bluuebunny/crossref_metadata_2025 huggingface dataset:
107-OR: Randomization to a Higher–Complex Carbohydrate or Conventional Diet in GDM Results in Equivalent Glycemic Control by Continuous Glucose Monitoring
Authors: HERNANDEZ TERI L. , DUNN EMILY Z. , HIRSCH NICOLE , ROLLOFF KRISTY P. , CORBETT JOHN P. , FARABI SARAH S. , FRIEDMAN JACOB E. , BARBOUR LINDA (LYNN) A.
Published: May 2022

Direct RCT evidence to support a range of nutrition options for treatment of GDM is lacking. We randomized women with diet-controlled GDM to either our CHOICE (60% complex carbohydrate (CHO) /25% fat) or a conventional diet (CONV; 40% CHO/45% fat) and previously reported equivalent newborn adiposity. We further tested the hypothesis that 6 wks on either diet would result in a similar 24-hr glucose (gluc) area-under-the-curve (AUC) by CGM. BMI-matched women were randomized to CHOICE or CONV by wk 31 (n=59; mean±SEM; BMI 32±1kg/m2) . All meals were provided, eucaloric, and simple sugars were controlled in both. A CGM was worn for 72 hrs in wk 31 and 36. Total gestational weight gain (GWG) (CHOICE vs. CONV; 9.8±0.9 vs. 10.8±1.2 kg) , GWG from 31 wks to delivery (2.0±0.4 vs. 1.8±0.3 kg) , physical activity, and days on diet were similar (48±2 vs. 54±2 days; p>0.all) . At wk 31 (n=23 vs. 25/group) , fasting (89±3 vs. 87±2 mg/dL) , 1-hr (127±4 vs. 127±4) and 2-hr postprandial (PP) (112±3 vs. 110±3) gluc, and time in range (TIR; 70-140mg/dL) (89±1 vs. 86±1%) , were not different on CHOICE vs. CONV as were the mean 24-hr gluc, 24-hr AUC, nocturnal and daytime AUC (p>0.5 all) . By wk 36, (n=22 vs. 21/group) , fasting (90±3 vs. 86±3) , 1-hr (117±4 vs. 119±3) , 2-hr PP (108±3 vs. 106±3) , 2-hr PP AUC, TIR (88±2 vs. 88±1%) , 24-hr AUC, nocturnal AUC and daytime AUC remained highly similar between diets (p>0.all) . In paired analyses (n=19-21/group) , women on CHOICE showed an actual reduction in 1-hr PP gluc between 31-36 wks (124±5 vs. 115±4; p=0.02) . Surprisingly, the fasting, 2-hr PP gluc, 24-hr AUC, daytime and nocturnal AUC did not increase (nor did TIR decrease) , over time in either group with the expected rise in the insulin resistance of pregnancy. These data directly support for the first time in an RCT with all provided meals that excellent glycemic control by CGM was achieved with either a higher complex CHO versus low CHO diet in GDM, with similar glycemic parameters that did not increase over time.

Disclosure

T.L.Hernandez: None. E.Z.Dunn: None. N.Hirsch: None. K.P.Rolloff: None. J.P.Corbett: Employee; Tandem Diabetes Care, Inc., Other Relationship; Dexcom, Inc. S.S.Farabi: n/a. J.E.Friedman: None. L.A.Barbour: None.

Funding

National Institutes of Health (R01DK101659) CTSA UL1 TR002535 Janssen Research and Development
1106-P: Real-World Confirmation of the Nonlinear Relationship between Glucose and Glycated Hemoglobin
Authors: DUNN TIMOTHY , XU YONGJIN , SCHNEIDER SHARON , GAWEL SUSAN , GOPINATH RAJKAMAL , BERMAN MARVIN , ORZECHOWSKI ANTHONY P.
Published: May 2022

Glycated hemoglobin (A1C) is a key biomarker for glycemic control in diabetes and has an important relationship with glucose. The objective of this study was to evaluate the relationship of real-world laboratory results for patient samples with both glucose and A1C. 213,698 paired glucose and A1C measurements from 709 laboratories in 39 countries were collected January to October 2021. Values within the measuring interval 70 to 400 mg/dL for glucose and 4% to 13% (NGSP) for A1C were analyzed. The pairs were analyzed in twenty equal-sized groups by composite rank order. The summed absolute relative differences (SARD) were compared between best-fit nonlinear and linear models. The group mean values presented a clear nonlinear relationship, with an SARD seven times lower than the best-fit linear model. The nonlinear Michaelis constant for glucose and glucose transporter 1 (GLUT1) was 4mg/dL, which agrees with literature values. The 95% prediction intervals at the diabetes diagnosis levels of 6.5% A1C and 126 mg/dL glucose were narrower for the nonlinear model. This model-based formula allows better prediction of the relationship of glucose and A1C which can lead to improved personalized clinical decisions.

Figure: Nonlinear (left) and linear (right) best-fit models, N = 213,698. Each point represents the mean of approximately n=10,680 paired measurements. Dotted lines are 95% prediction intervals.

Disclosure

T.Dunn: Employee; Abbott. Y.Xu: Employee; Abbott Diabetes. S.Schneider: None. S.Gawel: Employee; Abbott Diagnostics. R.Gopinath: Employee; Abbott Diagnostics. M.Berman: None. A.P.Orzechowski: Employee; Abbott.
1110-P: Algorithmic Identification of Atypical Diabetes in Electronic Health Record (EHR) Systems
Authors: CHEN VICTORIA , CROMER SARA JANE , HAN CHRISTOPHER , MARSHALL WILLIAM G. , EMONGO SHEKINA , MAJARIAN TIM , FLOREZ JOSE C. , MERCADER JOSEP M. , UDLER MIRIAM
Published: May 2022

Understanding atypical forms of diabetes may lead to personalized treatment regimens and discovery of novel pathophysiologic mechanisms of diabetes. We aimed to create a high-throughput method for identifying patients with atypical diabetes in large electronic health record (EHR) databases and validate this method in the Mass General Brigham (MGB) Biobank. Patients with likely type 2 diabetes (T2D) were identified using a validated machine-learning (ML) algorithm. “Typical” T2D was filtered out through a “base algorithm” that excluded individuals with body mass index (BMI) ever >30 kg/m2, HDL values ever < 50 mg/dL, and triglycerides ever >150 mg/dL. To remove people with typical type 1 diabetes (T1D) , we tested six additional “branch algorithms,” relying on clinical characteristics, including autoantibodies, medication usage, and T1D diagnosis determined by ML algorithm, resulting in six overlapping cohorts. Charts were then manually reviewed, and diabetes type was classified by two endocrinologists into one of three categories: atypical, not atypical, and indeterminate due to missing information.

We identified 1potentially atypical cases, of whom 16 individuals were confirmed to have atypical diabetes after expert review, across the six branch algorithms. The branch algorithm which excluded T1D by removing patients who had ever used outpatient insulin had the highest percentage yield (13 of 27; 48.2%) of atypical diabetes . The 16 atypical cases had significantly lower BMI and higher HDL compared to an unselected group of individuals with T1D or T2D diagnosis by ML algorithm. Compared to the ML T1D group, the atypical group had a significantly higher T2D polygenic score and lower hemoglobin A1c.

In summary, we designed an algorithm to identify individuals with atypical diabetes within an EHR database with up to 48% yield which may shed light on the heterogeneity of T2D and help generate cohorts of atypical cases for studies, such as the Rare and Atypical Diabetes Network (RADIANT) .

Disclosure

V.Chen: Other Relationship; Draeger. S.Cromer: Other Relationship; Johnson & Johnson Medical Devices Companies, Research Support; National Institute of Diabetes and Digestive and Kidney Diseases. C.Han: None. W.G.Marshall: None. S.Emongo: None. T.Majarian: Employee; Vertex Pharmaceuticals Incorporated. J.C.Florez: Consultant; AstraZeneca, Goldfinch Bio, Inc., Other Relationship; AstraZeneca, Merck & Co., Inc., Novo Nordisk. J.M.Mercader: None. M.Udler: None.
1112-P: Prevalence of Testing for Blood Glucose among Adults with Overweight or Obesity in the U.S.
Authors: CHEN YU , LUNDEEN ELIZABETH A. , KOYAMA ALAIN , KOMPANIYETS LYUDMYLA , ANDES LINDA J. , BENOIT STEPHEN R. , IMPERATORE GIUSEPPINA , ROLKA DEBORAH B.
Published: May 2022

An estimated 13% of all U.S. adults aged ≥18 years have diabetes, and 34.5% meet criteria for having prediabetes. Screening adults at high risk for prediabetes and diabetes may allow earlier detection, diagnosis, and treatment, thereby improving health outcomes. The U.S. Preventive Services Task Force (USPSTF) recommends screening every three years for abnormal blood glucose in adults aged 40-70 years who have overweight or obesity (this recommendation was updated to adults aged 35-70 years in August of 2021) . Using IQVIA Ambulatory Electronic Medical Records (EMR) via the IQVIA E360 platform, we aimed to estimate the proportion of adults aged 40-70 years with overweight or obesity who received a test for blood glucose in a 3-year period from 2016-2019. We defined overweight or obesity based on body mass index (BMI of 25-29.9 kg/m2 and ≥30 kg/m2, respectively) calculated using measured height and weight. Receipt of a blood glucose test was defined as having a hemoglobin A1c or fasting plasma glucose measured, as recommended by USPSTF. Our analysis identified adults aged 40-70 years with overweight or obesity in 2016 (the index year) and without preexisting diabetes, defined using a modified SUPREME-DM algorithm for EMR data[1]. We included adults who were present in the dataset for at least two years before their index BMI in 2016 (to exclude those with prevalent diabetes) and three years after the index BMI, during which we examined the occurrence of blood glucose testing. Among 1,360,095 adults who had overweight or obesity, 33.4% received a test for blood glucose in 2016-2019. The testing rate was 28.7% among adults with overweight and 37.3% among adults with obesity. Our findings could help inform clinical and public health promotion efforts to improve screening for blood glucose levels among adults with overweight or obesity. Future studies may identify factors associated with receiving timely blood glucose screening.

[1]https://pubmed.ncbi.nlm.nih.gov/25515167/

Disclosure

Y.Chen: None. E.A.Lundeen: None. A.Koyama: None. L.Kompaniyets: None. L.J.Andes: None. S.R.Benoit: None. G.Imperatore: None. D.B.Rolka: None.
1129-P: Rising Prevalence of Type 2 Diabetes in the Young in Southern India
Authors: NANDITHA ARUN , SUSAIRAJ PRISCILLA , RAGHAVAN ARUN , SATHEESH KRISHNAMOORTHY , VINITHA RAMACHANDRAN , NAIR DHRUV , SNEHALATHA CHAMUKUTTAN , RAMACHANDRAN AMBADY
Published: May 2022

This ancillary analysis (STRIDE-I study) compares the prevalence ratio (PR) of type 2 diabetes (T2DM) in persons aged ≤40 and >40 years in 20 and 2016 in Southern India. In 2016, prevalence of T2DM, generalized and abdominal obesity increased in both groups (Table 1) . Hypertension and dyslipidaemia were higher among the older and younger population respectively. Higher intake of fat and protein increased the total calorie consumption in both groups. Sedentary time increased in the younger group in 2016. Poisson regression analysis (Table 2) showed an increase in the PR in 2016 in both groups. However, the increase was significantly higher in the younger group (30%) when compared to the older group (10%) .

Disclosure

A.Nanditha: None. P.Susairaj: None. A.Raghavan: None. K.Satheesh: None. R.Vinitha: None. D.Nair: None. C.Snehalatha: None. A.Ramachandran: None.
1153-P: Association of Extracellular Matrix Remodeling Biomarkers with Complications of Type 2 Diabetes
Authors: MØLLER ALEXANDRA , BOJER ANNEMIE S. , GENOVESE FEDERICA , SØRENSEN MARTIN H. , GÆDE PETER , KARSDAL MORTEN A. , MADSEN PER L. , RASMUSSEN DANIEL G.
Published: May 2022

Background: Persons with diabetes have a high risk of complications related to the micro- and macrovascular circulation. One of the pathological processes involved in these complications is the onset of abnormal extracellular matrix (ECM) remodeling in different organs, leading to fibrosis. The quantification of ECM remodeling may identify patients that are at higher risk for adverse outcomes.

Method: We measured biomarkers of collagen type III (PRO-C3) and VI (PRO-C6) formation and MMP-mediated degradation of type I (C1M) , III (C3M) , and IV (C4M and Tumstatin; TUM) in serum from 267 persons with T2DM from the CMR in T2DM study (NCT02684331) . Myocardial fibrosis (LGE) and ECV were determined by gadolinium-contrast CMR. Serum samples from 79 healthy controls were measured for comparison.

Results: Levels of all biomarkers were significantly elevated in persons with T2DM compared to healthy controls (all P<0.0001) . Some of the markers were associated with complications, PRO-C6 levels were: significantly elevated in patients with hypertension compared to persons without known CVD (P<0.0001) ; could discriminate patients with CKD - eGFR < 60 ml/min/1.73m2 with an AUC of 0.83 (P<0.001) ; were significantly increased in patients with ischemic LGE (P<0.05) , suggesting an association of PRO-C6 with fibrosis; and in a multiple linear regression analysis, higher PRO-C6 levels were significantly associated with higher HbA1c (r=0.15, P=0.0397) , lower eGFR (r=−0.41, P<0.0001) , higher proANP (r=0.24, P=0.0005) , and higher ECV (r=0.24, P=0.0006) . PRO-C3 levels were significantly elevated in patients with CKD compared to non-CKD, and levels of C3M and C4M increased significantly with presence of albuminuria.

Conclusion: Biomarkers of ECM remodeling, particularly PRO-C6, may identify persons with active pro-fibrotic processes at risk for complications related to T2DM. The potential of the biomarkers to predict adverse outcomes will be investigated once follow-up data have been collected.

Disclosure

A.Møller: None. A.S.Bojer: None. F.Genovese: Employee; Nordic Bioscience A/S, Stock/Shareholder; Nordic Bioscience A/S. M.H.Sørensen: None. P.Gæde: Advisory Panel; AstraZeneca, Research Support; Novo Nordisk. M.A.Karsdal: Employee; Nordic Bioscience A/S, Nordic Bioscience A/S, Nordic Bioscience A/S. P.L.Madsen: None. D.G.Rasmussen: Employee; Nordic Bioscience A/S.
121-OR: Alternate-Day Fasting Combined with Endurance Exercise for the Treatment of Fatty Liver Disease
Authors: EZPELETA MARK , GABEL KELSEY , VARADY KRISTA , LIN SHUHAO , CIENFUEGOS SOFIA
Published: May 2022

Background: Approximately 65% of individuals with obesity have nonalcoholic fatty liver disease (NAFLD) . The primary treatment for NAFLD is regulating weight per diet and exercise. Alternate day fasting (ADF) has been shown to improve body composition and cardiometabolic risk factors in animals. This is the first human trial to compare the effects of ADF plus endurance exercise, ADF alone, endurance exercise alone versus a no intervention control, on body weight and metabolic disease risk factors in participants with obesity and NAFLD.

Methods: Subjects with obesity and NAFLD (n = 48) were randomized to 1 of 4 groups for 12 weeks:1) ADF (600 kcal “fast day”, alternated with an ad libitum intake “feast day”) ,2) exercise (endurance exercise 5 times/week for 60 min/d) ,3) combination (ADF + exercise) ,or 4) control (usual diet) .

Results: Body weight was reduced (P < 0.05) in the ADF group (-5.3 ± 1.0 %) and combination group (-4.9 ± 0.6 %) , but not the exercise group (-1.9 ± 0.6 %) , versus controls (-0.3 ± 1.2 %) . ALT was reduced (P < 0.05) in the combination group (-29 ± 9%) , but not in the ADF group (-9 ± 8%) , exercise group (1 ± 3%) , versus controls (17 ± 10%) . No significant changes were observed for liver fat, body composition, AST, lipid markers, or glucoregulatory factors. Subjects in the ADF and combination groups were adherent with the fast day energy goal (600 kcal) at week 12 (ADF: 548 kcal; combination: 657 kcal) . Subjects in the exercise and combination groups were adherent with attending the 5 workout sessions per week (exercise: 79% attendance; combination: 83% attendance) .

Conclusion: These preliminary findings suggest that combination of ADF plus exercise and ADF alone may be effective non-pharmacological therapies to reduce body weight and ALT. However, neither combination intervention nor ADF alone have had any effect on liver fat, metabolic risk factors, or glucoregulatory factors such as insulin.

Disclosure

K. Gabel: None. K. Varady: None. S. Cienfuegos: None.

Funding

NIH/NIDDK (R01DK119783-03)
1251-P: Aß Classification Defines Four Distinct Forms of Diabetes in Children
Authors: TOSUR MUSTAFA , DEEN SAIMA , UYSAL SERIFE , ASTUDILLO MARCELA , JAHOOR FAROOK , HAGOPIAN WILLIAM , ORAM RICHARD A. , REDONDO MARIA J. , BALASUBRAMANYAM ASHOK
Published: May 2022

A comprehensive classification accounting for the heterogeneity of pediatric diabetes is lacking. The Aβ classification system, based on islet autoantibody status (A+ or A-) and preserved beta-cell functional reserve (β+ or β-) , was used successfully to define variable phenotypes in adults with Ketosis-prone Diabetes. We set out to investigate the utility of the Aβ classification system in children with new-onset diabetes. “A+” was defined as the presence of ≥1 islet autoantibodies (GAD65, ICA512, insulin or ZnT8 autoantibodies) and "β+" as random C-peptide level ≥0.6 ng/mL at diagnosis. We calculated T1D genetic risk score 2 (T1D GRS2) for each participant, and compared clinical characteristics at diabetes onset and T1D GRS2 between the groups. The study cohort (n=76) was 50% female, 29% non-Hispanic white, 46% Hispanic, 22% non-Hispanic black, and 3% Other. The mean age was 11.7 years and the mean BMI was 58.3%ile. Aβ classification at diagnosis defined the following groups: A+β- (34%) , A+β+ (30%) , A-β+ (33%) and A-β+ (3%) . Results are summarized in Table 1.

The Aβ classification system defines phenotypically and genetically distinct diabetes groups in children with new-onset diabetes. This classification system may be useful in clinical settings as well as the design of clinical trials.

Disclosure

M.Tosur: Advisory Panel; Provention Bio, Inc. S.Deen: None. S.Uysal: n/a. M.Astudillo: None. F.Jahoor: None. W.Hagopian: Research Support; Janssen Research & Development, LLC. R.A.Oram: Consultant; Janssen Research & Development, LLC, Research Support; Randox R & D. M.J.Redondo: Advisory Panel; Provention Bio, Inc. A.Balasubramanyam: None.

Funding

Texas Children's Pilot Award
130-LB: Linagliptin vs. Sitagliptin for Type 2 Diabetes Inpatient Glycemic Management and Cardiovascular Outcomes—Is There a Difference between DPP-4 Inhibitors?
Authors: BARAKAT SAMI , HABIB HELEN A. , CHUN CATHERINE , OH ERIN
Published: May 2022

Background: Oral DPP-4 inhibitors provide adjunctive therapy to insulin in hospitalized patients with blood glucose (BG) < 400 mg/dL. Results from trials comparing sitagliptin or linagliptin to basal-bolus insulin showed mixed results, with no head-to-head comparison between sitagliptin and linagliptin. The aim of this study is to provide new evidence on their comparative efficacy and safety.

Methods: This was a retrospective, single-center, observational study of hospitalized general medicine and surgery adult patients with type 2 diabetes. Patients who received at least 2 doses of linagliptin or sitagliptin between January and December 2019 were assigned to either arms. Primary endpoint was the difference in mean daily BG. Secondary endpoint was a composite of 3-point major adverse cardiac events (MACE) and heart failure (HF) hospitalization. Safety endpoints included the number of hypoglycemic events (BG < 70 mg/dL) and the appropriateness of dosing based on eGFR.

Results: A total of 100 patients were included. The mean daily BG was similar in the linagliptin arm (167.6 ± 43.5 mg/dL) compared to the sitagliptin arm (162.1 ± 37.5 mg/dL) (p=0.5) . In a subgroup analysis, patients who received linagliptin plus correctional insulin had more BG readings within the range of 140-180 mg/dL (50% vs. 36%, p=0.2) . The composite of 3-point MACE and HF hospitalization was similar between both arms. Hypoglycemia occurred more frequently with linagliptin versus sitagliptin (4 vs. 1 event, p=0.2) . Only 70% of sitagliptin orders were appropriately dosed based on eGFR.

Conclusion: There was no difference between linagliptin and sitagliptin in regards to mean daily BG and cardiovascular outcomes. However, there were numerically more BG readings within range with linagliptin. Our results favor the utilization of linagliptin in the inpatient setting considering it does not require renal dose adjustments.

Disclosure

S. Barakat: None. H. A. Habib: None. C. Chun: None. E. Oh: None.
1306-P: In Vivo Downregulation of Pancreatic Amylin in Diabetic Mice Improves Recognition Memory
Authors: VISWANATHAN VELMURUGAN GOPAL , VERMA NIRMAL , WINFORD EDRIC D. , KOTIYA DEEPAK , RADULESCU LAURA E. , LEIBOLD NOAH , CHEN KUEY C. , DESPA SANDA , HILL DEMITRIUS A. , MUEHLBAUER MICHAEL , BAIN JAMES R. , DESPA FLORIN
Published: May 2022

Hypersecretion of amylin, a β-cell hormone that regulates satiation, is common in individuals with prediabetes and is associated with pancreatic amyloid deposition and type-2 diabetes. Evidence has emerged that increased circulating levels of amyloid-forming human amylin may potentially impair brain function. Because mouse amylin is non-amyloidogenic, we generated transgenic mice with conditional pancreatic expression of amyloid-forming human amylin to study how in vivo knockdown of human amylin expression influences brain function during the development of type-2 diabetes. Males and females were fed a high-fat diet starting at 3 months of age to induce amylin hypersecretion and glucose dysregulation. Males developed hyperglycemia at 5 months of age, whereas females showed glucose dysregulation 3-4 months later. At 5 months of age, human amylin-expressing male mice were randomly assigned to either amylin downregulation (by peritoneal tamoxifen injection) or control (maintained amylin expression) groups (n = 10/group) . Two months later, we assessed brain function with a novel object recognition test and performed comparative non-targeted metabolomics and global RNA-seq analyses of hippocampal tissue. Mice with downregulated human amylin showed enhanced recognition memory index (p < 0.001) and lower blood glucose levels (p < 0.001) compared to those that continued to express human amylin. This was associated with increased hippocampal levels of glycolysis metabolites, including lactic acid (p < 0.01) , glucose-6-phosphate (p = 0.06) , and fructose (p = 0.07) . Hippocampal gene-expression patterns between the two mouse groups revealed extensive compensatory changes in gene expression related to glucose metabolism.

In conclusion, amylin downregulation in diabetic mice improves systemic glucose homeostasis and memory. Molecular processes associated with improved memory involve increased hippocampal glycolytic fluxes and compensatory gene expression.

Disclosure

V.Gopal viswanathan: None. M.Muehlbauer: None. J.R.Bain: Other Relationship; CardioEphEx, LLC. F.Despa: None. N.Verma: None. E.D.Winford: None. D.Kotiya: None. L.E.Radulescu: None. N.Leibold: None. K.C.Chen: None. S.Despa: None. D.A.Hill: None.

Funding

National Institutes of Health NS116058, AG057290, AG053999
1319-P: Gabra5 Plays a Sexually Dimorphic Role in POMC Neuron Activity and Glucose Balance
Authors: PEI ZHOU , HE YANLIN , HE YANG , XU YONG , WANG CHUNMEI
Published: May 2022

Pro-opiomelanocortin (POMC) neurons are important for body weight and glucose balance. The inhibitory tone to POMC neurons is mediated primarily by GABA receptor complex. However, the detailed mechanisms and functions of GABA receptors are not well understood. We found that α5 subunit of GABA receptor complex, Gabra5, is highly expressed in POMC neurons. To explore the function of Gabra5 in POMC neurons, we deleted Gabra5 specifically from mature POMC neurons using the CRISPR-Cas9 strategy. Body weight and food intake were not affected in either male mice or female mice by the deletion of Gabra5 from POMC neurons. We found that the deletion of Gabra5 caused a significant increase in the firing frequency and rest membrane potential, and a decrease in the amplitude of mIPSC in male POMC neurons. However, the deletion of Gabra5 just modestly decreased the frequency of mIPSC in female POMC neurons. Consistently, loss of Gabra5 from POMC neurons significantly improved the glucose tolerance in male mice but not in female mice. These results revealed a sexually dimorphic role of Gabra5 in POMC neuron activity and glucose balance, independent of body weight control.

Disclosure

Z.Pei: None. Y.He: None. Y.He: None. Y.Xu: None. C.Wang: None.

Funding

National Institutes of Health (KDK119471)
132-OR: Trends in Total Payments, Net Payments, and Rebates for a 30-Day Supply of Glucose-Lowering Drugs (GLDs) from 2010–2017
Authors: DING YAO , SHI LIZHENG , LIN YILU , SHAO HUI
Published: May 2022

The rapid increase in total payments for GLDs may not reflect the change in actual economic burden, because a growing portion of the total payments were returned to the payers in the form of manufacturer rebates. This study explored trends in rebates for GLDs from 2010-17. We defined total payments as the retail amount the pharmacy received, including two components:1) rebates, the estimated proportion of the total payments retroactively passed through to pharmacy benefit managers and the payers; and2) net payments, the net spending for the GLDs. We used data from the 2010-17 Medical Expenditure Panel Survey to estimate the total payments including out-of-pocket payments, and data from the SSR Health and Medicaid programs to estimate the net payments and rebates. Four high-cost GLDs were included in this study: basal insulin, bolus insulin, GLP-1 Receptor Agonists (GLP-1RA) , and SGLT2 inhibitors (SGLT2i) . Costs were adjusted to 2017 U.S. dollars. While the total payments for a 30-day supply of bolus insulin, basal insulin and GLP-1RA increased by almost 200% from 20 to 2017, the rebates increased by more than 300%, attenuating the increase in net payments. By 2016-17, rebates accounted for 59%, 54%, 37%, and 49% of total payments for bolus insulin, basal insulin, GLP-1RA, and SGLT2i, respectively (Figure 1) . Our study is the first to quantify rebates for GLDs by class from a payer’s perspective.

Disclosure

Y.Ding: None. L.Shi: None. Y.Lin: None. H.Shao: Board Member; BRAVO4HEALTH, LLC.
1329-P: A RIPK2 Inhibitor Protects against Saturated-Fat–Induced Glucose Intolerance in Mice
Authors: TSAKIRIDIS NICOLE , IVOVIC ALEKSANDAR , RAHMAN S M NIAZUR , TAN YAO , GIACCA ADRIA
Published: May 2022

Background: Obesity and type 2 diabetes (T2D) are associated with chronic low-grade inflammation. Elevated free fatty acids (FFAs) , as seen in obesity and T2D, can act as damage associated molecular patterns (DAMPs) activating the innate immune system. Recent studies have identified nucleotide binding oligomerization domain 1 (NOD1) , an intracellular pattern recognition receptor, can be activated by saturated fatty acids (sFA) . NOD1 activates inflammatory kinase RIPK2, leading to increased cytokine production by the innate immune system. Our study aimed to determine whether wild type mice treated with GSK583, a RIPK2 inhibitor, are protected against FFA-induced glucose intolerance.

Material and Methods: C57Bl/6J mice were surgically cannulated in their jugular veins and were infused with ethylpalmitate (EtP) for 48h, which results in increased plasma palmitate levels and mimics the elevated FFA levels seen in vivo. Furthermore, mice were also infused with EtP and GSK583 for 48h. After infusion, the mice were subjected to a hyperglycemic clamp and the glucose infusion rate was measured to assess glucose tolerance that under hyperglycemic clamp conditions, is mainly determined by the beta cell ability to compensate for FFA-induced insulin resistance.

Results: Preliminary data revealed that mice infused with EtP and GSK583 had a higher glucose infusion rate (GIR; mg/kgmin) (83+20, mean+SEM) than mice infused with EtP alone (57+4) . The EtP and GSK583 was comparable to the GIR of control (EtP vehicle infused) mice (84+7) .

Conclusions: Our data indicate that pharmacological inhibition of NOD1 signaling protects against FFA-induced glucose intolerance in mice. Targeting NOD1 may be an effective strategy for treating beta cell dysfunction in T2D.

Disclosure

N.Tsakiridis: None. A.Ivovic: None. S.Rahman: None. Y.Tan: None. A.Giacca: None.
1330-P: Longitudinal Multiyear Prospective Study in 87 Diabetic Primates: Lack of Support for a Mechanistic Basis for the Disposition Index
Authors: SHIVER LACHLAN , BELLIDO CARLOS , ROSADO ALANIS , HANSEN BARBARA C.
Published: May 2022

Cross-sectional studies of individuals before, during, and after the development of overt type 2 diabetes (ADA definition) , as well as those in which 3 to 5 subgroups have been analyzed, typically have applied DM progression analyses using the parameters of the Disposition Index (DI) . In such correlation-based analyses, the inferences drawn do not reflect the relationships we and others have drawn from longitudinal analyses of the same data obtained within-subject across time during the development of diabetes. The problems with the DI and its interpretation have been a subject of concern for many years, but, nevertheless, its assumptions and interpretations have dominated the diabetes scientific literature. As recently noted by Arreola, et al 2022, the form of the relationship between two measures, insulin sensitivity as measured by the “gold standard” euglycemic hyperinsulinemic clamp and beta-cell responsiveness based on the intravenous glucose tolerance test induced Acute Insulin Response (AIR, 0 to min) is clearly nonlinear, and likely is not hyperbolic. In our longitudinal laboratory study of adult nonhuman primates, 87 developed overt type 2 diabetes[LS1] while under study. The laboratory provided standard monkey chow ad libitum to all individually caged Macaca mulatta rhesus monkeys throughout the study. We found that ß cell function was not a result of or associated with a decline in insulin sensitivity as measured by a euglycemic hyperinsulinemic clamp. Furthermore, hyperglycemia is clearly not the stimulus for nor cause of hypersecretion of insulin, the latter significantly preceding the development of impaired glucose tolerance followed by progression to overt DM. We conclude that the disposition index failed to predict the natural progression from normal to overt type 2 diabetes mellitus in this longitudinal data analysis, and its value is best considered only in the context of an epidemiological study using cross-sectional data.

Disclosure

L.Shiver: None. C.Bellido: None. A.Rosado: None. B.C.Hansen: None.

Funding

National Institutes of Health (NO1 AG3 1012)
1334-P: Hepatocyte D-ß-Hydroxybutyrate Dehydrogenase Deficiency Improves Glucose Homeostasis and Prevents Diet-Induced Liver Fibrosis
Authors: STAGG DAVID B. , SEAY ALISHA R. , NELSON ALISA B. , D’AVIGNON DANA ANDRE A. , HUGHEY CURTIS C. , PUCHALSKA PATRYCJA , CRAWFORD PETER A.
Published: May 2022

Interest in intermittent fasting, ketogenic diets, and exogenous ketone therapies for prediabetes, diabetes, and nonalcoholic fatty liver disease (NAFLD) is increasing, with numerous studies showing connectivity between ketone body metabolism and NAFLD progression. Previous studies from our group showed that exogenously administered ketone bodies have divergent effects on liver health: acetoacetate (AcAc) ameliorated, while its reduced redox partner D-B-hydroxybutyrate (D-BOHB) exacerbated lobular fibrosis. Here, we study the role of hepatic redox dependent interconversion of AcAc and D-BOHB in the setting of obesity and insulin resistance. Mice deficient in hepatocyte D-BOHB dehydrogenase (BDH1) and their littermate controls were maintained on high fat western diet (WD) for 18 weeks. Post WD challenge, these mice showed similar body weight, glucose, insulin, and circulating lipids in comparison to littermate controls. While livers of hepatocyte-specific BDH1-deficient mice lost the ability to generate D-BOHB, these mice remained capable to interconvert ketone bodies in extrahepatic tissues, leading to substantial circulating D-BOHB. Hepatocyte-specific BDH1 deficient mice maintained on WD displayed diminished glucose production and hepatic oxidative fluxes. Surprisingly, BDH1 deficient mice maintained normal static energy charge and NAD+/NADH ratios. Although insulin signaling in the liver and muscle was comparable between genotypes, knockout mice exhibited improved insulin sensitivity after acute insulin challenge. In addition, livers of knockout mice showed diminished liver fibrosis and oxidative stress. Taken together, these data support the notion for salutary roles of local AcAc, but detrimental roles of local D-BOHB on liver health and suggest that hepatic BDH1-dependent ketone body interconversion is a significant contributor to liver physiology in the setting of obese insulin resistance.

Disclosure

D.B.Stagg: None. A.R.Seay: None. A.B.Nelson: None. D.A.D’avignon: None. C.C.Hughey: None. P.Puchalska: None. P.A.Crawford: Advisory Panel; Abbott Diabetes, Johnson & Johnson Global Services.

Funding

NIH DK091538, and NIH AG069781
1336-P: FoxO1-ATGL-Sirt1-FoxO1 Feed Forward Signaling Mediates Effects on Hepatic Gene Expression and Glucose Homeostasis in LIRKO Mice
Authors: O-SULLIVAN IN SUG , BHATTACHARYYA SUMIT , LIEW CHONG WEE , LEE SAM M. , CORDOBA-CHACON JOSE , PERRY RACHEL J. , SHULMAN GERALD I. , UNTERMAN TERRY
Published: May 2022

FoxO1 is a major target of insulin action and regulates expression of ATGL and its inhibitor, G0S2, in the liver (Cell Rep 15:349, 2016) . Here, we asked whether ATGL mediates effects of FoxO1 in liver-specific insulin receptor knockout (LIRKO) mice. Studies in LIRKO and IR/FoxO1 double knockout (LIRFKO) mice show ATGL expression is increased and G0S2 is suppressed in a FoxO1-dependent fashion when insulin signaling is disrupted in the liver. ATGL knockdown (KD) reduces high plasma glucose and insulin concentrations, HOMA-IR and fatty acid oxidation, and improves glucose tolerance in LIRKO mice. Hyperinsulinemic-euglycemic clamp studies show ATGL KD improves insulin sensitivity due to effects on both HGP and glucose utilization, reflecting changes in WAT lipolysis, BAT metabolism and hepatic gene expression. The expression of FoxO1-regulated gluconeogenic genes (PEPCK, G6Pase, PCO, PGC-1α) , hepatokines (e.g., follistatin) and IGFBP-1 is increased in LIRKO mice and reduced by ATGL KD, reflecting changes in acetylation of FoxO1 and its co-activator, PGC-1α (decreased in LIRKO, increased by ATGL KD) . Rictor acetylation, which promotes activation of Akt and phosphorylation of FoxO1, also is increased by ATGL KD in LIRKO mice and isolated hepatocytes. Since ATGL promotes activation of Sirt1 (Mol Cell 77:810, 2020) and Sirt1 deacetylates FoxO1, PGC-1α and rictor, these studies suggest FoxO1 promotes increased ATGL and Sirt1 activity, and that Sirt1 activation enhances the effects of FoxO1 on gene expression and glucose homeostasis in a feed forward fashion (FoxO1 -> ATGL -> Sirt1 -> FoxO1) . Targeting the FoxO1/ATGL/Sirt1 pathway may provide a useful strategy for improving glucose homeostasis when insulin signaling is impaired in the liver.

Disclosure

I.O-sullivan: None. S.Bhattacharyya: None. C.Liew: None. S.M.Lee: None. J.Cordoba-chacon: None. R.J.Perry: None. G.I.Shulman: Advisory Panel; 89bio, Inc., AstraZeneca, Equator Therapeutics, Inc., Janssen Research & Development, LLC, Merck & Co., Inc., Consultant; DiCerna Pharmaceuticals, Inc., Novo Nordisk, Other Relationship; Generian Pharmaceuticals, iMetabolic Biopharma Corporation, Maze Therapeutics, The Liver Company, Stock/Shareholder; Levels Health, Inc. . T.Unterman: None.

Funding

Department of Veterans Affairs (5I01BX001968)
1343-P: The Acute Effects of Glucagon on Glucose Dynamics Are Not Impaired in Individuals with Nonalcoholic Fatty Liver Disease
Authors: KJELDSEN SASHA , JENSEN NICOLE J. , NILSSON MALIN , HEINZ NIKLAS , NYBING JANUS D. , LINDEN FREDERIK H. , HØGH-SCHMIDT ERIK , BOESEN MIKAEL P. , MADSBAD STEN , VILSTRUP HENDRIK , SCHIØDT FRANK V. , MØLLER ANDREAS , RASHU ELIAS B. , GLUUD LISE , HAUGAARD STEEN B. , HOLST JENS J. , RUNGBY JOERGEN , WEWER ALBRECHTSEN NICOLAI J.
Published: May 2022

Glucagon is essential for glucose control and increased levels of glucagon (hyperglucagonemia) observed in patients with type 2 diabetes contribute to their hyperglycemia. Recently, hyperglucagonemia has also been found in individuals with non-alcoholic fatty liver disease (NAFLD) as well as impaired actions of glucagon on amino acid catabolism. Whether glucagon actions on hepatic glucose production are impaired is unknown. We investigated the acute effects of a single bolus of glucagon (0.2mg) on glucose dynamics in 18 normoglycemic individuals (age: 51±3 years, BMI; 31± 0.8kg/m2, hepatic fat content: 20±2%, fasting glucose: 5.5±0.1mM) with magnetic resonance imaging verified NAFLD and 22 controls (age: 38±3 years, BMI; 24± 0.8kg/m2, hepatic fat content: 4±0.1%, fasting glucose: 5.0±0.1mM) . On a separate day, a mixture of amino acids (14 g/L; 331 mg/min/kg body weight) was infused intravenously for 45min to evaluate the actions of endogenous glucagon on glucose dynamics. Glucose levels (see figure) were significantly increased in individuals with NAFLD 60min after the glucagon bolus and during the amino acid infusion with a maximal difference of 0.5mM 30min into the infusion. These data suggest that the actions of glucagon on hepatic glucose production are not impaired by NAFLD. Therefore, the hyperglucagonemia in patients with NAFLD may constitute a diabetogenic risk factor.

Disclosure

S.Kjeldsen: None. H.Vilstrup: None. F.V.Schiødt: Advisory Panel; Novo Nordisk. A.Møller: None. E.B.Rashu: None. L.Gluud: Advisory Panel; Novo Nordisk, Consultant; Pfizer Inc., Research Support; Alexion Pharmaceuticals, Inc., Gilead Sciences, Inc., Novo Nordisk, Sobi. S.B.Haugaard: None. J.J.Holst: Advisory Panel; Novo Nordisk, Board Member; Antag Therapeutics, Bainan Biotech. J.Rungby: Advisory Panel; Abbott, Boehringer Ingelheim International GmbH, Speaker’s Bureau; AstraZeneca, Bayer AG, Novo Nordisk, Pfizer Inc. N.J.Wewer albrechtsen: Research Support; Mercodia AB, Novo Nordisk, Regeneron Pharmaceuticals Inc., Speaker’s Bureau; Merck & Co., Inc., Mercodia AB. N.J.Jensen: None. M.Nilsson: None. N.Heinz: None. J.D.Nybing: None. F.H.Linden: None. E.Høgh-schmidt: n/a. M.P.Boesen: None. S.Madsbad: None.

Funding

NNF Excellence Emerging Investigator Grant – Endocrinology and Metabolism (Application No. NNF19OC0055001) , EFSD Future Leader Award (NNF21SA0072746) and DFF Sapere Aude.
1344-P: Engineering Physiologically Relevant Models of Hepatic Insulin Resistance
Authors: TEVONIAN ERIN , JEPPESEN JACOB F. , LAUFFENBURGER DOUGLAS , GRIFFITH LINDA G.
Published: May 2022

An estimated 70% of individuals with type 2 diabetes also suffer from nonalcoholic fatty liver disease (NAFLD) . Insulin resistance is pathologically fundamental to both NAFLD and T2D, however the mechanisms of insulin resistance linking these complex diseases remains incompletely understood. Microphysiological systems provide an avenue to simulate disease parameters in the context of human biology, however current in vitro models of hepatic insulin resistance often include nutrient and insulin concentrations orders of magnitude above in vivo levels. Here, we established an in vitro 3D model culturing primary human hepatocytes and non-parenchymal cells in physiologically relevant media conditions simulating both baseline physiological and T2D conditions. Albumin secretion and cytochrome p450 assays indicate hepatocytes remain functional over two weeks in culture for both physiological and T2D conditions. Results further show hepatocytes cultured in physiological conditions maintain insulin responsiveness after 12 days in culture, measured by glucose output following dose response of insulin stimulation. Conversely, cells cultured in T2D media conditions have significantly attenuated response to insulin stimulation compared to the physiological condition. Measuring insulin clearance from the media also showed reduced clearance over time for the T2D conditions. Together, these results demonstrate the induction of hepatic insulin resistance through culture with insulin concentrations found in the portal vein of T2D patients. Studies further applying this in vitro model to understand insulin resistance mechanisms are ongoing.

Disclosure

E.Tevonian: Research Support; Novo Nordisk. J.F.Jeppesen: Employee; Novo Nordisk A/S. D.Lauffenburger: None. L.G.Griffith: Research Support; Novo Nordisk A/S, Novo Nordisk A/S, Novo Nordisk A/S, Novo Nordisk A/S, Novo Nordisk A/S, Novo Nordisk A/S, Novo Nordisk A/S.
1354-P: Alternate-Day Intermittent Fasting Improves Diabetes and Protects Beta-Cell Function in Polygenic Mouse Models of T2DM
Authors: PATEL SUMIT , YAN ZIHAN , REMEDI MARIA S.
Published: May 2022

Type 2 diabetes (T2DM) , caused by the interaction of multiple genes and environmental factors, is characterized by hyperglycemia, insulin secretion deficiency and insulin resistance. Chronic hyperglycemia induces β-cell dysfunction and loss of β-cell mass/identity, increased apoptosis and β-cell dedifferentiation. Intermittent fasting (IF) , either alternate-day fasting (ADF) or time-restricted feeding, commonly used regimens for weight-loss, also induces metabolic benefits including reduced blood glucose, improved insulin sensitivity, reduced adiposity, inflammation and oxidative-stress, and increased fatty-acid oxidation; however, the mechanisms underlying these effects remain elusive. KK and KKAy, mouse models of polygenic T2DM spontaneously develop hyperglycemia, glucose intolerance, glucosuria, impaired insulin secretion and insulin resistance. To determine the long-term effects of IF on T2DM, 6-weeks old KK and KKAy mice were subjected to ADF for 16-weeks. While KKAy mice fed ad-libitum demonstrated severe hyperglycemia (˜500mg/dL) , increased plasma insulin, impaired glucose tolerance and insulin resistance at 8 weeks of age, KK mice showed blood glucose levels of ˜200mg/dL, but progressively became as severely diabetic as KKAy mice by 22-weeks. Strikingly, both KK and KKAy mice subjected to ADF showed reduced blood glucose and plasma insulin levels, decreased body weight gain despite increased food intake, reduced plasma triglycerides and cholesterol, and improved insulin sensitivity. They also demonstrated enhanced expression of the β-cell transcription factors PDX1 and NKX6.1, suggesting protection from loss of β-cell identity/dedifferentiation by IF. In addition, respiratory exchange ratio (RER) and movement were significantly enhanced in the ADF group, indicating peripheral benefits of IF. These results have important implications as an optional intervention for preservation of β-cell mass and function in T2DM.

Disclosure

S.Patel: None. Z.Yan: None. M.S.Remedi: None.

Funding

National Institutes of Health (R01DK123163)
1364-P: Low-Dose Whey Protein (WP) Microgel Improves Preprandial Satiety in People with Type 2 Diabetes (T2D) and Prediabetes
Authors: JOHANSEN ODD ERIK , SAVANT LOTIKA , MAGOS ZOLTAN , PHILIPPE DAVID , APRIKIAN OLIVIER
Published: May 2022

Whey proteins (WP) , found in dairy products, are rich in branched chain aminoacids that may stimulate mediators of satiety (anorexigenic hormones, gastric emptying [GE]) . We recently reported that a low-dose (10g, 40 Cal) pre-meal drink (125 mL) , generated with novel micelle-technology (WP microgel [WPM]) , ingested 15 min before lunch increased GLP-1 and delayed early GE in people with T2D, while lowering glucose. We wanted to quantify the effect of WPM on self-reported hunger/fullness on a 1-9 likert scale (1: “Ravenously hungry”, 9: “Stuffed”) in people with T2D, or prediabetes, before and 15 min after WPM-drink consumption, ahead of lunch. “Hungry” was defined with scores 1-3, “satisfied” with 4-6, and “full” with 7-9. Categorical change, and the overall numbers of participants that improved/reduced their satiety by 1 or 2 units, were analyzed with sign tests. A total of 102 (40 males) people, aged 30-70 (71% 50-70 yrs) , with T2D (61%) , or prediabetes (39%) , were involved. A higher number of participants reported to be less hungry or more satisfied (Fig) 15 min after WPM-consumption, and a significantly larger proportion experienced a ≥ 1 unit increase (n=44/50) relative to a comparable negative change (p<0.0001) , as well as a ≥ 2 unit increase (n=15/17, p=0.002) . These data suggest that low-dose, low-caloric, pre-meal WPM might improve satiety/reduce hunger, but further studies are needed.

Disclosure

O.Johansen: Employee; Boehringer Ingelheim International GmbH, Nestlé Health Science. L.Savant: None. Z.Magos: Consultant; Nestlé Health Science. D.Philippe: Employee; Nestlé Health Science. O.Aprikian: None.

Funding

Nestlé Health Science
139-OR: Large-Scale Sex-Stratified Additive and Recessive GWAS Identifies Novel Large-Effect Variants and Improves Polygenic Prediction for Type 2 Diabetes
Authors: SCHROEDER PHILIP H. , COLE JOANNE B. , LEONG AARON , FLOREZ JOSE C. , MERCADER JOSEP M.
Published: May 2022

Introduction: Most genome-wide association studies (GWAS) of type 2 diabetes (T2D) assume an additive mode of inheritance and equal effects in men and women. These assumptions can preclude the discovery of variants with effects that are non-additive and/or sex-specific. Focused exploration of these effects may reveal novel genetic variation associated with T2D and improve the predictive performance of polygenic risk scores (PRS) .

Methods: We performed a sex-stratified GWAS, using additive and recessive models for T2D, in individuals of European ancestry in the UK Biobank (UKBB) and Genetic Epidemiology Research on Aging cohort. We also generated sex-specific and non-sex-specific T2D PRSs, using PRS-CS, and assessed their performance in Mass General Brigham Biobank (MGBB) .

Results: As the largest sex-stratified additive and recessive GWAS of T2D performed to date, this study included 30,625 cases and 223,442 controls. In the recessive analysis, we identified 7 novel variants, of which 1 was female-specific and 1 was male-specific. Among these variants, 4 were associated with over 10-fold increase in risk for T2D. The male-specific variant, rs35725476 (OR = 1.49, p = 3×10- 9) , is associated with higher expression of a long non-coding RNA in pancreatic islets (p = 3×10- 14) . In the additive analysis, we identified a novel female-specific protective variant, rs12109272 (OR = 0.91, p = 3×10-8) , which is associated with lower PCSK1 expression, lower risk of gestational diabetes (p = 1×10- 6) and lower fasting glucose (p = 6×10- 32) in independent cohorts. Finally, the sex-specific PRS outperformed the non-sex-specific PRS at predicting T2D in MGBB (AUC of 0.653 versus 0.643, p [of difference] = 2×10-4 in males; AUC of 0.674 versus 0.656, p [of difference] = 3×10-4 in females) .

Conclusions: These findings demonstrate the value of non-additive and sex-stratified analyses for both variant discovery and improving polygenic prediction for T2D.

Disclosure

P.H.Schroeder: None. J.B.Cole: None. A.Leong: None. J.C.Florez: Consultant; AstraZeneca, Goldfinch Bio, Inc., Other Relationship; AstraZeneca, Merck & Co., Inc., Novo Nordisk. J.M.Mercader: None.

Funding

American Diabetes Association (1-19-ICTS-068) ; National Human Genome Research Institute (U01HG011723)