slit3 undergoes proteolytic cleavage in adipocyte progenitors, generating Slit3 N-terminal (Slit3-N) and C-terminal (Slit3-C) fragments. Overexpression of Slit3-N and Slit3-C in BAT revealed distinct and overlapping functions of Slit3 fragments in the regulation of angiogenesis and sympathetic innervation. Collectively, this study provides important mechanistic insights into the role of Slit3 in regulating angiogenesis and sympathetic innervation in BAT. These findings could lead to the development of new approaches to enhance thermogenesis and combat obesity and related metabolic disorders.

Disclosure

F. M. Neto: None. H. E. Cervantes: None. T. Duarte afonso serdan: None. F. Shamsi: None.

Funding

National Institutes of Health (K01DK125608)
237-OR: Gastrin Improves Single Islet Transplant Outcomes
Authors: HACKER-STRATTON JEANNETTE , ORR CHRIS , OMORI KEIKO , QI MEIRIGENG , FOROUHAR ELENA , EL-SHAHAWY MOHAMED , KANDEEL FOUAD R.
Published: June 2023

Background: Multiple allogenic islet transplants (ITs) are usually required to supply adequate islet mass (~10,000 IEQ/kg) to induce insulin independence. Improving outcomes of a SINGLE islet transplant are needed. Gastrin is a gut hormone that is involved in normal fetal pancreas development. Evidence by our group and others have shown gastrin can support islet cell expansion/function and have anti-inflammatory and pro-angiogenesis effects. We compared outcomes of IT alone across 3 clinical trials using: Edmonton-based (ITA), T-cell depleting (TCD), and TCD immunosuppression with an investigational gastrin analogue (GAS).

Methods: Between 2004-2022, a total of 31 evaluable T1D patients without a prior history of transplant received IT-alone under the ITA (n=17), TCD (n=7), and GAS (n=7) clinical trials. Participants in ITA and TCD were eligible to receive up to 3 ITs each. GAS participants received only a single IT and two 30-day courses of gastrin (SQ, BID) at the time of IT and again 6 months later. Immunosuppression included basiliximab or daclizumab + etanercept (ITA) and T-cell depletion (anti-thymoglobulin) + etanercept + anakinra (TCD and GAS).

Results: Progressive improvements in engraftment were observed in the ITA, TCD, and GAS trials. Average insulin requirements were reduced by 18, 26, and 33 u/day. GAS subjects showed the most rapid reduction of 30.9 u/day (94%) in the first 2 weeks post-IT, compared to 17.5 u/day (67%) in TCD. Rates of subjects achieving insulin independence with a SINGLE islet transplant were 0, 15, and 57%. Subjects required an average of 3 ITs in ITA, 2 in TCD, and only one IT in GAS to achieve insulin independence. Average numbers of islets required to achieve insulin independence were 13,280, 8,433 and 4,837 IEQ/kg.

Conclusion: Gastrin use in the peri-transplant period leads to rapid engraftment, larger magnitude of insulin reduction, and permitted achievement of insulin independence in more than half of subjects after a single islet transplant of less than half the normally targeted islet dose.

Disclosure

J.Hacker-stratton: None. C.Orr: None. K.Omori: None. M.Qi: None. E.Forouhar: None. M.El-shahawy: None. F.R.Kandeel: None.

Funding

National Institutes of Health (U24DK098085)
238-LB: Cold-Dependent Regulation of GOT1 Activity in Brown Adipose Tissue and Its Effect on Thermogenesis
Authors: PARK CHUL-HONG , SUK CHANG JI
Published: June 2023

The malate-aspartate shuttle (MAS) is a biochemical system that can transfer electrons from cytosolic NADH to the mitochondrial electron transport chain. The MAS regulates various biological processes in a tissue-specific manner, but its function in brown adipose tissue (BAT) thermogenesis has not been investigated. We found that glutamic-oxaloacetic transaminase 1 (GOT1), one of the key MAS enzymes, exists at very low levels in BAT but is markedly induced during cold exposure or pharmacological stimulation of β3-adrenergic receptors (β3AR) while other MAS enzymes (GOT2 and MDH1/2) remain unchanged. Our studies showed that cold-activated transcriptional coactivator PGC-1α and its splice variant NT-PGC-1α were recruited to the Got1 promoter at the estrogen-related receptor response element (ERRE), leading to an increase in Got1 gene expression. Moreover, GOT1 protein stability was increased by reduced targeting to the proteasomal degradation. BAT-specific overexpression of Got1 in mice by using the Cre-loxP system increased energy expenditure at room temperature and improved BAT theromogeneis upon cold exposure or β3-adrenergic stimulation. Collectively, our data suggest that the β3AR-FL/NT-PGC-1α-GOT1 axis enhances BAT activity through the activation of the malate-aspartate shuttle.

Disclosure

C. Park: None. J. Chang: None.
238-OR: Changes In Renal Function after Islet Transplantation in a Single-Centre Cohort in Canada over 20 Years
Authors: CARR ALICE L.J. , MARFIL-GARZA BRAULIO A. , LING YING , ORAM RICHARD A. , LAM ANNA , ANDERSON BLAIRE L. , O'GORMAN DOUG , KIN TATSUYA , BIGAM DAVID , JAMES SHAPIRO A.M. , SENIOR PETER A.
Published: June 2023

Islet transplantation (ITx) is an established treatment for recurrent, severe hypoglycemia in type 1 diabetes, but requires lifelong immunosuppression (IS) which can be nephrotoxic. We examined long term changes in renal function after ITx, through estimated GFR (eGFR), in a single centre cohort followed for up to 20 years. We used data from adults undergoing islet after kidney or ITx alone (94%) at the University of Alberta Hospital between March 11 1999 and Oct 1 2019 with >1 year of follow up. IS included tacrolimus and sirolimus/mycophenolate, balancing side effects with graft and renal function. We calculated individuals mean CKD EPI eGFR (ml/min/1.73m2) at baseline (≤1y pre transplant), 6m and yearly timepoints across follow up. We assessed the overall slope/year of eGFR against time from first transplant in 3 time periods; ≤1y, 1-5y and 5-20y, using mixed effects models. We also compared slopes between subjects with preserved (>60, n=217) vs. reduced (<60, n=38) eGFR at baseline. We included 255 adults (42% M) followed for 88.3m [50.2, 144.9] (median [IQR]). Whole cohort eGFR declined over follow up, most rapidly in the first year; -28.3 [-31.8, -24.5], with slower decline later post transplant 1-5y; -2.9 [-3.5, -2.3] and 5-20y; -1.2 [-1.4, -1.04]. Those with preserved baseline eGFR experienced steeper decline across all time phases as compared to those with reduced eGFR, with the steepest decline ≤1y post transplant (-29.8 [-33.8, -25.9], -18.3 [-27.8, -8.9], p=0.027). Between 5-20y post transplant renal function continued to decline slowly in those with preserved baseline eGFR but was stable in those with reduced baseline eGFR, (-1.4 [-1.6, -1.2], 0.2 [-0.3, 0.7] p<0.001). Nine (3.5%) developed ESRD. Initiation of IS associates with a rapid decline in eGFR the first year post ITx, with minimal decline beyond 5y. With careful IS management, rates of eGFR decline are not greater in those with reduced baseline eGFR. Effective IS regimens without nephrotoxicity remain an important goal.

Disclosure

A.L.J.Carr: None. A.Shapiro: n/a. 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. B.A.Marfil-garza: None. Y.Ling: None. R.A.Oram: Consultant; Janssen Research & Development, LLC, Research Support; Randox R & D. A.Lam: None. B.L.Anderson: None. D.O'gorman: None. T.Kin: None. D.Bigam: None.
239-LB: Erythropoietin Alters Fat Mass and Gut Microbial Composition
Authors: YIN WEIQIN , ROGERS HEATHER , AN XIULI , GASSMANN MAX , NOGUCHI CONSTANCE T.
Published: June 2023

Erythropoietin is an essential hormone for promoting erythropoiesis. Erythropoietin also stimulates angiogenesis, affects fat metabolism and can promote survival in cells expressing erythropoietin receptor. Here, we found that erythropoietin reduces fat mass, decreasing epididymis fat pad mass and subcutaneous fat pad mass of Tg6 male mice that express high transgenic erythropoietin. However, how erythropoietin activity in the gut improves fat mass and glucose metabolism is not known. Tg6 male mice have increased microvilli height and intestine length. High erythropoietin changes the gut microbiota by altering β-diversity that includes increasing the abundance of Bifidobacterium and reducing the Lactobacillaceae in Tg6 male mice. EPO decreased lactate dehydrogenase (LDHa) expression and reduces lactate production from intestinal endothelial cells that affects the gut microbiota components. Accompanying the altered microbiome are increased intestinal short-chain fatty acid levels that can affect fat metabolism. Transplantation of fecal pellet from Tg6 male mice into antibiotic treated male wild type mice reduces fat mass and mimics the lean phenotype of Tg6 mice. Conversely, transplanting feces from WT mice into Tg6 mice resulted in increased fat mass in Tg6 mice. Wild type male mice treated with erythropoietin show improved glucose tolerance and also exhibit increased intestine length and changes in the gut microbiota with increase in Bifidobacterium and decrease in Lactobacillaceae, analogous to changes in Tg6 male mice. Our results on erythropoietin activity in the gut to change gut morphology and remodel the gut microbiome provide a new mechanism by which EPO affects fat metabolism. Key words: EPO; EPOR; gut microbial composition; fat mass

Disclosure

W. Yin: None. H. Rogers: None. X. An: None. M. Gassmann: None. C. T. Noguchi: None.
24-LB: Diabetic Microvascular Disease Is Associated with Left Ventricular Hypertrophy in Patients with Type 2 Diabetes Mellitus
Authors: KE JING , FENG XIAOTONG , ZHU LIN , XU YONGSONG , LIU SIMO , YANG LONGYAN , ZHAO DONG
Published: June 2023

Background: Left ventricular hypertrophy (LVH) is an important feature in patients with diabetes mellitus and increased the risk of cardiac events. The pathophysiology of LVH in diabetes mellitus remains unclear and is not fully explained by hyperglycemia and hypertension. Microvascular diseases, the most common and specific complications of diabetes mellitus, which may be involved in LVH. Therefore, we aimed to explore the association between diabetic microvascular diseases and LVH in patients with type 2 diabetes mellitus (T2DM).

Material and methods: In the cross-sectional study, we enrolled 2912 patients with T2DM, including 360 patients with LVH. Demographic data, medical history, anthropometric indices, laboratory examination, diabetic microvascular diseases and cardiac ultrasound index were collected. Correlation analysis and regression analysis were performed to analyze the relationship between diabetic microvascular diseases and LVH in whole population and in gender subgroup.

Result: Patients with LVH were older and had larger BMI, waist circumference and hip circumference. And a higher proportion of males had LVH compared with females. Patients with LVH had a larger proportion of hypertension, coronary heart disease, diabetic retinopathy (DR), and diabetic kidney disease (DKD). After adjusting potential confounding factors, patients with one or two microvascular diseases especially DR and DKD, had more possibility of LVH (OR = 1.287 and OR = 2.118 respectively). In gender subgroup analysis, microvascular diseases obviously increased the risk of LVH, especially in males. Moreover, the risk of LVH gradually increased with the number of diabetic microvascular diseases.

Conclusions: Diabetic microvascular diseases, especially DR and DKD, were positively and independently associated with LVH in T2DM. In addition, the risk of LVH obviously increased with the number of microvascular diseases in male.

Disclosure

J. Ke: None. X. Feng: None. L. Zhu: None. Y. Xu: None. S. Liu: None. L. Yang: None. D. Zhao: None.
240-LB: Unrestrained Sympathetic Signaling Is a Key Driver of Obesity-Induced Insulin Resistance
Authors: SAKAMOTO KENICHI , MAURIZI GIULIA , CHEN BANDY , SHAWKAT ADHAM , PATLOLLA LIKHITHA , TAHIRI AZEDDINE , BUTERA ALICE , BUETTNER CHRISTOPH
Published: June 2023

Obesity is the major driver of type 2 diabetes. The mechanisms that account for overnutrition induced insulin resistance are yet to be delineated as impaired cellular insulin signaling may or may not account for the impaired insulin action. We find that overnutrition rapidly impairs insulin action and increase plasma norepinephrine, suggesting heightened activation of the sympathetic nervous system (SNS), possibly due to brain insulin resistance as earlier studies from our group suggested. Here, we hypothesize that unrestrained SNS activity (SNA) is a key driver of obesity induced insulin resistance. To test this hypothesis, we examined a mouse model of inducible and peripherally restricted tyrosine hydroxylase (th) gene deletion (THΔper) that have profoundly lower catecholamine levels in peripheral tissues is protected from high fat diet (HFD) induced insulin resistance. Despite similar food intake, obesity and cellular insulin signaling in liver and adipose tissue, THΔper mice were protected from both short-term and long-term HFD feeding-induced glucose intolerance, increases in plasma catecholamines and hyperglucagonemia. Hyperinsulinemic euglycemic clamp studies revealed that overnutrition induced hepatic insulin resistance was markedly ameliorated in the THΔper mice, even though cellular insulin signaling in liver and adipose tissue was comparable. Moreover, THΔper mice were protected from HFD-induced adipose tissue dysfunction characterized by reduced lipogenic capacity, unrestrained lipolysis and increased low-grade inflammation as well as hepatic steatosis, possibly due to decreased lipolytic flux and hepatic de novo lipogenesis. In addition, fibrosis genes were markedly reduced in the liver of the THΔper mice, suggesting that reducing SNA can prevent metabolic dysfunction-associated fatty liver disease. These results demonstrate that unrestrained SNA is a pivotal driver of insulin resistance, hyperglucagonemia and metabolic dysfunction in obesity.

Disclosure

K. Sakamoto: None. G. Maurizi: None. B. Chen: None. A. Shawkat: None. L. Patlolla: None. A. Tahiri: None. A. Butera: None. C. Buettner: None.
241-LB: Inhibition of TXNIP-Thioredoxin Redox Switch Improves Insulin Sensitivity on a High-Fat Diet
Authors: HOANG MEGAN F. , DAGDEVIREN SEZIN , MEIER VANESSA , BENOIT JAKE , MELNIK VERONIKA Y. , LEE RICHARD
Published: June 2023

Thioredoxin interacting protein (TXNIP) is a regulator of glucose metabolism and oxidative stress. It is the only arrestin-domain protein known to bind to reduced thioredoxin (Trx) at a C247 residue. This binding site is conserved in mammals, but its specific purpose is unclear. Here, we studied TXNIP's metabolic roles through the binding of Trx in vivo. We hypothesized that the TXNIP-Trx interaction may regulate a High-Fat Diet (HFD) induced insulin resistance triggered by redox stress. To abolish this interaction, we generated a new mouse model with a single C247S amino acid substitution in the txnip gene using CRISPR-Cas9. Over 8 weeks, we fed male C57BL/6J WT, C247S, and TXNIP KO mice (n=10/group) chow and HFD and performed insulin and glucose tolerance tests. Notably, C247S mice on HFD exhibited improved insulin sensitivity compared to WT, but this was not observed on a chow diet (Figure 1). Additionally, these mice had lower glucose tolerance on a chow diet and higher glucose tolerance on a HFD compared to WT. Moreover, KO mice were hypoglycemic and hypersensitive to insulin compared to C247S and WT mice in both diets. Our data reveals that inhibiting the TXNIP-Trx interaction on a HFD (stressed condition) can improve insulin sensitivity, suggesting a protective effect against insulin resistance. Future studies are needed to unravel this relationship between redox and arrestin biology in regulating metabolism.

Disclosure

M. F. Hoang: None. S. Dagdeviren: None. V. Meier: None. J. Benoit: None. V. Y. Melnik: None. R. Lee: Advisory Panel; Elevian, Inc., Research Support; BlueRock Therapeutics.

Funding

National Institutes of Health (1F32DK126289, R01DK126688)
242-LB: A Novel FoxO Target, LRRC2, Preserves Mitochondrial Function in Muscle from Insulin-Deficient Mice
Authors: PENNIMAN CHRISTIE M. , BHARDWAJ GOURAV , NOWERS COLETTE , O'NEILL BRIAN T.
Published: June 2023

Uncontrolled diabetes impairs muscle strength and mitochondrial metabolism, leading to increased mortality. FoxOs are key mediators of insulin signaling and we demonstrated that FoxOs mediate muscle atrophy and mitochondrial dysfunction in mice with streptozotocin (STZ) diabetes. Unfortunately, FoxOs are also tumor suppressors and knockout of FoxOs in proliferative tissues causes cancer. We aimed to investigate FoxO targets restricted to skeletal muscle in hopes of improving strength in diabetic conditions. RNA-seq from STZ mice with/without FoxO1/3/4 triple knockout showed several diabetes-induced FoxO targets, with the most robust being LRRC2 (Leucine rich repeating containing 2). The function of LRRC2 is unknown, but gene expression databases show LRRC2 is restricted to muscle and heart, and LRRC2 is enriched in human heart with dilated cardiomyopathy. Adenoviral overexpression of LRRC2 in C2C12 cells localized to mitochondria and showed increase mRNA levels of biogenesis marker PGC1α, and antioxidant genes SOD2 and Gpx3. However, LRRC2 overexpression did not change basal respiration measured in Seahorse. To determine LRRC2's effect on exercise tolerance and mitochondrial bioenergetics in vivo, we created muscle specific LRRC2 knockout (LKO) mice and rendered them diabetic with STZ. Diabetic LKO mice did worse than their littermate controls on treadmill exercise to exhaustion. Soleus permeabilized fibers showed significantly decreased ATP production that was uncoupled from respiration with glutamate/malate. Interestingly, soleus muscles from LKO mice were significantly larger than their littermate controls, whereas extensor digitorum longus and quadriceps were smaller in the diabetic LKO mice. Lastly, mRNA expression of mitochondrial subunits was not changed and thus did not explain the mitochondrial defects. In conclusion, LRRC2 is a novel FoxO target that helps preserve mitochondrial function and exercise tolerance in a Type 1 diabetes mouse model.

Disclosure

C. M. Penniman: None. G. Bhardwaj: None. C. Nowers: None. B. T. O'neill: Stock/Shareholder; Bristol-Myers Squibb Company, Pfizer Inc., Johnson & Johnson.

Funding

U.S. Department of Veterans Affairs (lO1BXOO4468)
242-OR: Defining Targets for Continuous Glucose Monitoring (CGM) after Total Pancreatectomy with Islet Autotransplantation (TPIAT)
Authors: SOMANI ZAYNAB , HODGES JAMES S. , RAMANATHAN KARTHIK , CHINNAKOTLA SRINATH , BEILMAN GREG , BELLIN MELENA
Published: June 2023

Targets for continuous glucose monitoring (CGM) are well established for type 1 and type 2 diabetes. In total pancreatectomy with islet auto-transplant (TPIAT), stricter glycemic targets are needed to avoid metabolic stress on transplanted islets, but no guidelines exist for CGM targets. We aimed to determine CGM targets for TPIAT clinical management by associating CGM metrics with goal hemoglobin A1c (HbA1c) ≤6.5%. Targets for time in range (TIR) 70-140, TIR 70-180, mean CGM glucose, and time in hyperglycemia (>140, >180, >250 mg/dL) were chosen to give good sensitivity and specificity for identifying HbA1c ≤6.5%. We included 256 episodes of 14-day CGM metrics with a concurrent HbA1c value (n=82 patients, age 32.8 [SD 16.6] years at surgery, 70% female) who were ≥0.5 years post TPIAT (median 4.1 years) and wearing Dexcom G6. Most patients had more than 1 HbA1c and corresponding CGM available (median 3.1 per patient). As expected, CGM metrics correlated highly with each other. Table 1 shows “best” (Youden criterion) CGM thresholds and sensitivity for HbA1c ≤6.5%. TIR 70-140 mg/dL ≥50% and TIR 70-180 mg/dL ≥75% may be reasonable targets for patients and providers using CGM data to manage diabetes long-term after TPIAT. Also, time in hyperglycemia should be kept to <20% above 180 mg/dL and <3% above 250 mg/dL. Failure of these goals should prompt re-starting or adjusting insulin therapy.

Disclosure

Z.Somani: None. J.S.Hodges: None. K.Ramanathan: None. S.Chinnakotla: None. G.Beilman: None. M.Bellin: Consultant; Insulet Corporation, Vertex Pharmaceuticals Incorporated, Research Support; Dexcom, Inc., ViaCyte, Inc.
243-LB: C5a Receptor (C5aR1) Antagonism Ameliorates Saturated Fatty Acid–Induced Mitochondrial Dysfunction in Skeletal Muscle Cells
Authors: SHAH DINESH S. , MCNEILLY ALISON D. , MCCRIMMON RORY J. , HUNDAL HARI
Published: June 2023

The complement system is an integral component of the innate immune response and plays a vital role in adaptive immunity. Activation of the system produces peptide fragments, such as C5a, that target G-protein coupled receptors expressed on immune-related cells, such as macrophages, that initiate pro-inflammatory responses. We have discovered that the C5a receptor 1 (C5aR1) is also expressed in skeletal muscle, a primary insulin target tissue. Sustained exposure of muscle cells to palmitate (PA), a saturated fatty acid, or C5aR1 activation is associated with impaired insulin sensitivity. We have studied the role that C5aR1 activation plays in in fatty-acid induced insulin resistance by exploring whether targeted receptor antagonism mitigates PA-induced mitochondrial dysfunction and insulin resistance. Mitochondrial health in rat skeletal muscle cells were examined by assessing mitochondrial morphology and mitophagy via microscopy, and cellular respiration using the XF24 seahorse flux analyser, following overnight incubation with PA in the absence/presence of C5aR1 antagonists. C5aR1, which was detected in mouse gastrocnemius muscle by immunoblot, increased in expression, in parallel with circulating levels of C5a, the peptide agonist for C5aR1, during a high-fat diet (HFD). PA treatment of rat L6 muscle cells suppresses insulin sensitivity as indicated by a reduction in PKB308 phosphorylation and glucose uptake. PA also reduced cellular mitochondrial respiration and promoted mitochondrial fragmentation and mitophagy. C5aR1 antagonism mitigated the PA dependent loss in insulin sensitivity, mitochondrial respiration and restrained mitochondrial fragmentation and the rates of mitophagy. Elevated C5aR1 activity, as might be observed during a HFD, may promote metabolic dysfunction in skeletal muscle, the antagonism of which could have therapeutic implications for mitigating HFD mediated insulin resistance.

Disclosure

D. S. Shah: None. A. D. Mcneilly: None. R. J. Mccrimmon: Advisory Panel; Sanofi, Speaker's Bureau; Novo Nordisk A/S. H. Hundal: None.

Funding

Diabetes UK
244-LB: The GABA Neurons in the Multiple Autonomic Areas of the Central Nervous System Mediate the Cardiovascular Regulation by SGLT-2 Inhibitors
Authors: WEN SONG
Published: June 2023

Purpose: This study investigates the possible effect and central mechanism of novel antidiabetic medication sodium glucose transporter-2 (SGLT-2i) on the cardiovascular activity.

Material and methods: Thirty-four normal male C57BL/6 mice were randomly assigned to receive single Dapagliflozin (1.52mg/kg) dose via intragastric gavage or a comparable dose of saline. Glycemic level (BG), blood pressure (BP) and heart rate (HR) were measured 2 hours after administration of the respective treatments. Immunohistochemical tests were performed to determine the effect of SGLT-2i on neural localization of SGLT-2 and c-Fos.

Results: Administration of SGLT-2i significantly decreased BP but did not affect the HR. There was no difference in BG between the two groups. Results showed that SGLT-2 was localized to specific regions involved in autonomic control. Expression of c-Fos was significantly higher in major critical nuclei in the aforementioned regions in groups treated with Dapagliflozin.

Conclusion: This study demonstrates that SGLT-2 is expressed in CNS tissues involved in autonomic control and possibly influence cardiovascular function. Dapagliflozin influences central autonomic activity via unidentified pathways by inhibiting central or peripheral SGLT-2. These results provide a new concept that sympathetic inhibition by SGLT-2i can be mediated by central autonomic system, a mechanism that explains how SGLT-2i improves the cardiovascular function.

Disclosure

S. Wen: None.

Funding

Pudong New Area Health Planning Commission (PWZZK2017-03); Shanghai Municipal Health Planning Committee (ZHYY-ZXYJHZX-2-201712); National Natural Science Foundation of China (81370932, 21675034); Pudong Health Bureau of Shanghai (PWR12014-06); Outstanding Clinical Discipline Project of Shanghai Pudong (PWYgy-2018-08); Shanghai Natural Science Foundation (19ZR1447500)