bluuebunny/crossref_metadata_2025_split huggingface dataset:
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 &gt;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 (&gt;60, n=217) vs. reduced (&lt;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&lt;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 (&gt;140, &gt;180, &gt;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 &lt;20% above 180 mg/dL and &lt;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)
244-OR: Signs of Glucagon Resistance after a Two-Week Hypercaloric Diet Intervention
Authors: SUPPLI MALTE P. , BAGGER JONATAN I. , HOLST JENS J. , KNOP FILIP K. 
Published: June 2023

Hyperglucagonemia is observed in individuals with obesity and contributes to the hyperglycemia of persons with diabetes. Hyperglucagonemia may arise due to reduced hepatic amino acid turnover and ensuing elevations in glucagonotropic amino acids. We recently observed reduced glucagon sensitivity and hyperglucagonemia in individuals with obesity and hypothesized it to be a consequence of steatosis. Here, we evaluated whether reduced glucagon sensitivity could be induced by a short-term hypercaloric diet intervention designed to increase hepatic fat content in healthy individuals.
We recruited 20 healthy, lean individuals (BMI: 23 ± 0.3 (mean ± SD) kg/m2) to follow a hypercaloric diet (~5,000 kcal/day) and a sedentary lifestyle for 2 weeks. Amino acid turnover in response to infusion of glucagon was assessed during a pancreatic clamp with somatostatin and basal insulin. Participants were examined before and after the lifestyle-intervention and again after 8 weeks to assess the reversibility of any metabolic changes. Hepatic steatosis was assessed by magnetic resonance spectroscopy.
The intervention led to increases in body weight (3.5 [2.8;4.2] (mean [95% confidence interval]) kg, P &lt; 0.0001) and hepatic fat content (382 [206;705]%, P &lt; 0.001). Insulin resistance was evident with unchanged fasting blood glucose levels and a 56% increase in fasting insulin (P &lt; 0.001). Glucagon infusion led to a decrease in the concentration of total amino acids, but the percentage change in total amino acids was reduced (−2.5 ± 0.5 vs. −0.2 ± 0.7%, P = 0.015) and the average slope of the total amino acid curve was less steep (−2.0 ± 1.2 vs. −1.2 ± 0.3 μM/min, P = 0.016) after the intervention compared to baseline. All metabolic changes were normalized at follow-up.
Our results indicate that short-term unhealthy behavior increasing hepatic fat content causes a reversible resistance to the effect of glucagon on amino acid turnover in healthy individuals, which may explain hyperglucagonemia associated with obesity and diabetes.

Disclosure
M.P.Suppli: None. J.I.Bagger: Speaker's Bureau; Novo Nordisk A/S. J.J.Holst: Advisory Panel; Novo Nordisk A/S, Eli Lilly and Company, Board Member; Bainan Biotech, Antag Therapeutics, Consultant; Alphasights, Eli Lilly and Company, ShouTi Pharma Inc., Zealand Pharma A/S, Other Relationship; Novo Nordisk, Novo Nordisk Pharma, Mayo Clinic, Boehringer-Ingelheim, Scohia Pharma Inc., Research Support; ARLA, European Union, Novo Nordisk Foundation. F.K.Knop: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Novo Nordisk, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Lundbeck.