bluuebunny/crossref_metadata_2025 huggingface dataset:
2250-PUB: Lower Blood Glucose Values Lead to Higher Sleep Efficiency in Adolescents with Type 1 Diabetes
Authors: MONZON ALEXANDRA , MCDONOUGH RYAN , CLEMENTS MARK A. , PATTON SUSANA R.
Published: June 2020

Objective: Sleep disturbances occur frequently in youth with type 1 diabetes (T1D) with only 20% of adolescents meeting recommendations for sleep duration during the week. Few studies have directly evaluated the relationship between objectively measured sleep behaviors and mean blood glucose (BG) as measured by continuous glucose monitors (CGM).

Methods: Twenty adolescents with T1D (Age: M= 14.69, SD= 1.58, Sex= 50% female; Race= 80% Caucasian) participated. Youth’s average HbA1c was 9.0% (SD= 1.70), and all participants used an insulin pump. Youth wore an accelerometer on their non-dominant wrist and a CGM for seven consecutive days. We estimated multilevel models using SAS PROC MIXED and reverse-lagged nighttime sleep variables to specifically examined the impact of BG values on each sleep variable the following night. We examined total sleep time (TST), sleep efficiency (i.e., percentage of time spent asleep while in bed), and onset latency (i.e., minutes between going to bed and falling asleep) independently, as proxies for sleep behavior. We entered a dichotomous weekday/weekend variable in the model as a level 2 moderator. Results: Participants averaged 9.1 hours (SD= 84.9 minutes, range= 2.82-11.15 hours) of TST. Sleep variables did not differ on weekdays versus weekends. Our multilevel models did not reveal a significant association between sleep variables predicting mean BG. We did observe an association between within-person mean BG values significantly predicting sleep efficiency (β= -0.06802). This suggests an adolescent’s sleep efficiency may increase when their BG is lower than typical for themselves.

Conclusions: The results of the study add support to previous laboratory studies that indicate lower BG levels associate with better sleep efficiency in youth with T1D. Clinicians may consider assessing sleep patterns in youth with T1D as an additional treatment target for optimal T1D self-management.

Disclosure

A. Monzon: None. R. McDonough: None. M.A. Clements: Consultant; Self; Glooko, Inc. Other Relationship; Self; Glooko, Inc. S.R. Patton: None.
226-OR: The Mediterranean Diet Increases GLP-1 and Oxyntomodulin Compared with Vegetarian Diet in Type 2 Diabetes Subjects
Authors: MAURO ANTONIO DI , TUCCINARDI DARIO , TORO ROSSELLA DEL , MONTE LAVINIA , GIORGINO RICCARDO , RAMPA LORENZO , ROSSINI GIOVANNI , KYANVASH SHADI , SOARE ANDREEA , ROSATI MILENA M. , KHAZRAI YEGANEH MANON , PICCOLI ALESSANDRA , NAPOLI NICOLA , POZZILLI PAOLO , MANFRINI SILVIA
Published: June 2020

Aim: To compare a Mediterranean dietetic pattern with a vegetarian pattern in terms of hunger-satiety perception through post-prandial assessment of appetite-related hormones glucagon-like peptide 1 (GLP-1) and Oxyntomodulin (OXM), as well as self-rated Visual Analogue Scale (VAS) quantification, in overweight/obese type-2 diabetes (T2D) subjects.

Methods: Twelve T2D subjects (M:F = 7:5), mean age 63 ± 8.5 years, were enrolled in our randomized, controlled, crossover study. Participants were given a vegetarian meal high in complex carbohydrate and dietary fiber (HFV, 35g fiber/1000 Kcal) as well as a Mediterranean (MED) meal in two different days over a one-week washout period. The two meals were isocaloric. Appetite ratings, glucose/insulin and gastrointestinal hormone concentrations were measured at fasting and every 30’ until 4 hours following meal consumption.

Results: GLP-1 and OXM levels were significantly higher following MED meal consumption compared with HFV meal (240’ AUC, P <.022 and P <.023, respectively). Both MED and HFV meal resulted in a biphasic secretion pattern of GLP-1 and OXM, although MED meal was related to a delayed, significantly higher second GLP-1 peak at 150’ compared with that of HFV meal (P <.05). MED meal was related to lower glucose trend compared with HFV meal (P <.039), whereas we did not observe significant changes in terms of self-reported VAS scores and insulin trend.

Conclusions: In T2D overweight/obese subjects, a MED-like meal is more effective than a vegetarian meal in terms of post-prandial plasma glucose homeostasis and GLP-1 and OXM release. These changes were not confirmed by VAS appetite self-assessment over a 4 hours period.

Disclosure

A. Di Mauro: None. D. Tuccinardi: None. R. Del Toro: None. L. Monte: None. R. Giorgino: None. L. Rampa: None. G. Rossini: None. S. Kyanvash: None. A. Soare: None. M.M. Rosati: None. Y. Khazrai: None. A. Piccoli: None. N. Napoli: None. P. Pozzilli: Advisory Panel; Self; Abbott, AstraZeneca, Eli Lilly and Company. Research Support; Self; Medtronic, Sanofi. S. Manfrini: None.
2294-PUB: Investigating Medial Amygdala Circuits in Glucose Homeostasis
Authors: DEVARAKONDA KAVYA , CONNER KAETLYN , GARIBAY DARLINE , STANLEY SARAH
Published: June 2020

One out of every 10 Americans has diabetes, increasing their risk of death by 50% and more than doubling their health care costs. Delineating how the brain regulates metabolism, including feeding behavior and glucose homeostasis, may shed light on how those processes are altered in disease. The medial amygdalar nucleus (MeA) regulates the intersection of stress, social behavior, and metabolism. Fos expression in the MeA of mice is altered by changes in energy availability - fasting/re-feeding and hyper-/hypoglycemia - suggesting this nucleus may regulate feeding behavior and blood glucose levels in response to internal cues. The primary downstream targets of the MeA are the principle nucleus of the bed nucleus of the stria terminalis (prBNST) and ventromedial hypothalamus (VMH), regions previously shown to regulate metabolism. Cfos immunohistochemistry and retrograde labeling show that MeA neurons that project to the VMH (MeA-->VMH) are preferentially activated by a 36h fast, compared to ad libitum feeding and a 1h refeed. Selectively activating MeA-->VMH neurons using chemogenetics induces hyperglycemia independent of changes to circulating insulin and changes in feeding. Ongoing fos, axonal tracing, and behavioral studies aim to delineate the contributions of different MeA cell types to glucose homeostasis in the context of other competing behaviors including social interaction and stress.

Disclosure

K. Devarakonda: None. K. Conner: None. D. Garibay: None. S. Stanley: None.

Funding

American Diabetes Association/Pathway to Stop Diabetes (1-17-ACE-31 to S.S.); American Heart Association (18PRE33960254)
23-LB: Overexpression of microRNA-16 Derepresses the Mitochondrial Function to Exacerbate Cardiomyopathy in Streptozotocin-Induced Diabetic Mice
Authors: ZHOU JING , ZHU YINGHONG , FAN JING
Published: June 2020

Introduction: Diabetic cardiomyopathy is initially characterized by myocardial fibrosis, dysfunctional remodeling, and associated diastolic dysfunction, later by systolic dysfunction, and eventually by clinical heart failure. MicroRNAs (miRNAs), the endogenous small non-coding RNAs, were recognized to play significant roles in diabetes. But, it remains unknown whether mitochondrial function is modulated by miRNAs during diabetic cardiomyopathy.

Aim: This study investigates the potential role of microRNA-16 (miR-16) in modulating mitochondrial function during diabetic cardiomyopathy.

Methods and Results: To assess the function of miR-16 in vivo, miR-16 was expressed using a adeno-associated virus serotype 9 (AAV9) viral vector in male 1-week-old mice C57BL/6J mice. At 6-week-old, these mice received three consecutive daily i.p. injections of STZ (55 mg/kg body weight) combined with 18 weeks of high-fat diet to induce T2DM. We demonstrated that miR-16 expression was slight increased in diabetic mice. Overexpression of miR-16 exacerbated diabetic cardiomyopathy which reflected by increasing myocardial fibrosis and displaying a diastolic dysfunction in STZ-induced mice. Impaired mitochondrial function was observed in electron microscopy of myocardium in mice with overexpression of miR-16. In vitro, high glucose (HG) treated cultured cardiomyocytes with overexpression miR-16 showed a worse mitochondrial damage, and inhibition of miR-16 induced a protective effects role in HG-treated cardiomyocytes. Molecular mechanisms linked to the underlying pathophysiological changes include abnormalities in AMP-activated protein kinase, p38 MAPK and PGC1α.

Conclusions: In conclusion, our results show that miR-16 plays an important role in the development of diabetic cardiomyopathy in T2DM mice, which can be targeted for therapeutic intervention.

Disclosure

J. Zhou: None. Y. Zhu: None. J. Fan: None.
2300-PUB: Activation of GLP-1 Signaling Attenuates FFAs-Induced Muscle Dysfunction and Senescence
Authors: LI HSIN-HUA , LIN CHIH-LI , HUANG CHIEN-NING , KORNELIUS EDY , YANG YI SUN , PENG CHIUNG-HUEI , LI CHING RU , LIU SHIANG-TING
Published: June 2020

Obesity and insulin resistance are frequently associated with type 2 diabetes (T2D). Evidence is now revealed that plasma free fatty acid (FFA) levels are often elevated in most T2D patients, and this can cause peripheral insulin resistance directly. As a result, these FFAs inhibit insulin-stimulated glucose uptake, thus contributing to the onset of insufficient energy within cells. Among various T2D-related complications, the continuously loss of muscle is one of the most important adverse effects. Blocked insulin signaling in skeletal muscle is manifested by decreased insulin sensitivity and impaired muscle cell function including glucose transport, glucose phosphorylation, reduced glucose oxidation and glycogen synthesis that might ultimately lead to muscle loss. Interestingly, recent studies have found that GLP-1 agonists appear to slow muscle wasting during T2D. Since GLP-1 receptors are abundantly expressed on the membrane of muscle cells, indicating that they may play some important roles in muscle physiology. However, the detailed mechanism is still not well understood. In this study, we investigated the effect of GLP-1 agonist against FFA-induced muscle wasting. We used mouse C2C12 myotubes to evaluate effects of GLP-1 agonists FFA-induced muscle loss and dysfunction. Our data indicated that FFA induces insulin resistance, oxidative stress muscle loss and cell senescence in muscle cells. Moreover, FFA also decreased glucose uptake and reduced myotube mass and function. Conversely, GLP-1 agonists could protect against FFAs-induced myotube dysfunctions, including insulin resistance, oxidative stress, cell loss and senescence, that eventually reversed myotube mass and function through AMPK/SIRT1 pathway. We expect our results can extend the contributing role of GLP-1 signaling in FFA-induced insulin resistance of muscle cells, and the modulation of GLP-1 signaling may be a workable strategy for muscle wasting prevention.

Disclosure

H. Li: None. C. Lin: None. C. Huang: None. E. Kornelius: None. Y. Yang: None. C. Peng: None. C. Li: None. S. Liu: None.

Funding

Ministry of Science and Technology of Taiwan (108-2320-B-040-029-MY2)
2308-PUB: A Protective Role of H2S from Obesity-Associated Metabolic Stress in GLP-1 Regulation
Authors: MEZOUARI ANIA , GAGNON JEFFREY , NANGIA RADHIKA
Published: June 2020

Background: Obesity is a risk factor in the development of a variety of diseases including cardiovascular disease and type 2 diabetes. Circulating fatty acids (including palmitate) and protein glycation are both increased in obesity and diabetes and are known to cause metabolic stress. This includes the impairment of the glucoregulatory hormone glucagon-like peptide-1 (GLP-1) secreted from intestinal L-cells. Recently, the gastrointestinal microbiome has been implicated in the regulation of GLP-1. We believe that the bacterial metabolite hydrogen sulfide (H2S) can play a protective role in L-cell metabolic stress.

Methods: Our study was conducted on both human NCI H716 and mouse GLUTag GLP-1 secreting L-cells. L-cell stress was assessed using the total reactive oxygen species (ROS) dye DCF-DA. ROS levels were examined during incubation with palmitate (PA), glycated albumin (GA), and the bacterial gas donor GYY4137(H2S). Next, GLP-1 secretion was measured after treating cells with PA and GA, along with H2S using a GLP-1 ELISA.

Results: We have demonstrated that elements of the obese physiological environment: PA and GA, cause an increase of reactive oxygen species (ROS) in L-cells. Specifically, 500μm PA and 200μg/mL GA caused a 75% and 50% increase in ROS generation, respectively. Furthermore, these treatments led to a 25% reduction of GLP-1 secretion in human L-cells. Finally, the microbial gas H₂S reduced basal and PA-induced ROS by nearly half.

Conclusion: The microbial gas H2S reduces metabolic stress in GLP-1 cells. This study will lay the foundation for future work exploring how bacterial products such as prebiotics and probiotics may be used as a treatment for complications associated with obesity and diabetes.

Disclosure

A. Mezouari: None. J. Gagnon: None. R. Nangia: None.

Funding

Natural Sciences and Engineering Research Council of Canada (RGPIN-2016-05905)
235-OR: Incidence of Significant Changes in Pulmonary Function during a 2-Year Study with Inhaled Technosphere Insulin
Authors: JONES MARISA C. , TRAN TIFFANY S. , KRUEGER JOHN A. , MOREY PATRICK M. , HOOGWERF BYRON J. , KENDALL DAVID M.
Published: June 2020

The impact of inhaled Technosphere Insulin (TI) on measures of pulmonary function remain an important component of clinical use. TI is an ultra rapid-acting prandial insulin delivered via deep pulmonary inhalation allowing for prompt absorption in the alveoli. Prior studies have demonstrated that, on average, changes in pulmonary function testing (PFT) are limited to small changes (∼1%) in forced expiratory volume in 1 second (FEV1). This comprehensive post-hoc analysis examined the incidence of significant decline in FEV1 over two years in subjects with type 1 and type 2 diabetes treated with TI. Subjects were included if they had at least five FEV1 measurements (including baseline and month 24). FEV1 must have been ≥70% of predicted at baseline. At each time point, subjects were classified as having a significant change in FEV1 if there was a ≥15% decline from baseline. Of the 377 subjects, 331 (87.8%) had no measure with ≥15% decline in FEV1 at any time point. Of subjects who had at least one measure with a decline of ≥15%, the majority (n=38) experienced this decline on a transient basis (defined as occurring at two or fewer time points). Eight individuals (2.1%) demonstrated a persistent decline in FEV1 (occurring at three or more time points). Four subjects in the comparator arm (0.7%, n=586) had persistent decline.

In conclusion, persistent significant decline in FEV1 during the use of TI was uncommon.

Disclosure

M.C. Jones: Employee; Self; MannKind Corporation. T.S. Tran: Employee; Self; MannKind Corporation. J.A. Krueger: Employee; Self; MannKind Corporation. Stock/Shareholder; Self; Eli Lilly and Company, MannKind Corporation. P.M. Morey: Employee; Self; MannKind Corporation. B.J. Hoogwerf: Consultant; Self; MannKind Corporation. Employee; Spouse/Partner; MannKind Corporation. Stock/Shareholder; Spouse/Partner; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. D.M. Kendall: Employee; Self; MannKind Corporation. Stock/Shareholder; Self; Eli Lilly and Company.
24-OR: Electronic Decision Support for Insulin Therapy Is Safe and Efficient in Inpatients with Type 2 Diabetes
Authors: HOCHFELLNER DANIEL A. , ZIKO HARIS , SAGMEISTER MAXIMILIAN H. , ELSAYED HESHAM , CIGLER MONIKA , POETTLER TINA , ABERER FELIX , SENDLHOFER GERALD , BECK PETER , MADER JULIA K.
Published: June 2020

Attainment of good glycemic control in hospitalized patients with type 2 diabetes (T2D) is often hampered by fear of hypoglycemia and insufficient knowledge in insulin therapy. An electronic algorithm-based decision support system (GlucoTab®, decide Clinical Software GmbH, Graz, Austria) for inpatient management was developed and has proven efficacy in clinical trials. After implementing GlucoTab® in routine care, a retrospective analysis of T2D patients requiring subcutaneous insulin therapy on an Endocrinology ward was performed. Data from days when patients received algorithm-steered basal-bolus insulin therapy (BBI) was compared with days when insulin therapy was performed according to local standard care (SC) provided by an endocrinologist. As the treating physician was free to start/stop decision support during inpatient stay, patients switched between BBI and SC. During the first six months following GlucoTab® implementation, a total of 71 T2D patients required subcutaneous insulin therapy and subsequently were included in this analysis. Incomplete treatment days (e.g., admission and discharge days; days, where both therapy schemes applied) were excluded, resulting in 261 BBI and 274 SC days. Baseline characteristics were as follows: 39 % women, 99 % Caucasian, age 73.5 ± 12.5 years, diabetes duration 15.4 ± 10.6 years, HbA1c 70.4 ± 24.2 mmol/mol, BMI 29.0 ± 5.5 kg/m² and creatinine 1.6 ± 1.2 mg/dL. Mean daily glucose was lower for BBI vs. SC: 156.9 ± 35.7 mg/dL vs. 172.1 ± 47.3 mg/dL. Total daily insulin dose was higher for BBI vs. SC: 42.2 ± 25.2 U vs. 33.7 ± 20.9 U. Blood glucose (BG) in target (70-180 mg/dL) was higher for BBI vs. SC: 70 % vs. 61.2 %. BG <70 mg/dL was 1.6 % vs. 1.9 % and BG <54 mg/dL was 0.2 % vs. 0.6 % (BBI vs. SC, respectively). Continuous use of BBI resulted in a BG decline from 182 (day 1) to 147 mg/dL (day 10) while it remained elevated in SC (188 to 177 mg/dL). BBI showed beneficial glycemic control compared to SC in routine use during inpatient diabetes management.

Disclosure

D.A. Hochfellner: None. H. Ziko: None. M.H. Sagmeister: None. H. Elsayed: None. M. Cigler: None. T. Poettler: None. F. Aberer: None. G. Sendlhofer: None. P. Beck: Employee; Self; decide Clinical Software. Stock/Shareholder; Self; decide Clinical Software. J.K. Mader: Advisory Panel; Self; Becton, Dickinson and Company, Eli Lilly and Company, Medtronic, Prediktor Medical, Sanofi-Aventis. Speaker’s Bureau; Self; Abbott, Eli Lilly and Company, Medtronic, Novo Nordisk A/S, Roche Diabetes Care, Sanofi-Aventis.
248-LB: Spexin Promotes Insulin Secretion and ß-Cell Proliferation
Authors: LIU RUI
Published: June 2020

Spexin was firstly discovered as a neuropeptide and was also detected in peripheral tissues including liver, fat and pancreatic islets. Recently, studies documents that diabetes patients had lower circulation level of Spexin. It is unclear whether Spexin exerts glucose homeostasis regulating effects. Here, we provide evidence that Spexin stimulates β cell proliferation and insulin secretion in mice and human islets. Acute administration of Spexin prior glucose challenge promoted insulin secretion and improved glucose tolerance in a dose dependent manner (35-200 μg/kg BW). Meanwhile, Spexin treatment had no effect on insulin tolerance. The addition of Spexin to mouse islets increased β cell proliferation demonstrated by 2-fold increase of BrdU(+) β-cells. Spexin promoted cell growth of INS-1 cells in a dose dependent manner with maximum effect at dose of 25 ng/ml. In a high-fat diet (HFD)-induced β cell proliferation and β cell mass expansion model, the percentage of Ki67(+) β-cells increased by 2-fold compared to chow diet (CD)-fed mice. Spexin provoked further 80% increase. Consistently, HFD feeding increased β-cell mass by 2-fold and Spexin made further 58% increase. To identify the mechanism of Spexin-stimulated β cell proliferation, we tested whether the expression of well-established β cell cycle regulators was controlled by Spexin. Spexin treatment of INS-1 cells for 24 h significantly increased mRNA levels of cyclin D1 and Cyclin E1 compared with controls. Spexin stimulated the phosphorylation of CREB (p-CREB) with a peak at 10 min. The addition of H89, a potent PKA inhibitor blocked the effect of Spexin on activation of p-CREB and stimulation of the expression of Ki67, Cyclin D1 and Cyclin E1. Furthermore, Spexin stimulated the p-CREB, promoted insulin secretion and increased β cell proliferation in human islets. Thus, Spexin is an important factor for islet β cell proliferation, and our study provides previously unrecognized evidence of a factor governing endocrine pancreas growth and function.

Disclosure

R. Liu: None.

Funding

National Natural Science Foundation of China (81200622, 81570518, 81630020)
248-OR: Visualizing Heterogeneous Islet Autoantibody Trajectories of Children Who Develop T1D from Multisite Birth Cohort Studies
Authors: KWON BUM CHUL , ACHENBACH PETER , ANAND VIBHA , DUNNE JESSICA L. , HAGOPIAN WILLIAM , LUNDGREN MARKUS , VEIJOLA RIITTA , FROHNERT BRIGITTE I. ,   THE T1DI STUDY GROUP
Published: June 2020

We investigated evolution of islet autoantibodies (IAs) prior to onset of T1D from 5 large-scale birth cohort studies. Our analysis revealed three distinct IA trajectories leading up to diagnosis of T1D. Of 24673 children from five prospective studies (DAISY, DiPiS, DIPP, DEW-IT, and BABYDIAB), 688 who were diagnosed with T1D and had 3 or more visits were included in this analysis. Hidden Markov Models were developed to label visit-level observation of each subject based on three IAs: GADA, IAA, and IA-2A. Interactive visualizations were then applied to explore model outcomes, identify IA evolution trajectories, and examine their clinical characteristics. Three trajectories were identified (Figure 1) with a majority of children having multiple IA (Tr1: n=265) or IAA first (Tr2: n=282) at seroconversion; the minority seroconverted with GADA first (Tr3: n=131). The Tr3 group had seroconversion and T1D onset at an older age in months (58, 132) than Tr1 (42, 96) and Tr2 (31, 88), P < .01. Distribution of HLA DR/DQ differed between groups: higher DRX/X and lower DR3/4 in Tr3 (18%, 24%) than Tr1 (11%, 26%) and Tr2 (10%, 31%). The three IA trajectories show distinctive antibody patterns, ages of seroconversion and T1D onset and HLA DR/DQ group distributions among them. Furthermore, heterogeneity is also shown within each trajectory in terms of progression time and needs further investigation.

Disclosure

B. Kwon: None. P. Achenbach: None. V. Anand: None. J.L. Dunne: None. W. Hagopian: Consultant; Self; Novo Nordisk Inc. M. Lundgren: None. R. Veijola: None. B.I. Frohnert: None.

Funding

JDRF (1-IND-2019-717-I-X, 1-SRA-2019-722-I-X, 1-SRA-2019-723-I-X, 1-SRA-2019-719-I-X, 1-SRA-2019-721-I-X, 1-SRA-2019-720-I-X)
25-LB: SGLT2 Inhibitor Attenuates Inflammatory Response in Diabetic Kidney Disease by Inhibiting GSDMD-Related Pyroptosis
Authors: REN SHIJING , XUE YAOMING
Published: June 2020

Background: Pyroptosis is a form of programmed cell death mediated by inflammatory responses.This research aimed to study the potential mechanism of pyroptosis pathway played in promoting diabetic kidney disease (DKD) progression, and to investigate Canagliflozin(CANA), a sodium glucose cotransporter-2 (SGLT2) inhibitor, protect kidneys by inhibiting the activation of pyroptosis pathway. This research can provide new ideas for the prevention and treatment of DKD.

Methods: Human tubular (HK-2) cells were cultured in DMEM medium and were divided into normal control group (NC group), high glucose group (HG group), high glucose with CANA group, bovine serum albumin group(BSA group), BSA with CANA group. After 24 hours of culture, qPCR, Western blotting and ELISA were used to detect the activation, expression and secretion of classic NLRP3/Caspase(Casp)-1/Gasdermin D (GSDMD) pyroptosis pathway, including NLRP3, Casp-1, interleukin (IL)-1β, IL-18 and GSDMD,etc. Detect the expression of NKAIN4, a Na+-K+-ATP enzyme-acting protein. LDH release test and Light microscopy was used to analyze cell death and rupture of the cell membrane.

Results: Compared with NC group, in HG group and BSA group, the amount of dead HK-2 cells is higher, the expression levels of NLRP3, Casp-1, IL-1 β, IL-18, GSDMD and NKAIN4 were significantly up-regulated, the concentration of IL-1 β, IL-18 and LDH in the cultured medium were elevated. When using Canagliflozin, these data mentioned above were suppressed compared with HG group and BSA group .

Conclusions: 1. Pyroptotic cell death of HK-2 cells induced by HG and BSA may promotes DKD progression, renal function deterioration, and inflammation. 2. SGLT2 inhibitor Canagliflozin can attenuate inflammatory response by inhibiting GSDMD-related pyroptosis in DKD. This may because CANA attenuate the activation of Na+-K+-ATP enzyme, transport of K+ and activation of NLRP3. Its specific mechanism and animal experiments are being further studied.

Disclosure

S. Ren: None. Y. Xue: None.
25-OR: Acid–Base Changes during Diabetic Ketoacidosis (DKA) in T1DM with and without SGLT2 Inhibitor (SGLT2i)
Authors: MURSIC INES , SVEHLIKOVA EVA , REGITTNIG WERNER , AUGUSTIN THOMAS , MAGNES CHRISTOPH , EBERL ANITA , HEISE TIM , KLEIN OLIVER , WOLF MICHAEL , URSCHITZ MARTINA , BRUNNER MARTINA , SOURIJ HARALD , PIEBER THOMAS
Published: June 2020

Objectives: To evaluate the effect of SGLT2i on the development of DKA during insulin depletion in T1DM.

Methods: Sixteen male, C-peptide negative T1DM subjects were enrolled in this open, randomized, crossover, bicentric trial with two 7-day treatment periods (with/without SGLT2i). At the end of each treatment period, insulin was withdrawn for a maximum of 12h, followed by recovery phase (12h).

Results: SGLT2i led to significantly lower plasma glucose (PG) values during insulin depletion (PGmax with/without SGLT2i: 174±40 (mean±SD) vs. 302±48 mg/dL; 95% CI for ratio: 0.51-0.60), but to higher beta-hydroxybutyrate (BHB) values (Figure) and a steeper BHB increase (delta BHB: 8.1±2.0 vs. 6.0±1.7 µmol/L/min; 95% CI for ratio: 1.22-1.49). pH, bicarbonate and base excess during insulin depletion were comparable. Baseline glucagon (7.8±2.5 vs. 5.0±1.6 pmol/L; 95% CI for ratio: 1.26-1.95) and FFA levels (0.65±0.27 vs. 0.43±0.31 mmol/L; 95% CI for ratio: 1.08-2.28) were higher with SGLT2i, but data indicate that after increase during insulin depletion comparable concentrations were reached for both.

Conclusions: SGLT2i keeps PG in near normal ranges during DKA development and recovery, potentially impeding DKA diagnosis. While SGLT2i leads to higher ketone levels, increased baseline glucagon and FFA, an effect on pH and acidosis was not demonstrated.

Disclosure

I. Mursic: None. E. Svehlikova: None. W. Regittnig: None. T. Augustin: None. C. Magnes: None. A. Eberl: None. T. Heise: Advisory Panel; Self; Mylan, Novo Nordisk A/S. Research Support; Self; ADOCIA, Aerami, Becton, Dickinson and Company, Biocon, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Gan & Lee Pharmaceuticals, MedImmune, Merck KGaA, Mylan, Nordic Bioscience, Novo Nordisk A/S, Poxel SA, Sanofi, Xeris Pharmaceuticals, Inc., Zealand Pharma A/S. Speaker’s Bureau; Self; Eli Lilly and Company, Novo Nordisk A/S. O. Klein: None. M. Wolf: None. M. Urschitz: None. M. Brunner: None. H. Sourij: Advisory Panel; Self; Amgen, AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. Research Support; Self; Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. Speaker’s Bureau; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Sanofi. T. Pieber: Advisory Panel; Self; ADOCIA, Arecor, AstraZeneca, Eli Lilly and Company, Novo Nordisk A/S, Sanofi. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker’s Bureau; Self; Novo Nordisk A/S, Roche Diagnostics K.K.
260-OR: Transdifferentiation of a-Cells and Redifferentiation of InsulinLo ß-Cells Dominate ß-Cell Regeneration in Late-Stage Diabetic NOD Mice Cured with Induction of Mixed Chimerism and Administration of Gastrin and Epidermal Growth Factor
Authors: TANG SHANSHAN , ZHANG MINGFENG , SANTAMARIA PERE , RIGGS ARTHUR D. , JIN LIANG , ZENG DE-FU
Published: June 2020

Type 1 diabetes (T1D) results from the autoimmune destruction of β cells. Cure of established T1D requires both reversal of autoimmunity and regeneration of β cells. Autoimmune NOD mice closely resemble human T1D. We have reported that administration of gastrin and epidermal growth factor (GE) allows β cell regeneration and cure of late-stage T1D in NOD mice after reversal of autoimmunity by induction of MHC-mismatched mixed chimerism. β cell regeneration in non-autoimmune diabetic mice can come from differentiation of Sox9+ pancreatic ductal progenitors, parenchymal progenitors, and transdifferentiation of α cells. However, the source of β cell regeneration in autoimmune NOD mice remains unclear.

Using NOD mice with inducible Sox9-EGFP, we found that Sox9+ pancreatic ductal progenitors only accounted for a small fraction of total β cell regeneration. Using Nestin-EGFP mice, we did not see any β cells originating from Nestin+ parenchymal progenitor cells.

Using NOD mice with inducible glucagon-RFP, we found that ∼50% of regenerated β cells were from α cell transdifferentiation in mice after induction of mixed chimerism and GE, although mixed chimerism alone induced few α to β cell transdifferentiation in mice. In addition, using NOD mice with inducible insulin-EGFP, we found that the majority of residual β cells in late-stage diabetic NOD mice were insulinlo, and they became insulinhi after induction of mixed chimerism and GE treatment.

Taken together, transdifferentiation of α to β cells and re-differentiation of insulinlo cells are the major sources of β cell regeneration in late-stage diabetic NOD mice after induction of mixed chimerism and administration of GE. How hyperglycemia and GE differentially regulate α cell transdifferentiation and β cell re-differentiation is under investigation. This work is supported by the Wanek Family fund.

Disclosure

S. Tang: None. M. Zhang: None. P. Santamaria: Board Member; Self; Parvus Therapeutics. A.D. Riggs: None. L. Jin: None. D. Zeng: None.

Funding

Todd and Karen Wanek Family Foundation Ltd.
281-OR: Type 2 Diabetes Diagnosed between 16-30 Years in South Asian and White Individuals Is Phenotypically Similar
Authors: MISRA SHIVANI , GODSLAND IAN F. , BHARDWAJ NIKITA , OLIVER NICK , OWEN KATHARINE R. , JOHNSTON DESMOND G. ,   ESQ.
Published: June 2020

Aim: The incidence of type 2 diabetes is increasing rapidly in young adults. Older south Asian people (SA) develop type 2 diabetes at leaner BMI compared to white and are less likely to be obese. We hypothesised that obesity may be a bigger driver of young-onset type 2 diabetes in SA people and studied the BMI difference in white and SA people with young adult-onset type 2 diabetes.

Methods: Data from two UK cross-sectional cohorts were examined to identify adults diagnosed with any type of diabetes <30 years. We defined type 2 diabetes as a fasting C-peptide level >600pmol/L and negativity to GAD-antibodies (YDX study) and GAD, IA-2 and ZnT8 antibodies (MY DIABETES study). We studied phenotypic differences between SA and white ethnicity.

Results: Sixty white and 71 SA people with type 2 diabetes diagnosed <30 years were identified, of which 92% (n= 55) white and 83% (n=59) SA were diagnosed 16-30 years. Median age-at-diagnosis (25 vs. 24 years, p=0.6) and duration (8.8 vs. 9.5 years, p=0.8) were similar between white and SA ethnicity. BMI, though lower in SAs than white (29 vs. 32 kg/m2, p=0.0007), was consistent with ethnic-specific obesity. HbA1c (68 vs. 60 mmol/mol, p=0.1), HDL (1.0 vs. 1.1mmol/L) and triglycerides (2.2 mmol/L vs. 1.7) were similar in white vs. SA. Fasting C-peptide was no different between ethnicities 847 pmol/L white vs. 1018 SA, p=0.1. Percentage insulin-treated was similar between both groups: white 54%, SA 66% p=0.2.

Conclusion: Type 2 diabetes diagnosed between 16-30 years is associated significantly with the presence of obesity in both ethnicities. The similarity observed in glycaemia, lipid profiles and fasting C-peptide along with similar durations, suggest the degree of insulin resistance to be equal across ethnic groups. This young-onset south Asian phenotype may contrast older-onset cases where SA people are observed to be significantly leaner and more insulin resistant than white counterparts.

Disclosure

S. Misra: None. I.F. Godsland: None. N. Bhardwaj: None. N. Oliver: Advisory Panel; Self; Medtronic, Roche Diabetes Care, UNEEG. Research Support; Self; Dexcom, Inc., Roche Diabetes Care. K.R. Owen: None. D.G. Johnston: None.

Funding

Diabetes Research & Wellness Foundation; European Foundation for the Study of Diabetes
295-OR: Estrogen Receptor a Controls Energy Homeostasis in White and Brown Adipose Tissue by Regulating Polg1 Expression and Mitochondrial Remodeling
Authors: ZHOU ZHENQI , HEVENER ANDREA L.
Published: June 2020

Obesity is heightened during aging. Although the role of the estrogen receptor (ER)α to prevent obesity is supported by our previous work, ERα actions in adipocytes remain inadequately understood. Gene expression analysis from UKTwins Study, METSIM Study, and the study of the UCLA Hybrid Mouse Diversity Panel show that ESR1/Esr1 is inversely associated with adiposity and markers of metabolic health in both humans and mice. To determine the mechanistic role(s) of ERα in fat, we generated 2 adipose tissue-specific knockout mouse lines by selectively deleting Esr1 from white and brown adipose tissue (FERKO and ERαKOBAT, respectively). In white adipose tissue, Esr1 controls oxidative metabolism by reducing the E3 ubiquitin ligase Parkin-mediated mitochondrial degradation. Indeed, we report that adipose tissue-selective Parkin knockout mice have reduced body fat and elevated adipocyte mtDNA content. In brown adipose tissue, Esr1 is a requisite for mitochondrial remodeling and cold-induced thermogenesis. Although the role of mitochondrial metabolism differs between white and brown fat, the unique mitochondrial phenotypes observed in white and brown Esr1-deficient adipocytes, appear to be the consequence of reduced expression of the mtDNA polymerase, Polg1. We provide direct evidence that ERα binds the Polg1 promoter to control its expression, and that selective phenotypes of ERα deficiency are recapitulated by Polg1 deletion. Collectively our findings show that ERα has strong heritability in adipose tissue and support strategies targeting cell-specific actions of ERα to combat diseases associated with metabolic dysfunction.

Disclosure

Z. Zhou: None. A.L. Hevener: None.

Funding

National Institutes of Health (U54DK120342)
296-OR: Identification and Characterization of New Players in Insulin-Controlled GLUT4 Trafficking
Authors: SHEN JINGSHI
Published: June 2020

The anabolic hormone insulin promotes glucose uptake by triggering the translocation of the glucose transporter GLUT4 from intracellular storage vesicles to the cell surface through exocytosis. Upon the termination of insulin signaling, GLUT4 gradually returns to intracellular storage compartments through endocytosis. Defects in GLUT4 translocation are a hallmark of insulin resistance (IR) and type 2 diabetes (T2D). Our team has performed genome-scale genetic screens to systematically dissect GLUT4 exocytosis and endocytosis. The screens recovered known GLUT4 trafficking regulators but most of the hits were not previously linked to the GLUT4 pathway. A regulator of GLUT4 endocytosis identified in the screens is AAGAB, a soluble factor of 34 kDa. AAGAB controls the stepwise assembly of AP2 adaptor, a central cargo adaptor in clathrin-mediated endocytosis. Unexpectedly, we found that AAGAB also binds to Munc18c and directly inhibits SNARE-Munc18-mediated GLUT4 vesicle fusion. Thus, AAGAB plays a dual role in GLUT4 trafficking. I will also discuss OSBPL8 and OSBPL10, two negative regulators of GLUT4 translocation identified in our screens. OSBPL8 and OSBPL10 are putative lipid transfer proteins operating between intracellular organelles. We propose that OSBPL8 and OSBPL10 regulate lipid dynamics required for insulin signaling, thereby influencing the activities of GLUT4 exocytic regulators. These genetic studies will likely facilitate the identification of new therapeutic targets for IR and T2D.

Disclosure

J. Shen: None.

Funding

American Diabetes Association (1-19-IBS-305); National Institutes of Health (DK095367, GM126960)
323-OR: Synergism between Protein Quality Control Pathways to Maintain Alpha-Cell Mass and Function
Authors: REINERT RACHEL B. , CUI XIANWEI , SHRESTHA NEHA , QI LING
Published: June 2020

Endocrine cells rely on efficient prohormone synthesis, folding, and elimination of misfolded peptides for proper function. Endoplasmic reticulum-associated degradation (ERAD) and autophagy are two primary mechanisms of cellular protein quality control, and each are required for normal beta cell function. However, their role in alpha cells has largely been unexplored. ERAD is mediated by two highly conserved ER membrane proteins: Hrd1, a ubiquitin ligase that retrotranslocates and ubiquitinates misfolded ER proteins for proteasomal degradation, and Sel1L, an adaptor protein required for Hrd1 stability and function. Autophagy is a conserved mechanism for recycling ER and cytosolic products via lysosomal degradation and requires a precise signaling sequence for activation, involving key autophagosome protein Atg7. To investigate the role of ERAD and autophagy in alpha cells, we targeted deletion of Sel1L and/or Atg7 with the Cre-lox system, using mice expressing Cre recombinase under the proglucagon promoter. Sel1LΔGcg, Atg7ΔGcg, and Sel1L;Atg7ΔGcg mice all showed normal growth and oral glucose tolerance. Sel1LΔGcg mice had dilated ER and reduced glucagon content in alpha cells following ERAD inactivation, but glucagon secretory capacity in vivo was largely maintained. In contrast, disruption of autophagy in Atg7ΔGcg mice led to alpha cell hypertrophy and vacuolization, and reduced glucagon secretion in vivo following insulin-induced hypoglycemia and 2-deoxyglucose-mediated glucoprivation. These secretory defects were exacerbated in Sel1L;Atg7ΔGcg mice, which also had reduced glucagon secretion after a 24 hour fast and a 77% reduction in pancreatic glucagon content. By immunohistochemistry, very few alpha cells were present in islets of adult Sel1L;Atg7ΔGcg mice. Our data demonstrate that alpha cells are more susceptible to defective autophagy rather than defective Sel1L-Hrd1 ERAD, but that these pathways act synergistically to maintain functional alpha cell mass.

Disclosure

R.B. Reinert: None. X. Cui: None. N. Shrestha: None. L. Qi: None.

Funding

National Institutes of Health (T32DK007245)
332-OR: Medicare Part B Fee-for-Service Claims for Diabetes-Related Eye Diseases
Authors: LUNDEEN ELIZABETH A. , REIN DAVID B. , WITTENBORN JOHN , SAADDINE JINAN B.
Published: June 2020

Background: Diabetic retinopathy is the leading cause of incident blindness among working age U.S. adults. Only slightly more than half of Medicare beneficiaries with diabetes receive an annual eye exam, and this rate is lower among Hispanic and black beneficiaries compared to white beneficiaries.

Objective: We examine racial/ethnic differences in diabetes-related eye disease and treatment claims, among Medicare beneficiaries with diabetes.

Methods: We analyzed 2017 Medicare claims for 8,341,000 beneficiaries (both ≥65 years and <65 years with disabilities) with diagnosed diabetes who were continuously enrolled during 2017 in Part B fee-for-service (FFS) insurance. Diagnoses for diabetes and diabetes-related eye diseases were defined using ICD-10-CM diagnosis codes and treatments were classified using procedure codes in the claims. We present crude national percentages.

Results: In 2017, 28% of FFS beneficiaries had diabetes. Of these, 9.6% had a claim for any diabetes-related eye disease; this annual rate was higher among Hispanic (13.1%), non-Hispanic black (11.2%), and Asian/Pacific Islander (11.4%) beneficiaries than among white beneficiaries (8.7%). Early/mild diabetic retinopathy was the most prevalent form (6.3%) and diabetic macular edema was the least prevalent (0.6%). Of beneficiaries with diabetes-related eye disease, 15.2% had at least one type of treatment; treatment types received were anti-vascular endothelial growth factor injections (11.8%), laser photocoagulation (4.7%), vitrectomy (1.3%), and retinal detachment repair (0.7%). Annual prevalence of any treatment was higher among Hispanic (19.0%) and non-Hispanic black (15.5%) beneficiaries compared to white beneficiaries (14.7%); it was lowest among Asian/Pacific Islander beneficiaries (12.9%).

Conclusions: Annually, around one-in-ten Medicare Part B FFS beneficiaries with diabetes has a claim for diabetes-related eye disease, and this rate is higher among Hispanic and black beneficiaries.

Disclosure

E.A. Lundeen: None. D.B. Rein: None. J. Wittenborn: None. J.B. Saaddine: None.
337-OR: Continuous Glucose Monitoring Shared Medical Appointments Improve A1C and Diabetes Self-Efficacy
Authors: ISAACS DIANA , SIMONYAN ANA , BLANCHETTE JULIA E. , LEKIC SANELA , NOE DAWN , GALLOWAY NICHOLAS R.
Published: June 2020

Background: Personal continuous glucose monitoring (CGM) is patient owned and often inaccessible due to cost and insurance requirements. Professional CGM is clinic owned, worn for 3-14 days and is an affordable, underutilized option. The present study combined diabetes education and professional CGM into a shared medical appointment (SMA). The SMA allows providers to deliver diabetes education in the setting of medical management and peer support. It was hypothesized that the SMA method of delivering professional CGM would positively impact clinical outcomes (improvements in self-efficacy, A1c and medication doses).

Methods: Adults with type 1 and type 2 diabetes who attended the two-part CGM SMA at a large academic medical center were included in this retrospective, single-center study. The CGM SMA included 4-6 patients, diabetes educator and pharmacist. Participants wore professional CGM for 7 days. The primary outcome was change in diabetes self-efficacy through a validated 8-item Likert scale. Secondary objectives were changes in A1c, and changes in diabetes medications (dosage adjustments, time of administration). Paired t-tests were used to analyze change in A1c and diabetes self-efficacy scores.

Results: Diabetes self-efficacy scores increased by a mean of 1.63 ± 2.09 points (p<.001) out of 10 points. The A1c decreased by a mean of 0.80 ± 1.52% (p<.001) with a mean follow-up A1C of 7.80 ± 1.60%. Those with baseline A1c ≤8.0% (n=70) experienced a decrease in A1c of 0.24% compared to 1.20% in those with A1c > 8.0% (n=101). Participants utilizing the real time device (n=133) experienced a decrease in A1c by 0.75% compared to 1.0% in those with the blinded device (n=38). Most medication changes made in the CGM SMA were dosage adjustments and changes in administration time.

Discussion: The CGM SMA is a novel practice model incorporating diabetes education, peer support, professional CGM, and inter-professional care that demonstrated improvements in diabetes self-efficacy and A1c.

Disclosure

D. Isaacs: Consultant; Self; Companion Medical, LifeScan, Inc. Speaker’s Bureau; Self; Dexcom, Inc., Novo Nordisk Inc., Xeris Pharmaceuticals, Inc. A. Simonyan: None. J.E. Blanchette: Other Relationship; Self; Tandem Diabetes Care. S. Lekic: None. D. Noe: Consultant; Self; Pyure Organic Stevia. N.R. Galloway: None.
339-OR: Increased Diabetes Self-Efficacy and Transition Readiness in Teens with Uncontrolled Type 1 Diabetes Receiving a Group Education Curriculum
Authors: GARVEY KATHARINE , DEAN TAYLOR , CHRISTENSEN SINEAD , RICE KRISTEN , RICH VIRGINIA B. , TERRIO SHANNON , BERBERT LAURA , LIU ENJU , LAFFEL LORI M.
Published: June 2020

Suboptimal teen self-care is associated with poor transition outcomes in T1D. Innovative curricula may optimize self-care engagement and transition preparation. We evaluated a pilot RCT to improve self-care and transition readiness in teens with uncontrolled T1D. Teens (N=40) were randomized to Self-Management, Adherence and Readiness for Transition in T1D (SMART T1D) curriculum or control group. The SMART T1D group participated in 3 evening peer group sessions facilitated by RN/CDEs over ∼9 months. Controls received 3 educational newsletters. All maintained routine 1:1 T1D care. Outcomes included diabetes self-care (SCI-R), transition readiness (RISQ), burden (PAID), self-efficacy (DMSE), and quality of life (Peds-QL Diabetes) and HbA1c, all assessed as change from baseline in intent-to-treat analyses with paired 1-sided t-tests. Teens were 50% male, 85% white, age 15.7±1.2 years, T1D duration 6.4±3.9 years, A1c 9.5±1.2%; 63% pump users. 38/40 completed the study. The SMART T1D group demonstrated significantly improved diabetes self-efficacy and transition readiness and a trend of improved HbA1c while control group did not (Table 1). Other domains showed no change, with a trend for increased burden in controls. SMART T1D feedback was highly positive. Peer group education may be promising for enhancing teen self-care and transition preparation.

Disclosure

K. Garvey: None. T. Dean: None. S. Christensen: None. K. Rice: None. V.B. Rich: None. S. Terrio: None. L. Berbert: None. E. Liu: None. L.M. Laffel: Advisory Panel; Self; Roche Diabetes Care. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., ConvaTec Inc., Dexcom, Inc., Insulet Corporation, Insulogic LLC, Janssen Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk Inc., Sanofi US.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (1K23DK202655)
343-OR: HOMA2ß Stratifies Risk for Type 1 Diabetes (T1D) Development among TrialNet Pathway to Prevention Participants
Authors: FELTON JAMIE L. , LOHANO KULDEEP , MEAH FARAH , SOSENKO JAY , EVANS-MOLINA CARMELLA
Published: June 2020

Identification of individuals at high risk for T1D is essential for the successful implementation of disease modifying interventions. Progression to T1D can be predicted by stimulated measures of β cell function, including oral glucose tolerance tests and hyperglycemic clamp studies. However, these assays are both time consuming and invasive. The homeostasis model assessment (HOMA2β) is a validated mathematical tool commonly used in type 2 diabetes cohorts to assess β cell function using fasting glucose and insulin measurements from a single time point. The utility of HOMA2β in predicting T1D progression has not been tested. To this end, HOMA2β at study entry was assessed in nondiabetic relatives of individuals with T1D who were positive for one or more β cell autoantibodies (aab) and followed longitudinally in the TrialNet Pathway to Prevention cohort. A total of 6598 subjects (mean age 17.2 ± 12.8 yrs) were screened and monitored for T1D. Of these, 40.2% (n=2652) were single aab+ (mean age 21.1 ± 14.0 yrs) and 57.5% (n=3794) were multiple aab+ (mean age 14.5 ± 11.2 yrs). During follow-up, 117 single and 1020 multiple aab+ individuals progressed to T1D. Kaplan-Meier survivor estimates by HOMA2β tertiles demonstrated that risk of T1D was inversely related to HOMA2β tertiles for multiple aab+ subjects. Multivariate Cox proportional hazards analysis was performed for the lowest tertile using the highest HOMA2β tertile as the reference group. After adjustments for age, sex, HLA, and BMI, T1D HRs were significant for the lowest HOMA2β tertile in single (HR 1.91, 95% CI 1.12, 3.24, p = 0.017), multiple (HR 2.43, 95% CI 2.03, 2.91, p<0.001), and combined single and multiple aab+ cohorts (HR 2.36, 95% CI 1.99, 2.79, p<0.001). Overall, low HOMA2β levels were able to identify a high-risk subgroup of PTP participants, suggesting that HOMA2β may have utility as a single time point measurement in stratifying individuals with established autoimmunity who are at increased risk of T1D development.

Disclosure

J.L. Felton: None. K. Lohano: None. F. Meah: None. J. Sosenko: None. C. Evans-Molina: Consultant; Self; Bristol-Myers Squibb.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (U01107014)