bluuebunny/crossref_metadata_2025_split huggingface dataset:
231-LB: GLP-1 Promotes Cortical and Medullary Perfusion in Human Kidney and Maintains Tissue Oxygenation during Na Loading
Authors: HADDOCK BRYAN , JENSEN BOYE L. , ASMAR ALI 
Published: May 2022

Purpose: GLP-1 receptor agonism has shown beneficial cardiovascular effects which could include the kidneys. In the human kidney, the high GLP-1 extraction and its natriuretic effect depend on the GLP-1 receptor and is accompanied by suppression of angiotensin II, independent of changes in renal plasma flow. Preclinical data showed that angiotensin II constricts the vasa recta and lowers medullary perfusion. The current randomized, controlled study was designed to test the hypothesis that GLP-1 increases renal medullary perfusion in healthy humans.
Methods: Healthy male participants (n=10, 27 ± 4 years) ingested a fixed sodium intake for 4 days and were examined twice during a 1-hour infusion of either GLP-1 (1.5 pmol/kg/min) or placebo together with infusion of 0.9% NaCl (750 mL/h) . Interleaved measurements of renal artery flow, oxygenation (R2*) , and perfusion were acquired in the renal cortex and medulla during infusions, using magnetic resonance imaging.
Results: GLP-1 infusion increased medullary perfusion (32 ± 7%, p&lt;0.001) and cortical perfusion (13 ± 4%, p&lt;0.001) compared to placebo. Here, NaCl infusion decreased medullary perfusion (-5 ± 2%, p=0.007) while cortical perfusion remained unchanged. R2* values increased by 3 ± 2% (p=0.025) in the medulla and 4 ± 1% (p=0.008) in the cortex during placebo, indicative of decreased oxygenation but remained unchanged during GLP-1. Renal arterial blood flow was not altered significantly by either intervention.
Conclusions: GLP-1 increases predominantly medullary but also cortical perfusion in healthy human kidneys and maintains oxygenation during NaCl-loading. In perspective, GLP-1 may exert protective effects against renal hypoperfusion and ischemia.

Disclosure
B. Haddock: n/a. B. L. Jensen: None. A. Asmar: None.
233-LB: Ranolazine Fails to Improve Glycemia in Obese Liver-Specific Pyruvate Dehydrogenase–Deficient Mice
Authors: SAED CHRISTINA T. , AMIRHOSSEIN TABATABAEI DAKHILI SEYED , GREENWELL AMANDA A. , CHAN JORDAN S.F. , YANG KUNYAN , GOPAL KESHAV , EATON FARAH , USSHER JOHN R. 
Published: May 2022

Background: Nonalcoholic fatty liver disease (NAFLD) increases risk for obesity-related insulin resistance and type 2 diabetes. Recent studies have demonstrated that stimulating pyruvate dehydrogenase (PDH) , the rate-limiting enzyme in glucose oxidation, can reverse obesity-induced NAFLD. Moreover, our lab has observed that treatment with the antianginal drug, ranolazine, augments hepatic PDH activity, leading to a reversal of obesity-induced glucose intolerance and NAFLD in mice. Our aim herein was to determine whether ranolazine's ability to mitigate obesity-induced NAFLD and hyperglycemia requires increases in hepatic PDH activity.
Methods: We generated liver-specific PDH deficient (PDHLiver-/-) mice by crossing floxed Pdha1 mice with albumin-Cre (Alb-Cre) mice. PDHLiver-/- and Alb-Cre mice were placed on a high-fat diet for 12-weeks to induce obesity, whereas their lean controls were fed a low-fat diet. Mice were randomized to treatment with either vehicle control or ranolazine (50 mg/kg) once daily via oral gavage for 5-weeks, following which we assessed glucose homeostasis and hepatic steatosis.
Results: Lean PDHLiver-/- mice exhibited no overt phenotypic differences (e.g. adiposity, glucose tolerance) from their Alb-Cre littermates, though a mild but nonsignificant worsening of pyruvate tolerance was observed. Similar findings were observed in obese PDHLiver-/- mice compared to their Alb-Cre littermates. Of interest, ranolazine treatment produced mild improvements in glucose tolerance in obese Alb-Cre mice, but not in obese PDHLiver-/- mice. However, this improvement in ranolazine treated Alb-Cre mice appears to be independent of decreases in hepatic triacylglycerol content.
Conclusions: Although hepatic PDH activity appears to contribute to the glucose-lowering actions of ranolazine, this appears to be dissociated from its actions on hepatic steatosis, and impaired hepatic PDH activity per se is not sufficient to produce an NAFLD phenotype.

Disclosure
C. T. Saed: None. S. Tabatabaei dakhili: None. A. A. Greenwell: None. J. S. F. Chan: None. K. Yang: None. K. Gopal: None. F. Eaton: None. J. R. Ussher: None.
239-OR: Physical Activity, Hypoglycemia, and Type 1 Diabetes: A Data-Driven Approach
Authors: PRASANNA SAHANA , BARUA SOUPTIK , JOHNSON JEREMIAH J. , SILLER ALEJANDRO F. , SABHARWAL ASHUTOSH , DESALVO DANIEL 
Published: May 2022

Physical activity (PA) provides numerous health benefits for individuals with T1D. However, the threat of exercise-induced hypoglycemia may impede the desire for regular PA. We aimed to study the association between three common types of PA (walking, running, and cycling) and hypoglycemia risk in 50 individuals with T1D. Real-world data including characteristics of PA, CGM values, and insulin doses were available from the Tidepool Big Data Donation Project. Participants were aged 38.0 ± 13.1 yrs with 21.4 ± 12.9 yr duration of diabetes and avg 26.2 weeks of CGM data available.
We built a linear regression model for each of the three PA types to predict the probability of level 1 hypoglycemia (&lt;70 mg/dL) during the 2 hours after start of PA using the following predictors: PA duration (mins) , PA intensity (calories burned) , 2-hr pre-exercise glucose AUC, glucose value at start of PA, and total bolus insulin within 2 hrs before PA.
Regression results are provided in Table 1. Our models indicated that glucose value at the start of exercise (p&lt;0.0for all three activities) and pre-exercise glucose AUC (p&lt;0.0for walking and cycling) were the most significant predictors of hypoglycemia. Duration and intensity of PA and 2-hr bolus insulin were weakly associated with hypoglycemia for certain exercises. These findings may provide T1D individuals with a data-driven approach in preparing for PA that minimizes hypoglycemia risk.

Disclosure
S.Prasanna: None. S.Barua: None. J.J.Johnson: None. A.F.Siller: None. A.Sabharwal: None. D.Desalvo: Consultant; Dexcom, Inc., Insulet Corporation, Research Support; Insulet Corporation.

Funding
National Science Foundation (1648451)
24-OR: Podocyte Targeted Pyruvate Kinase M2 (PKM2) Activation Normalized Glomerular VEGF Expression, Mitochondrial Function, Fuel Metabolism, and Diabetic Nephropathy
Authors: FU JIALIN , SHINJO TAKANORI , LI QIAN , PARK KYOUNGMIN , YU MARC GREGORY , YOKOMIZO HISASHI , HUANG QIAN , WU I-HSIEN , KING GEORGE L. 
Published: May 2022

Diabetic nephropathy (DN) is the result of abnormal systemic and local changes in metabolism and hemodynamics. We have reported that many glycolytic enzymes, such as pyruvate kinase M2 (PKM2) , were elevated in the renal glomeruli of type 1 and type 2 diabetic patients who were protected from DN. TEPP46, a small-molecule which activates PKM2 by inducing oligomerization, reversed glomerular pathology in diabetic mice. Here, mice with PKM2-specific overexpression in podocytes (PPKM2Tg) were generated to uncover its renal protective function as potential therapeutic target, which prevented elevated albumin-creatinine ratio (ACR) , mesangial expansion, basement membrane thickness and podocyte foot process effacement after 7-months of STZ-induced diabetes. Further, diabetes-induced impairment of glycolytic rate and mitochondrial function were normalized in diabetic PPKM2Tg glomeruli, in concordance with elevated Ppargc1a and Vegf expressions. Restored VEGF expression improved glomerular maximal mitochondrial function in diabetic PPKM2Tg and WT mice. Elevated VEGF levels were observed in the glomeruli of DN-protected patients with chronic type 1 diabetes, and clinically correlated with estimated GFR, but not glycemic control. Mechanistically, the preservations of mitochondrial function and VEGF expression were dependent on tetrameric structure and enzymatic activities of PKM2 in podocyte. Thus, these findings show that PKM2 activation in the podocyte can regulate mitochondrial metabolism of the entire glomeruli and prevent mitochondrial dysfunction induced by chronic diabetes and even reverse metabolic memory. PKM2 structures and enzymatic activities are necessary to mediate glomerular metabolism against toxicity of hyperglycemia via paracrine factors such as VEGF. Thus, PKM2 activation in podocyte is a potential therapeutic target to protect against DN.

Disclosure
J.Fu: None. T.Shinjo: None. Q.Li: None. K.Park: None. M.Yu: None. H.Yokomizo: None. Q.Huang: None. I.Wu: None. G.L.King: Advisory Panel; Medtronic, Research Support; Janssen Pharmaceuticals, Inc.
240-OR: Quantifying Glucose Utilization and Endogenous Glucose Production during Resistance Exercise in People with Type 1 Diabetes (T1D)
Authors: YOUNG GAVIN , JACOBS PETER G. , TYLER NICHOLE S. , NGUYEN THANH-TIN P. , CASTLE JESSICA R. , WILSON LEAH M. , BRANIGAN DEBORAH , GABO VIRGINIA , GUILLOT FLORIAN H. , RIDDELL MICHAEL , YOUSSEF JOSEPH EL 
Published: May 2022

Glucose dynamics during and after resistance exercise in people with T1D is not well understood. We recruited 25 people with T1D to perform 3 separate sessions of in-clinic resistance exercise under low (basal) , medium (1.5x basal) , or high (3.0x basal) insulin infusion levels. Blood glucose was clamped by intravenous dextrose infusion 3 hours prior to, and 4 hours after a 45-minute session of strength training. Glucose tracer was infused to match the rate of endogenous glucose production (EGP) . Glucose and tracer data were used to fit a two-compartment model and quantify the rate of glucose disposal (Rd) and EGP. For 58 sessions across 25 participants, blood glucose levels remained constant during and after resistance exercise. The mean change in area under the curve (AUC) for Rd was not higher during resistance exercise compared to baseline (+1.2 mM, p=0.69) , but increased during previously published aerobic exercise (+12.5 mM, p&lt;0.01) . Mean AUC for EGP rose during resistance exercise (+6.5 mM, p&lt;0.01) primarily due to non-insulin mediated factors and the increase was higher than during aerobic exercise (+2.mM, p&lt;0.01) . Resistance exercise is characterized by a strong rise in EGP that is predominantly driven by non-insulin mediated effects. This may mitigate drops in blood glucose caused by increased glucose utilization in peripheral tissues during anaerobic activity.

Disclosure
G.Young: None. M.Riddell: Advisory Panel; Zealand Pharma A/S, Zucara Therapeutics, Consultant; Eli Lilly and Company, Jaeb Center for Health Research, Speaker's Bureau; Dexcom, Inc., Eli Lilly and Company, Novo Nordisk. J.El youssef: None. P.G.Jacobs: Other Relationship; Pacific Diabetes Technologies, Research Support; Dexcom, Inc. N.S.Tyler: None. T.P.Nguyen: None. J.R.Castle: Advisory Panel; Insulet Corporation, Novo Nordisk, Zealand Pharma A/S, Stock/Shareholder; Pacific Diabetes Technologies. L.M.Wilson: n/a. D.Branigan: None. V.Gabo: None. F.H.Guillot: Stock/Shareholder; Pacific Diabetes Technologies.

Funding
National Institutes of Health (5R01DK110175, 1F30DK128914)
242-OR: Bilateral Dorsolateral Prefrontal Cortex High-Definition Transcranial Direct-Current Stimulation (HD-tDCS) Improves Time-Trial Performance in Elite Cyclists with Type 1 Diabetes (T1D)
Authors: CODELLA ROBERTO , FILIPAS LUCA , GALLO GABRIELE , LUZI LIVIO 
Published: May 2022

HD-tDCS is capable to increase the focality of neuromodulation and has been recently applied to improve endurance performance in healthy subjects. Here, in a double-blind, counterbalanced, randomized order, elite cyclists (27 ± 4.3 years; BMI: 20.2 ± 1.2 kg/m2; VO2peak: 67.5 ± 1.2 mL/min/kg) with T1D (no complications) underwent either HD-tDCS (F3, F4) or control (SHAM) and completed a constant-load trial at 75% of the 2nd ventilatory threshold plus a 15-km cycling time-trial (TT) . After HD-tDCS, the total time to cover the TT was 3.8 % faster (P&lt;.01) and associated with higher mean power output (P&lt;.01) and a lower rate of perceived exertion/power at iso-time (F=5.7; P&lt;.01) than the SHAM condition. Cadence, lactate, glycemia, heart rate did not differ in both conditions. These findings suggest that upregulation of the prefrontal cortex could safely enhance endurance performance in elite cyclists with T1D, without altering physiological and perceptual responses at moderate intensity. Present data open to future applications of HD-tDCS to a wider population of active T1D-subjects.

Disclosure
R.Codella: None. L.Filipas: None. G.Gallo: None. L.Luzi: Advisory Panel; Eli Lilly and Company, Speaker's Bureau; Eli Lilly and Company, Novo Nordisk.
25-LB: Peripheral Neuropathy and Associated Factors in Patients with Type 2 Diabetes Mellitus in Vietnam—A Cross-Sectional Study
Authors: TRANG NGUYEN T.T. , FONG TSORNG-HARN , DO TUNG D. 
Published: May 2022

Peripheral neuropathy and associated factors in patients with type 2 diabetes mellitus in Vietnam: A cross-sectional study Diabetes peripheral neuropathy (DPN) is the most common complication associated with diabetes mellitus. We aimed to establish the characteristic and associated factors of DPN in Vietnam. In total, 140 patients with type 2 diabetes mellitus (T2DM) were screened and enrolled consecutively over a six month period at the endocrinology department in 103 Military hospital. Questionnaires, demographic details, clinical examination, and blood tests were used to collect data from all patients. DPN was evaluated using diabetes neuropathy symptom score and nerve conduction study. Potential factors related to DPN were explored including body mass index, years with disease (&lt;10 vs. ≥10 years) , glycemic control (HbA1C &lt;7.5% vs. ≥ 7.5%) , glomerular filtration rate (GFR) , lipid profile. The prevalence of DPN was 43.5% (61/140) in the number of patients with T2DM. The main manifestation of peripheral nerve damage in subject is numbness 54,1%, decreased rough touch 52,56%. The majority of patients did not have movement disorders 95.08% and normal sense of deep sensation 93,4%. The percentage of patients with a burning sensation, reduction in raw tactile and movement disorders was higher in the group with duration of disease over 10 years (n=23) , compared to the group less than 10 years (n=38) (p &lt;0.05) . The neurotransmitter index in the group of patients with HbA1C ≥ 7.5% (n=17) was significantly different compared to the group with HbA1C &lt; 7.5% (n=44) (p &lt; 0.05) . The group with GFR &lt;70 ml/ph/1.73m2 (n=12) showed the significant change in nerve conduction parameters compared to the group with GFR ≥ 70 ml/ph/1.73m2 (n=49) (p &lt; 0.05) . DPN is highly frequent among patients with T2DM in Vietnam. Associated factors to DPN included duration of disease, HbA1C level and GFR index. The good glycemic control and early clinical manifestation as well as evaluating the kidney function would play an important role in this problem.

Disclosure
N. T. T. Trang: None. T. Fong: None. T. D. Do: None.
251-OR: Maternal Diabetes during Pregnancy and Incidence of Depression and Anxiety in Offspring from Childhood to Young Adulthood
Authors: XIANG ANNY , CARTER SARAH A. , LIN JANE C. , CHOW TING , MARTINEZ MAYRA P. , ALVES JASMIN M. , PAGE KATHLEEN A. , MCCONNELL ROB , NEGRIFF SONYA 
Published: May 2022

Many mental health disorders have roots in childhood; diabetes during pregnancy may play a role. We assessed risks of depression and anxiety in offspring associated with maternal pre-existing type 1 (T1D) , type 2 (T2D) , and gestational diabetes (GDM) with and without antidiabetic medications during pregnancy. The cohort included 439,590 singletons born in 1995-2015; followed up to Dec. 2020. Mother’s diabetes status during pregnancy, covariates, and child’s first clinical diagnosis of depression and/or anxiety since age 5 were obtained from electronic medical records. Cox regression was used to assess the associations for all ages and separately for ages 5-12, &gt;12 to 18, and &gt;18 to 26 years. During follow-up, 6.8% of offspring had a clinical diagnosis of depression and 13.4% had a diagnosis of anxiety. Figure 1 shows cumulative incidence of depression and anxiety by maternal diabetes exposure and covariate adjusted hazard ratios for diabetes types relative to unexposed. T1D, T2D, GDM requiring medications were all significantly associated with depression and anxiety in offspring (p&lt;0.for all) ; whereas GDM without medications was not (p&gt;0.5) . The significant associations were observed for ages 5-12 and &gt;12-18 years. These data suggest that severity of diabetes during pregnancy may increase offspring’s vulnerability for depression/anxiety during childhood and adolescence.

Disclosure
A.Xiang: None. S.A.Carter: None. J.C.Lin: None. T.Chow: None. M.P.Martinez: None. J.M.Alves: None. K.A.Page: None. R.Mcconnell: None. S.Negriff: None.
255-LB: Defining Functional Phenotype in Human Islets across Endocrine Cell Composition, Donor Age, Sex, and Ancestry
Authors: BRISSOVA MARCELA , DURAI HEATHER H. , MEI SHAOJUN , COLDREN ANASTASIA , DAVIS COREY , REIHSMANN CONRAD , HOPKIRK ALEXANDER L. , GIBSON DANNIELLE , ARAMANDLA RADHIKA , POFFENBERGER GREG , SAUNDERS DIANE C. , POWERS ALVIN C. , NILAND JOYCE C. , EVANS-MOLINA CARMELLA 
Published: May 2022

The Integrated Islet Distribution Program (IIDP) is currently the largest source of human islets for research in the U.S. The IIDP Human Islet Phenotyping Program (HIPP) provides standardized islet assessment and makes these data available to researchers. Since 2016, HIPP has phenotyped 337 islet samples from nondiabetic organ donors (40%F / 60%M, 45±12 years, BMI 29.0±5.4; 52% European, 26% Latino, 8% African, 3% Asian, and 11% other ancestry) . To define the islet structure-function relationships, we integrated physiological profiling of hormone secretion with islet cell composition measured by immunohistochemistry­. We found that % β cells varied significantly (range 34 - 92%; CV 21%) and had a strong negative correlation with % α (range 3 - 59%; CV 33%; r -0.95; p&lt;1.78E-163) and % δ cells (range 1 - 19%; CV 44%; r -0.32, p=2.69E-09) . This variation did not impact basal insulin secretion at 5.6 mM glucose, but insulin secretory responses stimulated by high 16.7 mM glucose, cAMP-evoked potentiation, and KCl-mediated depolarization, were all negatively correlated with % α and δ cells. By contrast, glucagon response to basal 5.6 mM glucose had the strongest negative correlation with % β cells (r -0.31, p=4.25E-09) , but not % δ cells (r 0.03, p=0.63) . Furthermore, the β cell composition did not correlate with age or BMI, but was higher in males vs. females (59.1±12.2% vs. 55.7±11.0%, p=0.0107) and in islets from donors of Asian ancestry (71.2±14.7%, p&lt;0.01) . Finally, we noted that insulin response to KCl-mediated depolarization was significantly lower in islets from donors of African vs. European or Asian ancestry (8.3±4.0 vs. 16.5±8.8 and 13.0±7.0ng/IEQ; p&lt;0.01) . Thus, these data highlight the importance of endocrine cell composition in islet hormone secretion possibly influencing β-α cell paracrine interactions and setpoint of glucagon secretion in response to low glucose. In addition, they suggest that β cell composition and insulin secretion are influenced by sex and ancestry.

Disclosure
M. Brissova: None. G. Poffenberger: None. D. C. Saunders: None. A. C. Powers: None. J. C. Niland: None. C. Evans-molina: Advisory Panel; Avotres Inc., DiogenX, Isla Technologies, MaiCell Therapeutics, Provention Bio, Inc., Other Relationship; Astellas Pharma Inc., Dompé, Lilly, Research Support; BMS, Nimbus Therapeutics. H. H. Durai: None. S. Mei: None. A. Coldren: None. C. Davis: None. C. Reihsmann: None. A. L. Hopkirk: None. D. Gibson: None. R. Aramandla: None.
256-LB: GABA and Sitagliptin Prevent Impairment of ß-Cell Function Caused by High-Fat Diet
Authors: WANG ZHIHONG , FAN LINLING , NI YUNZHI , MA ANRAN , WU DI , CUI QIAOLI , ZHOU YUE , LOU YAN-RU , PRUD'HOMME GERALD J. , WANG QINGHUA 
Published: May 2022

Excessive loss of islet beta cells is a major cause for the development of type 2 diabetes (T2D) , and seeking an effective method to enhance beta cell proliferation is a promising therapeutic strategy for T2D. In this study, we examined whether combined therapy of GABA and sitagliptin is effective in promoting beta cell proliferation and ameliorating the impairment of beta-cell function caused by high-fat diet (HFD) feeding in mice. Male C57BL/6J mice were fed with normal chow diet, HFD, or HFD combined with GABA, sitagliptin, or both drugs. Daily oral drug administration was initiated one week before HFD and maintained for two weeks. After two weeks of intervention, we found that GABA or sitagliptin administration ameliorated the impairment of glucose tolerance induced by HFD. This was associated with improved insulin secretion in vivo. Notably, combined administration of GABA and sitagliptin significantly enhanced these effects as compared to each of the monotherapies. Combined GABA and sitagliptin was superior at increasing beta-cell mass, and associated Ki67+ and PDX-1+ beta-cell counts. In addition, we found that HFD-induced compensatory beta-cell proliferation was associated with increased activation of unfolded protein response (UPR) , as indicated by BiP expression. This could be an important mechanism of compensatory beta-cell proliferation, and beta cells treated with GABA and sitagliptin showed greater UPR activation. Our results suggest that the combined use of these agents produces superior therapeutic outcomes.

Disclosure
Z. Wang: None. Q. Wang: None. L. Fan: None. Y. Ni: None. A. Ma: None. D. Wu: None. Q. Cui: None. Y. Zhou: None. Y. Lou: None. G. J. Prud'homme: None.

Funding
The National Natural Science Foundation of China (No.81630020, 81570518, and 81800751) , the Ministry of Science and Technology (No. 2017ZX09303001) , Shanghai Science and Technology Department (No. 2017ZX09303001) , and Juvenile Diabetes Research Foundation (JDRF, 2-SRA-2017-64-G-R to G P, QW, and T J; and 2-SRA-2015-64 to Q W, G P and T J) .