bluuebunny/crossref_metadata_2025_split huggingface dataset:
358-OR: ß-Cell Function and Insulin Sensitivity with Islet Alone and Islet-after-Kidney Transplantation for Type 1 Diabetes in the Clinical Islet Transplantation (CIT) Consortium
Authors: RICKELS MICHAEL R. , EGGERMAN THOMAS , BAYMAN LEVENT , QIDWAI JULIE , NAJI JOSEPH , NGUYEN HUONG-LAN T. , ALEJANDRO RODOLFO , BELLIN MELENA , SENIOR PETER , HUNSICKER LAWRENCE G. ,   CLINICAL ISLET TRANSPLANTATION CONSORTIUM
Published: June 2020

Phase 3 studies of islet transplant alone (ITA) and islet-after-kidney (IAK) transplantation in type 1 diabetes were completed by the CIT Consortium using the same procedures for islet manufacturing and induction immunosuppression but differing in maintenance immunosuppression. Both studies met their criteria for safety and efficacy over 2 and 3 year planned follow-up, respectively. The insulin sensitivity index, SI, was derived from an insulin-modified frequently sampled intravenous glucose tolerance (FSIGT) test using the minimal model approach before (repeated annually) and after islet transplantation, with post-transplant tests also used to assess β-cell function from the acute insulin response to glucose (AIRg) and the disposition index (DI = AIRg SI). Seventy subjects (48 ITA and 22 IAK) completed 79 tests before and 203 tests between 75 days and 3 years after islet transplantation. SI increased post-transplant in both groups and displayed an apparent hyperbolic relationship with post-transplant AIRg. Post-transplant SI was greater in ITA vs. IAK (P &lt; 0.001). Log-transformed AIRg and SI indicate that SI is ∼24% lower at any given AIRg for IAK than ITA. Neither AIRg nor DI was significantly different between ITA and IAK post-transplant. Log-transformed AIRg and DI demonstrate significant prediction of islet graft failure (defined by mixed-meal tolerance test stimulated C-peptide &lt; 0.3 ng/mL) such that each log increase of AIRg and DI reduces the hazard of islet graft failure by 45% and 42%, respectively. These results indicate that while insulin sensitivity improved after islet transplantation, post-transplant measures of β-cell function may better predict islet graft survival. Whether the differences in maintenance immunosuppression (low-dose tacrolimus and sirolimus, ITA; tacrolimus and mycophenolic acid, IAK) may explain the greater insulin sensitivity in ITA vs. IAK requires further study.

Disclosure
M.R. Rickels: Consultant; Self; Semma Therapeutics, Inc. Research Support; Self; Xeris Pharmaceuticals, Inc. T. Eggerman: None. L. Bayman: None. J. Qidwai: None. J. Naji: None. H.T. Nguyen: None. R. Alejandro: None. M. Bellin: Research Support; Self; Dexcom, Inc., Viacyte, Inc. Other Relationship; Self; Insulet Corporation. P. Senior: Research Support; Self; Allergan, Novo Nordisk. L.G. Hunsicker: Advisory Panel; Self; Allergan plc., Bristol-Myers Squibb.

Funding
National Institutes of Health; JDRF (1-SRA-2019-728-A-N)
365-OR: Glycemic Outcomes at One Year Post Pediatric TPIAT
Authors: SWAUGER SARAH , HORNUNG LINDSEY , ELDER DEBORAH A. , NATHAN JAIMIE D. , ABU-EL-HAIJA MAISAM 
Published: June 2020

Total pancreatectomy with islet autotransplantation (TPIAT) is indicated to alleviate pain and mitigate diabetes in patients with chronic pancreatitis when medical/endoscopic therapies have failed. Predictors of insulin independence and graft function have not been well studied in pediatric TPIAT patients. Our aim was to evaluate predictors of insulin requirement at one year post-TPIAT. This was a retrospective review of 35 patients (&lt;20 years old) who were followed for at least one year post-TPIAT. Primary outcome was insulin use at one year, categorized as either: insulin independent, low insulin (&lt; 0.5 u/kg/day) requirement, or high insulin (≥ 0.5 u/kg/day) requirement. Clinical and pre- and postoperative metabolic data were collected including c-peptide, glucose and insulin levels from mixed meal studies and transplanted islet equivalents per body weight (IEQ/kg). At one year post-TPIAT, 9/35 (26%) patients were insulin independent, 18/35 (51%) had low insulin requirement and 8/35 (23%) had high insulin requirement. Insulin independent patients were younger than those with low and high insulin requirement (median age 9.6 vs. 14.6 vs. 13.1 years, respectively; p=0.05). Patient groups were similar in gender, IEQ/kg transplanted, BMI, disease duration and genetic risks. Preoperative exocrine insufficiency was associated with higher insulin requirement (p=0.04). Pre-TPIAT metabolic markers were not associated with one year insulin outcomes. Higher fasting glucose at 9 months post-TPIAT was significantly associated with increased odds of higher insulin requirement at one year (p=0.007). Higher peak c-peptide at 3, 6 and 9 months post-TPIAT was associated with decreased odds of being on higher insulin requirements after controlling for baseline BMI percentile. Insulin independence at one year post-TPIAT was associated with younger age and exocrine sufficiency at time of operation. Higher peak c-peptide at 3, 6 and 9 months post-TPIAT were associated with lower insulin requirements at one year following operation.

Disclosure
S. Swauger: None. L. Hornung: None. D.A. Elder: None. J.D. Nathan: None. M. Abu-El-Haija: None.
368-OR: Activation of Hepatic Gluconeogenesis Is Required to Suppress DNL and Stimulate Ketogenesis during Fasting
Authors: DEJA STANISLAW , DUARTE JOAO , FLETCHER JUSTIN A. , KUCEJOVA BLANKA , FU XIAORONG , VALE GONÇALO , YOUNG JAMEY , BROWNING JEFFREY , BURGESS SHAWN C. 
Published: June 2020

Carbohydrates and lipids are primary energy sources in mammals; thus, their oxidation and synthesis are carefully controlled. The tricarboxylic acid (TCA) cycle is necessary to oxidize these substrates, and in liver it also supports their synthesis. However, its role in regulating these processes, particularly de novo lipogenesis (DNL) is underappreciated. We report that activation of hepatic gluconeogenesis (GNG) is required to trigger the canonical lipid and carbohydrate response to fasting in mice. Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes cataplerotic flux from the TCA cycle and is required for GNG from lactate, pyruvate and amino acids. Knockdown (KD) or knockout (KO) of PEPCK caused the massive accumulation of TCA cycle intermediates and KO mice developed fatty liver after an overnight fast. Lipidomic profiling of liver suggested increased lipid desaturation and elongation with loss of PEPCK. 2H NMR analysis of liver lipids following 2H2O administration demonstrated elevated fasting DNL in KO mice, which was similar to fed WT mice. In addition, fasting ketogenesis, estimated by infusions of [U-13C]BHB and [3,4-13C]AcAc, was decreased in KO mice. Despite an impaired fasting response, the expression of genes related to control of fat oxidation and DNL were not decreased, suggesting that loss of regulation was mediated by a metabolic mechanism. Inhibition of GNG produced a reduced mitochondrial redox state which limited oxidative pathways and decreased acetyl-CoA concentration. Inhibition of GNG also decreased fasting ATP requirements, resulting in a high energy charge which suppressed activation of AMPK, its canonical suppression of acetyl-CoA carboxylase and caused increased malonyl-CoA during fasting. Hence, PEPCK mediated cataplerosis and GNG during fasting is not only an important source of glucose, it is also necessary to shift cellular redox and energetics to states necessary to suppress lipogenesis and maintain ketogenesis during fasting.

Disclosure
S. Deja: None. J. Duarte: None. J.A. Fletcher: None. B. Kucejova: None. X. Fu: None. G. Vale: None. J. Young: Board Member; Self; Metalytics. Consultant; Self; Pfizer Inc. J. Browning: None. S.C. Burgess: None.

Funding
National Institutes of Health (R01DK078184, P41EB015908); Robert A. Welch Foundation (I-1804)
37-LB: GLP-2 Regulation of Dietary Fat Absorption and Intestinal Lipoprotein Production: The Role of the Enteric Nervous System via nNOS Signaling
Authors: GRANDE ELISABETH M. , ADELI KHOSROW 
Published: June 2020

Objective: Postprandial dyslipidemia, a condition commonly presented in individuals with type 2 diabetes (T2D), is characterized by the overproduction of triglyceride (TG)-rich lipoproteins (TRL). This results in excess atherogenic chylomicron (CM) remnants in circulation, significantly increasing the risk of cardiovascular disease (CVD). Using a Syrian golden hamster model, our laboratory has revealed that intestinal hormone glucagon-like peptide-2 (GLP-2) regulates dietary fat uptake and increases CM production in insulin-resistant states. However, the mechanisms by which GLP-2 enhances CM production remain unclear. Previous studies have implicated nitric oxide (NO) in the actions of GLP-2, demonstrating the requirement of NO in CM secretion. Therefore, this study investigated the role of neuronal NO synthase (nNOS)-mediated NO generation in lipid uptake and CM formation.
Methods: nNOS-/- and C57BL/6 (WT) mice received an intraduodenal injection of olive oil, followed by an acute intraperitoneal (i.p.) injection of GLP-2 (0.25mg/kg; n=7) or vehicle (PBS; n=8). Blood samples were collected over a 2-hour period to assess postprandial lipid accumulation, and TRL fractions were isolated via ultracentrifugation. Immunoblotting was used to measure plasma apolipoprotein B48 (apoB48) protein expression.
Results: While GLP-2-treated WT mice showed characteristic rises in postprandial TG and cholesterol in whole plasma and TRL fractions, the effect of GLP-2 in nNOS-/- mice was abolished. The effect of GLP-2 on postprandial plasma apoB48 protein expression was also abolished in nNOS-/- mice relative to GLP-2-treated WT mice.
Conclusions: These findings demonstrate a novel mechanism in which nNOS-generated NO is crucial for GLP-2-mediated lipid absorption and CM production in the postprandial state. Understanding this pathway will provide insight for future therapeutic interventions to treat lipid disorders in T2D.

Disclosure
E.M. Grande: None. K. Adeli: None.

Funding
Canadian Institutes of Health Research
37-OR: Racial and Socioeconomic Disparities in the Use of Newer Classes of Diabetes Medications
Authors: ELHUSSEIN AHMED , BANCKS MICHAEL , KNOWLER WILLIAM C. , PETERS ANNE L. , VAUGHAN ELIZABETH M. , MARUTHUR NISA M. , CLARK JEANNE , PILLA SCOTT J. 
Published: June 2020

Among patients with type 2 diabetes (T2D), racial/ethnic minorities and those of lower socioeconomic status (SES) have a higher burden of coronary artery disease, chronic kidney disease, and hypoglycemia. Therefore, these groups may especially benefit from newer diabetes medication classes (GLP-1 receptor agonists, DPP-4 inhibitors, SGLT2 inhibitors), but high cost may limit access. We conducted a secondary analysis of the Look AHEAD (Action for Health in Diabetes) randomized trial to assess the associations of race/ethnicity and SES with newer diabetes medication use. Look AHEAD compared an intensive lifestyle intervention to diabetes support and education among U.S. adults with obesity and T2D enrolled from 2001-2004. Medications, all prescribed outside of the study, were ascertained yearly. We used Cox proportional hazards models to estimate the association between self-reported race/ethnicity and SES factors and time to initiation of any newer diabetes medication through October 2019, adjusted for time-varying HbA1c, BMI, and number/type of diabetes medications; and baseline study arm, demographics, and comorbidities; fully-adjusted results are presented. Of 4,892 participants, 64%, 16%, 13%, and 8% were white, black, Hispanic, and other race/ethnicities, respectively. Over a median follow-up of 8.3 years, 44% initiated a newer diabetes medication. Black race was associated with significantly lower initiation of newer medications compared to whites (HR 0.81; 95% CI 0.80-0.94); there was no difference by other race/ethnic group. Yearly family income was inversely associated with the outcome: HR 0.69 (95% CI 0.55-0.87) comparing the lowest vs. the highest income group. Education, employment, and health insurance were not significantly associated with the outcome. These findings provide evidence of racial and SES disparities in use of newer diabetes medications, independent of glycemic control, that may impede access to these drugs for the individuals who need them most.

Disclosure
A. Elhussein: None. M. Bancks: None. W.C. Knowler: None. A.L. Peters: Advisory Panel; Self; Abbott, Bigfoot Biomedical, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MannKind Corporation, Medscape, Novo Nordisk Inc., Sanofi US. Consultant; Self; Livongo Health. Research Support; Self; Dexcom, Inc., vTv Therapeutics. Other Relationship; Self; Livongo Health, Mellitus Health, Omada Health, Stability Healthcare, Whole Biome Inc. E.M. Vaughan: None. N.M. Maruthur: Other Relationship; Self; Johns Hopkins HealthCare Solutions. J. Clark: None. S.J. Pilla: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (U01DK057149)
376-P: Analysis of the Fasting and Postprandial Plasma Metabolome Reveals Metabolic Signatures of Postbariatric Hypoglycemia
Authors: FERRAZ-BANNITZ RAFAEL , MULLA CHRISTOPHER M. , DREYFUSS JONATHAN , PAN HUI , PATTI MARY-ELIZABETH 
Published: June 2020

One severe complication of gastrointestinal and bariatric surgery is post-bariatric hypoglycemia (PBH). Affected patients may develop severe hypoglycemia, typically 1-3 hours after meals. While exaggerated postprandial incretin hormone and insulin secretion has been implicated, additional contributors to hypoglycemia remain uncertain. We performed untargeted semiquantitative metabolomic analysis of plasma samples collected in the fasting state and at 30 and 120 minutes after a liquid mixed meal (Ensure) in 13 individuals with PBH post-RYGB, 10 asymptomatic post-RYGB, and 8 overweight/obese individuals without history of gastrointestinal surgery. Multiple analytes were reduced in the fasting state in PBH, including 10 amino acids (Leu, Ile, Val, Ala, Phe, Tyr, Met, Trp, Thr, Asn, nominal p&lt;0.05 vs. asymptomatic, FC -1.2 to -1.4), multiple lipid species (C22:6 LPC, C22:6 LPE, C20:4 LPE, C56:7 TAG, C54:5 TAG, C50:5 TAG, p&lt;0.05 vs. asymptomatic,FC -1.3 to -1.5). We also observed robust reduction (2-10 fold, p&lt;0.05) in multiple tryptophan pathway metabolites, including kynurenic acid, xanthurenate, and serotonin. Markers of insulin resistance and T2D risk, such as 2-aminoadipate and alpha-hydroxybutyrate, and multiple B complex vitamins (B3, B5, B6) were also decreased in PBH in the fasting state. By contrast, tricarboxylic acid (TCA) cycle intermediates such as aconitate, isocitrate, succinate and malate and the ketone beta-hydroxybutyrate were all increased in PBH (p&lt;0.05). In summary, we identify several metabolic signatures of PBH including reduction in multiple circulating AA, lipid species, and tryptophan intermediates as well as increased TCA cycle intermediates. Together these could potentially contribute to alterations in glucose metabolic flux in both the fasting and postprandial state in individuals with PBH.

Disclosure
R. Ferraz-Bannitz: None. C.M. Mulla: None. J. Dreyfuss: None. H. Pan: None. M. Patti: Consultant; Self; Fractyl Laboratories, Inc. Research Support; Self; Dexcom, Inc., Xeris Pharmaceuticals, Inc. Other Relationship; Self; Academy of Nutrition and Dietetics, American Diabetes Association, American Society of Metabolic and Bariatric Surgery, Endocrine Society, Insulet Corporation, King Abdullah International Medical Research Center, SUNY Downstate.

Funding
National Institutes of Health (R01DK121995, P30DK046200)
380-P: Hypoglycemia among Nursing Home Residents with Diabetes Detected by Continuous Glucose Monitoring (CGM)
Authors: LIPSKA KASIA J. , DOYLE MARGARET M. , CENGIZ EDA , DROZDOWICZ BONNIE , GILL THOMAS M. , MURPHY TERRENCE E. , INZUCCHI SILVIO E. 
Published: June 2020

Few data exist on the frequency of hypoglycemia among nursing home residents with diabetes.
We recruited patients 65 years or older, with type 1 or type 2 diabetes, on standing insulin or sulfonylureas, who were long-term residents at 10 Connecticut nursing homes. After informed consent, Freestyle Libre CGM devices were placed for 14 days of blinded monitoring. After omitting the first 24 hours of data, we calculated the percentage (%) of 24-hr periods with at least 2 consecutive blood glucose (BG) levels &lt;70, &lt;60, &lt;50 mg/dl for all patients with at least 7 days of data. We examined the association between selected variables and the % of 24-hr periods with hypoglycemia using Spearman rank correlation and Wilcoxon rank sum tests.
Among 35 patients who completed the study, 33 had at least 7 days of CGM data. Median age was 80 [IQR 71-86], 46% men, 36% nonwhite, HbA1c 7.3 [IQR 6.5-8.5], ADL disability score 26 [IQR 22-27, max possible value=35], 52% had dementia, 39% chronic kidney disease, and 97% were on insulin. More than 1 in 3 (38% (IQR 15-62%)) of the patient-24 hr CGM periods contained at least 2 consecutive BGs &lt;70mg/dl. The corresponding values for &lt;60 mg/dl and &lt;50 mg/dl were nearly 1 in 4 (23% (8-38%)) and nearly 1 in 12 (8% (0%-25%)), respectively. Hypoglycemia by fingerstick (FS) was extremely rare, with a total of just 4 FS &lt;70 mg/dl during all observation periods combined, comprising a median of 29 FS/patient (IQR 27-41). In bivariate analyses, age was positively correlated (Spearman 0.37, p=0.03), weight loss in past 3 months negatively correlated (-0.37, p=0.03), and hypertension negatively associated (median for hypertensives=0, non-hypertensives=38%, p=0.01) with the % of 24-hour periods with hypoglycemia. Other factors, including HbA1c, were not significantly related but power was limited by small sample size.
Hypoglycemia detected by flash CGM is common but otherwise under-recognized among older, long-term residents of nursing homes treated with insulin or sulfonylureas.

Disclosure
K.J. Lipska: None. M.M. Doyle: None. E. Cengiz: Advisory Panel; Self; ADOCIA, Arecor, Lexicon Pharmaceuticals, Inc., MannKind Corporation, Novo Nordisk Inc. Speaker’s Bureau; Self; Novo Nordisk Inc. B. Drozdowicz: None. T.M. Gill: None. T.E. Murphy: None. S.E. Inzucchi: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lexicon Pharmaceuticals, Inc., Novo Nordisk A/S, Sanofi. Consultant; Self; Abbott, Merck & Co., Inc., vTv Therapeutics.

Funding
National Institutes of Health (P30DK045735)
382-P: Exhaled Isoprene Products Change during Hypoglycemia in Type 1 Diabetes and Home Breath Capture Is Feasible as a Diagnostic Tool
Authors: LOS EVAN A. , STONE WILLIAM L. , FORD GEORGE 
Published: June 2020

Detection of hypoglycemia is important to reduce risk and optimize glucose in T1D. Noninvasive glucose detection methods have not been fully explored. Exhaled breath isoprene, a component of sterol metabolism, has been associated with hypoglycemia in controlled studies in a limited population in the laboratory setting. Home-monitoring of breath isoprene levels may permit noninvasive hypoglycemia detection. We conducted an exploratory study measuring exhaled volatile organic compounds (VOCs) in breath samples collected during hypoglycemia (CBG &lt;70 mg/dL) compared to euglycemia (CBG 70-180 mg/dL) under free-living conditions in 10 subjects age 7-74 with T1D. Breath samples were collected using designated breath capture bags and processed 1-4 weeks later by proton-transfer-reaction time-of-flight (PTR TOF) mass spectrometry. Over 100 VOCs were identified in 52 breath samples (25 hypoglycemia, 27 euglycemia). During hypoglycemia, isoprene increased 37% (p&lt;0.05) and its oxidation products methyl vinyl ketone (MVK) and methacrolein (MACR) decreased 59% (p&lt;0.05). However, predictive modelling using metabolite concentration as the input could not reliably predict whether the breath sample was collected during hypoglycemia or euglycemia. All other measured VOCs were not statistically different. This is the first free-living study to evaluate exhaled VOCs in patients with T1D. We successfully replicated findings of a prior study done in a controlled laboratory setting suggesting isoprene concentration in human breath increases during hypoglycemia. We further describe decreased MVK and MACR during hypoglycemia and home breath capture may be feasible for diagnostics in medical conditions. In addition, the physiology of glucose changes on sterol metabolism is worthy of further study. Finally, identification of an exhaled marker of glucose levels hints at a possible mechanism of detection by so-called diabetes alert dogs.

Disclosure
E.A. Los: Advisory Panel; Self; Medtronic. W.L. Stone: None. G. Ford: None.

Funding
East Tennessee State University (18-025M)
392-P: Development of a Fear of Hypoglycemia Screener: Type 1 Diabetes Health Care Provider Insight
Authors: MITCHELL BETH , BISPHAM JEOFFREY , HUGHES ALLYSON , LIU JINGWEN , PEREZ-NIEVES MAGALY , POON JIAT LING , FAN LUDI , MCAULIFFE-FOGARTY ALICIA 
Published: June 2020

Fear of hypoglycemia (FoH) contributes to poor behavioral and glycemic outcomes. The ADA position statement on psychosocial care for people with diabetes recommends screening for FoH, with referral if positive. A clinically useful screener for FoH does not exist, hindering further actions by clinicians to address FoH in their patients. As part of a multi–phase study to develop a validated screener for FoH, we conducted semi–structured interviews with 10 healthcare providers (HCPs) (6 endocrinologists, 4 certified diabetes educators) who treat patients with T1D. The objective was to understand current clinical methods of identifying, diagnosing, and/or assessing FoH, HCP perceptions of T1D patients’ fear of, and experience with, hypoglycemia. Interviews were transcribed, de–identified, and thematically analyzed. Key themes were summarized for each interviewee and common themes across interviews were identified. All HCPs reported assessing patients for FoH through discussion. Most HCPs (7/10) did not use formal screeners for psychosocial issues. Instead, they evaluated patients with open ended questions about their feelings and experiences about low blood sugar. Some HCPs identified FoH behaviors based on CGM and insulin pump usage data; however, this method was not applicable for patients not using these technologies. Most HCPs (9/10) were not familiar with Blood Glucose Awareness Training as a formal program, which is recommended by the ADA to re–establish awareness of hypoglycemia and reduce FoH. Most HCPs made mental health referral decisions after observing anxiety, depression, or chronic poor management behaviors. Results suggest that although clinicians are aware of FoH, due to the lack of a formal screening tool, most HCPs rely on subjective judgment to determine the need for further psychosocial care referral. Creation of a screener will provide a standardized tool to better implement the ADA position statement of psychosocial care on the management of FoH.

Disclosure
B. Mitchell: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. J. Bispham: None. A. Hughes: None. J. Liu: None. M. Perez-Nieves: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. J. Poon: Employee; Self; Eli Lilly and Company. L. Fan: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. A. McAuliffe-Fogarty: None.

Funding
Eli Lilly and Company