bluuebunny/crossref_metadata_2025 huggingface dataset:
2049-P: The Chd4 Helicase of the Nucleosome Remodeling and Deacetylase Complex Modulates Pdx1 Target Gene Expression In Vitro
Authors: DAVIDSON REBECCA K. , CASEY NOLAN , SPAETH JASON
Published: June 2020

During the progression of type 2 diabetes, β-cells fail and a subset lose features associated with their identity including reduced expression of key transcription factors (TFs). Among these is Pdx1, which is necessary for maintaining β-cell function and identity by controlling the expression of numerous β-cell genes including insulin, MafA, Glut2, and Ucn3. Pdx1, like most TFs, depends on the recruitment of coregulators to modulate its transcriptional activity. Numerous Pdx1-interacting proteins have been identified including Chd4, an ATP-dependent helicase of the chromatin remodeling NuRD complex. NuRD controls cellular processes including maintenance of cellular identity and mitochondrial function in a variety of tissues. The role Chd4 plays in modulating Pdx1 activity in the β-cell has yet to be explored. In this study, we performed co-immunoprecipitation and proximity ligation assay (PLA) in the Min6 murine insulinoma β-cell line and PLA in 8-week old C57BL/6 mouse pancreatic tissue, confirming Chd4:Pdx1 interactions in the nuclei of β-cells in both cell lines and tissue. Transient, RNAi-mediated knockdown of Chd4 in mouse β-cell lines altered the expression of Pdx1-regulated genes involved in β-cell function and identity including the MafA TF, which was reduced at both the RNA (41% ± 3 (p < 0.05)) and protein level. Moreover, the nuclear-encoded mitochondrial Tfam TF (reduced 30% ± 10 (p = 0.09)), the mitochondrial Mipep enzyme (reduced 35% ± 18 (p = 0.10)), and pre-Ins2, the unprocessed Ins2 transcript (reduced 38% ± 9 (p = 0.13)) were also altered, although they did not reach significance. These data suggest that Chd4 plays an important role in modulating the expression of genes controlled by Pdx1 in the β-cell. Future efforts are focused on further characterizing the role of Chd4 in the β-cell with CRISPR/Cas9 Chd4 knockout β-cell lines in vitro and β-cell specific Chd4 knockout mice.

Disclosure

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

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (K01DK115633)
2067-P: Cell Therapies for Diabetes Using Spontaneous Canine Diabetes as a Translational Model
Authors: WILDEY ALDYN , WILLIAMS SUSAN J. , HAMILTON MEGAN , HARRINGTON STEPHEN , OTT LINDSEY , KARANU FRANCIS
Published: June 2020

FDA approved Clinical Trials are already under way using stem cell-derived insulin-producing cells (IPCs) for the treatment of type 1 diabetes in humans. Differentiation methods used to derive beta-cell like IPCs have greatly improved over the last few years, resulting in highly efficacious treatment of high blood glucose in diabetic animals models. However, there still remains major challenges of developing an effective cure in humans due to challenges of delivery and long term survival and function of grafts. Like humans, spontaneous canine diabetes is a commonly diagnosed, multifactorial endocrine disorder in dogs which clinically presents as a type 1 diabetes disorder. In order to develop successful human diabetes therapies using stem cells, spontaneous canine diabetes offers a very attractive translational model. Dogs have major similarities to humans including the clinical signs, pathophysiology and long-term clinical management of the disease by use of exogenous insulin injections. Using cadaveric canine islets and our Core-Shell Spherification (CSS) microencapsulation methods, we have successfully reversed hyperglycemia in dogs for varying time periods. Our data confirms that similar to humans, islet transplantation is a viable option for diabetes treatment in dogs. To further develop canine diabetes as a translational model for human diabetes, while developing stem cell therapies for dogs, we have successfully generated IPCs from human pluripotent stem cells. The IPC clusters express key beta-cell biomarkers including PDX1, NK6.1, NeuroD1, and insulin. The majority of endocrine cells in clusters are single hormonal where separate cells express ARX and glucagon. These cell clusters corrected induced diabetes in mouse models when transplanted under the kidney capsule. Our studies will further allow us to further test the use of the canine model, both in allo- and xenogeneic transplant environments, for further pre-clinical development in humans.

Disclosure

A. Wildey: None. S.J. Williams: None. M. Hamilton: None. S. Harrington: None. L. Ott: Employee; Self; Likarda, LLC. F. Karanu: Employee; Self; Likarda, LLC.
2076-P: Increased Gap Junction Coupling in the Islet of Langerhans following Caloric Restriction
Authors: AMARAL MARIA C. , KRAVETS VIRA , DWULET JAEANN M. , FARNSWORTH NIKKI L. , PISCOPIO ROBERT A. , SCHLEICHER WOLFGANG , MIRANDA JOSE , BENNINGER RICHARD K.
Published: June 2020

Intercellular communication mediated by connexin 36 gap junction channels coordinate and regulate the dynamics of islet calcium oscillations and insulin secretion. Impaired gap junction coupling occurs in prediabetic mice under a high fat diet. Dietary interventions, such as calorie restriction, can regain weight and modulate insulin secretion. However, it is unknown whether caloric restriction can recover impaired gap junctions coupling and calcium regulation in islets of mice fed a high fat diet. Here, we tested if caloric restriction can protect against obesity-induced decreases in connexin36 coupling and altered islet function. We used C57BL6 mice under a normal diet (Envigo 2020X), or a high fat diet (HFD) (Envigo TD.03584) which causes prediabetes after three months. HFD mice were also submitted to 40% caloric restriction (2g/day) for one month. We performed intraperitoneal glucose tolerance tests, insulin tolerance tests, in vivo insulin level measurements. In isolated islets we measured glucose-stimulated insulin secretion, islet Ca2+ dynamics, metabolic activity, along with gap junction permeability. We observed that caloric restriction improved glucose tolerance (p=0.002), insulin sensitivity (p=0.001), and islet function. This included normalization glucose-induced insulin secretion (p=0.01), enhanced Ca2+ oscillation amplitude (p=0.002) and greater coordination (p=0.04). These improvements correlated with restoration in gap junction permeability (p=0.02). Caloric restriction also promoted a slight increase in NAD(P)H increase by elevated glucose (p=0.04) indicating improved metabolic activity and viability of these cells. We conclude that the decline in gap junction coupling. mediated by connexin 36 in islets that occurs in diet-induced obesity, is improved by short term caloric restriction. This improvement contributes to improved islet function.

Disclosure

M.C. Amaral: None. V. Kravets: None. J.M. Dwulet: None. N.L. Farnsworth: None. R.A. Piscopio: None. W. Schleicher: None. J. Miranda: None. R.K. Benninger: None.

Funding

JDRF (5-CDA-2014-198-A-N); National Institutes of Health (R01DK102950, R01DK106412 to R.K.B.); Fundação de Amparo à Pesquisa do Estado de São Paulo (2018/04536-6)
2116-P: MAFA S64F Missense Mutation Causes Islet Beta-Cell Aging and Senescence
Authors: CHA JEEYEON , WALKER EMILY M. , TONG XIN , GUO MIN , LIU JIN HUA , YU SOPHIA , IACOVAZZO DONATO , MAUVAIS-JARVIS FRANCK , FLANAGAN SARAH E. , KORBONITS MARTA , STAFFORD JOHN M. , STEIN ROLAND
Published: June 2020

A missense mutation of the pancreatic islet-enriched transcription factor MAFA (S64F) was identified in patients characterized by familial diabetes or insulinomatosis, with males more prone to diabetes. This variant converts the normally unstable MAFA protein to be unusually stable. A heterozygous germline mouse model expressing this variant (S64F MafA Het) mimics the sex-dependent phenotype in humans: Het males have impaired glucose tolerance while Het females have hypoglycemia. Het males also showed increased MafA protein stability preceding glucose intolerance (Figure 1) and upregulation of genes involved in aging/senescence (Figure 2). These results implicate accelerated aging/senescence in islet β-cell dysfunction in males with the S64F MAFA mutation. Future studies will evaluate the broader significance of these processes in diabetes.

Disclosure

J. Cha: None. E.M. Walker: None. X. Tong: None. M. Guo: None. J. Liu: None. S. Yu: None. D. Iacovazzo: None. F. Mauvais-Jarvis: None. S.E. Flanagan: None. M. Korbonits: None. J.M. Stafford: None. R. Stein: None.

Funding

National Institutes of Health (T32DK007061, F32DK109577, R01DK090570); JDRF (3-PDF-2019-738-A-NDK109577)
2147-PUB: Change in Matrix Metalloproteinase Activity Is Associated with Zinc Level in the Development of Renal Changes in a Diabetic Preclinical Model
Authors: TAO ANH , MCQUILTY ROBERT , SUTANTO SURYA S. , BAN LINDA A. , TWIGG STEPHEN M. , MCLENNAN SUSAN
Published: June 2020

Zinc is required for activation of Matrix Metalloproteinases (MMPs). Circulating zinc levels are decreased in diabetes1 and decreased activity of some MMPs is associated with the development of diabetic nephropathy (DN). The association between MMP activity and zinc in the development of DN has not been investigated and was examined in a preclinical model in this study. In this study, diabetic (DM: STZ: 3x 65mg/kg) male BALB/c mice were euthanized after 5, 10 and 30wks of diabetes. Age-matched mice acted as controls. At termination, kidneys, plasma and urine were collected for histopathology, measurement of biochemical parameters, total MMP activity using a broad spectrum MMP fluorogenic substrate and zinc level by ICPMS. In DM mice, blood glucose levels were increased at 5, 10 and 30wks (P<0.01) as were kidney/body weight (P<0.05) and urinary albumin/creatinine ratios (P<0.05). After 5wks of diabetes histopathological changes were evident and albumin/creatinine ratio increased (P<0.05). Urinary MMP activity was decreased (P<0.001) at 5wks and preceded a decrease in kidney and plasma MMP activity at 10 and 30wks (both P<0.05). DM decreased plasma but not urinary zinc levels at 10 and 30wks (both P<0.05). In DM mice, the kidney MMP activity correlated positively with plasma MMP activity (r=0.3774, P<0.03) and diabetes duration. Plasma zinc correlated with plasma MMP activity (r=-0.77, P=0.04) but only at 30wks. These results suggest an association between plasma MMP activity and zinc but only after a long duration of diabetes. The early decrease in urinary total MMP activity suggests it may have utility as a marker of early kidney disease. Whether this is so for human kidney disease is currently not known and requires further study. 1 Chabosseau and Rutter, Archives of Biochemistry and Biophysics (2016).

Disclosure

A. Tao: None. R. McQuilty: None. S.S. Sutanto: None. L.A. Ban: None. S.M. Twigg: Advisory Panel; Self; Abbott, AstraZeneca, Sanofi. Speaker’s Bureau; Self; Abbott, AstraZeneca, Novo Nordisk Inc., Roche Diabetes Care, Sanofi. S. McLennan: None.
2164-PUB: Community Expansion of Peer Support for Diabetes Management in Shanghai
Authors: LIU YUEXING , TANG PATRICK Y. , QIAN YIQING , COUFAL MUCHIEH M. , FISHER EDWIN B. , JIA WEIPING
Published: June 2020

Peer support can be effective but dissemination is a challenge. In the context of the Shanghai Integration Model linking specialty/hospital with primary/community care, trained volunteer peer leaders (PLs) based in 9 Community Health Centers (CHCs) implemented peer support. Results included improved glycemic control and reduced BMI, diabetes distress and depression, each more pronounced among those with poorer baseline status. Benefit varied however according to CHCs’ ability to organize peer support. Dissemination needs to recruit additional agencies to support CHCs. Accordingly, a current phase includes additional government and citizen-led organizations in an additional 12 of Shanghai’s 240 communities. District-level and sub-district or community health staff work with each community’s CHC as well as citizen led Community Self Management Groups (> 5,000 in Shanghai) and government affiliated, local Residential Committees. Reports through regular monitoring and meetings with CHC and community staff during the first 8 months (May-December, 2019) indicate CHC and community staff work together in a complementary manner. CHC staff take responsibility for diabetes education (e.g., teaching 6 basic diabetes education modules) and designing activities. Community staff organize or facilitate activities, e.g., the 6 modules, cooking events, discussion groups, or recreational activities that provide a sense of solidarity among those with diabetes. District-level staff coordinate key responsibilities, integrate resources, organize large-scale activities, and train community level groups. Other community organizations include, e.g., an NGO in one district with extensive experience in community services. Across the 12 communities, an average of 6.33 PLs have been trained not including community groups that lead activities. Communities have held an average of 14.08 classes drawing from the 6 diabetes education modules.

Disclosure

Y. Liu: None. P.Y. Tang: Research Support; Self; Merck Foundation. Y. Qian: None. M.M. Coufal: None. E.B. Fisher: Research Support; Self; Merck Foundation, Sanofi China. W. Jia: None.

Funding

Shanghai Municipal Grants (GWIV-3.1 to W.J.); Shanghai 6th People’s Hospital (YNLC201812 to Y.L.); Shanghai Municipal Health Commission (20194Y0141 to Y.L.); Merck Foundation; Sanofi China; Michigan Center for Diabetes Translational Research; National Institute of Diabetes and Digestive and Kidney Diseases (P30DK092926)
2167-PUB: Effect of Low-Available Carbohydrate Diet Containing Okara and Konjac on Blood Glucose Levels in Spontaneous Diabetic Torii Fatty Rats
Authors: SURUGA KOHEI , TOMITA TSUYOSHI , KOBAYASHI MASAKAZU , MITSUI TADAHIKO , KADOKURA KAZUNARI
Published: June 2020

Background: The ADA and Diabetes UK reported the efficacy of low-carbohydrate diets (LCD) in medical nutrition therapy for blood glucose and lipid management. However, following an LCD may be difficult for many people with diabetes, especially those who consume noodles regularly. To remedy this, we developed a low-available carbohydrate noodle (LACN) using a by-product of Soybean (Glycine max) processing (commonly called “okara”) and Amorphophallus konjac (commonly called Konjac). In this initial study, the effects of the LACN (Figure A) on blood glucose levels (GL) were investigated in Spontaneously Diabetic Torii fatty rats (SDT-fr).

Methods: Male, 5-week-old SDT-fr were allocated into two groups based on diet; Group I was fed standard chow (SC) as a control group (n = 6), while Group II was fed SC with 50% LACN (n = 6). The animals were allowed free access to food for 28 days.

Results: The plasma GL in the LACN group (Group II) were significantly lower than those in the control group (Figure C), in which body weight (BW) gain was observed (Figure B). Our results, in concurrence with other papers, provide evidence that BW increase in Group II was associated with increase in lean body mass, and that the change in muscle mass of SDT-fr was mainly caused by the LACN intake.

Conclusions: LACN might be useful for patients with diabetes or celiac disease who wish to maintain a noodle-based diet.

Disclosure

K. Suruga: None. T. Tomita: None. M. Kobayashi: None. T. Mitsui: None. K. Kadokura: None.
2178-PUB: Validating a New Classification Method for SMBG Logging Habits in Real-World Data
Authors: BIVEN RICHARD P. , WREDE JAN , BANKOSEGGER RAFAEL P. , KOBER JOHANNA , PETERSEN BETTINA , RINGEMANN CHRISTIAN , HUSCHTO TONY
Published: June 2020

Objective: Assessing diabetes therapy performance in Real World Data (RWD) is difficult as the data quantity of SMBG measurements shows strong variability. In a previous study, we proposed a new metric, Gkn/N ⇔ n out of N days :|SM BG| ≥ k, which ensures data quality so patients with skewed SMBG values or highly motivated users are not overrepresented. The classification separates users by logging habits, e.g., G1 ≅ 1 log a day . The aim of this study is to validate our metric with CGM data and determine if more logs a day increase metrics accuracy.

Method: We analyzed 299 users of a data set with CGM and SMBG logs . The inclusion criteria was 70% CGM logs for 1 month with associated SMBG logs. Each user was classified into a G-group. The distribution was biased to the G4-G5 groups. Therefore, users were randomly selected and had logs randomly removed to create lower G-group users, providing an equal distribution. The percent errors of the users’ mean BG, standard deviation (SD), and tests-in-range (TIR) between the SMBG and CGM logs were analyzed. With random sampling the analysis was repeated and mean results used.

Results: Results had G1 users with the largest error in all metrics tested (Mean Error:BG =8%, SD =15.4%, TIR =17.5%). The error did not substantially decrease as the logs increased (correlating to a higher G-groups). Because differences were not apparent in the mean BG, SD, or TIR;t-tests were performed for each group to determine statistical differences from the other groups based on BG or SD error. The only G-group to be statistically different (p<0.05) was G1 from all higher groups.

Conclusion: Results allow separating users into two groups. The error between G2 and all higher logging groups was not significant, implying metric accuracy does not increase with more logs. The validation allows the use of metrics based on mean BG or SD to a larger portion of users while limiting the bias on users’ logging habits. Further analyses are necessary to compare values from each G-class with clinically reported metrics.

Disclosure

R.P. Biven: None. J. Wrede: None. R.P. Bankosegger: Employee; Self; mySugr. J. Kober: Employee; Self; mySugr. B. Petersen: Employee; Self; Roche Diabetes Care. C. Ringemann: Employee; Self; Roche Diabetes Care. T. Huschto: Employee; Self; Roche Diabetes Care.
2186-PUB: Comparison of Insulin Degludec (IDeg)/Insulin Aspart (IAsp) Coformulation Therapy Twice Daily with Free Combination of GLP-1 Receptor Agonist Liraglutide plus Insulin Degludec in Tochigi: IDEAL Trial
Authors: ASO YOSHIMASA , JOJIMA TERUO , SAKURAI SHINTARO , IIJIMA TOSHIE , TOMARU TAKUYA , USUI ISAO
Published: June 2020

Objective: To compare the efficacy and safety of insulin degludec/insulin aspart co-formulation (IDegAsp) twice daily with free combination of basal insulin degludec and GLP-1 receptor agonist liraglutide once daily in type 2 diabetic patients inadequately controlled on insulin therapy with oral antidiabetic drugs.

Subjects and Methods: Eligible patients were randomly allocated at a 1:1 ratio to receive once-daily IDeg plus liraglutide given separately (n=24) or twice daily IDegAsp (n=28). IDeg+Lira were separately administered before breakfast. The primary endpoints were the change in HbA1c from baseline to 52 weeks of treatment, as well as the percentage of participants achieving HbA1c less than 7.0% at 52 weeks.

Results: After 52 weeks, HbA1c was decreased by 0.3% in the IDegAsp group and by 0.7% in the IDeg+Lira group. Reduction in HbA1c tended to be greater in the IDeg+Lira group than in the IDegAsp group (P=0.070). Nineteen percent of patients on IDegAsp versus 40% on IDeg+Lira achieved HbA1c<7.0%. Pre-breakfast and -dinner FBP at 52 weeks were significantly lower in the IDeg+Lira group than in the IDegAsp group. A reduction in body mass index (BMI) was greater in the IDeg+Lira group than in the IDegAsp group throughout the study period. In the IDeg+Lira group, mean insulin degludec and liraglutide at 52 weeks were 15.1 U and 0.84 mg, respectively.

 Conclusions: In patients with inadequately controlled type 2 diabetes on insulin and oral antidiabetic drugs, treatment with insulin degludec and liraglutide separately injections compared with IDegAsp co-formation twice daily showed no significant difference in glycemic control, but with somewhat greater reduction in HbA1c at 52 weeks, and a statistically superior weight loss.

Disclosure

Y. Aso: None. T. Jojima: None. S. Sakurai: None. T. Iijima: None. T. Tomaru: Research Support; Self; Merck & Co., Inc., Teijin Pharma Limited. I. Usui: None.
219-LB: The Hepatocyte Clock and Feeding Interdependently Control Chrono-Homeostasis of Multiple Liver Cell Types
Authors: GUAN DONGYIN , LAZAR MITCHELL A.
Published: June 2020

Most cells in the body contain a cell autonomous molecular clock, but the requirement of peripheral clocks for circadian rhythmicity, and their effects on physiology, are not well understood. Here we show that deletion of core clock components REV-ERB alpha and β in adult mouse hepatocytes disrupted circadian rhythmicity of many liver genes, as expected, but also led to maintained and even gained rhythmicity of other genes without altering feeding behavior. The loss of REV-ERBs from hepatocytes led to an exaggerated circadian rhythm of de novo lipogenesis. Liver function is also influenced by non-hepatocytic cells, and remarkably the loss of REV-ERBs in hepatocytes remodeled the circadian transcriptomes and metabolomes of multiple cell types within the liver, indicating that hepatocytes communicated time signals to non-hepatocytic cells. Finally, alteration of food availability demonstrated strong interdependence of the cell-autonomous hepatocyte clock mechanism and non-cell-autonomous environmental change. Together these studies reveal previously unsuspected roles of the hepatocyte clock in the physiological coordination of nutritional signals and cell-cell communication controlling rhythmic metabolism.

Disclosure

D. Guan: None. M.A. Lazar: Board Member; Self; Pfizer Inc. Consultant; Self; Calico, Madrigal Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (F32DK116519)
2198-PUB: The Impact of Basal Insulin Initiation to Background Sulfonylurea Treatment on Hypoglycemia Occurrence: Evaluation of the Balkan Cohort of Dune Study
Authors: JANEZ ANDREJ , LUNDER MOJCA , JANIC MIODRAG , GRULOVIC NATASA , ZDRAVKOVIC DRAGAN , JOTIC ALEKSANDRA Z. , LALIC KATARINA , LALIC NEBOJSA
Published: June 2020

Background: Optimal glycemic control and proper basal insulin initiation timing when non-insulin treatment becomes insufficient is critical in type 2 diabetes mellitus (T2DM). The DUNE study investigated the effectiveness and safety of newly initiated basal insulin in T2DM patients compared to those who already received insulin. The impact of background therapy with sulfonylureas (SU) on insulin dose and hypoglycemia occurrence was also explored.

Methods: The DUNE study was a 12-week, prospective, single-arm, observational study of adults with T2DM. The present sub-analysis included the patients from the Balkan region (Slovenia and Serbia). The first group (n=83) included patients with newly initiated basal insulin and the second group (n=94) included patients who were already treated with basal insulin for up to 12 months. Patients also received other non-insulin antihyperglycemic drugs.

Results: The proportion of patients receiving SUs was higher in the group with newly initiated basal insulin (72.3% vs. 55.3%; p<0.001). Basal insulin treatment included NPH or 1st generation basal insulin analogues (BIA) (98.8% vs. 1.2% for newly initiated basal insulin and 83% vs. 17% for already initiated basal insulin), due to local reimbursement policy. Daily insulin doses were lower in newly initiated basal insulin group (11.7±5.58U vs. 18.6±9.18U; p<0.001), the difference remained significant also after 12 weeks of observation (17.5±11.8U vs. 22.6±10.69U; p<0.01). A trend towards higher hypoglycemia occurrence in the newly initiated basal insulin group was observed, despite the lower insulin dose, but with higher percentage of treatment with SUs as a background treatment.

Conclusions: Continuation of SUs in T2DM patients, both newly initiated and already initiated with basal insulin therapy (NPH or first-generation insulin analog), should be considered with caution due to the potentially enhanced effect on the risk of hypoglycemia.

Disclosure

A. Janez: None. M. Lunder: None. M. Janic: None. N. Grulovic: None. D. Zdravkovic: None. A.Z. Jotic: None. K. Lalic: Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim, Merck, Novo Nordisk, Sanofi. N. Lalic: None.
2200-PUB: Application of Data Envelopment Analysis in Health Economic Evaluation of Insulin Pump Treatment during Perioperative Period
Authors: SONG WEI , WEN JIANXUAN , ZHAO LING , FAN GUANJIE , LUO MENG , LIANG JIAJIAN , ZHANG JINMING , YANG CAIFENG , WANG QIUPING , GAO ZHIJUAN , MA LIU
Published: June 2020

Objective: To evaluate the effect of insulin pump on perioperative patients with type 2 diabetes and the role of health economics by applying data envelopment analysis (DEA).

Method: This retrospective study involved 639 patients with type 2 diabetes undergoing surgery in Guangdong Provincial Hospital of Traditional Chinese Medicine from January 2009 to November 2017. All patients were treated with insulin during the perioperative period. They were divided into a insulin pump group for diabetes (perioperative blood glucose control with insulin pump, 369 cases) and a Non-insulin pump group (perioperative blood glucose control with subcutaneous insulin injection, 270 cases). Data Envelope analysis was applied to compare the input indicators of the two groups to total cost and total length of hospital stay. The output indicators of the two groups were blood glucose control time before surgery, mean fasting blood glucose, blood glucose in the first sky after surgery, days of antibiotic use, and hospital stay after surgery.

Result: In the aspect of comparison of scale efficiency, the efficiency values of the pump set in the C2R model and BC2 model are better than those of the unused pump set. In Another aspect of the relaxation variables, the higher the surgical level, the closer the pump group is to the ideal state compared with the non-pump group, in terms of improving average fasting blood glucose, antibiotic use days, preoperative blood glucose control time, first day postoperative fasting blood glucose, and postoperative hospitalization days.

Conclusion: Insulin pump can quickly and stably control blood glucose levels and shorten the length of hospital stay during the perioperative period of type 2 diabetes patients. It is suggested that the application of insulin pump in perioperative period may have better benefits and is worthy of clinical promotion.

Disclosure

W. Song: None. J. Wen: None. L. Zhao: None. G. Fan: None. M. Luo: None. J. Liang: None. J. Zhang: None. C. Yang: None. Q. Wang: None. Z. Gao: None. L. Ma: None.
2206-PUB: Efficacy of Fixed-Dose Combination of Empagliflozin and Linagliptin in Addition to the Ongoing Treatment in Type 2 Diabetes: Real-World Observational Study
Authors: GUPTA ABHINAV , KHALSE MANEESHA , BHARGAVA AMIT
Published: June 2020

Empagliflozin (SGLT2 inhibitor) and linagliptin (DPP-4 inhibitor) is a Fixed Dose Combination (FDC) with limited real-world evidence. We assessed the efficacy of this novel FDC in the real world Indian setting by analyzing the mean change in 12-week values of the glycemic (HbA1c and FPG) and extra-glycemic parameters (SBP, DBP, eGFR and body weight) as compared to the baseline values at the point of initiation of FDC in 498 patients. (Table). The patients enrolled were independently naïve to both DPP IV inhibitor and SGLT2 inhibitor therapy. Unpaired t test and ANOVA were utilised for statistical analysis. The mean age was 61 years (SD ± 7.6). The ongoing treatment in 20% (n=100), 43% (n=214), 38% (n=189), 26% (n=127) were metformin (M), combination of M and sulfonylureas (SU), combination of M, SU and voglibose, and insulin, respectively. The mean change in HbA1c, FPG, SBP, DBP, eGFR and body weight was -1.1%, -45 mg/dl, -12 mmHg, -5 mmHg, 5 mL/min/1.73m2, -5 kg (p<0.0001), respectively. 23.9 % patients (n=119) achieved HbA1c < 7%. 36.8% (n=183) patients achieved FPG reductions ≥100mg/dl. Six patients reported clinically evident hypoglycaemia which was managed symptomatically. There was a meaningful change and a substantial quantum of improvement in glycemic, metabolic and renal parameters. The results need to be validated through a long-term larger study.

Disclosure

A. Gupta: None. M. Khalse: None. A. Bhargava: None.
221-LB: Association between Muscle Strength and Advanced Fibrosis in Nonalcoholic Fatty Liver Disease: Korean Nationwide Survey
Authors: KANG SUNYOUNG , MOON MIN KYONG , KOO BO KYUNG
Published: June 2020

Background: We investigated the association between muscle strength and the prevalence of advanced fibrosis among individuals with nonalcoholic fatty liver disease (NAFLD) using a nationwide cross-sectional survey.

Methods: Individuals, 20 to 79 years of age, from the Korean National Health and Nutrition Examination Surveys (KNHANES) from 2014 to 2016 were selected (n = 14,861), with sample weights applied. Muscle strength was quantified as the hand grip strength (HGS) divided by the body mass index (BMI); low muscle strength (LMS) was defined as the lowest quartile (Q1) of the HGS/BMI scores for our sample population. NAFLD was defined by hepatic steatosis index (HSI) >36 (NAFLDHSI). The highest quartile of NAFLD fibrosis score (NFS) (FibrosisNFS) was used to define advanced fibrosis.

Results: In a crude analysis, LMS was associated with the increased prevalence of NAFLDHSI (OR 3.62, 95% CI 3.25-4.03), which remained significant even after adjustment for age, sex, obesity, and insulin resistance (OR 1.69, 95% CI 1.30-2.18). Even in those without obesity, individuals with LMS had a higher prevalence of NAFLDHSI compared to those without LMS (OR 1.93, 95% CI, 1.42-2.63). Among individuals with NAFLDHSI (n = 3,320), LMS was also associated with the presence of advanced fibrosis (FibrosisNFS) even after adjustment for age, sex, obesity, and insulin resistance (OR 1.68, 95% CI 1.09-2.58).

Conclusion: Muscle strength is independently associated with NAFLD and advanced fibrosis.

Disclosure

S. Kang: None. M. Moon: None. B. Koo: None.
222-LB: Diabetes Induces Liver Inflammation and FGF21 through C-Jun NH2-Terminal Kinase Pathways
Authors: CHEN LEE-WEI
Published: June 2020

Fibroblast growth factor 21 (FGF-21) is a hormone that regulates important metabolic pathways. Serum fibroblast FGF-21 levels were significantly higher in obesity and type 2 diabetes mellitus (T2DM). Previously, we have found that the JNK pathway played a critical role in diabetes-induced Kupffer cell activation, and pJNK1 inhibition decreases Kupffer cell activation induced by diabetes. We aim to study the involvement c-Jun NH2-terminal kinase pathways in the regulatory mechanisms of liver inflammation and FGF-21 in diabetes. Type 1 diabetic Akita mice (C57BL/6J-Ins2Akita) and type 2 diabetic Leprdb/db mice (C57BL/6J- Leprdb/db) were used. Leprdb/db-JNK1-/- and Ins2Akita-JNK1-/- mice were produced and used to study the role of pJNK in the regulatory mechanisms of diabetes on liver inflammation and FGF-21. Diabetic mice demonstrated increased ICAM, iNOS, interleukin 1 beta (IL-1β), FGF-21, and FMO3 expression of liver; and tumor necrosis factor alpha (TNF-α), and iNOS expression in Kupffer cells; and plasma FGF-21 levels. Ins2Akita-JNK1-/- and Leprdb/db-JNK1-/- mice demonstrated decreased ICAM, iNOS, IL-1β, and FMO3 expression of liver; and ICAM, iNOS, and FMO3 expression in aorta, tumor necrosis factor alpha (TNF-α), and iNOS expression in Kupffer cells, plasma IL-6 and TNF-α levels; dipeptidyl peptidase (DPP-4) activity. JNK inhibitor, SP600125, injection into adipose tissue of Leprdb/db mice significantly decreased ICAM, iNOS, IL-1β, and FMO3 expression of liver and serum FGF-21 levels. Altogether, our data suggest that diabetes induces liver inflammation, FGF-21, and insulin resistance through c-Jun NH2-terminal kinase.

Disclosure

L. Chen: None.

Funding

National Science Council (MOST 107-2314-B-010-043-MY3)
2239-PUB: Best Practices for Implementing Diabetes Prevention in Health Care Settings
Authors: WILLIAMS JANET , SACHDEV NEHA , MOIN TANNAZ , DURU O. KENRIK
Published: June 2020

One in 3 adults in the U.S. has prediabetes and 90 percent don’t even know they have it. If left untreated or treated with usual care, many will go on to develop type 2 diabetes. The Centers for Disease Control and Prevention’s National Diabetes Prevention Program (DPP) was created in 2010 to address the increasing burden of prediabetes and type 2 diabetes in the United States. Despite the demonstrated effectiveness of an intensive lifestyle invention program, there are still millions of undiagnosed and untreated individuals with prediabetes. Identification of prediabetes and referral of eligible adults to a lifestyle change program is recommended in both the ADA and USPSTF clinical guidelines and standards of care. However, only a minority of clinicians are systematically addressing prediabetes in their patient population or referring their patients to a lifestyle change program. Although existing research has evaluated the uptake of clinical guidelines regarding diabetes prevention and the availability of coverage for lifestyle change programs, there is a gap in collecting and sharing best practices for building a diabetes prevention strategy that includes the CDC’s National DPP lifestyle change program. The AMA convened a diverse group of leading health care organizations that were successful in establishing system-based strategies. This session will describe a best practice implementation framework for health systems to consider when establishing or expanding a diabetes prevention strategy and engaging with clinical champions to improve identification and treatment of patients with prediabetes.

Disclosure

J. Williams: None. N. Sachdev: None. T. Moin: None. O. Duru: None.
2246-PUB: "There’s a Disconnect Here": A Study Evaluating Blood Glucose Trends at a Youth Diabetes Camp
Authors: RANDALL MARTIN , DEGNAN BERNARD M.
Published: June 2020

Introduction: Camp Midicha is an American Diabetes Association summer camp for children aged 8-17 with type 1 diabetes mellitus located in Fenton, Michigan. Blood glucose (BG) levels of campers are closely monitored so that hypoglycemia and hyperglycemia can be treated and ideally prevented. Hyperglycemia is a particular concern for campers who use insulin pumps because of an increased risk for ketoacidosis. It has been previously observed that campers who disconnect their pumps for swimming have higher BG levels later in the day. Swimming occurs for approximately 1.5 hours between lunch and dinner for all campers daily. This study aims to compare trends in BG for campers who wear insulin pumps that are removed prior to afternoon swimming versus those who do not.

Methods: This study was conducted as a retrospective review of the camp’s medical records. Trends in BG at lunch and dinner were compared between campers who A) wear a removable insulin pump and B) wear a non-removable pump or utilize insulin injections. This study included all campers at Camp Midicha from 2017 and 2018, encompassing 862 campers. Multivariate linear regression was used to compare the two groups.

Results: The average change in BG from lunch to dinner was 38.13 mg/dL for campers who removed their insulin pumps (174.62 to 212.75 mg/dL) and 16.42 mg/dL for campers who did not (177.14 to 193.59 mg/dL). The difference in BG change between the groups was 21.68 mg/dL (P < 0.0001) with variance between the different days analyzed.

Conclusion: This study showed a significant difference in the change in BG from lunch to dinner between the two groups despite insulin pumps being disconnected for only 1.5 hours. While the magnitude of this difference may not necessitate follow-up studies to assess potential interventions, further analysis to evaluate differences in BG change between days could be valuable for insulin dosing at future camps.

Disclosure

M. Randall: None. B.M. Degnan: None.
2301-PUB: The Role of Muramyl Dipeptide in Glucagon-Like Peptide-1 Regulation
Authors: WILLIAMS LAURA , ALSHEHRI AMAL , MUSTAFA SALMA , GAGNON JEFFREY
Published: June 2020

The host’s intestinal microbiota contributes to endocrine and metabolic responses, but a dysbiosis in this environment can lead to obesity and insulin resistance. A new area a research is focused on understanding how bacterial metabolites contribute to intestinal glucagon-like peptide-1 (GLP-1) release. Muramyl dipeptide (MDP) is a bacterial cell wall component which has been shown to improve insulin sensitivity and glucose tolerance in diet-induced obese mice. The purpose of this study was to understand MDP’s mechanism of action in glucose regulation. We hypothesized that MDP enhances glucose tolerance by inducing intestinal GLP-1 secretion. We observed a significant increase (P<0.001, n=7) in GLP-1 secretion when mouse L-cells were treated with an MDP derivative at 10ug/ml. Using fluorescent immunohistochemistry and RT-PCR we located MDP’s receptor, nucleotide oligomerizing domain 2 (NOD2), in mouse intestine and mouse L-cells. In mice, two intraperitoneal injections of MDP (5mg/kg body weight) or PBS caused a significant increase (P=0.0009, n=15-19) in fasting total GLP-1. Understanding how bacterial products influence GLP-1 secretion and subsequent insulin release, could be translated into novel treatments options for improving glucose regulation in metabolic disease.

Disclosure

L. Williams: None. A. Alshehri: None. S. Mustafa: None. J. Gagnon: None.

Funding

Natural Sciences and Engineering Research Council of Canada (2016-05905)
233-OR: Ultra-Rapid Lispro (URLi) Demonstrates Similar Time-in-Target Range to Humalog with the Medtronic MiniMed 670G Hybrid Closed-Loop System
Authors: BODE BRUCE W. , CARLSON ANDERS L. , LIU RONG , HARDY THOMAS , BOYD JENNIFER , BERGENSTAL RICHARD M. , MORRETT SCOTT , IGNAUT DEBRA A.
Published: June 2020

URLi is a novel ultra rapid formulation of insulin lispro that shows improved postprandial glucose control and similar compatibility with continuous subcutaneous insulin infusion (CSII) vs. Humalog. In this study URLi was evaluated for the first time in a hybrid closed-loop system using the Medtronic MiniMed 670G. Primary objective was to compare URLi to Humalog with respect to the percentage of time with glucose values within target range 70-180 mg/dL (%TIR). This double-blind, crossover study included two 4-week treatment periods with URLi or Humalog. After a 2-week lead-in on Humalog, 42 adults with type 1 diabetes using personal MiniMed 670G pumps were randomized to 1 of the 2 treatment sequences with boluses initiated 0-2 minutes before meals. Both treatments achieved good glycemic control with mean TIR >75% (Fig 1). Mean time above and below range met consensus recommendations for both treatments. The percentage of time in Auto Mode was similar between treatments: URLi 92.0%; Humalog 91.4%. Insulin doses and pump settings were generally similar between treatments. There were no serious adverse events or early discontinuations. Overall incidence of treatment-emergent adverse events was similar between treatments. URLi demonstrated comparable glycemic control and a similar safety profile to Humalog with the MiniMed 670G system in patients with type 1 diabetes.

Disclosure

B.W. Bode: Advisory Panel; Self; InPen, Medtronic. Consultant; Self; ADOCIA, Eli Lilly and Company, Lexicon Pharmaceuticals, Inc., Novo Nordisk A/S, Pfizer Inc. Research Support; Self; Dexcom, Inc., Diasome Pharmaceuticals, Inc., Eli Lilly and Company, Gan & Lee Pharmaceuticals, Medtronic, Novo Nordisk A/S, Provention Bio, Inc., Senseonics, Xeris Pharmaceuticals, Inc. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., InPen, Janssen Pharmaceuticals, Inc., MannKind Corporation, Medtronic, Novo Nordisk A/S, Sanofi, Sanofi, Senseonics, Xeris Pharmaceuticals, Inc. Stock/Shareholder; Self; Glytec. A.L. Carlson: Consultant; Self; Medtronic. Research Support; Self; Abbott, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Medtronic, Novo Nordisk A/S, Sanofi, UnitedHealth Group. R. Liu: Employee; Self; Eli Lilly and Company. Employee; Spouse/Partner; Eli Lilly and Company. T. Hardy: Other Relationship; Self; Eli Lilly and Company. J. Boyd: None. R.M. Bergenstal: Consultant; Self; Ascensia Diabetes Care, Johnson & Johnson. Other Relationship; Self; Abbott, Dexcom, Inc., Hygieia, Lilly Diabetes, Medtronic, Novo Nordisk A/S, Onduo, Roche Diabetes Care, Sanofi, UnitedHealth Group. S. Morrett: Other Relationship; Self; Eli Lilly and Company. D.A. Ignaut: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company.

Funding

Eli Lilly and Company
235-LB: Postprandial Short-Chain Fatty Acid Concentrations in the Intestinal Lumen and Plasma
Authors: MEYER RACHEL , LANE ADELINA I.L. , KANGATH ARCHANA , WENINGER SAVANNA N. , MARTINEZ TAYLOR , DUCA FRANK
Published: June 2020

Obesity continues to be a global health risk affecting over 650 million adults worldwide. Fiber intake is negatively correlated with obesity, and increased fiber intake is associated with weight loss. Fiber is digested by the gut microbiota to produce short chain fatty acids (SCFA), which may have a beneficial effect on metabolic disease. While it is well known that SCFAs are mostly utilized by enterocytes as a fuel source, the timing of postprandial production and absorption of SCFAs from a meal, as well as the effect of high-fat feeding, has yet to be characterized. In the present study, we aimed to determine the levels of acetate, butyrate, and propionate, the major SCFAs, after a meal in rats maintained for 4wks on a chow, high-fat diet (45% kcal from fat; HFD) or HFD with 10% oligofructose (OFS), a well-studied prebiotic known to induce weight loss. SCFA levels were measured in the distal small intestine, cecum, and colon of rats, as well as the portal vein and vena cava at 0, 2, 4, 6, and 8 hours following consumption of an isocaloric meal of the maintenance diet. Chow rats had significantly increased levels of SCFAs as early as 2h postprandially, in the cecum, colon, portal vein, and vena cava compared to baseline levels, whereas HFD-fed rats displayed minimal increases in SCFAs. Addition of OFS rescued SCFA production, peaking at 4h postprandial; however, concentrations were not rescued to chow values at all timepoints. Increased body weight and adiposity was not associated with baseline SCFA levels in any compartment, but was negatively associated with postprandial SCFA levels in the cecum, colon, and portal vein. Overall, this study demonstrates that SCFAs exhibit a post-prandial rise similar to ingested macronutrients, and that baseline fasting levels of SCFAs may be an inaccurate indication of SCFA production in rodents. These data lay the groundwork for future studies to examine how rises in SCFA levels from breakdown of non-digestible carbohydrates can contribute to improve metabolic disease.

Disclosure

R. Meyer: None. A.I.L. Lane: None. A. Kangath: None. S.N. Weninger: None. T. Martinez: None. F. Duca: None.
240-OR: Combining Type 2 Diabetes Polygenic Scores Improves Prediction in 36,000 European and Non-European Participants in the Partners Healthcare Biobank
Authors: MERCADER JOSEP M. , FLOREZ JOSE C. , LEONG AARON , KAUR VARINDERPAL , UDLER MIRIAM , MEIGS JAMES B. , PORNEALA BIANCA
Published: June 2020

Polygenic scores constructed by the aggregation of effect sizes of associated genetic variants have been shown to predict type 2 diabetes (T2D). Polygenic scores can be defined as “restricted-to-significant polygenic scores” (rsPS), and “globally expanded polygenic scores” (gePS), which can include millions of variants beyond those that are genome-wide significant. Most polygenic scores have been generated based on genome-wide association studies (GWAS) conducted predominantly in participants of European ancestry (EU); how these polygenic scores perform in non-European individuals in the healthcare system has not been thoroughly evaluated.

We applied the rsPS and gePS for T2D in 30,240 EU participants, 3,029 Latinos (LA), and 2,201 African Americans (AA) from the Partners HealthCare Biobank, which maintains blood and DNA samples from patients seen at Partners HealthCare-affiliated hospitals in Boston. We compared rsPS based on the DIAMANTE consortium meta-analysis, with 398 variants (rsPS_398), rsPS based on the latest Million Veterans Program meta-analysis, with 682 variants (rsPS_682), and a gePS based on ldpred, including 6.9M variants adjusted for their effects based on linkage disequilibrium.

rsPS_682 was most strongly associated with T2D in all ancestries (OR per SD in EU=1.73 p=7×10-142, OR per SD in LA =1.88, p=7×10-19, OR per SD in AA =1.47, p=1×10-8 compared to the other polygenic scores. We observed that rsPS_682 and the gePS provided both complementary information, and that combining them into the model improved the prediction in all ancestries, with 16%, 22%, and 16% increase in accuracy in EU, LA, and AA, respectively.

We show the advantage of combining rsPS and gePS to improve prediction of T2D in multi-ethnic populations within a healthcare system. The results suggest that larger and multi-ethnic T2D GWAS are needed to avoid major health disparities.

Disclosure

J.M. Mercader: None. J.C. Florez: Advisory Panel; Self; Doris Duke Charitable Foundation. Other Relationship; Self; Novo Nordisk Inc., Park Street School. A. Leong: None. V. Kaur: None. M. Udler: None. J.B. Meigs: Consultant; Self; Quest Diagnostics. B. Porneala: None.

Funding

American Diabetes Association (1-19-ICTS-068 to J.M.M.)
262-OR: The Transcription Factor Yin Yang 1 (YY1) Is Critical to Beta-Cell Maintenance and Glucose Homeostasis
Authors: PEÇANHA FLAVIA LETÍCIA M. , BERNAL-MIZRACHI ERNESTO
Published: June 2020

Diabetes is characterized by loss of β cell mass and function. mTORC1 has an important role in the control of insulin secretion, β cell proliferation and death. YY1 is important in development, apoptosis, metabolism and growth in several tissues. In muscle, mTORC1 regulates the expression of insulin signaling genes by controlling YY1 binding to the promoter region. However, YY1 role in β cells was not addressed so far. Here we observed that diabetic and diet-induced obese mice exhibited lower levels of YY1 in the β cells. To understand the role of YY1 in β cell, we developed a new β cell YY1 depleted mouse model (β-YY1KO) by crossing our floxed YY1 mouse with a Ins-cre mouse. Haploinsufficiency of YY1 (β-YY1HET) did not impair fed or fasting glycemia, blood insulin levels and glucose tolerance. Even after 10 weeks in HFD, β-YY1HET did not differ from littermate controls in terms of glucose tolerance and glucose-stimulating insulin secretion. However, β-YY1KO mice exhibited a profound diabetic phenotype. While glucose and insulin levels in newborn β-YY1KO were normal, blood glucose begun to rise in the β-YY1KO mice at 2 weeks. All β-YY1KO became diabetic at 3 weeks presenting fed hyperglycemia and lower fed insulin levels, suggesting decreased β cell function and/or β cell loss. Remarkably, β cell mass is reduced at 2 and 3 weeks. To understand the decrease in β cell mass, we assessed β cell proliferation and death by IHF for Ki67 and flow cytometry for active Casp 3, respectively. Although β cell proliferation was normal at 2 weeks, there was a reduction Ki67+ β cell at 3 weeks. However, active casp 3 was already increased at 2 weeks. One striking role of YY1 is to regulate mitochondrial function and structure, therefore, we evaluated mitochondrial morphology by electron microscopy. We found that β-YY1KO mice presented less mitochondrial area and abnormal structure. Altogether, these results show that YY1 is important for appropriate control of glucose homeostasis and β-cell maintenance.

Disclosure

F.M. Peçanha: None. E. Bernal-Mizrachi: None.