bluuebunny/crossref_metadata_2025 huggingface dataset:
1215-P: Effects of Exogenous Secretin on Postprandial Plasma Glucose and Lipids and Gallbladder Motility and Hemodynamics in Man
Authors: BENTZEN MARIA J. , HEIMBÜRGER SEBASTIAN M. NGUYEN , HARTMANN BOLETTE , HOLST JENS J. , CHRISTENSEN MIKKEL B. , KNOP FILIP K.
Published: June 2021

Secretin is best known for its effect on pancreatic exocrine secretion. It also has osmoregulatory effects and was recently identified as a potential target for the treatment of obesity. We investigated the effects of a 5-hour intravenous (iv) secretin infusion on postprandial plasma glucose and lipids and gallbladder motility as well as hemodynamics in healthy males.

In a randomized, double-blind, placebo-controlled, crossover study, 25 healthy males (25.7 ± 6.1 (mean ± SD) years; BMI 23.4 ± 1.8 kg/m2) underwent two 5-hour iv infusions of secretin (1 pmol/kg/min) or placebo (saline), with an interposed 8-week washout period. After 30 minutes of infusion, a standardized liquid mixed meal was ingested. Prior to and with regular intervals during the 5-hour infusions, blood samples were drawn, ultrasonography of the gallbladder performed, and hemodynamics measured.

Steady-state plasma concentrations of secretin amounted to 113 ± 2 pmol/L, i.e., ~20-fold higher than physiological levels. Postprandial plasma triglyceride excursions were higher during secretin than placebo infusions (baseline-subtracted area under curve: 111 ± 49 vs. 83 ± 36 min × pmol/L [P = 0.012]), whereas excursions in glucose, glycerol and free fatty acids were similar during placebo and secretin infusions. Compared to placebo, secretin reduced maximum gallbladder ejection fraction by 32 ± 27% (P <0.001) and increased mean systolic and diastolic blood pressure by 5.3 ± 4.5 (P <0.039) and 2.2 ± 3.2 mmHg (P <0.001), respectively, and increased heart rate by 5.5 ± 3.6 bpm (P <0.001).

We conclude that a 5-hour iv infusion of secretin in healthy males has no effect on fasting and postprandial glucose levels, but reduces postprandial gallbladder contraction, while increasing plasma triglycerides, blood pressure and pulse.

Disclosure

M. J. Bentzen: None. S. M. Nguyen heimbürger: Speaker’s Bureau; Self; AstraZeneca. B. Hartmann: None. J. J. Holst: Consultant; Self; Novo Nordisk, Other Relationship; Self; Antag Therapeutics, Bainan Biotech, MSD Corporation, Novo Nordisk, Other Relationship; Spouse/Partner; Antag Therapeutics, Bainan Biotech, Synklino ApS. M. B. Christensen: None. F. K. Knop: Advisory Panel; Self; MSD Corporation, Novo Nordisk A/S, Sanofi, Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk A/S, Pharmacosmos, Zealand Pharma A/S, Research Support; Self; Novo Nordisk A/S, Zealand Pharma A/S, Speaker’s Bureau; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MSD Corporation, Novo Nordisk A/S.
122-LB: In Vitro Pharmacodynamic Studies of IDG-16177, a Potent GPR40 Agonist, for the Treatment of Type 2 Diabetes
Authors: YOON JONGMIN , SONG HAENGJIN , LEE DON-GIL , KIM JUNG HO , HONG DAHAE , SHIN CHORONG , JANG EUNHYE , KIM JISU , LEE SEOLHEE , JUN YEARIN , AN KYUNGMI , HONG CHANG-HEE , KWAK HYUN-JUNG , JE IN-GYU , SONG HYO-JUNG
Published: June 2021

G-protein-coupled receptor 40 (GPR40/FFA1/FFAR1), a clinically validated anti-diabetes target, enhances insulin secretion in type 2 diabetes. It is known that the effect of glucose-stimulated insulin secretion (GSIS) in pancreatic β cells is mediated primarily through Gq. However, in a recent study, it was found that GPR40 plays a role in both G protein-mediated and β-arrestin-mediated mechanisms, and fasiglifam (TAK-875), a partial GPR40 agonist discontinued in phase 3 clinical trials, induces insulin secretion by mediating β-arrestin rather than Gq. Therefore, by using stable GPR40 cell lines and β cells, we tried to confirm the signaling mechanism and efficacy of IDG-16177, which is being developed by Ildong Pharma in first-in-human study, as a GPR40 agonist. In cells expressing recombinant human, rat, and cynomolgus monkey GPR40, IDG-16177 dose-dependently increases intracellular free Ca2+ level, with EC50 of 114.3, 103.9, and 758.8 nM, respectively, showing no significant differences between human and rat (fasiglifam EC50= 75.2, 140.4, and 906.2 nM). IDG-16177 enhances β-arrestin recruitment, which has been shown to contribute to GPR40-mediated GSIS, with an EC50 of 68.0 nM and Emax of 99.4%, and is more efficacious and potent than fasiglifam (EC50= 154.0 nM; Emax= 88.0%). IDG-16177 exhibits EC50 of 0.8 nM and 110.6 nM, in inositol phosphate 1 (IP1) accumulation assay and extracellular signal-regulated kinase (ERK) activation assay, respectively. Although IDG-16177 shows no signal at the cAMP pathway like fasiglifam, IDG-16177 (0.1~3 μM)-treated group enhances more insulin secretion than fasiglifam (1~10 μM) in HIT-T15 β cells. These studies support the potential utility of IDG-16177 for the treatment of type 2 diabetes.

Disclosure

J. Yoon: None. Y. Jun: None. K. An: None. C. Hong: None. H. Kwak: None. I. Je: None. H. Song: None. H. Song: None. D. Lee: None. J. Kim: None. D. Hong: None. C. Shin: None. E. Jang: None. J. Kim: None. S. Lee: None.
1230-P: Isolation of Functional Endothelial Progenitor Cells from Human Adipose Tissue
Authors: CACCIOPPOLI CRISTINA , PERRINI SEBASTIO , GENCHI VALENTINA ANNAMARIA , DORIA ROSSELLA , PALMA GIUSEPPE , CIGNARELLI ANGELO , NATALICCHIO ANNALISA , LAVIOLA LUIGI , GIORGINO FRANCESCO
Published: June 2021

Endothelial progenitor cells (EPCs) are key for angiogenic responses in multiple tissues and mediate a coordinate augmentation of the capillary network as adipose tissue (AT) expands in response to positive energy balance. However, isolation and culture of EPCs from human AT has been difficult. Here we describe a new method for obtaining well-characterized EPCs from human AT. Subcutaneous and visceral AT specimens (approximately 1-2 g) were obtained from 10-20 obese subjects by needle biopsy of abdominal subcutaneous AT and removal of omental AT fragments during abdominal surgery, respectively. Human EPCs were isolated from both the digested (SVCI) and undigested (SVCII) stromal vascular fractions of AT by anti-CD31 beads. After 5 days of in vitro culture, EPCs from SVCII exhibited an endothelial-like cobblestone morphology as compared to EPCs from SVCI. Flow cytometry analysis showed that the percentage of CD31+ and CD144+ cells was much higher in the SVCII compared to SVCI fraction (SVCII: CD31 97.9±2.9%, CD144 93.3±4.7%; SVCI: CD31 4.0±1.2%, CD144 3.8±0.7%). Immunofluorescence staining demonstrated that CD31+ EPCs from SVCII expressed Von Willebrand Factor (vWF) and VE-cadherin. Additionally, significantly higher mRNA and protein levels of CD31, E-selectin, e-NOS, VEGFR, and CD34 were found in CD31+ EPCs from SVCII than in control cells (CD31- cells from SVCI). EPCs from SVCII maintained the expression of endothelial markers (CD144 mRNA and protein levels) up to the fourth cell passage. Lastly, CD31+ EPCs from SVCII, but not control cells, were able to form tubes in 3D scaffolds (Matrigel) resembling capillary structures, as well as to incorporate acetylated LDL in vitro. Thus, we have successfully isolated EPCs with high proliferative potential and specific functional properties from the human AT. This will potentially increase our understanding of AT biology particularly in relation to altered expansion of distinct AT depots in human obesity.

Disclosure

C. Caccioppoli: None. S. Perrini: None. V. Genchi: None. R. Doria: None. G. Palma: None. A. Cignarelli: None. A. Natalicchio: Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Sanofi. L. Laviola: Advisory Panel; Self; A. Menarini Diagnostics, Abbott, AstraZeneca, Lilly Diabetes, Novo Nordisk Inc., Roche Diabetes Care, Sanofi-Aventis, Speaker’s Bureau; Self; Boehringer Ingelheim International GmbH, Medtronic. F. Giorgino: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novo Nordisk, Roche Diabetes Care, Sanofi, Research Support; Self; Lilly Diabetes, Roche Diabetes Care.
124-LB: Development of IDG-16177, a Selective and Safe GPR40 Agonist for the Treatment of Type 2 Diabetes
Authors: YOON JONGMIN , SONG HAENGJIN , KIM JUNG HO , LEE SEOLHEE , SHIN CHORONG , JUN YEARIN , HONG DAHAE , LEE DON-GIL , JANG EUNHYE , KIM JISU , AN KYUNGMI , HONG CHANG-HEE , KWAK HYUN-JUNG , JE IN-GYU , SONG HYO-JUNG
Published: June 2021

GPR40 has been considered a potential therapeutic target for type 2 diabetes because activation of GPR40 stimulates insulin secretion when glucose levels increased. Fasiglifam, a GPR40 agonist, was withdrawn from clinical development in Phase III due to DILI. Therefore, we evaluated the safety profiles of IDG-16177, a novel GPR40 agonist. The potential for IDG-16177 to have off-target effects was assessed in a panel of 173 binding assays. 10 μM IDG-16177 demonstrated activity (>50% inhibition) against DP, EP2, EP3 and EP4 with 81, 83, 57 and 67 % inhibition, respectively. In a functional assay against the same targets, IDG-16177 was inactive in agonist and antagonist mode except for DP with 62.2% activity inhibition at a concentration of 10 μM. IDG-16177 and fasiglifam showed the similar level of hepatotoxic response in HμRELToxTM assay. Formation of reactive metabolite and covalent binding to proteins was evaluated in human hepatocytes. IDG-16177 shows lower covalent binding burden at expected human efficacious dose (0.3~1 mg) than fasiglifam. Transporter inhibitory potential of IDG-16177 was assessed in hepatic transporter-expressing membrane vesicles. IDG-16177 and fasiglifam showed the similar inhibition level of BSEP, MRP2, MRP3, and MRP4. But clinically predicted plasma concentration of IDG-16177 is lower than that of fasiglifam, so the safety margin of IDG-16177 is wider than that of fasiglifam. A core battery of safety pharmacology was evaluated and IDG-16177 did not induce adverse effect in all studies. A 4-week toxicity study was conducted in rats and monkeys, and the liver was determined as the target organ in monkeys. The NOAEL was over 60-fold than in vivo efficacy dose. IDG-16177 was not genotoxic in Ames test, in vitro and in vivo micronucleus test. And no phototoxicity was observed in in vitro 3T3 NRU study. These results shows that the potential for IDG-16177, a safe and effective GPR40 agonist, to treat patients with type 2 diabetes.

Disclosure

J. Yoon: None. J. Kim: None. K. An: None. C. Hong: None. H. Kwak: None. I. Je: None. H. Song: None. H. Song: None. J. Kim: None. S. Lee: None. C. Shin: None. Y. Jun: None. D. Hong: None. D. Lee: None. E. Jang: None.
1242-P: Defining the Nkx6.1 Interactome in Beta Cells Reveals a Novel Interaction with Pdx1
Authors: LITTLEFIELD CONNOR C. , JENSEN NATHANAEL C. , HILL JONATHON T. , PRICE JOHN C. , TESSEM JEFFERY S.
Published: June 2021

The beta cell transcription factor Nkx6.1 plays a critical role in pancreatic progenitor cell differentiation, mature beta cell proliferation and insulin secretion. The pathways regulated by Nkx6.1 that results in these phenotypes are still being defined. Given that transcription factors generally function in complexes, we sought to determine proteins that interact with Nkx6.1 and may be harnessed to expand functional beta cell mass. INS-1 832/13 beta cells were transduced with AdCMV-Nkx6.1-BioID, AdCMV-GFP-BioID or left untreated. Biotinylated proteins were isolated and the Nkx6.1 interactome was defined using liquid chromatography-tandem mass spectrometry (LC-MS/MS). We defined 176 biotinylated proteins in cells transduced with AdCMV-Nkx6.1-BioID that were not observed with AdCMV-GFP-BioID or naturally biotinylated proteins from untreated lysates (P≤0.05, n=9). These 176 proteins are enriched in terms of nucleotide binding (P=3.6E-5), ribosomal proteins (P=9.1E-4), and transcription factors (P=4.3E-4). Among the enriched transcription factors, we validated that Pdx1, Mef2d and Nr2c2 were biotinylated in response to transduction with AdCMV-Nkx6.1 using biotin-targeted immunoprecipitation and western blot. To examine if these transcription factors are likely to interact with Nkx6.1 on the genome, we analyzed the frequency of proximal binding sites for Nkx6.1 and our candidate genes. Nr2c2 and Pdx1 binding sites in close proximity to Nkx6.1 binding sites were statistically overrepresented in the genome (P≤0.01). Given the role of Pdx1 on functional beta cell mass, we further characterized the interaction of endogenous Nkx6.1 and Pdx1 by co-immunoprecipitation (Co-IP). Our data demonstrates a significant Pdx1 binding by Nkx6.1 Co-IP, as compared to Co-IP with the IgG control (P=0.015, n=3). These data define potential Nkx6.1 binding partners in INS-1 832/13 cells, as well as a novel interaction between two essential beta cell transcription factors, Nkx6.1 and Pdx1.

Disclosure

C. C. Littlefield: None. N. C. Jensen: None. J. T. Hill: None. J. C. Price: None. J. S. Tessem: None.

Funding

Thomas J. Beatson, Jr. Foundation (2019-003)
1246-P: Microcirculatory Circuit of Pancreatic Islets in Diabetic Fetopathy and Congenital Hyperinsulinism
Authors: PROSHCHINA ALEXANDRA , GUBAEVA DILIARA , KRIVOVA YULIYA , OTLYGA DMITRY , MELIKYAN MARIA
Published: June 2021

The main cause of diabetes is the loss or dysfunction of beta cells that leads to insulin deficiency and hyperglycemia. However, there are some opposite pathologies, in which insulin secretion results in hypoglycemia. Data on the islets morphology in such diseases may be useful for understanding of the pathogenesis of diabetes. Diabetic fetopathy (DF) is a complication of gestational diabetes or preexisting maternal diabetes mellitus, which is characterized by the accelerated fetal growth and neonatal hypoglycemia. These complications mainly develop due to fetal hyperinsulinemia as a compensatory response to the increased delivery of the glucose to the fetus. Congenital hyperinsulinism (CHI) is a severe genetic disease, in which hypoglycemia is caused by excessive insulin secretion. There are two main CHI forms based on histology: diffuse and focal. Pancreatic samples of 4 newborns with DF from mothers with diabetes, 7 infants with diffuse CHI, and 7 infants with focal CHI were compared to 6 control infants without hypoglycemia. The diagnosis of CHI and histological form were established based on increased insulin level during hypoglycemia, presence of pathologic mutations in ABCC8/KCNJ11 genes, and immunohistochemistry results. All pancreatic samples were examined by immunohistochemistry with antibodies against insulin, glucagon, and vimentin. Histological changes such as nuclei enlargement in some beta-cells, islets hypertrophy, and prominent islets vascularization were observed in the endocrine pancreas of infants with DF as well as in patients with CHI. Swelling of the perivascular space was the distinguishing feature, which was revealed only in newborns with DF. In children with CHI, the abundant vascularization in large islets was not accompanied by swelling. We assume that a long-term increase of blood glucose in fetuses with DF leads to vasodilatation, which subsequently causes impaired endothelial permeability and swelling.

Disclosure

A. Proshchina: None. D. Gubaeva: None. Y. Krivova: None. D. Otlyga: None. M. Melikyan: None.
1250-P: Reg3g Mediates Sex-Specific Islet Dysfunction in Offspring of Obese Mice via Heparan Sulfate Glycan Polymerization
Authors: JARRELL JAMES C. , CASASNOVAS JOSE , KUA LIM
Published: June 2021

Human offspring of obese mothers suffer higher risk of developing type 2 diabetes due to insufficient islet insulin secretion. Preclinical maternal obesity models demonstrated the sex-differences in offspring islet function, but the mechanistic targets are unknown. We found that a higher islet Regenerating Islet Derived Protein 3-Gamma (Reg3g) is associated with the maintenance of islet function in female offspring of obese dams. Reg3g binds to EXTL3 glycosyltransferase that polymerizes heparan sulfate glycosaminoglycan (HSG). To date, the role of Reg3g mediated HSG polymerization in modulating β-cell health in offspring of obese mice is unclear. We hypothesize that the upregulation of Reg3g-mediated HSG polymerization protects offspring of obese mice from glucose intolerance and islet dysfunction. We evaluated islet GSIS, islet Reg3g gene/protein, and pancreatic HSG with SAX-HPLC in offspring born to chow-fed mice (Con) and diet-induced obese mice (MatOb) on postnatal day 21 (P21). To define the causality of Reg3g, wildtype (WT) and heterozygous Reg3g mutant (Reg3g+/-) offspring of Con and MatOb were generated. Lastly, we tested the therapeutic effect of intraperitoneal recombinant Reg3g (rReg) and heparan sulfate analogue (HS) from P14-20 in male MatOb pups. Compared to same-sex controls, P21 female MatOb pups had higher islet Reg3g gene/protein* (n=3-6), higher islet (n=3/3) and pancreatic (n=6/6) HSG*, and unchanged GSIS. Male MatOb pups had unchanged islet Reg3g and a lower pancreatic HSG* (n=8/8). Male MatOb pups also had a lower glucose tolerance* (n=9-19) and 30% decrease in GSIS* (n=5/5). The sex-difference in glucose tolerance was ablated in Reg3g+/- mice, where female MatOb Reg3g+/- pups had significantly impaired GTT. Lastly, rReg3g or HS improved glucose tolerance in male MatOb pups* (n=3-7). *p<0.05.

In conclusion, our findings supported the role of Reg3g as an amenable mechanistic target mediating islet dysfunction in MatOb offspring.

Disclosure

J. C. Jarrell: None. J. Casasnovas: Employee; Self; Thermo Fisher Scientific. L. Kua: Stock/Shareholder; Spouse/Partner; Dexcom, Inc., Thermo Fisher Scientific.

Funding

Riley Children’s Foundation (to L.K.); Showalter Research Trust (EPAR1143 to L.K.); Center for Diabetes and Metabolic Diseases (P30DK097512)
1258-P: Il-1ß-Induced Transcription of Nf-kB Target Genes Is Repressed by Bet Bromodomain Inhibitors in Pancreatic ß-Cells
Authors: NORD JOSHUA , WYNIA-SMITH SARAH , SMITH BRIAN C. , LIPINSKI RACHEL JONES
Published: June 2021

Autoimmune diabetes is characterized by chronic inflammation of pancreatic islets which ultimately destroys insulin-producing β-cells. In the islet, elevated proinflammatory cytokines lead to increased transcription of inducible nitric oxide synthase (iNOS) and its downstream product, nitric oxide (NO). Elevated levels of NO for prolonged periods lead to β-cell apoptosis. The exact causes of autoimmune diabetes are not well defined and, although genetic predisposition is a factor, low concordance rates of autoimmune diabetes among monozygotic twins indicates a role for epigenetic factors. Recent studies suggest that the bromodomain and extraterminal domain (BET) family of epigenetic regulatory proteins contribute to the onset and progression of autoimmune diabetes. BET proteins are epigenetic readers of sites of lysine acetylation found commonly on histones and have emerged as promising drug targets for a wide variety of diseases. We hypothesize that BET proteins increase proinflammatory cytokine-induced transcription in β-cells leading to β-cell damage and that selective inhibition of BET bromodomains with small molecules will prevent or reverse the progression of autoimmune diabetes. Here, we show that BET bromodomain inhibitors decrease the β-cell response to proinflammatory cytokines in an insulinoma β-cell line (INS832/13) and primary rat islets. BET inhibitors attenuated cytokine-induced transcription of inflammatory mediators, including iNOS. This decreased transcription is mediated through inhibition of the NF-κB signaling pathway by BET inhibitors. Using knockdown of individual BET proteins in a β-cell line, we identified the importance of individual BET family members in the altered transcriptional profile characteristic of autoimmune diabetes. This work uncovers important mechanisms of disease onset and progression of autoimmune diabetes, laying the groundwork for more targeted treatments with drug-like small molecules.

Disclosure

J. Nord: None. S. Wynia-smith: None. B. C. Smith: None. R. Jones lipinski: None.

Funding

American Diabetes Association (1-18-IBS-068 to B.C.S.); National Institutes of Health (R01DK119359, T32HL134643)
1260-PUB: Type 2 Diabetes and Congestive Heart Failure Are Mutually Independent Predictors of the Presence of Albuminuria
Authors: MAECHLER MAXIMILIAN , VONBANK ALEXANDER , LARCHER BARBARA , MADER ARTHUR , SPRENGER LUKAS , MUTSCHLECHNER BEATRIX , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ , SAELY CHRISTOPH H.
Published: June 2021

Albuminuria is a well-known characteristic of diabetic nephropathy and it is also present in a large portion of patients with congestive heart failure (CHF). However, the single and joint effects of type 2 diabetes mellitus (T2DM) and CHF on albuminuria are unknown. This issue therefore was addressed in the present study.

We investigated 180 patients with CHF, of whom 83 had T2DM (CHF+/T2DM+) and 97 did not have diabetes (CHF+/T2DM-) and 223 controls without CHF, of whom 39 had T2DM (CHF-/T2DM+) and 184 did not have diabetes (CHF-/T2DM-).

The prevalence of albuminuria was lowest in CHF-/T2DM- subjects (8.7%). When compared to this group it was significantly higher in CHF-/T2DM+ (23.1%, p=0.010), CHF+/T2DM- (38.1%, p<0.001) and CHF+/T2DM+ patients (62.7%, p<0.001). It was highest in CHF+/T2DM+ patients, in whom it was higher than in CHF-/T2DM+ (p<0.001) and in CHF+/T2DM- (p=0.001) patients; a trend towards a higher prevalence of albuminuria in CHF-/T2DM+ patients vs. CHF+/T2DM- patients did not reach statistical significance (p=0.093). In logistic regression analysis, CHF and T2DM were mutually independent predictors of albuminuria, when adjusted for age, sex, body mass index, LDL cholesterol, history of smoking and hypertension, as well as for the use of statins and ACE inhibitors/angiotensin II receptor blockers (OR 2.57 [95% CI 1.47-4.51]; p=0.001 and OR 4.15 [2.18 - 7.88]; p<0.001, respectively).

We conclude that T2DM and CHF are mutually independent predictors of albuminuria.

Disclosure

M. Maechler: None. C. H. Saely: None. A. Vonbank: None. B. Larcher: None. A. Mader: None. L. Sprenger: None. B. Mutschlechner: None. A. Leiherer: None. A. Muendlein: None. H. Drexel: None.
1266-PUB: Correlation of Sex Hormones Levels and Glycated Hemoglobin in Nondiabetic Middle-Aged and Elderly
Authors: BAO YUQIAN , XU YITING , CAO WEIJIE , SHEN YUN , TANG JUNLING , WANG YUFEI , MA XIAOJING
Published: June 2021

Aims: Sex hormones are strongly linked to the occurrence and development of diabetes, and influence glycated hemoglobin (HbA1c) levels in diabetic population; but, the relationship between sex hormones and HbA1c in nondiabetic population remains unknown. This study aimed to explore the extent of influence of sex hormones on HbA1c levels in nondiabetic population.

Methods: A total of 1409 nondiabetic subjects, including 601 men and 808 postmenopausal women were recruited from Shanghai community. HbA1c was detected using high performance liquid chromatography, and hemoglobin level was determined by sodium lauryl sulfate colorimetry. Serum estradiol (E2), total testosterone (TT), and sex hormone binding globulin (SHBG) were measured by chemiluminescent microparticle immunoassays.

Results: The level of HbA1c was 5.6 (5.4-5.9) % in all subjects, with 5.6 (5.4-5.8) % in men and 5.7 (5.5-5.9) % in postmenopausal women. After adjusting for age, body mass index (BMI), and hemoglobin, E2 was positively correlated with HbA1c in men (r = 0.122, P = 0.003), and SHBG was inversely correlated with HbA1c (r = -0.125, P < 0.001) in women. Other hormones were not correlated with HbA1c (all P > 0.05). Multivariate linear regression analysis showed that, except for traditional factors, such as age, hemoglobin, and BMI, E2 was another determinant of HbA1c (standardized β = 0.137, P = 0.003) in men and the regression equation was HbA1c (%) = 0.001×E2 (pmol/ L) +5.465. In women, SHBG was another determinant of HbA1c (standardized β = -0.178, P < 0.001), except for age and systolic blood pressure (SBP), and the regression equation was HbA1c (%) = -0.002×SHBG (nmol)/L) +5.772.

Conclusion: After controlling for confounding factors, E2 is positively correlated with HbA1c in men, and SHBG is inversely correlated with HbA1c in postmenopausal women. Sex hormones influence HbA1c levels in nondiabetic population, but it is very limited to affect the level of HbA1c in the diagnose of diabetes.

Disclosure

Y. Bao: None. Y. Xu: None. W. Cao: None. Y. Shen: None. J. Tang: None. Y. Wang: None. X. Ma: None.
1275-PUB: Call to Action: COVID-19 Pandemic Prompts Subcutaneous Treatment Option for Diabetes Ketoacidosis (DKA) in Hospital
Authors: MEEHAN DORIS , TALAVERA LAURA , PHILIS-TSIMIKAS ATHENA , FORTMANN ADDIE L.
Published: June 2021

COVID-19 challenges organizations to modify approaches to optimize diabetes management while reducing Personal Protective Equipment (PPE) use and nurse time, and maintaining patient safety. In April 2020, Scripps Health, a five-hospital health system in southern California created a subcutaneous Diabetes Ketoacidosis (DKA) treatment option for use with adults, admitted with mild to moderate DKA. Primary aims were to achieve DKA resolution and glycemic targets similar to the intravenous (IV) insulin treatment option, and no hypoglycemia <70 mg/dL.

The new order set utilized weight-based dosing, with similar orders for labs, electrolyte and IV fluid replacement, and resolution criteria. Differences included automatic insulin dosing and basal/bolus insulin. Key changes were a reduced frequency of point of care testing (POCT) and ≤140 mg/dL hypoglycemia prevention orders. Post-implementation audits between April - July 2020 showed no hypoglycemia and resolution time similar to IV insulin. However, only 6% (N=17) of DKA cases were managed with subcutaneous, as compared to IV insulin. To help understand why there was such a limited uptake, a detailed retrospective chart review was undertaken on a subset of twenty-two DKA cases managed with IV insulin. Findings showed that 17 (77%) had type 2 diabetes, 5 (23%) had type 1 diabetes. 47% of cases had opportunities for subcutaneous management based on DKA classification and no contraindications for subcutaneous therapy.

Findings indicate organizations should consider a DKA subcutaneous option. Lack of knowledge of DKA severity may be a factor in low utilization, therefore an EHR DKA Classification tool was implemented to support providers. Research is needed to determine if this increases utilization of the subcutaneous treatment option and what other barriers exist.

Disclosure

D. Meehan: None. L. Talavera: None. A. Philis-tsimikas: Advisory Panel; Self; Bayer Inc., Lilly Diabetes, Medtronic, Novo Nordisk, Consultant; Self; Sanofi-Aventis, Employee; Spouse/Partner; Ionis, Other Relationship; Self; Merck & Co., Inc., Research Support; Self; Dexcom, Inc., Lilly Diabetes, Medtronic, Novo Nordisk, Sanofi-Aventis. A. L. Fortmann: None.
1277-PUB: Severe DKA in Adolescent at Onset of Type 2 Diabetes and COVID-19
Authors: BABY MERILYN , LITAO MELISSA KAORI S. , DAPUL HEDA R. , FRANKLIN BONITA , GALLAGHER MARY PAT
Published: June 2021

Introduction: Obesity and type 2 diabetes (T2D) increase severity of SARS-CoV2 in adults. In one review of DKA and COVID-19 in adults, 77% had pre-existing diabetes while 10% were newly diagnosed. We report an adolescent with severe DKA and new onset T2D in the setting of COVID-19 infection, who had a complex hospital course.

Case: A 14-year old male with BMI of 43.7 kg/m2 and learning disabilities presented with decreased mental status and 4 day history of polydipsia, polyuria and emesis. Initial labs: glucose 546 mg/dl, BOHB 4.4 mmol/L, venous pH 6.94, HCO3 3mmol/L, serum osm 287 mOsm/kg, A1C 12.3%, pancreatic antibodies negative. C-reactive protein, d-dimer, ferritin, CPK, troponin, lipase (4,610 U/L), and amylase (839 U/L) were elevated. Patient received mannitol. No cerebral edema on head CT. Chest/Abd CT showed bilateral lower lobe consolidation of lungs and heterogeneous pancreas with no fluid collection. IV fluids and insulin were started. Nine hours after presentation, mental status declined further and patient required intubation for respiratory failure. At 19 hours, ketosis had resolved but acidosis persisted with arterial pH=7.05. SARS-CoV-2 nasopharyngeal swab PCR was positive. Course was complicated by multi-organ failure, rhabdomyolysis, and fluid refractory shock requiring vasopressors and renal replacement therapy (max creatinine 5.13 mg/dL). Patient started anticoagulant therapy, but on day 12 left femoral DVT was diagnosed. On hospital day 20 a retroperitoneal hemorrhage was noted. Inflammatory markers normalized by day 43. The patient had significant neurologic deficits and required prolonged rehabilitation after discharge on hospital day 46.

Conclusion: To our knowledge, this case of a morbidly obese adolescent with neurocognitive delays, is the first report of an adolescent with COVID-19 presenting with new onset T2D and DKA, who had a hospital course similar in severity to those reported in adult patients. Adolescents with T2D and SARS-CoV2 infection should be monitored for severe disease.

Disclosure

M. Baby: None. M. S. Litao: None. H. R. Dapul: None. B. Franklin: None. M. Gallagher: None.
128-LB: Sodium–Glucose Cotransporter-2 Inhibitors and Risk of Retinal Vein Occlusion among Patients with Type 2 Diabetes: A Propensity Score–Matched Cohort Study
Authors: LEE MIN-KYUNG , HAN KYUNGDO , KWON HYUK-SANG , ROH YOUNG-JUNG
Published: June 2021

Objective: To assess the association between use of sodium-glucose cotransporter-2 (SGLT2) inhibitors and retinal vein occlusion (RVO) using data from the National Health Insurance Service in South Korea.

Research Designs and Methods: We used an active comparator, new user design and nationwide data from 2014 to 2017. Based on a 1:1 propensity score match, we included 47 369 new users of SGLT2 inhibitors and 47 369 users of other glucose-lowering drugs (oGLD). The mean follow-up time for the primary intention-to-treat analysis was 2.57 years. We used the Cox proportional hazards regression model to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for RVO. Based on the main outcome, a prespecified subgroup analysis was undertaken.

Results: During follow-up of 2.57 years, the incidence rate of RVO was 2.19 and 1.79 per 1000 person-years in patients treated with SGLT2 inhibitors and oGLD, respectively. The use of SGLT2 inhibitors was associated with an increased risk of RVO compared with oGLD use (HR 1.264, 95% CI 1.056-1.513). In the subgroup analyses, a significant interaction with SGLT2 inhibitors was observed for age and estimated glomerular filtration rate (eGFR); the HR for RVO was higher in patients aged ≥60 years and those with eGFR <60 mL/min/1.73m2 than in others.

Conclusions: In a matched cohort study, we found that SGLT2 inhibitors were associated with a significantly increased risk of RVO. The elderly and patients with chronic kidney disease were at higher risk for RVO.

Disclosure

M. Lee: None. K. Han: None. H. Kwon: None. Y. Roh: None.
129-OR: Glycolytic Enzymes and Creatine Kinase Locally Regulate KATP Channel Activity in Both ß- and a-Cells
Authors: HO THUONG , POTAPENKO EVGENIY , MERRINS MATTHEW J.
Published: June 2021

The ATP-sensitive potassium channel (KATP) is a key regulator of membrane potential and islet hormone secretion. In ß-cells, it has been previously showed that the local activity of pyruvate kinase (PK) can sufficiently raise ATP/ADP to induce KATP closure, thus providing a another route to trigger membrane depolarization parallel to mitochondrial oxidative phosphorylation. Here, using direct single-channel measurements of KATP in both ß-and the lesser studied α-cells, we provide evidence for a larger network of metabolic enzymes that operate in the vicinity of KATP channels to fine-tune their activity. We found that the phosphofructokinase product fructose-1,6-bisphosphate (FBP), which oscillates in ß-cells, can induce KATP closure by its metabolism through the glycolytic chain including aldolase, GAPDH, phosphoglycerate kinase, phosphoglycerate mutase, enolase and finally PK. Strikingly, while withholding the substrates at GAPDH, we observed that FBP can independently inhibit KATP channels by direct action. In addition, we further provide evidence that creatine kinase (CK) activity can either oppose or enhance KATP closure, depending on the reaction direction. Finally, we demonstrated that lactate has an activating effect on KATP.

In summary, these data provide evidence for the direct regulation of KATP by two metabolites, FBP and lactate, and identify two local ATP/ADP controllers, the glycolytic complex and the creatine kinase system in both ß-cells and α-cells.

Disclosure

T. Ho: None. E. Potapenko: None. M. J. Merrins: None.
132-LB: The Safety and Efficacy of Canagliflozin in Women with Polycystic Ovary Syndrome: A Randomized Control Trial
Authors: CAI MEILI , ZHANG YUQIN , QU SHEN , ZHANG MANNA
Published: June 2021

Objectives: To determine the safety and efficacy of canagliflozin in Polycystic Ovary Syndrome (PCOS) patients with insulin resistance (IR) and investigate whether canagliflozin was non-inferiority to metformin in PCOS patients with IR.

Methods: A randomized open-label study (ratio 1:1) was conducted in the department of endocrinology, Shanghai Tenth people’s Hospital between July 2019 and March 2021. PCOS women aged 18-45 years with IR were enrolled and randomly assigned to either canagliflozin 100 mg (n = 32) or metformin 1500-2000 mg (n = 35) daily for 12 weeks. The primary outcome was the changes in HOMA-IR before and after 12 weeks treatment. The secondary outcome were the changes in anthropometric, body composition, menstrual frequency, hormonal and metabolic parameters.

Results: A total of 53 subjects in the canagliflozin (n=27) and metformin group (n=26) have completed follow-up. Both canagliflozin (5.4±4.1 vs. 3.2±1.9; P=0.001) and metformin (4.7±3.5 vs. 3.6±3.0; P=0.009) can significantly improve HOMA-IR after 12 weeks in PCOS patients with IR. There was no significant difference in the changes of HOMA-IR (canagliflozin: −2.3 ± 3.2 vs. metformin: -1.4 ± 2.4; P = 0.222) between the two groups. According to a secondary endpoint analysis, the canagliflozin group resulted in significantly low uric acid than the metformin group. The changes in anthropometric, body composition, menstrual frequency, sex hormone and other metabolic parameters were comparable between two groups. Gastrointestinal reaction (including nausea, vomiting and Diarrhea) (57.14 %) and pruritus vulvae (6.25%) were the main adverse events in the metformin group and Canagliflozin group, respectively. There were none serious adverse events in both groups.

Conclusion: Our study showed that canagliflozin was not significantly inferior to metformin in PCOS patients with IR, which suggested SGLT2 inhibitor should be considered as an effective drug in the treatment of patients with PCOS.

Disclosure

M. Cai: None. Y. Zhang: None. S. Qu: None. M. Zhang: None.

Funding

National Natural Science Foundation of China (81601269)
134-LB: Efficacy and Safety of Dapagliflozin in Type 1 Diabetes: The RISING-STAR Study
Authors: HAMAGUCHI MASAHIDE , YAMAZAKI MASAHIRO , TANAKA TORU , ISHII MICHIYO , OKADA HIROSHI , MITSUHASHI KAZUTERU , KITAGAWA NORIYUKI , HASEGAWA GOJI , FUKUI MICHIAKI
Published: June 2021

Background and Objective: The safe method of instructing insulin dose reduction in combination with SGLT2 inhibitors, dapagliflozin for patients with type 1 diabetes mellitus has not been clarified. In this study, we conducted a stratified, two-arm, parallel comparative study with the primary endpoint of decreasing the frequency of hypoglycemia by instructing basal insulin dose reduction.

Method: The basal insulin dose to total daily insulin dose (TDD) ratio was defined as less than 40% in group A and more than 40% in group B. Group B was instructed to reduce basal insulin dose, while group A was not.

Results: Twenty-nine patients in group A and 28 patients in group B were included in the analysis due to withdrawal of consent before the start of the study. The frequency of hypoglycemia before and after the intervention was 0.23 times/day in group A to 0.26 times/day and 0.19 times/day in group B to 0.23 times/day, with no significant difference between the two groups (P=0.69). The frequency of ketosis, a secondary endpoint, also increased significantly after the intervention, from 0.013 times/day to 0.086 times/day in Group A (p=0.013) and from 0.013 times/day to 0.059 times/day in Group B (p=0.011). Time In Range on FGM improved from 63.6% to 69.7% in group A and from 59.0% to 69.1% in group B. MAGE improved from 121.7 mg/dL to 105.0 mg/dL in group A and from 123.4 mg/dL to 108.0 mg/dL in group B. DTSQ showed a significant improvement in question 2 regarding hyperglycemia in both groups after the intervention, from 3.6 to 2.5 (p=0.008) in group A and from 3.7 to 2.8 (p=0.017) in group B.

Conclusion: In the patients who were able to self-adjust their insulin dose, there was no significant difference in the number of hypoglycemia occurrences after concomitant use of dapagliflozin with or without instruction to reduce basal insulin dose. Concomitant use of dapagliflozin resulted in less glycemic variability, prolonged TIR and improved patient satisfaction regarding with hyperglycemia.

Disclosure

M. Hamaguchi: Research Support; Spouse/Partner; AstraZeneca K. K. M. Yamazaki: None. T. Tanaka: None. M. Ishii: None. H. Okada: None. K. Mitsuhashi: None. N. Kitagawa: None. G. Hasegawa: None. M. Fukui: None.

Funding

AstraZeneca K.K.; Ono Pharmaceutical Co., Ltd.
138-LB: Managing Hyperglycemia in Patients on an Insulin Pump: A Quality Improvement Study
Authors: YUEN ALEXA , TABATABAIE VAFA
Published: June 2021

During the transition from multiple daily injections to an insulin pump, diabetic patients need to engage in an intense period of learning to operate their pumps successfully. Inpatient endocrinology consultants note that some new users of insulin pumps fail to manage hyperglycemia correctly and present to the hospital in diabetic ketoacidosis. We found these patients often did not know when to use manual injections instead of their pumps or did not have backup insulin pens or syringes at home. To better understand this issue, a baseline survey of diabetic patients on insulin pumps was conducted from February to September 2020. The survey was administered to 52 subjects identified though appointments scheduled with the diabetes clinic. The questionnaire asked: 1) How would you respond if your sugar remained elevated an hour after administering a correction bolus through the pump? 2) Do you have insulin syringes or pens at home? The first question reflects events that would occur in the setting of an insulin pump failure. Any response that did not include a manual injection was considered incorrect. Our data showed that 85% of respondents had backup insulin supplies. 33% of patients overall responded appropriately to the pump failure scenario. Of the subjects who had insulin supplies, 39% responded correctly. Further analyses revealed that there is a significant relationship between having supplies and responding appropriately to hyperglycemia in pump failure. There was no relationship between patients’ answers and gender or age. Results of this survey will be used to modify the electronic template for diabetes clinic visits in order to help ensure that patients have appropriate supplies and training in identifying pump malfunctions and handling hyperglycemia. As part of this quality improvement project, patients will be surveyed again after implementation of the new template to assess whether the rates of possessing backup insulin supplies and of appropriate responses to hyperglycemia increased.

Disclosure

A. Yuen: None. V. Tabatabaie: None.
140-LB: Improving Translation of Diabetes Management Practices in Community Primary Care
Authors: THOMAS CELESTE C. , PEEK MONICA E. , PAUL CARLIE , ALLISON MARGARET , HEILBRUN ANNA , TILMON SANDRA , THOMPSON ROSHAWNDA , THOMAS DAVIEL P. , JOHNSON DANIEL C.
Published: June 2021

Objective: To evaluate the feasibility of using an innovative workforce development model, Project ECHO (Extension for Community Health Outcomes), to improve knowledge and self-efficacy around diabetes management practices among PCPs serving urban, under-resourced communities in the Chicago area.

Methods: The Project ECHO model was applied to the management of medically and socially complex diabetes. For this series, a multidisciplinary subject matter expert team met with 30 PCPs from 12 health centers across the Chicago area for 17 weekly videoconferencing telementoring sessions. PCPs completed knowledge tests and self-efficacy surveys prior to the first session. During each hourly session, after a short didactic, PCPs presented de-identified patient cases for discussion and received evidence-based guidance and mentorship with a focus on individualized care. After series completion, PCPs repeated surveys. Post-program semi-structured interviews were conducted.

Results: Increase in self-efficacy for treating complex diabetes reached the goal of 10% (p=.0007); the percentage of knowledge questions answered correctly increased from 39% to 62% (p<.0001). Participants reported increased comfort with and use of newer therapeutic agents. Participants reported taking the complicated psychosocial contexts of patients more in mind and adapting treatment regimens accordingly. One participant noted: “I was able to pick up pointers on how to talk to patients and how to motivate them asking the right questions about what is challenging for you, what can we do, and offer treatment, offer support accordingly.”

Conclusion: Among PCPs serving under-resourced communities in the Chicago area, ECHO-Chicago: Complex Diabetes improved confidence and knowledge in complex diabetes management. Interviews demonstrate changes in clinical practices. Continued application of the ECHO model to medically and socially complex diabetes care is likely to be useful in under-resourced communities.

Disclosure

C. C. Thomas: None. M. E. Peek: None. C. Paul: None. M. Allison: None. A. Heilbrun: None. S. Tilmon: None. R. Thompson: None. D. P. Thomas: None. D. C. Johnson: None.

Funding

Chicago Center for Diabetes Translation Research
145-LB: Glycemic Control Is Not an Independent Predictor of Mortality or Length of Stay for Patients Hospitalized with Coronavirus 2019 (COVID-19)
Authors: JAKOBY MICHAEL G. , WILLIAMS VANESSA , WARD STACEY , LEE SCOTT K. , BUHNERKEMPE MICHAEL , IZUORA KENNETH
Published: June 2021

Diabetes mellitus (DM) is an important prognostic factor for coronavirus 2019 (COVID-19). However, studies of hospital glycemic control and outcomes controlled for factors that affect morbidity and mortality in pneumonia (PNA) are limited. We conducted a multicenter retrospective cohort study of patients ≥ 18 years (N=108) admitted to either the ICU or noncritical units January 1, 2020 to September 29, 2020 with a clinical diagnosis or radiographic evidence of PNA, laboratory confirmation of COVID-19, and DM or newly diagnosed hyperglycemia, defined as admission plasma glucose > 126 mg/dL or one or more random plasma glucose measurements > 200 mg/dL. Co-primary endpoints were mortality, ICU length of stay (LOS), and total hospital LOS stratified by mean capillary blood glucose (CBG) for hospitalization. Endpoints were compared by logistic, linear, or Poisson regressions controlling for demographic variables, prehospital HbA1c, residence, pneumonia severity index score, Sequential Organ Failure Assessment score (ICU patients), pulmonary consultation, infectious diseases consultation, and study site. Patients treated with dexamethasone (N=42) were evaluated separately from untreated patients. There was no difference in mortality for patients with mean hospital CBG < 180 mg/dL (30.1%) or ≥ 180 mg/dL (20.0%, P=0.24). Median total hospital LOS was 8 (5-15) and 8 (6-16) days for patients with mean CBG < 180 mg/dL or ≥ 180 mg/dL, respectively (P=0.35), and there was no difference in ICU LOS by glycemic status (P=0.19). No measures of glycemic control were independent predictors of mortality or LOS in multivariable regression analyses, and results were unaffected by dexamethasone treatment status. In this study controlling for multiple validated PNA prognostic factors, hospital glycemic control did not have a significant effect on mortality or LOS for patients with DM or newly diagnosed hyperglycemia hospitalized with COVID-19.

Disclosure

M. G. Jakoby: None. V. Williams: None. S. Ward: None. S. K. Lee: None. M. Buhnerkempe: None. K. Izuora: None.
146-LB: Association of Serum 1,5-Anhydroglucitol with Severe COVID-19 in T2D patients
Authors: SONIA GAZTAMBIDE , BUTTON ERIC A. , ZULUETA MIRELLA , ARANA EUNATE , DE LA HOZ ANA B. , MENDIZABAL LEIRE , DEL OLMO JUAN , MUÑOZ RAQUEL , SIMON LAUREANO , CASTANO LUIS
Published: June 2021

Background: Hyperglycemia worsens the prognosis and severity in Covid-19 patients.

Objective: To assess the impact of glycemic control on COVID-19 severity.

Methods and Findings: Data from 460 individuals collected in Spain between April and July 2020 was analyzed in a cross-sectional study: healthy, Sars-Cov-2 negative (group 0, N = 197), Sars-Cov-2 positive, with mild COVID-19 symptoms (group 1, N = 113), Sars-Cov-2 positive, with severe COVID-19 symptoms who required hospitalization (group 2, N = 150) at Hospital Universitario Cruces in Bilbao, Spain. Fasting blood glucose, HbA1c and serum 1,5-anhydroglucitol (1,5-AG, indicator of hyperglycemic excursions over the prior 1-2 weeks) were measured. Differences in 1,5-AG (normal range >10µg/mL) were observed between all three groups (mean 1,5-AG of 21.19, 18.99, 14.64 µg/mL, respectively) when compared by an unpaired t-test. 1,5-AG levels across groups decreased with increasing severity, with the hospitalized patients (group 2) showing the greatest difference when compared to healthy individuals, p value < 0.0001. Logistic regression analysis showed that 1,5-AG had a mild positive association with increased COVID-19 severity (group 0 vs. group 2: AUC = 0.69, p value < 0.0001). A previous T2D diagnosis did not show association with COVID-19 severity (group 0 vs. group 2: AUC = 0.58, p value < 0.0001). Analysis of patients with a previous diagnosis of T2D showed a robust positive association between 1,5-AG and COVID-19 (group 0 vs. group 2, AUC = 0.79, p value 0.008). There was no association between HbA1c or fasting glucose with severity. Combination of 1,5-AG and HbA1c was similar than 1,5-AG alone (AUC = 0.80, p value 0.028).

Conclusions: Glycemic fluctuations in T2D patients may contribute to severe COVID-19. Measurement of serum 1,5-AG in T2D patients might help clinicians quickly identify diabetes patients at risk of severe COVID-19. These patients may benefit from more intensive management, treatment and vaccine prioritization.

Disclosure

G. Sonia: None. L. Castano: None. E. A. Button: Employee; Self; Precision Diabetes, Inc. M. Zulueta: Employee; Self; Patia Europe. E. Arana: None. A. B. De la hoz: None. L. Mendizabal: Employee; Self; PATIA. J. Del olmo: None. R. Muñoz: None. L. Simon: Board Member; Self; Oncomatryx Biopharma, S. L, Patia Biopharma, SA de CV, Patia Europe S. L., Permedika Entrepeneurs, S. L, SunRock, S. L, Employee; Self; Oncomatryx Biopharma, S. L, Patia Biopharma, SA de CV, Patia Europe S. L., PatiaCan, SA de CV, Permedika Entrepeneurs, S. L, Other Relationship; Self; Oncomatryx Biopharma, S. L, Patia Biopharma, SA de CV, Quimatryx, S. L, Stock/Shareholder; Self; Helenes Ventures, S. L, Nelum, Corp, Oncomatryx Biopharma, S. L, Patia Biopharma, SA de CV, Patia Europe S. L., PatiaCan, SA de CV, Permedika Entrepeneurs, S. L, Stemcell Therapeutics, S. L, SunRock, S. L.