bluuebunny/crossref_metadata_2025 huggingface dataset:
166-LB: Targeting Deprescribing in Type 2 Diabetes Mellitus Using a Pragmatic Electronic Health Record Measure of Frailty
Authors: USOH CHINENYE , LENOIR KRISTIN M. , PAJEWSKI NICHOLAS M. , CALLAHAN KATHRYN E.
Published: June 2021

Background: Guidelines recommend less stringent glycemic goals for older adults with type 2 diabetes mellitus (T2DM) and frailty or comorbidity. However, pragmatic, scalable approaches to identify candidates for de-intensification of T2DM regimens are lacking.

Methods: Analysis of electronic health record (EHR) data for patients ≥65 years with T2DM from an accountable care organization as of 11/1/2020. Frailty was determined based on a 54-item electronic Frailty Index (eFI) derived from the EHR. Other data included the level of glycemic control, use of higher-risk medications regimens (active prescription of insulin, sulfonylurea, or combinations of the two), the incidence of emergency department (ED) visits and hospitalizations, and all-cause mortality.

Results: Amongst 16973 patients, 53.9% were female, 77.8% white, with a mean age of 75.5 (SD=6.9) years. Based on the eFI, 6218 (36.6%) patients were classified as frail (eFI>0.21). During short-term follow-up (median=116 days), compared to fit patients (eFI≤0.10), patients classified as frail exhibited a higher incidence of ED visits and hospitalizations (hazard ratio = 3.05, 95% CI: 2.35 to 3.95) and all-cause mortality (hazard ratio = 7.33, 95% CI: 3.61 to 14.88). A large number of patients classified as frail based on the eFI had HbA1c levels <7.5% based on their most recent measure (N=4544, 73.1%). In this population, 1408 (31%) were prescribed no T2DM medication, 1013 (22.3%) were prescribed metformin alone, and 1755 (38.6%) were on a higher-risk T2DM medication (sulfonylurea or insulin). In frail patients with HbA1c<7.5%, patients taking metformin only exhibited the lowest rate of ED visits and hospitalizations (hazard ratio = 0.58, 95% CI: 0.44 to 0.77 compared to all other groups).

Conclusions: The eFI is a pragmatic and scalable tool to identify vulnerable older adults with T2DM that may benefit from de-prescribing consistent with guideline recommendations.

Disclosure

C. Usoh: None. K. M. Lenoir: None. N. M. Pajewski: None. K. E. Callahan: None.
167-LB: Pandemic Changes and Usage of At-Home Collected Hemoglobin A1c and Lipid Profiles
Authors: DION EMMA J. , HUMPHREYS DEVON , OLDS KAYLAN , SIRIWARDHANE THUSHANI , BAUER TIMOTHY
Published: June 2021

Background: Routine health screening and monitoring declined when COVID-19 was declared a global pandemic on March 11, 2020. Early reports found Hemoglobin A1c (HbA1c) testing declined nearly 50% among patients with diabetes from March to May in 2020 compared with 2019. At-home sample collection aligns with social distancing practices and mitigates potential exposure to SARS-CoV-2 in public settings, including clinics. This study sought to characterize utilization of at-home lab tests and resulting HbA1c and lipid profiles in pre-pandemic and pandemic cohorts.

Methods: Results from individuals who used at-home collection to measure HbA1c, total cholesterol, calculated LDL-C, HDL, triglycerides, and hs-CRP between October 2017 and December 2020 were identified from a commercial consumer database. A total of 19,076 test-takers were included, of which 12,587 had HbA1c measurements and 13,624 had lipid measurements.

Results: Use of tests measuring HbA1c increased 60.3% in February-May 2020, around the time of pandemic declaration, and to a lesser degree from June-December when compared with 2019 use. Use of tests measuring lipids increased 61.9% during the same time periods. The mean HbA1c (%) in the pre-pandemic vs. pandemic cohort was 5.47 ± 0.72 (N = 3476) vs. 5.69 ± 0.87 (N = 2851) among users ages 18-44, 5.85 ± 1.04 (N = 2740) vs. 6.12 ± 1.17 (N = 1709) among users ages 45-64, and 6.05 ± 0.91 (N = 703) vs. 6.47 ± 1.34 (N = 513) among users ages 65+. Overall, the percent of individuals with an HbA1c characteristic of prediabetes and diabetes (HbA1c ≥ 5.7% and ≥ 6.5%, respectively) was 23.4% and 7.0% in 2018 (N = 2342), 26.6% and 8.5% in 2019 (N = 3751), and 38.8% and 14.7% of total users in 2020 (N = 6173).

Conclusions: The impact of the COVID-19 pandemic on at-home lab testing demonstrates the feasibility and increased usage of at-home sample collection for routine health monitoring particularly among people with elevated HbA1c.

Disclosure

E. J. Dion: Employee; Self; Everlywell, Inc.. D. Humphreys: None. K. Olds: Employee; Self; Everlywell, Inc. T. Siriwardhane: None. T. Bauer: Employee; Self; Everlywell, Inc.
177-OR: The Swi/Snf Chromatin Remodeling Complex Controls the Specification, Expansion, and Differentiation of Pancreatic Endocrine Progenitor Cells
Authors: SPAETH JASON , DAVIDSON REBECCA K. , CASEY NOLAN
Published: June 2021

A key feature of type 1 and type 2 diabetes is insufficient functional β-cell mass. Strategies to augment functional β-cell mass include directed differentiation of embryonic stem cells towards a β-cell fate, which requires extensive knowledge of the transcriptional programs governing endocrine cell differentiation in vivo. Pdx1, an essential transcription factor involved in pancreas formation, endocrine progenitor cell expansion and β-cell function, dynamically recruits coregulators to drive gene expression programs in those cells vital for its activity. Pdx1 binds to numerous coregulators in the β-cell, including the ATP-dependent Swi/Snf chromatin remodeling complex. Previous work by our group revealed a critical role for Pdx1:Swi/Snf in both the developing pancreas and mature β-cell. Here we interrogate the role of Swi/Snf on governing Pdx1-dependent gene expression programs and chromatin accessibility in pancreatic endocrine cell development. We developed a mouse model to eliminate the activity of the two core ATPase subunits of Swi/Snf, Brg1 and Brm from endocrine progenitor cells using Neurogenin3-Cre (Δendo). Conditional knockout of Brg1 (Brg1ΔendoBrm+/-) from endocrine progenitor cells leads to severe glucose intolerance, ad-libitum fed hyperglycemia, reduced serum insulin, compromised glucose stimulated insulin secretion from isolated islets and reduced islet mass in 4-week old animals. Whereas Brg1Δendo/+Brm-/- mice are normal, remarkably, no DKOΔendo (double knockout (DKO): targeted both Brg1 and Brm) mice have been found at weaning, suggesting loss of all Swi/Snf activity from the endocrine progenitor cell pool is postnatally lethal. Future experiments will be directed at determining how Swi/Snf controls Pdx1-dependent gene expression programs and chromatin accessibility in endocrine progenitor cells that are critical for islet cell expansion, differentiation and maturation.

Disclosure

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

Funding

National Institutes of Health (R03DK127129, K01DK115633)
18-LB: Histone Modifications and CXCR4 Chemokine Receptor Signaling in Hyperglycemic DRG Neurons
Authors: SATTERFIELD NATALIE , THAKUR VIKRAM , CHATTOPADHYAY MUNMUN
Published: June 2021

Diabetes is a global epidemic that affects many individuals throughout the world and presents a major health challenge to society. The state of chronic hyperglycemia can have many devastating secondary effects including neuropathy, nephropathy, retinopathy, and cardiovascular disease. The diabetes mediated neuropathic complications are a substantial burden to society due to a lack of therapies as well as decreased quality of life and increased mortality. Approximately 50% diabetic patients suffer from neuropathy which is described as alterations of pain sensation in the feet that leads to increased risk for infection, ulcers, non-traumatic amputations and ultimately death. Painful diabetic neuropathy (PDN) affects individuals within 20 years after the onset of disease, mediated by the gradual degeneration of axonal structures in sensory neurons. It is known that hyperglycemia is involved in the pathogenesis of this disease, but specific mechanisms are not well understood. Previous studies have shown that inflammation and epigenetic changes may play a role in the development of PDN. Specifically, it has been demonstrated that the chemokine receptor CXCR4 is involved in inflammation relating to PDN while the histone deacetylases HDAC4 and HDAC6 are involved in mediating the epigenetic changes in sensory neurons under hyperglycemic conditions. This study investigated the alterations in inflammatory mediators and epigenetic changes in sensory neurons under normal glucose and high glucose environments. Western blot and immunocytochemistry techniques were used to measure any differences in these two conditions. The results from this study demonstrated an upregulation of histone deacetylases and CXCR4 in hyperglycemic conditions, while histone acetyltransferases were shown to be down-regulated in high glucose environments. These findings may lead to potential therapeutic targets for PDN since it is a life altering condition with minimal treatment options available today.

Disclosure

N. Satterfield: None. V. Thakur: None. M. Chattopadhyay: None.

Funding

Texas Tech University Health Sciences Center El Paso (183381SEED)
180-LB: Effects of Proton Pump Inhibitors on Glycemic Control and Risk of Incident Diabetes: A Systematic Review and Meta-analysis
Authors: PENG CAROL CHIUNG-HUI , BUKHARI KHULOOD , HUANG HUEI-KAI , TU YU-KANG , LEE GIN YI , CHANG HUAI-EN , HUANG YUTING , FU YUNTING , MUNIR KASHIF M.
Published: June 2021

Background and Aims: Whether proton pump inhibitors (PPI) can improve glycemic control is unclear. Also, incident diabetes from PPI use has not been elucidated. We conducted a meta-analysis and systematic review to determine the impact of PPI on glycemic control in individuals with diabetes and the risk of diabetes in those without diabetes.

Methods: PubMed, Embase, Scopus, and ClinicalTrials.gov were searched from inception to November 21, 2020. Studies reporting a change of glycemic indices, including glycosylated hemoglobin (HbA1c) or fasting blood glucose (FBG), in individuals with diabetes taking add-on PPI compared to standard therapy were included. Also, studies evaluating risk of incident diabetes in individuals taking PPI were assessed. We performed dual independent review, data extraction, and quality assessment. Weighted mean differences or relative risks were imputed using random-effects models.

Results: Seven studies (n = 342) for glycemic control, and five studies (n = 244,439) for risk of incident diabetes were included. Compared to standard therapy, add-on PPI was associated with a significant decrease in HbA1c (WMD = −0.36 %; 95% CI: −0.68 to −0.05; p = 0.025), and FBG (WMD = −10.0 mg/dL; 95% CI: −19.4 to −0.6; p = 0.037). However, PPI use was not significantly associated with the risk of incident diabetes (pooled RR = 1.10; 95% CI: 0.89 to 1.34; p = 0.385).

Conclusions: PPI along with standard care improved glycemic indices in individuals with diabetes but did not alter the risk of incident diabetes. The effects of PPI on glycemic control should be considered when treating upper gastrointestinal symptoms in patients with diabetes.

Disclosure

C. Peng: None. K. Bukhari: None. H. Huang: None. Y. Tu: None. G. Lee: None. H. Chang: None. Y. Huang: None. Y. Fu: None. K. M. Munir: None.
182-OR: Genetic Susceptibility to Diabetic Kidney Disease Is Linked to C/EBP-XOR Axis
Authors: WANG QIN , QI HAIYING , LI SHUYU , CASALENA GABRIELLA , YU LIPING , DAEHN ILSE S.
Published: June 2021

Diabetic kidney disease (DKD) is the leading single cause of end-stage renal disease in the United States. Approximately 30% of diabetics develop DKD with comparable blood glucose levels, indicating a significant genetic contribution for susceptibility. However, the underlying mechanisms that contribute to differential susceptibility are poorly understood. The glomerulus is the primary site of injury with hypertrophy and podocyte depletion being the hallmarks for progressive DKD. We have demonstrated that mitochondrial oxidative damage accumulation in glomerular endothelial cells, leads to podocyte loss via endothelial-to-podocyte crosstalk in DKD susceptible DBA/2J (D2) mice compared to DKD resistant C57BL/6J (B6) mice. To map genetic loci associated with podocyte depletion after long-term diabetes (6mth), we used the 39 strains of BXD, and parental B6 and D2 mice. We identified a significant cis-acting variant in the promoter of xanthine oxidoreductase (XOR). XORs catalyze the oxidation of purine substrates produce uric acid and reactive oxygen species. XOR expression in the kidney and circulating activity were significantly higher in diabetic D2 compared to B6. XOR inhibition significantly reduced albuminuria, oxidative damage in glomeruli and prevented podocyte depletion in diabetic D2 mice. We used CRISPR/Cas9 to knock-in the XOR risk variant into DKD-resistant B6 mice and generated mutant B6-XORem1 mice with significantly higher XOR activity than B6. This risk variant is a transcription factor binding site to C/EBPβ, we show higher C/EBPβ expression in glomerular endothelium from diabetic B6-XORem1 mice but not in diabetic B6. B6-XORem1 mice had increased mitochondrial oxidative stress in endothelial cells, podocyte depletion, basement membrane thickening, albuminuria, glomerulosclerosis and tubular injury, and these changes were prevented with XOR inhibition. Our data suggest that the identified promoter variant is causal for DKD susceptibility via the C/EBPβ-XOR axis.

Disclosure

Q. Wang: None. H. Qi: None. S. Li: None. G. Casalena: None. L. Yu: None. I. S. Daehn: None.

Funding

National Institutes of Health
183-LB: Incidence and Characteristics of Type 1 and Type 2 Diabetes among Youths in the COVID-19 Pandemic
Authors: NIP ANGEL , AHMAD TARIQ
Published: June 2021

Background: The impact of SARS-COV-2 on islet cell function and immune dysregulation is unclear. Though adults with diabetes suffer higher rates of morbidity and mortality from COVID-19, pediatric data is limited. We aimed to study the number and characteristics of new onset type 1 (T1D) and type 2 (T2D) diabetes pre- and during the pandemic.

Method: This was a retrospective study using inpatient data at UCSF Benioff Children’s Hospital Oakland. We examined newly diagnosed T1D and T2D, aged < 18 years old, from May 2019 to Jan 2021. COVID-19 pandemic was defined from Mar 2020 onward.

Results: Respectively, there were 59 and 64 new T1D, and 25 and 34 new T2D pre- and during COVID-19 pandemic. No difference was observed in time-adjusted incidence rate in T1D, but a rising trend in T2D was seen. A higher infection rate (PCR or IgG) was shown in T2D than T1D (11.8% vs. 3.1%, p = 0.05). During COVID-19, individuals with T1D had higher BMI z-scores (0.4 vs. -0.2, p = 0.03) and c-peptide levels (0.8 ng/ml vs. 0.5 ng/ml, p <0.01), and more Hispanics were diagnosed (46.9% vs. 27.1%, p = 0.02). Individuals with T2D were younger (mean age 12.8 yr vs. 14.5 yr, p = 0.02) and had more DKA on presentation (35.3% vs. 12.0%, p = 0.04) during the pandemic. Insurance and income were not associated with T1D nor T2D. No differences in patient demographics were observed in relation to COVID-19.

Conclusion: We observed a rising trend of new onset T2D in the pediatric population during COVID-19, who were younger and sicker at presentation, and had a higher COVID-19 positivity rate than T1D. T1D incidence was similar, but individuals were more obese, had greater beta cell reserve at presentation, and a higher proportion were Hispanic compared to pre-pandemic. The roles of COVID-19, stress, and/or lifestyle changes associated with shelter-in-place orders, contributing to increased BMI and c-peptide levels in T1D, or increasing the risk for new onset diabetes and DKA in youths with T2D needs to be elucidated further and studied.

Disclosure

A. Nip: None. T. Ahmad: None.
189-LB: Using Genetics to Separate Childhood from Adult BMI Shows That Higher Childhood BMI Has No Direct Effect on Reduced Insulin Secretion or Sensitivity in Later Life
Authors: HAWKES GARETH , RICHARDSON TOM G. , POWER GRACE M. , SMITH GEORGE DAVEY , FRAYLING TIMOTHY M.
Published: June 2021

Higher BMI during childhood is associated with an increased likelihood of remaining overweight later in life, leading to higher risk of developing type 2 diabetes (T2D). Using a Mendelian randomisation approach, a recent study found no evidence that childhood BMI has a direct causal effect on T2D. However, the extent to which high BMI in childhood directly alters insulin secretion and sensitivity in later life requires further investigation.

We aimed to use genetic variants associated with differential effects on childhood and adult BMI to test their separate effects on insulin secretion and insulin sensitivity. We first generated a measure of childhood BMI aged 10 using self-reported categories in the UK Biobank, which we approximated to a normal distribution. We then performed separate genome wide association studies (GWAS) of childhood and adult BMI. This approach increased the number of genetic instruments by a factor of two as compared to previous methods. We used a multivariable Mendelian Randomisation approach, with childhood and adult BMI as exposure variables, and 5 measures of insulin secretion and insulin sensitivity in nondiabetic adults from previous GWAS studies as outcome variables.

We found no evidence (at p<0.05) that higher BMI in childhood has a direct adverse effect on type 2 diabetes (OR 0.94, 95%CI 0.82-1.08), fasting insulin (OR 1.00, 0.95 - 1.05), insulin sensitivity (OR 1.11, 0.97-1.27) or sensitivity-index adjusted acute insulin response (OR 1.11, 0.88-1.42) in adults. There was some evidence of a protective effect, with higher childhood BMI associated with lower fasting glucose (OR 0.96, 0.93 - 1.00) and insulin secretion (OR 1.30, 1.04 - 1.63). Crucially, our results are consistent with no adverse direct effect of higher childhood BMI on adult type 2 diabetes, insulin secretion or sensitivity.

Disclosure

G. Hawkes: None. T. G. Richardson: None. G. M. Power: None. G. Davey smith: None. T. M. Frayling: None.

Funding

Innovative Medicines Initiative 2 Joint Undertaking (875534)
196-LB: Stem Cell–Derived Islet Replacement Therapy (VC-02) Demonstrates Production of C-Peptide in Patients with Type 1 Diabetes (T1D) and Hypoglycemia Unawareness
Authors: KEYMEULEN BART , JACOBS-TULLENEERS-THEVISSEN DANIEL , KROON EVERT J. , JAIMAN MANASI S. , DANIELS MARK , WANG RICHARD , PIPELEERS DANIEL , D’AMOUR KEVIN , FOYT HOWARD L.
Published: June 2021

Patients with T1D exhibit a major loss in beta cell mass, associated with low or undetectable circulating markers of beta cell function. C-peptide serves as a biomarker used to assess the residual mass of functional insulin-producing pancreatic beta cells present in patients with T1D on insulin replacement therapies; this measurement is not confounded by exogenous insulin. Novel cell replacement therapies to address T1D, including VC-02 (PEC-Direct), have demonstrated the ability to control disease state and mitigate diabetes-related complications due to the absence of insulin and glycemic variability.

In the current VC02-101 study, T1D patients were required to be C-peptide negative (during a mixed meal tolerance test) upon enrollment. Study participants received subcutaneous implanted VC-02 combination product containing pancreatic precursor cells (PEC-01 cells) derived from ViaCyte’s proprietary CyT49 pluripotent stem cell line. When effectively engrafted, these cells are capable of producing circulating C-peptide, as previously shown in rodent models, and now for the first time at clinically relevant levels in patients.

Preliminary data for one patient implanted with the most current device configuration are presented through 6 months study duration. Stimulated C-peptide Cmax concentrations increased from 0.1 ng/mL (baseline) to 0.5 ng/mL (week 26), and AUC0-4hr increased from 0.225 to 1.775 ng x hr/mL. These results are corroborated by histology evidencing successful engraftment and cell survival. This effect was accompanied by an increase in time-in-range from 56 to 86% and reduction in HbA1C by 0.5%. Together, these data provide clinical proof-of-concept that further optimization of this therapy can result in a functional cure for T1D.

Disclosure

B. Keymeulen: None. D. Jacobs-tulleneers-thevissen: None. E. J. Kroon: Employee; Self; Viacyte, Inc. M. S. Jaiman: Employee; Self; Viacyte, Inc., Stock/Shareholder; Self; Viacyte, Inc. M. Daniels: Employee; Self; Viacyte, Inc. R. Wang: Employee; Self; Viacyte, Inc. D. Pipeleers: Board Member; Self; Beta-Cell NV. K. D’amour: Employee; Self; Viacyte, Inc. H. L. Foyt: Employee; Self; Viacyte, Inc., Stock/Shareholder; Self; Viacyte, Inc.

Funding

European Commission, Horizon 2020 (681070); California Institute of Regenerative Medicine (CLIN2-09672); JDRF (2011)
211-OR: Differential Cerebral Blood Flow in Controlled and Uncontrolled Patients with Type 2 Diabetes Mellitus
Authors: CHOI SARAH E. , ROY BHASWATI , FREEBY MATTHEW , KUMAR RAJESH
Published: June 2021

Introduction: Patients with type 2 diabetes mellitus (T2DM) show variable brain tissue changes and mood and cognitive symptoms, which may result from altered cerebral blood flow (CBF). However, the regional CBF status in controlled and uncontrolled T2DM patients remains unclear, which can be examined with arterial spin labeling (ASL) imaging. Our aim was to examine regional CBF between controlled and uncontrolled T2DM patients using ASL imaging procedures.

Methods: We collected hemoglobin A1c (A1C) data and 3D pseudo-continuous ASL data from 32 T2DM patients (16 controlled [A1C < 7%], age, 56.5±6.5 years; BMI, 29.6±6.2 kg/m2; 8 female; 16 uncontrolled [A1C ≥ 7%], age, 57.6±7.5 years; BMI, 30.0±5.1 kg/m2; 11 female) using a 3.0-Tesla MRI. A1C was measured by point-of-care testing. Whole-brain CBF maps were calculated, normalized to a common space, smoothed, and compared between groups (controlled T2DM patients vs. uncontrolled T2DM patients) using analysis of covariance (SPM12; covariates, age and sex; p<0.05).

Results: No significant differences in age or sex appeared between groups. Multiple brain areas showed decreased CBF values in the cingulate, caudate, putamen, insula, hippocampus, amygdala, thalamus, hypothalamus, midbrain, cerebellum, prefrontal and frontal, and temporal cortices in uncontrolled T2DM patients over controlled T2DM patients. However, few brain sites in controlled T2DM patients, including the cerebellum, pons, medulla, parahippocampal gyrus, and temporal cortices showed reduced CBF over uncontrolled T2DM patients.

Conclusion: Uncontrolled T2DM patients show significant reduction in CBF compared to controlled T2DM in areas that are involved in mood and cognition regulation. The findings suggest that uncontrolled levels may contribute to reduce regional CBF leading to site-specific tissue changes resulting to mood and cognition deficits in the condition.

Disclosure

S. E. Choi: None. B. Roy: None. M. Freeby: Research Support; Self; Abbott Diabetes, Novo Nordisk Inc. R. Kumar: None.

Funding

National Institutes of Health (1R01NR017190-03, 3R01NR017190-03S1)
215-OR: Performance of a Dual Hormone Closed-Loop System vs. an Insulin-Only Closed-Loop System during Challenging Inpatient Conditions: A Single-Blinded Randomized Controlled Crossover Trial
Authors: RANJAN AJENTHEN G. , BOIROUX DIMITRI , LAUGESEN CHRISTIAN , SCHMIDT SIGNE , REENBERG ASBJØRN T. , JØRGENSEN JOHN B. , NØRGAARD KIRSTEN
Published: June 2021

Objective: To assess the efficacy and safety of an insulin-glucagon dual-hormone (DH) compared with an insulin-only single-hormone (SH) closed-loop system.

Methods: In a 33-h, randomized, crossover, inpatient study, 13 participants with type 1 diabetes used two modes of the DiaCon Artificial Pancreas system: DH and SH closed-loop control. During each study period, participants had two overnight stays, received an underbolus (50%) for their breakfast, normal bolus (100%) for lunch, overbolus (130%) for dinner and performed unannounced exercise for 45 min (bicycled at estimated 50% V02max). The co-primary endpoints were sensor-based percentage of time in hypoglycemia (<3.9 mmol/L) and the number of 15 g carbohydrate rescues whenever plasma glucose <3.0 mmol/L from 0 to 33 h after initiation of the systems.

Results: Overall, the average number of carbohydrate rescues was significantly lower during DH compared with SH (mean±SD: 0.8±1.3 vs. 1.4±1.4 per 33 h, p = 0.04). The percentages of time in hypoglycemia (3.6±2.1% vs. 3.8±3.3%, p = 0.46), target range (3.9-10.0 mmol/L: 67.2±15.4% vs. 65.3±12.4%, p = 0.41) and hyperglycemia (>10.0 mmol/L: 26.8±16.0% vs. 28.7±12.7%, p = 0.41) were similar between study arms. Mean glucose was lower for DH than SH (8.3±1.2 vs. 8.6±1.0 mmol/L, p = 0.04) with similar coefficient of variation (40±8.3 vs. 38±5.0%, p = 0.30). From exercise start and 4 h onwards, DH achieved more time in range (86.7±11.7 vs. 74.7±16.5%, p = 0.01), but similar time in hypoglycemia (10.5±18.7 vs. 12.6±24.3%, p = 0.32) and numbers of carbohydrate rescues (5±0.7 vs. 6±0. 7, p = 0.38). No differences were observed on visual analog scale-measured nausea (p = 0.47), headache (p = 0.77), hunger (p = 0.66), and palpitation (p = 0.11).

Conclusions: During challenging inpatient conditions, the DH system achieved similar glucose control but significantly reduced need for carbohydrate rescue compared with SH.

Disclosure

A. G. Ranjan: None. D. Boiroux: Consultant; Self; Novo Nordisk A/S, Employee; Spouse/Partner; Novo Nordisk A/S. C. Laugesen: None. S. Schmidt: None. A. T. Reenberg: None. J. B. Jørgensen: None. K. Nørgaard: Advisory Panel; Self; Medtronic, Other Relationship; Self; Novo Nordisk Inc., Zealand Pharma A/S, Speaker’s Bureau; Self; Medtronic.

Funding

Danish Diabetes Association; Danish Diabetes Academy (PD002-19)
220-LB: Serum Lipocalin-2 (LCN2): Potential Indices Associated with Weight Loss and Metabolic Improvement after Laparoscopic Sleeve Gastrectomy (LSG)
Authors: LI NANNAN , MUTAILIPU KELIBINUER , YOU HUI , HUANG YUEYE , ZHU BING , SU LILI , WEN XIN , LEI SHIHUI , QU SHEN , BU LE
Published: June 2021

Background: The aims of study are to observe laparoscopic sleeve gastrectomy (LSG) surgery mediated change in LCN2 level, and to ascertain relevance of LCN2 to efficacy indicators of LSG surgery.

Methods: The retrospective study of 58 obese individuals who have undergone LSG surgery was held between July 2016 and July 2017 in the Shanghai Tenth People’s Hospital in China. Anthropometric and biochemical measurements were recorded at baseline and 12 months after surgery. Body fat was measured by dual-energy X-ray absorptiometry. Serum LCN2 level was measured by enzyme-linked immunosorbent assay. We analyzed association between serum LCN2 level and efficacy indicators 12 months post-surgery, and further explored the dose-dependent relation across the baseline / decrease LCN2 tertiles.

Results: From baseline to 12 months after LSG, serum LCN2 level was significantly decreased; we found independent association between baseline / decreased LCN2 and efficacy indicators, including changes in weight, waist circumference, fat mass and triglyceride; further, across the decreased LCN2 tertiles, intragroup difference analysis showed significantly higher level of percent extra weight, waist circumference, and trunk fat mass loss, decreased total fat percent on the top tertile, compared to the lowest tertile; and binary logistic regression analysis showed direct dose-dependent relation between decreased LCN2 level and weight loss efficacy (the lowest tertile as reference, adjusted odds ratio (95%CI) = 42.66 (1.41-1290.28), 70.42 (1.82-2723.43), per decreased LCN2 tertile respectively); across the baseline LCN2 tertiles, we found significantly higher level of percent waist circumference on the top tertile, compared to the lowest tertile.

Conclusion: In our study, LCN2 level was decreased at 12 months after LSG surgery. Baseline and decreased LCN2 levels were associated with some weight loss efficacy indicators in a dose-dependent way.

Disclosure

N. Li: None. L. Bu: None. K. Mutailipu: None. H. You: None. Y. Huang: None. B. Zhu: None. L. Su: None. X. Wen: None. S. Lei: None. S. Qu: None.
223-LB: Jagged 1- Notch Signaling Determines ß-Cell Maturity and Function
Authors: SUDA NINA , PAJVANI UTPAL
Published: June 2021

Obesity-induced Type 2 Diabetes (T2DM) continues to increase at an alarming rate resulting in a substantial burden of long-term complications and healthcare costs. As such, understanding mechanisms of T2DM pathogenesis is key in tackling the growing prevalence. Although insulin resistance is the hallmark of T2DM, it manifests as hyperglycemia only in the setting of β cell insufficiency. Pathophysiologic mechanisms underlying this failure requires further elucidation. We have recently shown that Notch signaling is a novel regulator of β cell function, and glucose homeostasis. Notch activity is regulated by ligand (Jagged 1/2, and Delta-like 1/3/4) availability. We find that islets isolated from HFD-fed or leptin receptor-deficient db/db mice have increased Jagged1 expression as compared to chow or db/+ controls, without change in other Notch ligands, in parallel to increased Notch activity. These data led us to hypothesize that Jagged1 is both sufficient and necessary to transduce Notch signaling in β cells and is a potential regulator of β cell function, maturity and glucose homeostasis. To investigate this, we generated novel β cell specific Jagged1 gain-of-function and knock-out mice. Preliminary data from our inducible gain of function model show progressively impaired glucose intolerance through decreased insulin secretion in parallel with an increase in Notch activity, despite normal weight and adiposity. By identifying the ligand-receptor interaction, we postulate that we can take advantage of this knowledge for therapeutic benefit. To this end, we have generated dominant negative mutants of the Notch receptor lacking the intracellular Notch domain that specifically block either Jagged or Delta-like ligands. The current data on Notch signaling in β cells shows promise for furthering the understanding of the pathophysiology in T2DM. In studying this mechanism further, we hope to provide a novel therapeutic strategy in preventing a disease that continues to be a growing concern worldwide.

Disclosure

N. Suda: None. U. Pajvani: None.

Funding

Endocrine Fellows Foundation
224-OR: Cardiac Imaging and Metabolomics Studies Suggest Shared and Distinct Risk Factors for Atherosclerosis and Cardiomyopathy in Renoprotected, Long-Duration Type 1 Diabetes
Authors: YU MARC GREGORY , SHAH HETAL , WOLFSON EMILY , ADAM ATIF , GAUTHIER JOHN , JHA VIBHAV , TSAO CONNIE , KING GEORGE L.
Published: June 2021

Cardiovascular disease (CVD) is a major cause of mortality in long-duration type 1 diabetes (T1D) despite the absence of nephropathy (DN). However, its mechanisms are incompletely understood. Joslin 50-Year “Medalists”, with T1D≥50 years, are ideal for studying CVD in a renoprotected T1D cohort, as only 13% have DN, yet 40% have CVD. A Medalist subset underwent coronary artery calcification scans (CAC; n=75) and cardiac magnetic resonance (CMR; n=60) of left ventricular (LV) mass and volumes. In exploratory analyses, we studied the association of these imaging parameters with Medalists’ cardiometabolic profiles. Compared to males, females were less likely to have CAC>200 (p=0.02) and had lower (more favorable) values for CMR structure parameters such as LV mass index (MI) and end-systolic (ESV) and end-diastolic (EDV) volumes (all p<0.05). Higher HbA1C showed a trend towards association with CAC>200 and higher LV MI (both p=0.1). CAC>200 also associated with retinopathy (PDR; p=0.04) and lower superficial capillary density on retinal imaging (p=0.049), and a trend towards association with lower HDL and higher C-reactive protein (both p=0.09). LV MI and EDV were associated with DN (p=0.04 and p=0.05, respectively). In untargeted metabolomics, LV MI, EDV, and ESV were also associated with higher levels of short-medium chain acylcarnitines and histamine metabolites, and lower levels of tryptophan metabolites via the indole pathway (all FDR<0.1). These preliminary findings suggest that while sex and glycemic control are shared contributors to atherosclerosis and cardiomyopathy in T1D, PDR, lipids and inflammation appear distinctly tied to atherosclerosis; while DN and endogenous metabolites may play a role in cardiomyopathy. Our findings suggest the need for targeted therapeutic approaches for CVD in T1D, depending on whether manifestations are predominantly atherosclerotic or cardiomyopathic.

Disclosure

M. Yu: None. H. Shah: None. E. Wolfson: None. A. Adam: None. J. Gauthier: None. V. Jha: None. C. Tsao: None. G. L. King: Consultant; Self; Agios, Inc., Medtronic, Other Relationship; Self; Janssen Pharmaceuticals, Inc.

Funding

American Diabetes Association (9-18-CVD1-005 to M.G.Y.); Thomas J. Beatson Jr. Foundation (2185 20008 2800200)
26-LB: Glycemic Control in People with Type 1 Diabetes Mellitus after the First Portuguese COVID-19–Related State of Emergency
Authors: RAMALHO DIOGO , CORREIA SARA , ALMEIDA LÚCIA , ALVES HELENA , ROCHA GUSTAVO , FERREIRA MARTA , OLIVEIRA MARIA J.
Published: June 2021

Introduction: The first Portuguese COVID-19-related state of emergency (SE) extended between March and May 2020. The relevance of achieving the glycemic target for the person with type 1 Diabetes Mellitus (T1DM) is deepened in these circumstances, given the forced changes in daily routine.

Objective: To determine the influence of work activity (WA) on glycemic control (GC) of adults with T1DM after the first SE.

Material and methods: A retrospective cohort study was designed to enroll adults with ≥2 years from T1DM diagnosis. Cases of pregnancy/hospitalizations in 2019/2020, factors that affect interpretation of glycated hemoglobin (HbA1c) and/or SARS-CoV-2 infections were excluded. The participants were stratified into groups of WA after the SE: g1 (telework/lay-off/students), g2 (retired/unemployed) and g3 (WA without lockdown). HbA1c were obtained from 4 periods: t3 (4/1-6/1/2020); t4 (7/1-9/1/2020); t1 and t2 (homologous periods of 2019). Differences in HbA1c were calculated in both years and compared to each other in the same group and between groups in the same year. Hypoglycemia and insulin regimens (insulin pump and multiple injections daily) were analyzed in intragroup (t3 vs. t4) and intergroup (t3 and t4) comparisons.

Results: Two hundred and seven participants were included [106 (51.2%) men; median age of 35 (25;47) years]: 144 (69.6%) in g1, 44 (21.3%) in g2 and 19 (9.2%) in g3. HbA1c increased significantly between t4 and t3 (vs. t2 and t1) in g1 (p=0.001), but not in g2 (p=0.077) and g3 (p=0.744). In 2020, HbA1c raised significantly in the analysis "g1 vs. g3" (p=0.004), but not in "g1 vs. g2" (p=0.213) and "g2 vs. g3" (p=0.083). No differences were reported in 2019, along with all the comparisons involving hypoglycemia and insulin regimens.

Conclusions: This study found an overall worsening of GC in participants who returned to higher levels of activity after a total lockdown. This is probably explained by the time spent on T1DM self-care during the lockdown.

Disclosure

D. Ramalho: None. S. Correia: None. L. Almeida: None. H. Alves: None. G. Rocha: None. M. Ferreira: None. M. J. Oliveira: None.
263-OR: Higher Glycemic Threshold for Glucagon Suppression in Impaired Fasting Glucose and Impaired Glucose Tolerance
Authors: KOHLENBERG JACOB D. , LAURENTI MARCELLO C. , EGAN AOIFE M. , COBELLI CLAUDIO , MAN CHIARA DALLA , VELLA ADRIAN
Published: June 2021

Impaired glucagon suppression is an overlooked contributor to the transition of prediabetes to type 2 diabetes. Graded Glucose Infusion (GGI) is a technique used to assess Insulin Secretion Rate (ISR) in response to rising glucose concentrations. We used GGI to examine the relationship of ISR and Glucagon Secretion Rate (GSR) with rising glucose. We studied 32 nondiabetic, weight-stable individuals (54 ± 2 yrs, 29 ± 1 Kg/M2) categorized on the basis of fasting and glucose tolerance status following a 75g OGTT at the time of screening. After an overnight fast, at 07:00 a variable insulin infusion was used to maintain glucose at ~4.4 mmol/L (until 08:30) enabling the subsequent measurement of the glycemic threshold for ISR and GSR. At 09:00 GGI commenced, starting at 1 mg/kg/min and doubling every 60 min until 13:00. GSR and ISR were calculated by nonparametric deconvolution from plasma concentrations of glucagon and c-peptide respectively. β-cell responsivity (Φ) was estimated from the relationship of ISR to glucose. The glycemic threshold for glucagon suppression was higher in subjects with impaired fasting glucose (IFG) than normal fasting glucose (NFG), 10.9 ± 0.8 vs. 8.3 ± 0.5 mmol/L, p<0.01, IFG vs. NFG respectively. This was also the case in subjects with impaired glucose tolerance (IGT) compared to normal glucose tolerance (NGT), 10.3 ± 0.7 vs. 8.5 ± 0.7 mmol/L, p=0.05. Φ did not differ in subjects with IGT vs. NGT (p=0.33) or in subjects with IFG vs. NFG (p=0.48). The glycemic threshold for stimulation of ISR was higher in subjects with IFG than NFG, 5.7 +/- 0.3 vs. 5.0 +/- 0.1 mmol/L, p<0.01, IFG vs. NFG respectively, but no different in subjects with IGT vs. NGT, 5.3 +/- 0.2 vs. 5.0 +/- 0.1 mmol/L, p=0.06, IGT vs. NGT respectively. These data show that in nondiabetic humans, IFG but not IGT is associated with a higher glycemic threshold for insulin secretion, and both IFG and IGT are associated with a higher glycemic threshold for glucagon suppression.

Disclosure

J. D. Kohlenberg: None. M. C. Laurenti: None. A. M. Egan: None. C. Cobelli: None. C. Dalla man: Research Support; Self; Becton, Dickinson and Company, Sanofi-Aventis Deutschland GmbH. A. Vella: Research Support; Self; Novo Nordisk.

Funding

Endocrine Fellows Foundation (DK078646DK116231)
27-LB: Impact of the March–May 2020 Confinement on the Clinical-Biological Profiles of Diabetic Patients Hospitalized in Diabetology
Authors: MAHJOUB FATEN , AMOR NADIA BEN , BERRICHE OLFA , JAMOUSSI HENDA
Published: June 2021

Objective: In Tunisia, a total confinement was imposed from March 20 until May 4, 2020. The aim of our work was to assess the impact of this 2-month confinement on the clinical and biological profile of diabetic patients hospitalized in diabetology.

Patients and Methods: This is a cross-sectional, observational, descriptive study that involved 110 diabetic patients hospitalized in department A of the National Institute of Nutrition and Food Technology of Tunis (Tunisia) from June 1 until June 30, 2020.

Results : The mean age of the patients was 49.72±11.99years with ranges ranging from 16 to 77 years old; 63.6% of patients were female and 73.6% of patients were type 2. The average duration of diabetes was 11.53±8.62years, with extremes ranging from 0to24 years. The mean level of glycated hemoglobin was 12.03±3.97% and the Body-Mass-Index was 29.44kg/m² with extremes ranging from 16.26to40.19kg/m². Weight gain was reported in 73% of patients with an average of 4.77±1.98kg within 2 months of confinement, with extremes ranging from 2to11kg. Two patients (1.8%) were hospitalized for inaugural diabetic ketosis. The others were admitted for an imbalance(81.8%) or an acute decompensation of their diabetes(16.4%). The factors of imbalance or decompensation were: a poor compliance with hygienic-dietetic measures(90.9%); a medication poor compliance(41.8%), more than half of which(54.3%) was due to the inability of the patient to go to the local health center to obtain his medication; lipodystrophies(42.7% of patients on insulin); a stomatological infection(8.2%); an urinary tract infection(4.5%) and an acute coronary syndrome(0.9%).

Conclusions : The diabetic patient is at high risk of a severe form of Covid-19. However, the confinement imposed by the pandemic seems to be one of the factors of diabetes imbalance (in particular by weight gain and poor adherence to therapy). It is therefore essential to strengthen the education and treatment of diabetic patients.

Disclosure

F. Mahjoub: None. N. Ben Amor: None. O. Berriche: None. H. Jamoussi: None.
27-OR: Genome-Wide Association Analysis Identifies Ancestry-Specific Genetic Variation Associated with Medication Response in the Study to Understand the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH)
Authors: LI JOSEPHINE H. , KAUR VARINDERPAL , BRENNER LAURA , MERCADER JOSEP M. , FLOREZ JOSE C.
Published: June 2021

SUGAR-MGH is a pharmacogenetic resource for characterizing genetic influences on pharmacological perturbations relevant to type 2 diabetes (T2D). 1,000 participants who were naïve to T2D treatment received 5 mg glipizide, followed by 4 doses of 500 mg metformin and a 75-g oral glucose tolerance test (OGTT) a week later. Glucose and insulin were measured at pre-specified endpoints after glipizide and during the OGTT. Incretin levels were measured in a subset. We calculated physiologic endpoints reflecting insulin secretion, insulin sensitivity, and incretin secretion. The mean age was 47 years, 54% were women, >35% were non-white, and the mean BMI was 30.2 kg/m2. 890 participants underwent genome-wide genotyping using the Illumina Multi-Ethnic Genotyping Array, and high-quality imputation was performed with the TOPMed reference panel. Multiple linear regression using an additive model tested for association between genetic variants and endpoints. We identified 21 genome-wide significant variants, of which 3 met experiment-wide significance (P<8.3×10-9 for 2 drugs × 3 physiological hypotheses tested). The most significant association was between an African ancestry-specific variant (minor allele frequency=0.026) at rs149403252 and lower fasting glucose following metformin, adjusted for baseline glucose (P=1.9×10-9). We tested the influence of 429 known T2D-associated variants and found that the protective C allele of rs703972 near ZMIZ1 was associated with increased secretion of active GLP-1 in response to metformin (P=1.6×10-5), suggesting that an enhanced incretin response may be a mechanism by which this variant decreases T2D risk. We illustrate that a genome-wide approach in a multi-ethnic human perturbation study can uncover new variation associated with drug response and provide insight into mechanisms of action of known T2D genetic variation.

Disclosure

J. H. Li: None. V. Kaur: None. L. Brenner: Research Support; Self; Apple. J. M. Mercader: None. J. C. Florez: Consultant; Self; Goldfinch Bio, Inc., Other Relationship; Self; Novo Nordisk.

Funding

National Institutes of Health (R01DK088214, R03DK077675, P30DK036836, M01RR01066, 1UL1RR025758-04, 8UL1TR000170-05, T32DK007028)
277-OR: Use of Noncarbohydrate Fuels Is Associated with Materno-Fetal Complications in Type 1 Diabetes Pregnancy: Metabolomics Analysis of the CONCEPTT Trial
Authors: MEEK CLAIRE L. , STEWART ZOE , FURSE SAMUEL , YAMAMOTO JENNIFER M. , FEIG DENICE , KOULMAN ALBERT , MURPHY HELEN R.
Published: June 2021

Aims: We assessed metabolomic signatures in maternal and cord blood associated with suboptimal outcomes in the continuous glucose monitoring in women with type 1 diabetes in pregnancy trial (CONCEPTT).

Methods: Serum samples from 162 mothers (12, 24 and 34 weeks’ gestation) and 93 cord blood samples were analysed for 1049 metabolites and 1041 lipids using ultra-performance liquid chromatography-tandem mass spectroscopy. We used adjusted and unadjusted logistic regression of metabolomic variables using adjudicated outcomes: extremely-large-for-gestational-age (ELGA; >97.5th centile), pre-eclampsia and neonatal hypoglycaemia with modified Bonferroni false discovery rate p≤0.001.

Results: All materno-fetal complications studied were associated with reliance on non-carbohydrate sources of fuel. Lipids through beta oxidation were the main fuel source in ELGA (24 and 34 weeks), neonatal hypoglycaemia (12 weeks only) and pre-eclampsia (12 and 24 weeks). Marked protein catabolism was evident in neonatal hypoglycaemia (34 weeks) and pre-eclampsia (24 and 34 weeks). Cord blood in ELGA infants showed evidence of simultaneous beta oxidation and de novo lipogenesis, a biologically futile cycle of creating and destroying lipids, which consumes excess energy and substrate. Cord blood from infants with neonatal hypoglycaemia showed evidence of pronounced protein catabolism providing glucogenic amino acids for gluconeogenesis.

Conclusions: Reliance on lipid or protein sources for fuel was associated with ELGA, neonatal hypoglycaemia and pre-eclampsia. Carbohydrate metabolism was insufficient to meet cellular energy demands, possibly due to insufficient insulin, insufficient dietary carbohydrate or both. Improving outcomes in type 1 diabetes pregnancy may require greater focus on normalising carbohydrate metabolism through optimal carbohydrate intake and matched insulin dosing.

Disclosure

C. L. Meek: None. Z. Stewart: None. S. Furse: None. J. M. Yamamoto: None. D. Feig: Advisory Panel; Self; Novo Nordisk. A. Koulman: None. H. R. Murphy: None.

Funding

JDRF (17/2011/533, 80/2010/585); Diabetes UK (DUK-HKF 17/0005712, DUK-PG 17/0005633.BBSRC BB/M027252/1)
28-OR: Identification of Ancestry-Specific Alleles in a Genome-Wide Association Study (GWAS) for Metformin (MET) Response in the Diabetes Prevention Program (DPP)
Authors: LI JOSEPHINE H. , PERRY JAMES A. , JABLONSKI KATHLEEN A. , CHEN LING , SRINIVASAN SHYLAJA , TODD JENNIFER N. , HARDEN MAEGAN , MERCADER JOSEP M. , FRANKS PAUL W. , HANSON ROBERT L. , KAHN STEVEN E. , KNOWLER WILLIAM C. , POLLIN TONI I. , FLOREZ JOSE C. , GROUP DPP RESEARCH
Published: June 2021

Genome-wide significant (GWS) loci for glycemic response to MET in type 2 diabetes (T2D) reported elsewhere have not replicated in the DPP. Thus, to assess whether pharmacogenetic interactions may differ in impaired glucose tolerance (IGT), we conducted a GWAS in the DPP for MET response, defined by diabetes incidence and change in quantitative traits (fasting glucose, 2-hour glucose on oral glucose tolerance test, hemoglobin A1c [HbA1c], fasting insulin, insulin sensitivity index, and weight). Samples were genotyped on the Illumina HumanCore Exome array and imputed on the 1000 Genomes Phase3 panel. Cox proportional hazards models tested associations with diabetes incidence in MET (n=876) and placebo (PBO, n=887) arms. Multiple linear regression using an additive model evaluated for association with 1-year change in quantitative traits, adjusted for baseline trait, age, sex, and 10 ancestry principal components. We tested for gene-by-environment (G×E) interaction between MET and PBO. Results were filtered to minor allele frequency (MAF) >1% and imputation score >0.7. We identified 3 GWS variants after correcting for correlated traits (P<9×10-9). In MET, a variant near ENOSF1 was associated with an increase in % HbA1c (rs144322333, β=0.39 [95% CI 0.28, 0.50], P=2.8×10-12) and was mainly found in African ancestry participants (MAFAFR=0.07, MAFEUR=0.002). A variant near OMSR was associated with greater weight loss (kg) in MET (rs145591055, β=-7.55 [95% CI -9.88, -5.22], P=3.2×10-10) and found in 10% of Native Americans. Neither variant had an impact in PBO; the interaction with treatment arm was significant for rs144322333 (G×E P=1.4×10-6) and rs145591055 (G×E P=1.5×10-5). No GWS associations emerged for diabetes incidence.

In summary, a GWAS for MET response in participants with IGT revealed novel associations that require validation in ancestry-specific populations and may have implications for tailored therapy.

Disclosure

J. H. Li: None. R. L. Hanson: None. S. E. Kahn: Advisory Panel; Self; Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk, Pfizer Inc. W. C. Knowler: None. T. I. Pollin: None. J. C. Florez: Consultant; Self; Goldfinch Bio, Inc., Other Relationship; Self; Novo Nordisk. D. Research group: None. J. A. Perry: None. K. A. Jablonski: None. L. Chen: None. S. Srinivasan: None. J. N. Todd: None. M. Harden: None. J. M. Mercader: None. P. W. Franks: Advisory Panel; Self; Zoe Global Limited, Consultant; Self; Eli Lilly and Company, Novo Nordisk.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (U01DK048489)