bluuebunny/crossref_metadata_2025 huggingface dataset:
34-OR: SGLT2 Inhibitors: A Comparison of Cardiovascular, Medical, and Cost Outcomes
Authors: SCHWAB PHIL , BOWE ANDY , TINDAL MICHAEL , MEAH YUNUS A. , POONAWALLA INSIYA
Published: June 2020

Since 2016, empagliflozin (EFZ) has been known to reduce cardiovascular (CV) events in patients with type 2 diabetes; however, similar label expansions for dapagliflozin (DFZ) and canagliflozin (CFZ) are quite recent. To date, limited evidence has been published comparing these drugs in real-world practice. This retrospective cohort study address that gap, and used administrative claims data from a nationwide Medicare Advantage Prescription Drug and commercial health plan to compare CFZ, EFZ and DFZ on CV outcomes, treatment persistence, healthcare utilization and costs. Eligible patients naïve to the SGLT2 inhibitor drug class for 6 months from January 2015 to June 2017 were identified. Patients had at least 12 months of continuous enrollment pre- and post-index date (i.e., date of first new prescription). Propensity score method using inverse probability of treatment weighting was used to adjust outcomes. A total of 5,503, 2,052 and 587 patients used CFZ, EFZ and DFZ, respectively. Weighted comparisons showed no difference in the risk of primary composite CV outcome (myocardial infarction, stroke, or mortality) between treatments, but a lower risk of secondary CV outcome (heart failure or death) in the DFZ cohort (hazard ratio 0.82, 95% CI 0.75-0.88) compared to CFZ. Patients indexed to use EFZ were more likely to remain persistent to treatment (odds ratio [OR] 1.09, 95% CI 1.03-1.16), and patients who used DFZ had lower odds of an emergency department visit encounter (OR 0.85, 95% CI 0.79-0.92), relative to the use of CFZ. There were no differences in inpatient hospitalization stays and outpatient services between treatment groups. This population-based study showed minor differences in clinical and cost outcomes between CFZ, EFZ and DFZ, including a post-hoc analysis showing slight variations in use of adjuvant glucose lowering therapies across the SGLT2 inhibitor cohorts. With the ever-evolving landscape of treatment in the care of patients with diabetes, these findings may be helpful to providers.

Disclosure

P. Schwab: Employee; Self; Humana. Employee; Spouse/Partner; Humana. A. Bowe: Employee; Self; Humana. M. Tindal: None. Y.A. Meah: None. I. Poonawalla: None.
341-OR: Expanding Diabetes Self-Management Education to Include Chronic Kidney Disease Education
Authors: PRITHIVATHI PREETHA , SPIGLER MICHAEL , PARIS MELANIE , ALAWODE MOLLY , BELLO MORENIKE , FATIMA UROOJ
Published: June 2020

Background: Diabetes is the leading cause of kidney failure. Thirty million Americans have diabetes and 1 in 3 adults with diabetes has chronic kidney disease (CKD). While the Diabetes Self-Management Education and Support (DSMES) curriculum cites CKD risk within one of its eight core content areas, increasing rates of kidney failure among diabetics warrants more robust content devoted to diabetes’ association with CKD.

Methods: From October 2017-April 2019, TMF Health Quality Institute recruited clinical and peer educators in Arkansas, Missouri, Oklahoma, Puerto Rico, and Texas to complete the American Kidney Fund (AKF) Kidney Health Coach (KHC) online training as a means of equipping them with content and strategies to incorporate into DSMES or stand-alone CKD education sessions for Medicare beneficiaries at risk for CKD. Upon completing KHC, three CKD education delivery methods were piloted: 1) in-person educator-led 2) recorded video shown in class 3) video on-demand. The effectiveness of each method was determined by assessing participant knowledge and comprehension using the AKF Kidney Health Education Session pre/post-test.

Results: 615 educators became KHCs and delivered CKD education to a total of 2,250 individuals. Pre/post test scores indicated collective effectiveness among the three delivery methods in increasing understanding of the relationship between CKD and diabetes (relative improvement rate (RIR)= 36.5%). In-person CKD education showed most effective in increasing knowledge gain (RIR=38.8%), compared to the recorded video shown in class (RIR=25.3%) and on-demand video (RIR=18.7%) methods.

Conclusion: This study supports the expansion of KHC integration into DSMES, as educating people with diabetes on CKD prevention is critical to reducing the burden of CKD and improving health outcomes, and that an educator-led presentation modality was most effective in improving understanding of CKD.

Disclosure

P. Prithivathi: None. M. Spigler: None. M. Paris: None. M. Alawode: None. M. Bello: None. U. Fatima: None.

Funding

Centers for Medicare & Medicare Services (HHSM-500-2014-QIN0051)
345-OR: First Home Evaluation of the Omnipod Horizon Automated Glucose Control System at Specific Glucose Targets in Children with Type 1 Diabetes
Authors: FORLENZA GREGORY P. , BUCKINGHAM BRUCE A. , CRIEGO AMY B. , BROWN SUE A. , BODE BRUCE W. , LEVY CAROL J. , LY TRANG T. ,   OMNIPOD HORIZON STUDY GROUP
Published: June 2020

The Omnipod Horizon™ System is a hybrid closed-loop system (HCL) consisting of a tubeless insulin pump and Dexcom G6 sensor which provides automated insulin delivery with customizable glucose targets from 110-150mg/dL, adjustable by time of day to allow therapy personalization. This outpatient study assessed the safety and effectiveness of HCL use at higher targets of 130-150mg/dL.

Participants aged 6-13.9y with T1D>6mo and A1C<10.0% used the HCL system at home for 14 days (first 2 days hotel, n=8) over winter holidays with unrestricted eating and exercise. The target was 130, 140, and 150mg/dL for 3 days each, followed by 5 days of free choice of 110-150mg/dL. Primary outcomes were safety measures and percent time 70-180mg/dL over the first 9 days of HCL use, stratified by target glucose.

Participants thus far (n=15) had a mean±SD age of 11±2y, T1D duration 5±3y, and A1C 7.7±0.9%. At the 130, 140, and 150mg/dL targets, percent time from 70-180mg/dL was 63.4±7.9%, 64.2±11.6%, and 52.1±11.7%, respectively (Table). Percent time <54 and <70mg/dL was low, and tended to decrease with increased target. There were no severe adverse events.

The HCL system was safe and performed well in children with T1D when used at home with higher glucose targets. Participants were invited to continue in a 3mo outpatient study of the system, which is currently underway.

Disclosure

G.P. Forlenza: Advisory Panel; Self; Medtronic. Consultant; Self; Dexcom, Inc., Insulet Corporation, Tandem Diabetes Care. Research Support; Self; Abbott, Dexcom, Inc., Insulet Corporation, Medtronic, Tandem Diabetes Care. B.A. Buckingham: Advisory Panel; Self; ConvaTec Inc., Medtronic. Research Support; Self; Beta Bionics, Inc., Dexcom, Inc., Insulet Corporation, Medtronic, Tandem Diabetes Care. A.B. Criego: Other Relationship; Self; Dexcom, Inc., Lilly Diabetes, Medtronic, Omnipod. S.A. Brown: Research Support; Self; Dexcom, Inc., Insulet Corporation, Roche Diabetes Care, Tandem Diabetes Care, Tolerion, Inc. 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. C.J. Levy: Consultant; Self; Dexcom, Inc. Employee; Spouse/Partner; Allergan plc. Research Support; Self; Abbott, Dexcom, Inc., Insulet Corporation. T.T. Ly: Employee; Self; Insulet Corporation.

Funding

Insulet Corporation
348-OR: Metabolic Phenotype of Autoantibody Positive (AbPos) Long-Term Nonprogressors (LTNPs) to Type 1 Diabetes (T1D)
Authors: EVANS-MOLINA CARMELLA , SAEED ZEB I. , SOSENKO JAY , ATKINSON MARK A. , HEROLD KEVAN C. , ISMAIL HEBA M. , LARSSON HELENA ELDING , LUNDGREN MARKUS , MORAN ANTOINETTE , MOORE DANIEL J. , NATHAN BRANDON M. , PALMER JERRY P. , SIMS EMILY K. , STECK ANDREA , WHERRETT DIANE K. , REDONDO MARIA J.
Published: June 2020

Few studies have described the metabolic phenotype of AbPos individuals who remain T1D free for an extended period of time. We aimed to compare C-peptide and glucose (Glu) data from oral glucose tolerance tests (OGTTs) performed longitudinally in 646 AbPos TrialNet Pathway to Prevention (PTP) participants who remained T1D free for ≥5.0 yrs (LTNPs; mean follow-up: 7.8±2.3 yrs) versus 405 Rapid Progressor (RP) PTP participants who progressed to T1D within <2 yrs of study entry (mean follow-up 0.97±0.54 yrs) and 150 Ab negative (AbNeg) controls. At study entry, 48% of LTNPs were single AbPos and 52% were multiple AbPos; 45.8% of single AbPos LTNPs became multiple AbPos during follow-up. LTNPs were older (mean age 18.8 ± 14.1 yrs) compared to RPs (11.8 ± 9.3 yrs) and AbNeg individuals (16 ± 10 yrs) (p<0.001). LTNPS exhibited an intermediate metabolic phenotype, with age and BMIZ-adjusted C-peptide area under the curve (AUC) and 30-0 min C-peptide values that were lower than AbNegs but higher than RPs (p<0.001), and Index60 levels (a composite of glucose and C-peptide values from OGTTs) that were higher than AbNegs but lower than RPs (p<0.001). Longitudinal trends in LTNPs were analyzed using fitted linear mixed models. Multiple AbPos LTNPs had higher Glu AUC (p=0.01) and Index60 values (p=0.032) compared to single AbPos LTNPs. However within both AbPos groups, metabolic patterns were remarkably stable over extended follow-up. When measures were evaluated for non-linear interactions using a regression tree analysis, the combination of Index60<1.06 + Glu AUC<137.7 at baseline was associated with an odds ratio of 8.55 (p<0.001) of being a LTNP. These data suggest that, while β cell function is reduced in LTNPs at the time of AbPos identification, longitudinal Glu and C-peptide patterns are largely stable without evidence of a relapsing or remitting course. Baseline OGTT measures (here, Index 60 and Glu AUC) may be able to predict AbPos individuals with lower risk of progression to T1D.

Disclosure

C. Evans-Molina: Consultant; Self; Bristol-Myers Squibb. Z.I. Saeed: None. J. Sosenko: None. M.A. Atkinson: None. K.C. Herold: Consultant; Self; Provention Bio, Inc. H.M. Ismail: None. H. Elding Larsson: None. M. Lundgren: None. A. Moran: Research Support; Self; Abbott, Intrexon, JDRF, Medtronic, National Institute of Diabetes and Digestive and Kidney Diseases, Provention Bio, Inc. Other Relationship; Self; Novo Nordisk Inc. D.J. Moore: None. B.M. Nathan: None. J.P. Palmer: None. E.K. Sims: None. A. Steck: None. D.K. Wherrett: None. M.J. Redondo: None.

Funding

National Institutes of Health (U01107014, U01DK106993)
35-LB: Reliability of an Artificial Intelligence (AI) Diabetic Retinopathy (DR) Detection System
Authors: IPP ELI , LILJENQUIST DAVID R.
Published: June 2020

A prospective study (NCT04302012) evaluated the reliability of the EyeArt AI DR detection system (Eyenuk, Inc.) across repeated examinations, operators, and cameras. Using retinal images from off-the-shelf color fundus retinal cameras, this AI system is intended to detect patient eyes with referable DR (rDR) [moderate non-proliferative DR (NPDR) or higher on the International Clinical DR (ICDR) severity scale or clinically significant diabetic macular edema (CSDME)] and vision-threatening DR (vtDR) [severe NPDR or higher on the ICDR scale or CSDME].A total of 62 subjects with diabetes were enrolled at 2 U.S. primary diabetes care centers and completed digital DR examination using the AI system (including retinal imaging) multiple times. Of these, 31 subjects underwent 12 AI exams for each eye performed by 3 operators on 4 cameras, and another 31 subjects underwent 6 AI exams for each eye performed by 1 operator on 2 cameras. Subjects had a median age of 50 (22-70) years, 42% were female, 79% were White, 6.5% were Black or African-American, and 6.5% were Asian. Mean (± std. dev.) diabetes duration was 12.5 ± 9 years and 66% had type 2 diabetes. Of the 1116 repeated exams (= 31 subjects x 12 exams x 2 eyes/subject + 31 subjects x 6 exams x 2 eyes/subject), 16 eye exams had missing data (due to minor protocol deviations) and 22 eye exams (all from the same subject) did not have sufficient exam quality to rule out presence of disease. Of the remaining 1078 eye exams, 97.5% were in agreement for the referable DR detection results with a majority of the disagreements limited to only 5 eyes. For the vision-threatening DR detection results, 99.5% were in agreement. This study demonstrates that the EyeArt AI system is robust to variations and can be used to reliably detect diabetic retinopathy in non-ophthalmology settings across different operators and cameras.

Disclosure

E. Ipp: Research Support; Self; Eyenuk, Inc. D.R. Liljenquist: None.
35-OR: Risk of Cardiovascular Outcomes in Diabetes Patients following the Addition of SGLT2 Inhibitors vs. Sulfonylureas to Baseline GLP-1RA Therapy
Authors: DAVE CHINTAN , KIM SEOYOUNG C. , GOLDFINE ALLISON , GLYNN ROBERT , PATORNO ELISABETTA
Published: June 2020

SGLT2 inhibitors (SGLT2i) may provide cardiovascular (CV) benefit when added to GLP-1 receptor agonists (GLP-1RA) given the orthogonal mechanisms of action, although combined use is incompletely understood. Patients adding either SGLT2i or sulfonylureas to baseline GLP-1RA were identified within 3 U.S. datasets (2013-2018) and were 1:1 propensity score matched (PSM) adjusting for >95 baseline covariates. Primary outcomes were 1) a composite CV endpoint (comprised of myocardial infarction, stroke, or all-cause mortality) and 2) heart failure hospitalization. We estimated pooled hazard ratios (HR) and 95% confidence intervals (CI). Among 12,584 1:1 PSM pairs (mean [SD] age 58.3 [10.9]; male (48.2%)), there were 102 composite CV events (incidence rate per 1,000 person-years (IR) = 9.4) among SGLT2i initiators compared to 124 events (IR = 12.5) among sulfonylurea initiators, with an adjusted HR of 0.76 (95% CI: 0.59, 0.99), over a mean 10-month follow-up (Table). For the outcome of heart failure hospitalization, there were 141 (IR = 13.0) v 206 (IR = 20.8) events, with an adjusted HR of 0.65 (95% CI: 0.52, 0.80). Thus, adding SGLT2i to GLP-IRA therapy confers greater CV benefit compared to adding sulfonylureas, with a magnitude of risk reduction comparable to the benefit seen in CV outcome trials of SGLT2i vs. usual care in patients with minimal background GLP-IRA use.

Disclosure

C. Dave: None. S.C. Kim: Research Support; Self; AbbVie Inc., Bristol-Myers Squibb. A. Goldfine: Employee; Self; Novartis AG. R. Glynn: Research Support; Self; Amarin Corporation, AstraZeneca, Kowa Research Institute, Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc. E. Patorno: Other Relationship; Self; Boehringer Ingelheim International GmbH.
352-OR: Combination Therapy with Dapagliflozin plus Exenatide on Endogenous Glucose Production: A Mechanism of Action Study
Authors: ALATRACH MARIAM , AGYIN CHRISTINA , ADAMS JOHN M. , LAVRYNENKO OLGA , LAICHUTHAI NITCHAKARN , CERSOSIMO EUGENIO , TRIPLITT CURTIS L. , GASTALDELLI AMALIA , ABDUL-GHANI MUHAMMAD , DEFRONZO RALPH A.
Published: June 2020

Aim: To examine the mechanisms with which GLP-1 RA plus SGLT2i improve glycaemia versus each agent as monotherapy.

Study Design: 21 T2D patients (Age= 51±2; BMI=31.2±0.7; A1C=7.9±0.2%, FPG= 172±8; mean PG OGTT [0-5h] =249±8) received 5-hour double tracer (3-3H-glucose IV/1-14C-glucose orally) OGTT and then were randomized to dapagliflozin (DAPA) 10 mg/d, exenatide (EXEN) 2 mg/wk, dapagliflozin plus exenatide (DAPA/EXEN) for 4 months.

Results: Combination DAPA/EXEN therapy produced a completely additive effect to reduce HbA1c and near additive effect to decrease FPG and mean PG during OGTT. The additive effect of DAPA/EXEN resulted from: (1) decreased basal EGP; (2) increased urinary glucose excretion (UGE); (3) decreased rate of oral glucose appearance (RaO); (4) enhanced insulin secretion; (5) increased tissue glucose clearance. Of note, exenatide could not overcome the impaired suppression of EGP by dapagliflozin.

Disclosure

M. Alatrach: None. C. Agyin: None. J.M. Adams: None. O. Lavrynenko: None. N. Laichuthai: None. E. Cersosimo: None. C.L. Triplitt: Speaker’s Bureau; Self; AstraZeneca, Janssen Pharmaceuticals, Inc., Lilly Diabetes, Xeris Pharmaceuticals, Inc. A. Gastaldelli: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Gilead Sciences, Inc., Inventiva Pharma, Novo Nordisk Inc. M. Abdul-Ghani: None. R.A. DeFronzo: None.
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 < 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 < 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 (<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 (< 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<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<0.05 vs. asymptomatic,FC -1.3 to -1.5). We also observed robust reduction (2-10 fold, p<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<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 <70, <60, <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 <70mg/dl. The corresponding values for <60 mg/dl and <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 <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 <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<0.05) and its oxidation products methyl vinyl ketone (MVK) and methacrolein (MACR) decreased 59% (p<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
397-P: BETTER Understanding Hypoglycemia in Type 1 Diabetes (T1D)
Authors: CHENG RAN , TALEB NADINE , MESSIER VIRGINIE , TALBO MERYEM K. , ROY-FLEMING AMÉLIE , RABASA-LHORET RÉMI , BRAZEAU ANNE-SOPHIE
Published: June 2020

Introduction: For patients living with T1D, hypoglycemia is the most frequent complication and obstacle in achieving optimal glycemic control with potentially significant adverse implications on individuals’ quality of life. To improve hypoglycemia prevention and management, the BETTER registry for people living with T1D was launched in April 2019 in the province of Quebec, Canada.

Methods: Participants self-register online in the BETTER registry and are asked to answer a series of questionnaires (3 phases). We report the preliminary results of phase I among participants of ≥14 years old, which aims to provide a comprehensive portrait of the population with T1D.

Results: Mid-December 2019, 718 individuals (64.6% female, age 41.8±15.4 years old, duration of diabetes 22.4±14.7 years, 93.2% with T1D and 6.7% with LADA, 71.2% with HbA1c <8%) have registered. Of the participants, 99.6% were currently on insulin therapy (46.7% on insulin pumps, 51.2% on insulin injections, 1.7% using both), and 77.3% were using continuous or flash glucose monitoring. They reported, on average, 6.27±7.42 episodes of hypoglycemia (<54 mg/dl) in the last month. Since their diagnosis, 47.8% of participants had at least one episode of severe hypoglycemia (SH: requiring help from another person or use of glucagon or hospitalization or loss of consciousness). Among those who reported SH in the last 12 months (n=91), the average number of episodes was 2.34±3.37 during this period. When asked what hypoglycemia represents using one word, one-fifth of participants used the word “weak” or “weakness."

Conclusion: In a contemporary group of patients widely using technology for T1D management, hypoglycemia remains frequent. The growing BETTER registry will allow further understanding of this challenging reality and enable future research aiming to reduce hypoglycemia episodes.

Disclosure

R. Cheng: None. N. Taleb: None. V. Messier: Other Relationship; Self; Eli Lilly and Company. M.K. Talbo: None. A. Roy-Fleming: None. R. Rabasa-Lhoret: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Insulet Corporation, Janssen Pharmaceuticals, Inc. Board Member; Self; Merck & Co., Inc., Sanofi. Research Support; Self; Eli Lilly and Company, Novo Nordisk A/S, Novo Nordisk A/S, Sanofi. A. Brazeau: None.

Funding

Canadian Institutes of Health Research (JT1-157204); JDRF (4-SRA-2018-651-Q-R)
4-OR: Diabetes Duration and the Relative Importance of Cardiovascular Risk Factors in Type 1 Diabetes
Authors: FAHRMANN ELKE R. , DRISCOLL HENRY
Published: June 2020

Based on a Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) report and their own findings, Pittsburgh Epidemiology of Diabetes Complications investigators concluded that the relative impact of HbA1c and kidney disease in type 1 diabetes (T1D) on cardiovascular disease (CVD) varies according to T1D duration. We investigate the relative importance of HbA1c and other CVD risk factors during ∼ 30 years of DCCT/EDIC follow-up within the primary (RET-: subjects with a mean T1D duration of 2.6 years and without retinopathy at baseline) and within the secondary DCCT cohort (RET+: subjects with a mean T1D duration of 8.6 years and with mild to moderate retinopathy at baseline). CVD included fatal/nonfatal myocardial infarction (MI) or stroke, silent MI, revascularization, confirmed angina, or congestive heart failure. Cox regression models with robust error variances were used to find the most significant CVD risk factors (p<0.05) within RET- and within RET+. The importance of risk factors was determined by evaluating the z value, a measure of association strength between risk factor and CVD. In case of hazard assumption violation, time by covariate interaction was included in model. DCCT enrolled 1441 subjects (age 13-39); 115 of 715 RET+ subjects and 69 of 726 RET- subjects had a CVD event. For RET+, the most important risk factors were baseline (B) age (z ∼4.2), time dependent (T) mean (M) systolic blood pressure (SBP) (z ∼4.0), any severe hypoglycemia (z ∼3.7), and TM HbA1c (z ∼3.2). Other significant risk factors included B autonomic neuropathy, TM insulin dose, TM LDL, T current (C) ACE inhibitor use, TC insulin regimen and B severity of retinopathy but not T1D duration. For RET-, B age, TM HbA1c, TC triglycerides and TM SBP with an increasing CVD effect over follow-up time were significant. The relative importance of CVD risk factors in a young T1D cohort varies according to microvascular complications, which correlate with T1D duration.

Disclosure

E.R. Fahrmann: None. H. Driscoll: None.
400-P: High Levels of Glycemic Coefficient of Variation Are Associated with Higher Hypoglycemia Episodes in T1D Adults in a Brazilian Tertiary Hospital
Authors: BRASIL THAIS B. , SPOSITO ANDREI C. , ADACHI BEATRIZ , VOLPINI WALKYRIA M. , PAVIN ELIZABETH J.
Published: June 2020

People with type 1 diabetes (T1D) have a higher risk of hypoglycemia (H), especially in the presence of high glycemic excursion, increasing cardiovascular mortality. The coefficient of variation (CV) allows current assessment of glycemic control and therapeutic adequacy. This cross-sectional study investigated the associations among H episodes, CV, glycemic variability (GV), and T1D clinical and laboratory parameters. Sixty T1D patients aged ≥18 years and followed for at least six months in a Brazilian Public Tertiary Hospital were included. Three seven-point glycemic profiles were performed in consecutive days, totalizing 21 blood glucose tests. The indicators GV, standard deviation (SD)/glycemic mean (mg/dL) and CV, SD/glycemic mean were calculated from data record in the monitor. H was classified as H1:<70 and ≥54mg/dL and H2:<54mg/dL. Statistical analysis was performed with Spearman correlation and Mann-Whitney (p<0.05 was considered significant). Of all, 73.3% were women, aged 34.7 ± 2.3 years, T1D duration: 22.5 ± 9.7 years, HbA1c 8.8 ± 1.8%, GV 70.9 ± 25.9mg/dL (goal<50) and CV 42.8 ± 9.6% (goal<36%). H occurred in 76.7%, and H2 in 50% of T1D patients. H1 was positively correlated with CV (p<0.0001) and T1D duration (p<0.0271); negatively with mean of glycemia (p<0.0001), and glycemia above target (>180mg/dL) (p<0.0004). H2 was positively correlated with CV (p<0.0005); blood glucose below target (<70mg/dL) (p<0.0001), and reported weekly frequency of hypoglycemia (p<0.0470). T1D patients presented high VC and GV. Only CV had a significant correlation with H1 and H2 episodes. Education about quickly hypoglycemia treatment is highly required, mainly in the presence of asymptomatic episodes. Systematic glycemic monitoring and continuing education in diabetes, targeting insulin dose adjustments, glycemic goals, healthy food orientation, and physical activity may reduce life risks of this population.

Disclosure

T.B. Brasil: None. A.C. Sposito: None. B. Adachi: None. W.M. Volpini: None. E.J. Pavin: None.