bluuebunny/crossref_metadata_2025 huggingface dataset:
1247-P: The SND1 Coregulator Controls ß-Cell Function and Identity
Authors: KANOJIA SUKRATI , DAVIDSON REBECCA K. , CASEY NOLAN , SPAETH JASON
Published: June 2021

Pancreatic β-cells are crucial for glucose-stimulated insulin secretion (GSIS) and whole-body glucose homeostasis. Dysfunctional β-cell mass results in diabetes mellitus (DM), a growing pandemic causing global economic burden. Pancreas-enriched transcription factors (TFs) highly expressed in the β-cell that coordinate expression of genes essential for normal β-cell function, are commonly disrupted in β-cells from diabetic individuals. Therefore, it is of considerable importance to understand how TFs function normally and the mechanisms driving their dysfunction in settings of diabetes. Pdx1, an essential TF involved in β-cell function and identity, recruits transcriptional coregulators to coordinate expression of gene expression programs throughout the β-cell. Here we focus on the Staphylococcal Nuclease and Tudor domain containing protein (SND1) coregulator, which has been shown in other cellular contexts to facilitate transcriptional control through the recruitment of chromatin modifying enzymes. By co-immunoprecipitation and proximity ligation assays, we have found Pdx1 and SND1 interact in rodent and human β-cell lines and tissues. We generated SND1 CRISPR/Cas9 knockout cell lines in the Min6 mouse β-cells (SND1-KO) and performed mRNA-sequencing. Genes linked to insulin secretion, (vitamin D receptor (VDR)), and maintenance of β-cell identity (SIX2) were found to be differentially expressed in SND1-KO cells. Glucose-stimulated insulin secretion (GSIS) in INS1 832/13 rat insulinoma cell lines is trending down following Snd1 knockdown (p = 0.15). Future studies include measuring GSIS under different stimulatory conditions in following knockdown of SND1 in primary mouse and human islets. Moreover, we will define the chromatin occupancy footprint of SND1 and explore if chromatin accessibility is altered in SND1-KO β-cell lines. Lastly, we will explore how interactions between Pdx1 and SND1 are altered in models of diabetes and human donor tissues.

Disclosure

S. Kanojia: None. R. K. Davidson: None. N. Casey: None. J. Spaeth: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (K01DK115633, P30DK097512)
1248-P: Histone Deacetylase Inhibition Improves Store-Operated Calcium Entry and Glucose-Stimulated Insulin Secretion in Cytokine-Stressed Pancreatic ß-Cells
Authors: LEE CHIH-CHUN , KONO TATSUYOSHI , WEAVER STACI A. , SOHN PAUL , EVANS-MOLINA CARMELLA
Published: June 2021

Store-operated calcium entry (SOCE) functions to refill endoplasmic reticulum (ER) Ca2+ stores in response to ER Ca2+ depletion through gating of plasmalemmal Orai channels by the ER Ca2+ sensor STIM1. Dysfunctional β cell SOCE has been observed in response to cytokine-mediated stress, whereas select histone deacetylase (HDAC) inhibitors are able to protect against cytokine-mediated β cell death and have been shown to improve glucose homeostasis in diabetic mice. Here, we tested the relationship between HDAC inhibition and SOCE in the pancreatic β cell. To this end, we investigated the effects of the HDAC inhibitor sodium butyrate (NaB) on Ca2+ signaling, insulin secretion, and gene expression in cytokine-treated mouse islets, human islets, and STIM1 knockout (KO) 832/13 INS-1 β cells. In mouse islets treated with IL-1β, IFN-γ and TNF-⍺, NaB increased glucose-induced phase Ca2+ responses and restored Ca2+ oscillations. In IL-1β-treated INS-1 β cells, NaB rescued SOCE and ER Ca2+ store depletion, and increased glucose-stimulated insulin secretion (GSIS), while additionally improving cell viability and reducing apoptosis. Chronic (24hrs) but not acute (8hrs) NaB treatment prevented IL-1β-mediated reduction in the SOCE response, suggesting changes in gene expression may underlie these effects. To test this, RT-qPCR for SOCE molecular components was performed and revealed increased STIM1 expression in cytokine-treated mouse islets and INS-1 cells, while no change was observed in Orai1/2 levels. Consistent with these results, NaB was unable to restore SOCE in IL-1β-treated STIM1 KO INS-1 cells. Lastly, NaB treatment in human islets from donors with type 2 diabetes significantly increased levels of GSIS. Taken together, these data suggest that HDAC inhibition restores insulin secretion under pro-inflammatory conditions through improved SOCE and STIM1 upregulation.

Disclosure

C. Lee: None. T. Kono: None. S. A. Weaver: None. P. Sohn: None. C. Evans-molina: Advisory Panel; Self; Provention Bio, Inc., Consultant; Self; Dompe, Other Relationship; Self; Bristol-Myers Squibb Company, Nimbus Pharmaceuticals, Pfizer Inc.
126-OR: MIR192-5p Is a Novel Regulator of GLP-1R and Insulin Secretion That May Contribute to Risk of Statin-Induced Diabetes
Authors: KUANG YU-LIN , MUNOZ ANTONIO , QIN YUANYUAN , DOSÉ ANDRÉA , NALULA GILBERT , THEUSCH ELIZABETH , SANCHEZ GABRIELA , IRIBARREN CARLOS , KRAUSS RONALD M. , MEDINA MARISA W.
Published: June 2021

Statins are a commonly prescribed cardiovascular disease drug class that can increase risk of type 2 diabetes (T2D). To investigate molecular mechanisms underlying this effect, we created induced pluripotent stem cells (iPSCs) from normoglycemic patients identified from electronic health records of Kaiser Permanente of Northern California who developed T2D after statin initiation or controls who maintained normal fasting glucose on statin treatment (24 per group). RNAseq analysis of iPSCs incubated with 250nM atorvastatin, 500nM simvastatin or mock buffer for 24h identified MIR194-2HG as one of the transcripts exhibiting the greatest differential change between cases vs. controls. Both statins increased MIR194-2HG in the controls but decreased levels in cases. This long non-coding RNA encompasses two microRNAs: MIR-192 and MIR-194. MIR192-5p is predicted to bind the 3’ UTR of the glucagon like peptide 1 receptor gene (GLP1R), and we found that transfection of a rat insulinoma cell line (INS-1) with a MIR192-5p mimic caused increased Glp1r transcript (1.4-fold) and protein (2.1-fold) levels compared to a scrambled control. Using a luciferase reporter containing human GLP1R 3’ UTR, we observed similar increases in signal; however, this elevation remained even after disruption of the predicted MIR192-5p binding site demonstrating that MIR192-5p upregulates GLP1R through an indirect mechanism. GLP1R augments glucose-stimulated insulin secretion, and we found that the MIR192-5p mimic increased insulin levels in media of glucose-stimulated INS-1 cells (1.4-fold). Reduction in media insulin in INS-1 cells treated with 1 μM simvastatin was rescued by MIR192-5p overexpression, while a MIR192-5p antisense inhibitor abolished this effect. These findings implicate MIR192-5p in statin-induced impairment of glucose stimulated insulin secretion through the regulation of GLP1R, an effect that may contribute to the increased risk of T2D in statin users.

Disclosure

Y. Kuang: None. M. W. Medina: None. A. Munoz: None. Y. Qin: None. A. Dosé: None. G. Nalula: None. E. Theusch: None. G. Sanchez: None. C. Iribarren: None. R. M. Krauss: Advisory Panel; Self; Virta Health Corp.

Funding

National Institutes of Health (P50GM115318)
1261-PUB: Type 2 Diabetes Mellitus Is an Independent Predictor of Hand Grip Strength in Patients with Established Cardiovascular Disease
Authors: LARCHER BARBARA , VONBANK ALEXANDER , MADER ARTHUR , MAECHLER MAXIMILIAN , SPRENGER LUKAS , MUTSCHLECHNER BEATRIX , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ , SAELY CHRISTOPH H.
Published: June 2021

Low hand grips strength (HGS), a validated parameter for poor skeletal muscular function, has been shown to be a predictor for mortality and cardiovascular events. Patients with established cardiovascular disease are at an increased risk of death and cardiovascular events, especially those who also have type 2 diabetes (T2DM). Factors predicting HGS in this important population are unclear and are therefore addressed in the present study. We investigated a high-risk cohort of 874 patients with established cardiovascular disease, including 670 patients with angiographically verified coronary artery disease and 204 patients with sonographically verified peripheral artery disease. From our patients, 274 (31.4%) had T2DM according to ADA criteria. In analysis of covariance, the presence of T2DM significantly predicted higher HGS (F 8.8; p=0.003); further predictors of higher HGS were younger age (F=206.8; p<0.001), male sex (F 176.7; p<0.001), and greater body height (F= 77.1; p<0.001). We conclude that the presence of T2DM is a predictor of higher HGS in high-risk patients with established CVD.

Disclosure

B. Larcher: None. C. H. Saely: None. A. Vonbank: None. A. Mader: None. M. Maechler: None. L. Sprenger: None. B. Mutschlechner: None. A. Leiherer: None. A. Muendlein: None. H. Drexel: None.
127-OR: In Vivo Genetic Evidence That the Pyruvate Kinase Isoforms PKM1 and PKM2 Differentially Control Beta-Cell Fuel Sensing
Authors: FOSTER HANNAH R. , HO THUONG , POTAPENKO EVGENIY , LEWANDOWSKI SOPHIE L. , SDAO SOPHIA , VANDEUSEN HALENA R. , CARDONE REBECCA L. , KIBBEY RICHARD , MERRINS MATTHEW J.
Published: June 2021

Pancreatic β-cells couple nutrient metabolism with appropriate insulin secretion. Here, we examined the requirements of pyruvate kinase (PK) isoforms in fuel sensing through the β-cell specific deletion of consititutively active PKM1 and allosterically recruitable PKM2 (PKM1- βKO, PKM2-βKO). β-cell deletion of PEP carboxykinase (PCK2-βKO) was used to block mitochondrial PEP production, leaving glycolytic PEP production intact. In vivo, only the PKM1-βKO mice showed glucose intolerance, and ex vivo insulin secretion was correspondingly reduced. Glucose-dependent Ca2+ oscillations were comparable in PKM1 βKO and PKM2-βKO islets, while the oscillatory frequency and duty cycle in PCK2-βKO islets increased relative to controls, suggesting redundancy in the PK response to glycolytic but not mitochondrial PEP. Using direct single-channel measurements of KATP in intact β-cells, amino acids were sufficient to stimulate KATP closure in control and PKM2-βKO cells, but failed to do so in the PCK2-βKO and PKM1-βKO models. PK activators (PKa) rescued KATP closure in PKM1- but not PCK2-deficient β-cells, arguing that PKM1 and PCK2 mediate membrane depolarization in response to mitochondrial fuels. The dependence of PKM2 on glucose was confirmed by the ability of PKa to rescue KATP closure in excised membrane patches from PKM1-βKO mice. Consistently, calcium influx stimulated by amino acids at low glucose was deficient in islets from PKM1-βKO and PCK2-βKO mice. PKa was sufficient to rescue the calcium defect in the PKM1-βKO islets but did not fully rescue the PCK2-βKO. Our findings provide strong genetic and electrophysiological evidence that the PCK2-PKM1 pathway is uniquely suited to direct the active (secretory) phase of calcium oscillations through direct effects on KATP, when FBP is low and PKM2 is inactive. While more limited in function, PKM2 can be therapeutically targeted, endowing it with the ability to respond to mitochondrial PEP and boost insulin secretion.

Disclosure

H. R. Foster: None. T. Ho: None. E. Potapenko: None. S. L. Lewandowski: None. S. Sdao: None. H. R. Vandeusen: None. R. L. Cardone: None. R. Kibbey: Research Support; Self; Agios, Inc. M. J. Merrins: None.

Funding

Health Resources and Services Administration (T32HP10010); National Institute on Aging (T32AG000213); National Institutes of Health (R01DK113103)
1273-PUB: A Comparison of Efficacy and Safety of Remogliflozin and Vildagliptin as Second-Line Treatment in Patients with Type 2 Diabetes Inadequately Controlled with Metformin Alone over One Year in Real-World Settings in India
Authors: SINHA AJAY K.
Published: June 2021

Background: Remogliflozin had recently got approval in India as new SGLT2i and also there was a storm of Vildagliptin generics after it loses its exclusive marketing patent.

Method: This was a 48 weeks prospective observational study (N=254, age ≥ 35 years with HbA1c ≥ 7%). According to investigator decision, eligible patients were assigned either remogliflozin 100 mg BD ( N=980) or Vildagliptin 50 mg BD (N= 1420) in patients who were initially uncontrolled on metformin 1000 mg alone in single or divided doses for atlas 6 weeks. Primary outcome was change in HbA1c, FBS and PPBS, secondary outcome was proportion of patients with HbA1c<7% and change in SBP and DBP.

Results: Initially 300 patients were selected but 254 patients completed the study. At baseline, mean age was 57.8±6.3 years, HbA1c 8.2±1.2%, BMI 30.1±1.7 kg/m2, and diabetes duration 5.2±1.2 years. Mean HbA1c, FBS and PPBS was significantly reduced in both the group (p<0.001) from the baseline. Between the two groups there was no statistically significant differences in mean reduction of FBS and PPBS levels (p>0.05). However, mean HbA1c% was slightly more reduced in remogliflozin plus metformin group (-1.2±0.3%; 8.1±1% to 6.9±0.5%, p>0.001) than vildagliptin plus metformin (-1±0.3%;8.3±1.3% to 7.3±0.6%, p>0.001). 62% patients on remogliflozin were achieved target HbA1c level within 24 weeks where as it was 57% with vildagliptin group. Differences were found in: SBP -7.92 mmHg (p <0.0001); DBP -3.67 mmHg (p <0.0001) in remogliflozin group while in other group it was no significant. There was a significant change in weight (-2.34 kg, p <0.0001) with remogliflozin as compare to vilda group (-1.1 Kg, p<0.005). The incidence of hypoglycemia was low in all groups (<2%).

Conclusion: In conclusion, both therapies yielded similar improvements in glucose control. However, the adherence was better with remogliflozin.

Disclosure

A. K. Sinha: None.
1278-PUB: Acid-Base Alterations after Isotonic Fluid Resuscitation of Patients in Suspected DKA in the Pediatric Emergency Department
Authors: GERA SONIA , SHETH SALONI P. , KUTNEY KATHERINE A. , MALAY SINDHOOSHA
Published: June 2021

Introduction: Pediatric patients presenting to the emergency department (ED) for diabetic ketoacidosis (DKA) often present with dehydration, with admission to the intensive care unit (ICU) dependent on measures of dehydration and acidosis.

Objective: The objective of this study was to assess the effect of fluid resuscitation in the ED on patient disposition to the ICU or floor based on changes in markers of dehydration and acidosis.

Methods: This investigation was a single-center, retrospective study of patients 6 to 18 years old presenting to the ED for concern of DKA from 2016-2019. Patients with pre-bolus and post-bolus venous blood gas (VBG) were included. Each pre-bolus and post-bolus VBG was classified as meeting ICU or floor criteria. Based on the protocol developed at Rainbow Babies and Children’s Hospital, ICU criteria were pH < 7.3 and/or bicarbonate (HCO3) < 15 (on VBG or renal function panel). Dehydration was assessed using heart rate and blood urea nitrogen (BUN), adjusted by age. Continuous variables were analyzed using Kruskal-Wallis test, and categorical variables were analyzed with the chi-square test or Fisher’s exact test.

Results: In this study, 187 patients met inclusion criteria. Post-bolus pH was increased in 52%, decreased in 41%, and unchanged in 7%. Post-bolus bicarbonate was increased in 44%, decreased in 53%, and unchanged in 2%. Of 145 patients with initial disposition to the ICU, 26 (17.9%) met floor criteria post-bolus, and no marker for dehydration distinguished this cohort (p=0.054 for heart rate, p=0.93 for BUN). Of 40 patients with initial disposition to the floor, 7 (17.5%) met ICU criteria post-bolus, and no marker for dehydration distinguished this cohort (p=0.68 for heart rate and p=1 for BUN).

Conclusion: Patients presenting to the ED in DKA may have a decrease in pH or HCO3 following a normal saline bolus. In patients initially meeting criteria for the floor, up to 17.5% may change disposition to the ICU after a normal saline bolus.

Disclosure

S. Gera: None. S. P. Sheth: None. K. A. Kutney: None. S. Malay: None.
1287-PUB: SGK1-NDRG1 Signal Axis as a Key Marker Associated with Insulin Resistance and Impaired Incretin Profile in Subcutaneous and Omental Fat Depots among Obese Patients
Authors: STAFEEV IURII , SKLYANIK IGOR , MAMONTOVA ELIZAVETA , MICHURINA SVETLANA , SHESTAKOVA EKATERINA , YAHYAEV KAMIL , YURASOV ANATOLIY , RATNER ELIZAVETA , MENSHIKOV MIKHAIL , VOROTNIKOV ALEXANDER V. , PARFYONOVA YELENA V. , SHESTAKOVA MARINA V.
Published: June 2021

Objective: We have performed the comparative study of basal state of SGK-dependent signaling among obese patients with/without type 2 diabetes mellitus (T2DM). We have accomplished correlation analysis of glucose metabolism and incretin profile parameters against phosphorylation and expression parameters for SGK1 and its substrate NDRG1.

Methods: 36 patients with long (>10 years) and morbid (BMI>35 kg/m2) obesity, 18 of which had normal glucose tolerance (NGT) and 18 had T2DM were enrolled in this study. Hyperinsulinemic-euglycemic clamp test and HOMA-IR were used to evaluate the insulin resistance. Blood samples taken at 0, 30 and 120 min of food load test were used to assess incretin profile, insulin and glucose levels. Biopsies from subcutaneous and omental fat depots were obtained during bariatric surgery for all patients and signaling states were analyzed by western blot.

Results: Analysis of SGK signaling for subcutaneous fat has shown single significant intergroup difference: enhancing of pSGK-S422 phosphorylation in T2DM group, but also pNDRG-T346 level has tendency to accumulation in subcutaneous fat of NGT patients. Analysis of SGK signaling for omental fat has shown similar results: in this case accumulation of pNDRG-T346 in NGT patients was statistically significant. Correlation analysis has shown strong direct correlation of pNDRG-T346 level with BMI and AUC for GLP-1 and reverse correlation of pNDRG-T346 with Hb1Ac and AUC for glucagon. For pSGK-S422 we have observed opposite characters of correlations with the similar parameters of carbohydrate metabolism and incretin profile.

Conclusions: In present work we have taken more patients and have shown critical relevance and general character of stress-dependent SGK1-NDRG1 signal axis as a marker of insulin resistance for different fat depots.

Disclosure

I. Stafeev: None. A. V. Vorotnikov: None. Y. V. Parfyonova: None. M. V. Shestakova: None. I. Sklyanik: None. E. Mamontova: None. S. Michurina: None. E. Shestakova: None. K. Yahyaev: None. A. Yurasov: None. E. Ratner: None. M. Menshikov: None.

Funding

Russian Science Foundation (17-15-01435)
143-LB: Changes in Perceptions and Confidence of Health Care Professionals across Medical Specialties Regarding Use of SGLT2 and GLP-1 for Cardiorenal Benefit in Type 2 Diabetes
Authors: ZYTNICK DEENA , WOOLLEY RYAN , BRUNS MICHELLE , SHAY CHRISTINA M.
Published: June 2021

Sodium-glucose cotransporter (SGLT2) inhibitors and glucagon like peptide 1 (GLP-1) receptor agonists have been demonstrated to provide cardio-renal benefits in patients with type 2 diabetes (T2D). Little is known about confidence and perceptions of healthcare professionals (HCPs) across medical specialties to utilize these agents in clinical practice. An online survey was conducted among a national sample of 1,006 physicians, nurse practitioners, and physician assistants in cardiology, endocrinology, nephrology, and primary care. They were asked about current and past perceptions and confidence in prescribing SGLT2s and GLP-1s for cardio-renal benefit. Survey results were analyzed using weighting for gender, region, and practice type. Participants were 56% male, 53% had >10 years of experience, and 32% saw >100 patients/month with T2D. Two-thirds of HCPs reported greater confidence now in prescribing SGLT2s compared to one year ago, with highest proportions among cardiologists (77%) and nephrologists (76%). Over half of HCPs (55%) were more confident now compared to one year ago with prescribing GLP-1s. A greater proportion of participants felt HCPs across all specialties are more responsible now for prescribing SGLT2s and GLP-1s compared to one year ago. Specifically, cardiologists (84%) and nephrologists (76%) felt their own specialties are now responsible for prescribing these agents for cardio-renal protection. These results suggest confidence to prescribe SGLT2s and GLP-1s for cardio-renal benefit has recently increased among medical specialties involved in T2D care. Lower HCP confidence to prescribe GLP-1s compared to SGLT2s may be due to the injectable mode of administration for GLP1s. These results also indicate a growing perception that prescribing these agents is not just the responsibility of a single specialty but is a shared responsibility across the T2D care team.

Disclosure

D. Zytnick: None. R. Woolley: None. M. Bruns: None. C. M. Shay: None.
145-OR: Annual Wellness Visits Are Associated with Increased Use of Diabetes Preventive Services in the Diabetes Belt and Surrounding Counties
Authors: MCMURRY TIMOTHY L. , KIM SOYOUN , LOBO JENNIFER M. , KANG HYOJUNG , SOHN MIN-WOONG
Published: June 2021

Background: The Affordable Care Act created annual wellness visits (AWVs) for Medicare beneficiaries to have one yearly visit to primary care physicians and discuss preventive care for the upcoming year. We assessed whether AWVs were associated with increased use of these preventive services in Medicare patients with diabetes living in the Diabetes Belt and surrounding counties.

Methods: We used claims files from a longitudinal sample of ∼1,000,000 Medicare patients with diabetes living in the diabetes belt or surrounding counties, covering years 2014-2015. The Diabetes Belt was identified by the CDC as 644 counties across Appalachian and southeastern counties in the US that had diabetes prevalence ≥ 11% in 2008. We used these data to examine associations between AWVs and preventive service use in the next year. We examined four preventive services recommended annually for patients with diabetes by the ADA, including A1c tests, foot exam, eye exam, and microalbuminuria (MA) tests.

Results: Of all patients, only 19.6% used AWVs in 2015. Eye exams (61% vs. 56%), foot exams (92% vs. 83%), A1C tests (78% vs. 73%), and MA tests (42% vs. 31%) were more common among patients who had an AWV in the preceding year compared with those who did not. These differences remained after adjusting for patient demographics, comorbidities, county level medical resources, and geographic factors: eye exam (Odds Ratio 1.13, 95% CI 1.12-1.15); A1c Test (1.28, CI 1.26-1.31); Foot Exam (2.06, CI 2.01-2.11); MA Test (1.45, CI 1.42-1.47).

Conclusions: This study shows that AWVs were significantly associated with increased recommended preventive care use among patients with diabetes living in and near the diabetes belt. The low rates of AWV utilization by patients with diabetes in and around the Diabetes Belt is concerning and should receive more policy attention.

Disclosure

T. L. Mcmurry: None. S. Kim: None. J. M. Lobo: None. H. Kang: None. M. Sohn: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK113295)
15-LB: Prediction of Chronic Kidney Disease (CKD) in People with Diabetes
Authors: AFSHAR NADER , HUSCHTO TONY , ANDORRÀ MAGÍ , CHITTAJALLU SIVA , RINGEMANN CHRISTIAN , ODEGARD JOHN T. , MIKULSKI HEATHER , BABINSKY VALERIE N. , KÖNIG HELENA , SINGH INDERJIT
Published: June 2021

Background: People with diabetes in general have a higher risk of developing Chronic Kidney Disease (CKD). The early detection of CKD in people with diabetes helps their health care providers to adjust their therapy to slow down the disease progression to higher stages, prevent complications, and reduce cardiovascular-related conditions. It also takes a great financial burden off the insurance companies in the long run by way of future treatment costs. We have developed a model that uses the historical data from the past 2 years of people with diabetes (PwD) and predicts the chance of them having CKD in the next 3 years.

Methods: Our model employed the XGBoost (eXtreme Gradient Boosting) algorithm. It used more than 860,000 PwD data from the IBM EHR (Electronic Health Records) database for training and optimizing the model parameters. It was then independently verified using more than 500,000 PwD data from the CPRD (Clinical Praxis Research Datalink) database from the UK, and close to 140,000 PwD data from the INPC (Indiana Network for Patient Care) database from the US. We considered an incident of CKD based on the appearance of a relevant ICD code. The major benefit of the XGBoost algorithm in the context of risk prediction based on EHR data is that there is no need for imputation of the missing values.

Results: We evaluated the performance of the Roche XGBoost model for CKD in terms of the area under the receiver operating characteristic curve (AUC). While we obtain comparable results for the US-based data sets (prediction model: AUCExplorys=0.83, AUCINPC=0.84), we observe a performance decrease for the validation on CPRD data (AUCCPRD=0.74). However, on all data sources our XGBoost model shows a superior performance when compared to appropriate benchmark algorithms from literature.

Conclusions: The XGBoost model for CKD disease prediction has a superior performance over benchmark models from literature.

Disclosure

N. Afshar: Employee; Self; Roche Diabetes Care. I. Singh: Employee; Self; Roche Diabetes Care. T. Huschto: Employee; Self; Roche Diabetes Care. M. Andorrà: Advisory Panel; Self; Attune Neurosciences Inc., Employee; Self; Roche Diabetes Care, Stock/Shareholder; Self; Bionure, S. L., Goodgut, S. L. S. Chittajallu: Employee; Self; Roche Diabetes Care. C. Ringemann: Employee; Self; Roche Diabetes Care. J. T. Odegard: Employee; Self; Roche Diabetes Care. H. Mikulski: None. V. N. Babinsky: Employee; Self; Roche Diabetes Care. H. König: Employee; Self; Roche Diabetes Care.
150-LB: Changes in OGTT-Derived Biomarkers following Lifestyle Intervention among High-Risk Youth
Authors: PENA ARMANDO , KIM JOON YOUNG , REYES JESSICA A. , VANDER WYST KILEY B. , OLSON MICAH , AYERS STEPHANIE , WILLIAMS ALLISON , SHAIBI GABRIEL Q.
Published: June 2021

Background: Previous studies have identified biomarkers derived from glucose concentrations during a 2-h Oral Glucose Tolerance Test (OGTT) that differentiate type 2 diabetes risk phenotypes. Such markers include 1-h glucose concentrations (1hG), shape of the glucose response curve (GRC), and time to glucose peak (TGP). Lifestyle intervention is the first line approach to diabetes prevention, yet no studies have examined changes in OGTT-glucose phenotypes.

Methods: Latino adolescents with obesity (n=48, age 15.4±1.0, BMI% 98.2±1.4, Girls 56.3%) completed a 12-week lifestyle intervention that included physical activity (3 d/wk) and nutrition education (1 d/wk). At baseline and 12 weeks, youth completed a 2-h OGTT with glucose concentrations assessed at 0’, 30’, 60’, 90’, and 120’ to derive the 3 biomarkers used to classify low and high risk phenotypes. For 1hG, ≥155mg/dL served as the threshold that classified 1hG<155mg/dL (low risk) and 1hG≥155mg/dL (high risk) phenotypes. For GRC, Biphasic (low risk) phenotypes reached peak glucose levels before dropping ≥4.5mg/dL and increasing again ≥4.5mg/dL, whereas remaining youth were Monophasic (high risk). For TGP, phenotypes were distinguished by whether glucose peaked at 30’ (Early Peak, low risk) or ≥30’ (Late Peak, high risk). Changes in OGTT-glucose phenotypes were assessed by Chi-square test.

Results: At baseline, there was substantial heterogeneity in the prevalence of OGTT-glucose phenotypes with 38% 1hG≥155mg/dL, 81% Monophasic, and 58% Late Peak. In response to the intervention, the prevalence of Monophasic decreased to 14% (p=0.048), while the prevalence of 1hG≥155mg/dL decreased to 28% (p=0.054). The decrease in prevalence of Late Peak phenotypes was not significant (-29%, p=0.200).

Conclusion: Lifestyle intervention may improve OGTT-glucose phenotypes among high-risk youth populations. Whether changes in OGTT-glucose phenotypes are associated with changes in type 2 diabetes risk factors has yet to be established.

Disclosure

A. Pena: None. J. Kim: None. J. A. Reyes: None. K. B. Vander wyst: None. M. Olson: None. S. Ayers: None. A. Williams: None. G. Q. Shaibi: None.

Funding

National Institutes of Health (P20MD002316U54, MD002316R01, DK107579F31, DK125037)
151-LB: Impact of Concurrent Use of Selective Serotonin Reuptake Inhibitors and Second-Generation Antipsychotic Medications on Cardiometabolic Health in Children
Authors: THANDI RUPINDER , WIEDEMAN ALEJANDRA M. , DEVLIN ANGELA M. , PANAGIOTOPOULOS CONSTADINA
Published: June 2021

Around 20% of Canadian children are diagnosed with a mental health disorder. Selective serotonin reuptake inhibitors (SSRIs) and second-generation antipsychotics (SGAs) are common treatments. Treatment with SSRIs or SGAs is associated with increased cardiometabolic complications, and risk for type 2 diabetes in children. Little is known about the metabolic effects of concurrent use of SSRIs with SGAs. Our aim was to determine if the combination of SSRI and SGA treatment was associated with cardiometabolic complications in children. Cross-sectional data were collected from children with mental health disorders (aged 5-18 years), recruited from Child and Adolescent Psychiatry at BC Children’s Hospital. Children were classified as naïve (n=242), SSRI-treated (n=123), SGA-treated (n=112), or SSRI+SGA treated (n=98). Anthropometric data and a fasting blood sample were collected. Relationships between treatment groups and cardiometabolic risk factors were determined by adjusted linear and logistic regression models. SSRI+SGA-treated children had higher waist circumference z-scores (0.91 ± 0.89 vs. 0.48 ± 0.95; P<0.05) and a greater odds of waist circumference ≥90th percentile (OR=2.63, 95% CI: 1.34, 5.18; P<0.05) compared to SSRI-treated children. SSRI+SGA-treated children had higher plasma total cholesterol (4.63 ± 0.93 vs. 4.34 ± 0.84 mmol/L; P<0.05, adjusted by age, sex, and BMI z-scores) and a greater odds of plasma total cholesterol ≥5.18 mmol/L (OR=2.36, 95% CI: 1.05, 5.30; P<0.05, adjusted by age, sex, and BMI z-scores) than SGA-treated children. No differences in plasma fasting glucose, insulin, or insulin resistance (HOMA-IR) were observed between the treatment groups. Concurrent SSRI+SGA treatment is associated with elevated waist circumference and plasma total cholesterol in children. Our findings suggest greater cardiometabolic complications in children concurrently treated with SSRIs and SGAs.

Disclosure

R. Thandi: None. A. M. Wiedeman: None. A. M. Devlin: None. C. Panagiotopoulos: Advisory Panel; Self; Dexcom, Inc., Speaker’s Bureau; Self; Eli Lilly and Company.

Funding

BC Mental Health and Substance Use Services
152-OR: Glargine Timing during Fasting Ramadan in Patients with Type 1 Diabetes: A Randomized Controlled Trial
Authors: ALAMOUDI REEM , KHOGEER GHOFRAN S. , QARNI ALI AL , SALEH YOUSEF M. , ALJAWHRJI ABDULRHMAN , ALSUBAIEE MARAM R. , ZARIF HAWAZEN A. , ALAIDAROUS SALWA B. , KHASHWAYN SEHAM A. , HASSANEIN MOHAMED
Published: June 2021

IDF-DaR guidelines recommend change of basal insulin timing to early evening. Randomized trials examining timing of basal insulin during fasting are lacking.

Objective: To compare glucose profiles in T1DM patients taking Glargine at early evening (6-7 pm) versus bedtime (10-12 night) during fasting Ramadan.

Methods: Multicenter open label randomized controlled trial. Patients recruited in 4 centers from 4 cities in Saudi Arabia. Data collected using pre- and post-Ramadan questioners. Glucose data collected via self-monitoring (Roche AccuCheck glucometer/the Abbott Freestyle Libre), and Envision iPro CGM.

Results: 185 T1DM patients randomized; 91 to glargine at 6-7pm (early), and 94 at 10-12 night (late). 32.4% ≤18 years, 53% female, and average duration of DM 11 ±11. No significant differences between the two groups in demographics or DM complications. Early vs. late group: Pre Ramadan A1c 9 ±2.7 vs. 8.75 ±2.1, p=0.35, post Ramadan A1c 8.4 ±2.9 vs. 8.7 ±2.7, p=0.5. Breaking of fast reported in 66 (75.9%) vs. 71 (76.3%), p=0.94; average number of days 4±6 vs. 4±4, p=0.5, and due to hypoglycemia in >90% of cases for both groups. Hypoglycemia most common in Morning 32 (59.3%) vs. 38 (60.35%), p=0.85. Severe hypoglycemia reported in 2 vs. 5 patients, and 1 DKA admission in each group. Combined CGM data during Ramadan: A1c 7.6 ±1.7 vs. 7.7 ±2.1, p=0.63. Average Time in range of 70-180 mg/dl 44.6% vs. 46.1%, p=0.7, Time below range (<70mg/dl) 7.9% vs. 6.4%, p=0.35, and Time above range (>180mg/dl) 47.5 vs. 47.5%, p=0.99. Total hypoglycemic episodes detected by SMBG 4 ±6 vs. 3 ±8, p=0.3, and Low excursions detected by iPro CGM 5 ±6 vs. 4 ±5.5, p=0.22, with AUC below limit 0.5 ±1 vs. 0.15 ±0.85, p=0.03.

Conclusion: Changing glargine timing during Ramadan to early evening hours carries no significant advantage over keeping at bedtime in regards to hypoglycemia and overall glucose profiles.

ClinicalTrials.gov: NCT04383990.

Disclosure

R. Alamoudi: None. M. Hassanein: None. G. S. Khogeer: None. A. Al qarni: None. Y. M. Saleh: Advisory Panel; Self; American Association of Clinical Endocrinologists, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk, Research Support; Self; Servier Laboratories, Speaker’s Bureau; Self; Abbott Diabetes, Amgen Inc., Ascensia Diabetes Care, Lilly Diabetes, Sanofi-Aventis. A. Aljawhrji: None. M. R. Alsubaiee: None. H. A. Zarif: Advisory Panel; Self; Pfizer Foundation, Speaker’s Bureau; Self; Medtronic. S. B. Alaidarous: Other Relationship; Self; AstraZeneca, Novo Nordisk. S. A. Khashwayn: None.

Funding

King Abdullah International Research Center
158-LB: A Complete-Panel Islet Autoantibody Multiplex ECL Assay
Authors: HE LING , JIA XIAOFAN , MIAO DONGMEI , RASMUSSEN CRISTY GENO , REWERS MARIAN , YU LIPING
Published: June 2021

Background: Type 1 diabetes (T1D), a major chronic autoimmune disease starting mostly from childhood, is now predictable with the measurement of four major islet autoantibodies (IAbs) including IAA, GADA, IA-2A and ZnT8A. Currently, there are approximately 1.4 million people affected with T1D in the United States and the incidence has doubled in the last 20 years, especially in young children. Mass screening for eligible subjects and the general population remains inefficiency and laborious bottleneck.

Methods: With the platform of our extensively validated high affinity electrochemiluminescence (ECL) assay, we have developed a simple multiplexed ECL assay to combine all four major IAb assays in a single well. Two cohorts were studied including 80 samples from newly diagnosed patients with T1D and 1,140 from Autoimmunity Screening for Kids (ASK) study. Both multiplex ECL assay and standard radio-binding assay (RBA) were performed in parallel.

Results: With >99th percentile of specificity for both assays in over 1,000 samples from general population, sensitivity of multiplex ECL assay in new onset patients with T1D were similar to RBA, GADA 75% vs. 71%; IA-2A 91% vs. 90%; IAA 61% vs. 65%; ZnT8A 90% vs. 87%. In ASK cohort, multiplex ECL assay was concordant with RBA among children with multiple IAbs (42/44, 96%). In contrast, only 39% (21/54, p<0.0001) of children with single IAb by RBA were positive by multiplex ECL assay.

Conclusion: Multiplex ECL assay illustrated its high sensitivity/specificity as RBA in T1D patients. In general population screening, multiplex ECL assay, similar to single ECL assay, is capable to discriminate high risk IAbs from low risk IAbs generated by RBA. With a multiplexing feature, it provides a high throughput tool with low cost and low sample volume for large scale of population screening for T1D.

Disclosure

L. He: None. X. Jia: None. D. Miao: None. C. Geno rasmussen: None. M. Rewers: Advisory Panel; Self; Provention Bio, Inc., Consultant; Self; RTI, Research Support; Self; Janssen Research & Development, LLC, JDRF. L. Yu: None.

Funding

JDRF (2-SRA-2018-533-S-B, 1-SRA-2016-208-S-B); National Institutes of Health (DK32083); Diabetes Research Center (P30DK116073)
159-OR: Changes of Plasma Phospholipid Fatty Acids in Pregnancy in Relation to the Diagnosis and Treatment of Gestational Diabetes
Authors: LI LING-JUN , ZHU YEYI , WU JING , TOBIAS DEIRDRE K. , HINKLE STEFANIE , MA RONALD C. , TSAI MICHAEL Y. , ZHANG CUILIN
Published: June 2021

Background: Previous studies have shown that phospholipids fatty acid (FA) levels in early and mid-pregnancy were associated with incident gestational diabetes mellitus (GDM). However, the subsequent changes of such FAs profile following GDM diagnosis/treatment are understudied.

Methods: Within the National Institute of Child Health and Human Development Fetal Growth Studies-Singleton Cohort of 2,802 pregnant women, we ascertained 85 GDM cases according to Carpenter and Coustan criteria, and 85 non-GDM controls matched on maternal age, race/ethnicity, and gestational week at voluntary blood collection. We quantified participants’ plasma FAs concentrations via gas chromatography prior to GDM diagnosis (23-31 weeks) and after GDM treatment initiation (33-39 weeks), respectively. We estimated the GDM-specific FAs changes before and after GDM diagnosis, in reference to the controls using multiple linear mixed models adjusting for major confounders including pre-pregnancy BMI.

Results: Eleven FAs exhibited distinctive pre- and post-GDM diagnosis changes among GDM cases. Compared with controls, GDM cases tended to have greater reduction in GDM risk-related FAs such as 14:0 (β -0.22; 95% CI: -0.30, -0.14), 16:0 (-0.02; -0.04, -0.01) and palmitoleic acid (16:1n7) (-0.02; -0.04, -0.01), while greater increment in GDM protective FAs such as heptadecanoic acid (17:0) (0.17; 0.11, 0.22), vaccenic acid (18:1n7) (0.06; 0.03, 0.10) and DHA (22:6n3) (0.08; 0.02, 0.15).

Conclusion: Our data identified distinctive FAs changes between pre- and post GDM diagnosis among GDM subjects. These novel findings, along with prior evidence between antenatal FAs and incident GDM, shed lights on further understanding the FAs metabolism in the GDM etiological relevance.

Disclosure

L. Li: None. Y. Zhu: None. J. Wu: None. D. K. Tobias: None. S. Hinkle: None. R. C. Ma: Other Relationship; Self; AstraZeneca, Medtronic, Research Support; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Novo Nordisk, Pfizer Inc., Sanofi-Aventis, Tricida, Inc. M. Y. Tsai: None. C. Zhang: None.

Funding

Eunice Kennedy Shriver National Institute of Child Health and Human Development(HHSN275200800013C, HHSN275200800002I, HHSN27500006, HHSN275200800003IC, HHSN275200800014C, HHSN275200800012C, HHSN275200800028C, HHSN275201000009C, HHSN275201000001Z)
165-LB: Development of Subsequent Diabetes Mellitus after Gestational Diabetes among Immigrant Women: Population-Based Cohort Study
Authors: HO JESSICA S.S. , READ STEPHANIE H. , ROSELLA LAURA , BERGER HOWARD , FEIG DENICE , FLEMING KAREN , RAY JOEL G. , SHAH BAIJU R. , SARMA SHOHINEE , LIPSCOMBE LORRAINE
Published: June 2021

Objective: To evaluate which immigrant groups to Canada are at increased risk of diabetes (DM) after gestational diabetes (GDM), including the influence of time since migration.

Research Design and Methods: This retrospective cohort study used administrative data within a universal healthcare system. Included were women with GDM who had given birth in Ontario, Canada, 2006-2014. Women from each World region were compared to native-born/long-term residents of Canada for risk of DM using Cox regression. Results were further evaluated by time since immigration (0-5, 5-10, 10-20 years vs. native-born/long-term residents [referent]), adjusting for age at index pregnancy, income, BMI, parity and any hypertensive disorder of pregnancy.

Results: A total of 8630 women with GDM were followed for a median of 4.9 years. Relative to native-born/long-term residents (incidence rate 29.2 person-years), the age-adjusted hazard ratios (aHR) for DM were higher among women from South Asia (1.28, 95% confidence interval, CI 1.20-1.36), Latin America/the Caribbean (1.42, 95% CI 1.28-1.57), and Sub-Saharan Africa (1.59, 95% CI 1.39-1.83). Relative to native-born/long-term residents, the aHR for DM were 1.42 (95% CI 1.20-1.67) for those residing 0-5 years, 1.19 (95% CI 1.00-1.42) 5-10 years, and 1.41 (95% 1.20-1.65) 10-20 years since immigration.

Conclusions: Certain broadly-defined immigrant groups are at a significantly higher future risk of developing diabetes after having GDM, especially those who are recent immigrants.

Disclosure

J. S. S. Ho: None. L. Lipscombe: None. S. H. Read: Employee; Self; Certara. L. Rosella: None. H. Berger: None. D. Feig: Advisory Panel; Self; Novo Nordisk. K. Fleming: None. J. G. Ray: None. B. R. Shah: None. S. Sarma: None.
169-OR: Magnetogenetic Stimulation of Pancreatic Nerves Regulates Blood Glucose
Authors: LI ROSEMARY , GONZALEZ MARIA JIMENEZ , POMERANZ LISA E. , SCHWARTZ GARY J. , STANLEY SARAH
Published: June 2021

There is substantial evidence that neural regulation plays a critical role in glucose metabolism and hormone release. Targeting neural populations innervating the pancreas could provide an alternative therapy for diabetes. However, our understanding of the precise physiological roles of pancreatic nerves is incomplete because we lack tools to study these populations in a non-invasive, targeted, temporally controlled manner. Here, we developed and validated a novel magnetogenetic neuromodulatory construct in vitro and in vivo then targeted defined pancreatic nerves to assess their roles in glucose metabolism and hormone secretion. The construct, coding for TRPV1 ion channel fused to a nanobody binding endogenous ferritin (NbTRPV1), was transfected into neural cell lines and primary neurons. Magnetic stimulation significantly increased intracellular calcium in cells expressing NbTRPV1. For in vivo delivery, the construct was packaged into AAV and infused into the pancreas through the pancreatic duct, using serotypes and promoters to target β cells or pancreatic nerves. Ex vivo calcium imaging confirmed magnet activation of pancreas-projecting neurons expressing NbTRPV1. In vivo, targeting NbTRPV1 to β cells improved glucose tolerance in male and female mice, validating the efficacy of this construct to regulate cell activity in the pancreas of freely moving mice. Magnet treatment of ChAT-CRE mice expressing NbTRPV1 in parasympathetic pancreatic neurons significantly improved glucose tolerance and increased insulin secretion. Conversely, targeting vagal sensory nerves from the pancreas in Advillin-iCRE mice impaired glucose tolerance with no significant effect on hormone secretion. These data demonstrate for the first time a method for remote, temporally controlled, targeted modulation of pancreatic islets and nerves to regulate blood glucose. This approach can be used to study the contribution of pancreatic nerves in a wide range of diseases, from diabetes to pancreatic cancer.

Disclosure

R. Li: None. M. Jimenez gonzalez: None. L. E. Pomeranz: None. G. J. Schwartz: None. S. Stanley: None.

Funding

American Diabetes Association/Pathway to Stop Diabetes (1-17-ACE-31 to S.S.); National Institutes of Health (R01NS097184, OT2OD024912)
17-LB: Disruption of Circadian Clocks Promote Progression of Alzheimer’s Disease in Diabetic Mice
Authors: HUANG JIAOJIAO
Published: June 2021

Almost all plants and animals exhibit inherent 24-hour oscillations to adapt the Earth’s rotation. The main function of circadian rhythm was to prepare an organism for the potential outer opportunities and challenges. Alzheimer’s disease (AD) is a progressive neurodegenerative disease, which is more popular in patients with type 2 diabetes mellitus (T2DM). However, the effects of circadian disorder on mental and physical health for T2DM patients are not yet fully understood, even though circadian disruption has been confirmed to promote the progression of AD in population. By housing db/db mice on a disrupted (6:18 light/dark cycle) circadian rhythm, we assessed the circadian gene expression, body weight, cognitive ability and AD-related pathophysiology. Our results indicated housing in these conditions had disrupted diurnal circadian rhythms in hippocampus and contributed to weight gain. In the brain, circadian-disrupted db/db mice showed a decreased cognitive ability and an increased hyperphosphorylation of tau protein, even though no difference was found in Aβ deposition. We also found that the hyperphosphorylated tau protein exhibited more disruptive daily oscillations in db/db mice hippocampus under 6:18 light/dark cycle. In conclusion, circadian alterations could promote the development of AD in the patients of T2DM.

Disclosure

J. Huang: None.

Funding

National Natural Science Foundation of China (81670754, 81800686, 81974114)
170-LB: Obesity-Related Metabolites and Risk of Type 2 Diabetes in Chinese Adults
Authors: PAN XIONG-FEI , CHEN ZSU-ZSU , WANG THOMAS , ZHENG WEI , GERSZTEN ROBERT E. , SHU XIAO-OU , YU DANXIA
Published: June 2021

The mechanisms linking overall/central obesity with type 2 diabetes are not fully understood. In a nested case-control study of 1039 incident cases and 1039 matched controls from two prospective cohorts of Chinese adults, we measured 142 plasma metabolites using LCMS platforms. We identified and validated 28 metabolites associated with body mass index (BMI) and 34 metabolites with waist circumference (WC) in multivariable-adjusted linear models at false discovery rate<0.05. Using LASSO regression, we selected 15 and 21 metabolites, respectively, to create BMI- and WC-related metabolite composite scores (MCSs), including glutamate, branched-chain amino acids, tyrosine, uric acid, dimethylguanidino valeric acid, C5-carnitine, cis-aconitic acid, and homogentisic acid (positive associations) and 1,5-anhydrosorbitol, pyruvic acid, serine, glycine, and asparagine (inverse associations). Both MCSs showed strong linear associations with diabetes risk: OR (95% CI) in the highest vs. lowest quartiles was 3.92 (1.88, 8.15) for BMI-related MCS and 7.87 (3.53, 17.53) for WC-related MCS after adjusting for diabetes risk factors including plasma glucose (both P-trend<0.001). Strikingly, the MCSs showed even stronger associations with diabetes among participants with normal BMI or WC: OR (95% CI) across quartiles was 6.99 (3.97, 12.3) and 9.98 (6.11, 16.3), respectively. The MCSs mediated 50-70% of the BMI/WC-diabetes association. MCSs alone achieved similar prediction performance as traditional risk factors, including age, sex, lifestyles, diet, family history, and BMI/WC (all C-statistics~0.75). Adding MCSs to traditional risk factors and plasma glucose improved the C-statistics from 0.79 to 0.83 (P<0.001). In conclusion, we identified multiple obesity-related circulating metabolites strongly associated with diabetes risk, even among individuals with normal BMI or WC. Those metabolites could explain up to 70% of obesity-related diabetes risk and further improve diabetes risk prediction.

Disclosure

X. Pan: None. Z. Chen: None. T. Wang: None. W. Zheng: None. R. E. Gerszten: None. X. Shu: None. D. Yu: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK108159 to T.W., X-O.S., R.E.G.), (R01DK126721 to D.Y.); National Cancer Institute (UM1CA173640 to X-O.S.), (UM1CA182910 to W.Z.)