bluuebunny/crossref_metadata_2025 huggingface dataset:
157-OR: High-Fat–Diet Feeding Disrupts Thermal Responsiveness of AgRP Neurons
Authors: DEEM JENNIFER D. , DOAN TAMMY P. , PHAN BAO ANH N. , OGIMOTO KAYOKO , HU SHANNON J.W. , WU BRANDON , SCHWARTZ MICHAEL W. , MORTON GREGORY J.
Published: May 2022

To defend energy homeostasis in the cold requires energy expenditure (to support thermogenesis) and energy intake increase, enabling core temperature to be maintained with no change to body fat stores. When acutely housed at a mild cold (14°C) , mice increase both food intake and heat production rapidly (∼minutes) , and these responses occur in parallel. We hypothesized a role for Agouti-related peptide (AgRP) neurons in this response and find their activity is regulated by thermal sensory input, and they increase activity, measured by Fos induction and fiber photometry, upon cold sensation, and reduce activity as sensed temperatures rise. By inhibiting AgRP neurons during acute cold exposure, we also find this increase in AgRP neuron activity is required for the hyperphagic response to cold. Recent evidence found high-fat diet (HFD) feeding reduced AgRP neuron responsiveness to gastric hormones and standard chow diet presentation, and we hypothesized that their response to thermal input might also be blunted. We find that although 12-week HFD-fed mice exhibit intact thermogenic responses to cold and defend a normal core body temperature, they fail to increase energy intake and consequently experience weight loss not observed in chow-fed controls. This uncoupling of energy intake from energy expenditure is present even after a shorter, 2-week exposure to HFD-feeding, implying a role for diet separate from obesity in the phenotype. Using Agrp-Cre/GFP marker mice, we find acute cold exposure rapidly induces Fos in chow-fed mice, but this response is lacking in HFD-fed mice. This effect correlates with a failure to increase hypothalamic Agrp mRNA even after five days of mild cold exposure. Using photometry to measure AgRP neuron calcium activity, we find activity changes associated with thermal input, both cold and warm, are blunted with HFD feeding. Further testing will determine exactly how the food intake response to cold has become uncoupled from other thermoregulatory responses across the development of obesity.

Disclosure

J.D.Deem: None. T.P.Doan: None. B.N.Phan: None. K.Ogimoto: None. S.J.W.Hu: None. B.Wu: None. M.W.Schwartz: None. G.J.Morton: Research Support; Novo Nordisk A/S.

Funding

American Diabetes Association (1-19-PDF-103) ; NIDDK (K01 DK126793) , NIDDK (DK089056) , NIDDK (DK124238) , NIDDK (DK035816) , NIDA (P30 DA048736) , NIDDK (DK035816) , NIDDK (DK17047)
158-LB: Effect of Vitamin D Replacement on Glycemic Status and Pregnancy Outcomes in Vitamin D–Deficient Subjects with Gestational Diabetes Mellitus
Authors: BAIDYA ARJUN , PATHAK YASHASWI , SENGUPTA NILANJAN , KUMAR SAHANA PRANAB , GOSWAMI SOUMIK , TARENIA SILIMA , BANERJEE ABHIRUP , CHATTOPADHAYAY MOUNAM , HATHI DEEP , GAIKWAD PRASHANT MANOHAR , DAS NILADRI
Published: May 2022

Aims: To study the effect of Vitamin D replacement on glycaemic control and pregnancy outcomes in Gestational Diabetes Mellitus patient with Vitamin D deficiency.

Methods: In this prospective, open-label interventional study 60 GDM subjects with Vitamin D deficiency were divided into 2 groups of 30 each, and the intervention group received 60,000 IU of cholecalciferol weekly for 6 weeks and then monthly for the duration of pregnancy. while the control group did not. Vitamin D status was re-assessed at 32 weeks of gestation for both groups. The glycaemic status was assessed using fasting plasma glucose and 1-hour and 2-hour postprandial glucose at 30 weeks of gestation and at time of delivery. Feto-maternal outcomes: Time of delivery (weeks of gestation) , method of delivery, pre-eclampsia, still-birth, neonatal hypoglycaemia, neonatal jaundice, birth weight, head circumference of the baby, APGAR score at 5 minutes in both groups were also assessed.

Results: In the intervention group 87% (26 out of 30) of subjects had become vitamin D sufficient. None of the subjects in the control group had become vitamin D sufficient. Fasting Plasma Glucose was significantly lower in the intervention group as compared to the control group) at 30 weeks of gestation (99.57±18.12 vs. 107.90±17.53 mg/dl; p=0.039) and at time of delivery (98.53±15.41 vs. 104.47±18.71mg/dl; p=0.044) . Both 1 hour and 2-hour postprandial plasma glucose (136.81±20.29 vs. 152.58±16.76; p=0.004 and 118±22.10 vs. 132.64±18.48 mg/dl; p=0.017 respectively) values were also significantly lower in the intervention group at the time of delivery. Birth weight was significantly lower in the control group as compared to the intervention group (2348.13±388.965 vs. 2778.67±270.288 gm; p=0.034) . All other neonatal parameters were similar in the two groups. Two subjects in the control group had still-births.

Conclusion: Correction of Vitamin D deficiency in GDM subjects may result in better control of their plasma glucose levels. Low Vitamin D levels in GDM subjects may be associated with lower birth weight.

Disclosure

A. Baidya: None. P. Gaikwad: None. N. Das: None. Y. Pathak: None. N. Sengupta: None. P. Sahana: None. S. Goswami: None. S. Tarenia: None. A. Banerjee: None. M. Chattopadhayay: None. D. Hathi: None.
161-LB: Intensive Blood Pressure Lowering and the Risk of New-Onset Diabetes in Patients with Hypertension—A Post Hoc Analysis of the STEP Randomized Trial
Authors: YANG RUIXUE , CAI JUN
Published: May 2022

Background: The STEP (Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients) trial reported the cardiovascular benefit of intensive blood pressure (BP) control. The objective of this analysis was to evaluate the effect of intensive BP lowering on the new-onset diabetes incidence.

Methods: The patients of STEP who had a baseline fasting serum glucose (FSG) <7.0 mmol/L without diabetes history and hypoglycemic medication use were included in the main analysis. The primary outcome was the new-onset diabetes, defined as the time to first occurrence of a FSG ≥7.0 mmol/l. The secondary outcome was the new-onset impaired fasting glucose (IFG: FSG 5.6-6.9 mmol/l) among patients with normoglycemia. The competing risk proportional hazards regression model was used in the main analysis.

Results: Over a median follow-up of 3.42 years, 273 (9.6%) in the intensive group and 262 (9.5%) in the standard group developed new-onset diabetes (adjusted HR 1.03; 95% CI 0.87-1.22) . The adjusted hazard ratio for the secondary outcome was 1.05 (95% CI 0.92-1.19) . The mean of the highest FSG was 5.82 mmol/l for intensive group and 5.84 mmol/l for standard group. The sensitivity analyses showed no significant difference with respect to the effect of the treatment arms.

Conclusions: Intensive BP lowering (target, 110 to <130 mmHg) , as compared with standard BP lowering (target, 130 to <150 mmHg) , did not increase the risk of new-onset diabetes and IFG in patients with hypertension.

Disclosure

R. Yang: None. J. Cai: None.
164-LB: Association of Ceramide and Sphingolipid Species with Incident Prediabetes among Offspring of Parents with Type 2 Diabetes
Authors: MANDAL NAWAJES , WAN JIM Y. , STENTZ FRANKIE B. , DAGOGO-JACK SAMUEL
Published: May 2022

Objective: Sphingolipids (SPL) have been associated with type 2 diabetes (T2D) risk. Here, we examined plasma SPL profiles in relation to prediabetes risk in Black and White adults.

Methods: Assessments included OGTT, insulin sensitivity (Si-clamp) and insulin secretion (AIRg) . Baseline plasma levels of 54 SPL species (ceramides {CER}, monohexosyl ceramides, sphingomyelins {SM}, and sphingosine {SO}) were assayed using LC/mass spectrometry. The initially normoglycemic adult with parental T2D were followed for 5y for the occurrence of prediabetes.

Results: The subjects' mean age was 48.1 + 8.69 y, BMI 30.1 + 5.78 kg/m2, fasting plasma glucose (FPG) 92.7 + 5.84 mg/dl and 2-hrPG 121 + 23.3 mg/dl. We analyzed SPL data from 70 progressors to prediabetes (P) and 70 nonprogressors (NP) . After full adjustments, the levels of SO and saturated (Sat) SPLs (C26:0 CER, C26:0 SM) were higher, and unsaturated (Unsat) SPLs (C18:1 CER; C18:1 SM) and SM% of SPL were lower in P vs.NP (Table 1) . CER and SM levels correlated with Si-clamp and AIRg. The Sat/Unsat SPL ratios were higher in P vs. NP. The C18:0/C18:1 CER (OR 1.22, 95%CI [1.07 - 1.39], P=0.0028) and C26:0/C26:1 SM (OR 2.65, 95%CI [1.39 - 5.06], P=0.0032) ratios predicted prediabetes risk after adjusting for age, race, sex, BMI, FPG and 2hPG.

Conclusion: The Sat/Unsat ratios of CER and SM C18 and C26 predicted incident prediabetes in a diverse cohort, and may be potential biomarkers of prediabetes risk.

Disclosure

N. Mandal: None. J. Y. Wan: None. F. B. Stentz: None. S. Dagogo-jack: Consultant; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., Sanofi.

Funding

National Institutes of Health (5R01DK128129)
164-OR: Metoclopramide Restores the Counterregulatory Response to Hypoglycemia in Rodents
Authors: DEVORE MICAH H. , SHARMA SUNNY , FISHER SIMON
Published: May 2022

To test the hypothesis that metoclopramide (a dopamine antagonist) may restore hypoglycemic counterregulation, 10-week old rats underwent recurrent (insulin-induced) hypoglycemia (RH) to induce a blunted sympathoadrenal response. RH rats were treated with vehicle or metoclopramide (RH+MET: 3 mg/kg IP) . A third control group did not undergo recurrent hypoglycemia (RS: recurrent saline) . MET was administered either during RH phase (concurrent protocol) or after RH (post-induction protocol) . All rats (n=7-14/group) underwent a hyperinsulinemic (50mU/kg/min) hypoglycemic (45±5 mg/dl) clamp. In the concurrent protocol, epinephrine response to hypoglycemia in RS (1434±275 pg/ml) was blunted in RH (460±1pg/ml, p<0.vs. RS) and increased with MET (1072±141 pg/ml, p<0.vs. RH) . In the post-induction protocol, epinephrine in RS (1949±413 pg/ml) was again blunted in RH (581±199 pg/ml, p<0.vs. RS) and increased with MET (1460±202 pg/ml, P<0.vs. RH) .

In summary, 1) metoclopramide prevented the development of an impaired sympathoadrenal response to hypoglycemia, and 2) in rodents that had an impaired response to hypoglycemia, subsequent metoclopramide treatment restored the sympathoadrenal response.

In conclusion, 1) dopaminergic signaling plays a role in the development of impaired counterregulation, and 2) post hoc treatment with metoclopramide improves the sympathoadrenal response to hypoglycemia.

Disclosure

M.H.Devore: None. S.Sharma: None. S.Fisher: None.

Funding

NIH R01DK118082
167-OR: Inequities in Glycemic Outcomes for Patients with Type 1 Diabetes: Six-Year (2016–2021) Longitudinal Follow-Up by Race and Ethnicity of 36,390 Patients in the T1Dx-QI Collaborative
Authors: EBEKOZIEN OSAGIE , NOOR NUDRAT , KAMBOJ MANMOHAN K. , ODUGBESAN ORI , MAJIDI SHIDEH , HOPKINS RACHEL , DEWIT EMILY L. , IZQUIERDO ROBERTO , AGARWAL SHIVANI , ALBANESE-O'NEILL ANASTASIA , MAAHS DAVID M. , CLEMENTS MARK A. , COLLABORATIVE T1DX-QI
Published: May 2022

Introduction: The multi-center T1D Exchange QI Collaborative (T1DX-QI) is a learning health network sharing de-identified electronic medical record data for type 1 diabetes (T1D) care improvement.

Objectives: To investigate trends in racial and ethnic inequities in glycemic outcomes in children and adults with T1D from 2016 to 2021.

Methods: Children and adults with T1D for at least 6 months in participating T1DX-QI centers with data available from 2016 to 2021 were included. Temporal trends by race and ethnicity in HbA1c were analyzed using regression models. Age, gender, duration of diabetes, insurance type, were adjusted as covariates.

Results: Figure 1, among 36,390 children and adults with T1D, HbA1c outcomes for Non-Hispanic White (NHW) patients decreased from 8.5% in 2016 to 8.2% in 2021 (p-0.001) , remained stable across the six years for Hispanic patients (8.9%) and Asian (8.4%) but increased for Non-Hispanic Black (NHB) from 9.6% in 2016 to 9.9% in 2021 (p-0.001) . The use of Insulin Pumps and CGM increased significantly among all groups.

Conclusions: Six years of longitudinal follow-up revealed lower HbA1c over time in NHW patients but higher HbA1c for NHB patients despite adjusting for multiple confounders. It is critical to address the root causes of inequities in NHB and patients of other racial minorities with T1D.

Disclosure

O.Ebekozien: None. A.Albanese-o'neill: Consultant; Association of Diabetes Care & Education Specialists, Provention Bio, Inc., Other Relationship; Insulet Corporation, Tandem Diabetes Care, Inc. D.M.Maahs: Advisory Panel; Abbott Diabetes, Eli Lilly and Company, Medtronic, Novo Nordisk, Sanofi, Consultant; Aditx Therapeutics, Inc., Biospex. M.A.Clements: Consultant; Glooko, Inc., Research Support; Abbott Diabetes, Dexcom, Inc. T1dx-qi collaborative: n/a. N.Noor: None. M.K.Kamboj: None. O.Odugbesan: n/a. S.Majidi: None. R.Hopkins: None. E.L.Dewit: None. R.Izquierdo: None. S.Agarwal: Advisory Panel; Medtronic, Consultant; Beta Bionics, Inc.

Funding

Helmsley Charitable Trust
168-OR: Patterns of Continuous Glucose Monitoring Utilization in Adults with Type 1 Diabetes, 2016–2019
Authors: LEE KATHERINE E. , FOWLKES JOHN , LACY MARY E.
Published: May 2022

Background: Continuous glucose monitoring (CGM) improves diabetes control by reducing HbA1c and decreasing rates of hypoglycemia. Despite clinical benefits and clear guidelines from the American Diabetes Association, <20% of patients with T1DM use CGM. Studies report disparities in CGM among youth with T1D by race/ethnicity, socioeconomic status, and region, but, insight into patterns of CGM utilization in adults with T1D is limited.

Methods: We evaluate CGM utilization among individuals with T1D age ≥18 using Truven MarketScan and Medicare Supplementary databases from 1/1/2016-12/31/2019. CGM utilization was determined using CPT, NDC and HCPCS codes. Individuals with >365 days of continuous eligibility were followed from their first diabetes-related diagnosis code until: end of the study period, >120 day gap in coverage, or CGM claim. CGM utilization was analyzed by patient demographics (age, sex, region, employment status) , and clinical characteristics (insulin pump, diabetes complications) .

Results: A total of 228,846 enrollees with T1D were included. Average (SD) age at baseline was 52.2 (16.8) ; 47% of the sample was female, 26% were on an insulin pump and the regional distribution of was: 26% North Central, 21% Northeast, 41% South, 11% West. Overall, 36.5% (n=60,034) of beneficiaries had a claim for CGM. Rates of CGM utilization ranged from 59% in those aged 18-25 to 16% in those 65+ (p<0.0001) , 38% in women vs. 35% in men (p<0.0001) , and 34% in North Central and Northeastern US vs. 40.2% in West (p<0.0001) .

Conclusions: We found differential utilization of CGM by sex, age group and geographic region. Those aged 18-25 were 3 times more likely to utilize CGM compared to those 65+, a subgroup at high risk for severe hypoglycemic events and hypoglycemia unawareness. CGM is a highly effective tool for improving glucose control and preventing acute hypoglycemia, yet only 1/3 of the population sampled had evidence of use underscoring the need to understand barriers to utilization.

Disclosure

K.E.Lee: None. J.Fowlkes: None. M.E.Lacy: None.

Funding

National Institutes of Health (UL1TR000117, UL1TR001998, KL2TR001996)
170-LB: Identifying Atypical Diabetes Using i2b2 Algorithms in Electronic Health Records
Authors: KIKANI NUPUR , MONTES GRACIELA , GABA RUCHI , LIAO GLORIA , TOSUR MUSTAFA , REDONDO MARIA J. , BALASUBRAMANYAM ASHOK
Published: May 2022

Investigating atypical forms of diabetes (other than types 1 or 2, monogenic or secondary) is the focus of research in the Rare and Atypical Diabetes Network (RADIANT) . It is difficult to identify persons with atypical diabetes using standard electronic health record (EHR) queries because there are no specific ICD codes for these phenotypes and wide range of clinical features. We aimed to develop an algorithm to identify individuals with searchable characteristics of atypical diabetes within the Baylor Medicine EHR using Informatics for Integrating Biology at the Bedside (i2b2) . I2b2 enables integration, standardization, and analysis of heterogenous quantitative and qualitative data from healthcare and research databases. Our i2b2 algorithm intended to look for patients coded as type 2 diabetes (T2D) but were very lean and lacked clinical features suggestive of systemic insulin resistance. We included new patient visits with ICD codes for T2D in the past year but excluded those with BMI >20 kg/m2 and triglycerides >100 mg/dL, or ICD codes for hypertension and hyperlipidemia. Next, we excluded patients with secondary causes of diabetes (cystic fibrosis, acromegaly, Cushing's syndrome, chronic/acute pancreatitis or presence of islet autoantibodies (GAD65Ab, IA2Ab) . The algorithm identified 133 persons from a total EHR population of 3,685,797. Manual chart review confirmed that 18 patients (13.5%) met RADIANT criteria for atypical diabetes, while information was missing in the EHR to fully classify 8 patients (6%) and 1 patient was deceased (0.8%) . Those who fully met criteria for atypical diabetes had the following characteristics: 72% female, median BMI at diagnosis 19.8 kg/m2, median age at diagnosis 29 y, 75% with history of diabetic ketoacidosis and 19.5% currently on insulin. Algorithms built on data platforms such as i2b2 may be helpful in identifying patients who should be evaluated for atypical diabetes within standard EHR databases. They could optimize recruitment for research, identify disease trends and permit improved classification of diabetes subgroups.

Disclosure

N. Kikani: None. G. Montes: None. R. Gaba: None. G. Liao: None. M. Tosur: Advisory Panel; Provention Bio, Inc. M. J. Redondo: Advisory Panel; Provention Bio, Inc. A. Balasubramanyam: None.

Funding

The RADIANT Study is funded by U54 DK118638 and U54 DK118612 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
172-LB: Early-Onset Type 2 Diabetes Is Associated with Higher A1C and Glycemic Variability in a Cohort of Veterans followed Prospectively
Authors: AVRAMOVIC SANJA , SCHWARTZ MARK D. , ENQUOBAHRIE DANIEL , BOYKO EDWARD J. , WANDER PANDORA
Published: May 2022

Introduction: Early-onset type 2 diabetes in adults (eoT2D; T2D diagnosed between 18 and 39 years) is increasingly prevalent and is associated with high rates of diabetic complications. We hypothesized that eoT2D would be associated with adverse glycemic parameters (e.g., higher A1c and glycemic variability) .

Methods: We used data from the Veterans Administration Diabetes Risk Cohort, a dynamic cohort of all U.S. Veterans enrolled in the Veterans Health Administration since 1/1/08 who were free from diabetes at enrollment. Among participants who developed T2D (n=936,596) , we fit linear regression models examining associations of age at detection with A1c-based measures of glycemia.

Results: A ten-year younger age at detection was associated with a 0.24% higher A1c at T2D detection, a 0.29% higher mean A1c, a 0.02% higher A1c coefficient of variation (CV) , and a 0.02% higher A1c average real variability (ARV) . Compared to T2D with onset after 40 years, eoT2D was associated with a 0.73% higher A1c at T2D detection, a 0.82% higher mean A1c, a 0.05% higher CV, and a 0.04% higher ARV (all p<0.0001, Table 1) .

Conclusions: eoT2D is associated with higher A1c and glycemic variability. Further study of glycemic trajectories, modifiable risk factors, and clinical course in this T2D subgroup are needed.

Disclosure

S. Avramovic: None. M. D. Schwartz: None. D. Enquobahrie: None. E. J. Boyko: None. P. Wander: None.
176-LB: Metformin Use among Hospitalized Patients with Diabetes and COVID-19—Clinical Characteristics and Outcomes from a Multiracial, Multiethnic Urban Cohort
Authors: MIAO EMILY , ZHANG KALEENA , LIU JIANYOU , LIN JUAN , GEORGE CLAUDENE
Published: May 2022

Background: Diabetes mellitus (DM) confers a two-fold increased risk of death from COVID-19 and overall poorer prognosis compared to the general population. Metformin is a widely used first-line antidiabetic agent with anti-inflammatory and immunomodulatory effects. Several studies report reduced COVID-19-related mortality in patients with DM on metformin. Few studies have corroborated these findings within a multiracial, multiethnic population.

Methods: This was a retrospective cohort study of patients with DM admitted with COVID-19 to 1 of 3 urban academic hospitals from 1/1/20 to 5/7/20. We compared in-hospital mortality and length of stay (LOS) in COVID-19 patients with diabetes on metformin compared to those not on metformin. Patient demographic and clinical characteristics were summarized and compared between both groups. Logistic regression and linear regression analysis were applied to study the association between metformin treatment and in-hospital mortality and LOS, respectively.

Results: A total of 4462 patients were identified. Overall, 46.9% were female, with a mean age of 64.4 years; 41.3% were Black and 41.5% Hispanic. There were 1021 in the metformin group and 3441 in the non-metformin group. The prevalence of hypertension (58.2% vs.37.5%, P<.0001) and coronary artery disease (13.4% vs. 6.7%, P<0.0001) was higher in the metformin group compared to the non-metformin group. BMI (30.5 vs. 29.4) , HbA1c (8.2 vs. 6.5) creatinine (1.6 vs. 2.1) , and mean number of antidiabetic agents (1.2 vs. 0.22) were also significantly higher in the metformin group. The odds of death (OR 1.0, 95% CI 0.8-1.3; p=0.900) and mean LOS (p= 0.486) were not significantly different in the metformin vs. non-metformin group, after adjusting for confounding variables.

Conclusion: There was no significant difference in in-hospital mortality and LOS in the metformin vs. non-metformin group. The metformin group had a significantly higher comorbidity burden, as well as higher BMI, mean HbA1c, and creatinine. Further prospective studies are needed.

Disclosure

E. Miao: None. K. Zhang: None. J. Liu: None. J. Lin: None. C. George: None.
177-LB: Obesity Paradox Related to Severe COVID in Diabetes
Authors: KAZLAUSKAITE RASA , DESAI PANKAJA , JACKSON-MORRIS ANGELA M. , NGONGO CARRIE , CUPLINSKAS NERIJA , NUGENT RACHEL
Published: May 2022

The “obesity paradox” refers to an association between obesity and better outcomes (contrary to expected worse outcomes) . For example, lower mortality has been observed in diabetes patients with obesity compared to normal/overweight. An analytical cohort of n=5712 patients with diabetes was selected from the RUSH COVID Registry and electronic medical records data, spanning 21 months. Sociodemographic and diabetes characteristics were obtained on or before COVID diagnosis. Severe COVID was defined as fatal or requiring hospitalization. After excluding 23 cases without BMI, univariate and multivariate logistic regression with restricted cubic spline models were conducted to evaluate the association of BMI with severe COVID after adjustment for age, sex, race/ethnicity. The resulting diverse cohort included 37.6% Latino, 37.5% Black, 19.5% White, and 5.3% other; 53.7% were women. Type 1 diabetes was identified in n=140, Type 2 diabetes in n=2730, and other/hybrid diabetes in n=2820. After adjustment for sex, age, race/ethnicity, diabetes type, and A1c a U-shaped relationship was observed between BMI and severe COVID with a nadir at BMI=30-45 kg/m2 (see figure) . A similar U-shaped relationship was seen in the association of fatal COVID in British diabetes patients with a nadir at BMI=25-29 kg/m2. The proposed explanation for the “obesity paradox” may be related to unintentional weight loss in diabetes patients with multimorbidity.

Disclosure

R. Kazlauskaite: None. P. Desai: None. A. M. Jackson-morris: None. C. Ngongo: None. N. Cuplinskas: None. R. Nugent: Consultant; AstraZeneca, Other Relationship; Novo Nordisk A/S, Speaker's Bureau; Abbott Diagnostics.

Funding

RTI International, and Rush University (R3 pilot grant 0272101.001.001)
177-OR: Sodium–Glucose Cotransporter-2 Inhibitors and the Risk of Incident Atrial Fibrillation in Older Adults with Type 2 Diabetes
Authors: ZHUO MIN , PAIK JULIE M. , WEXLER DEBORAH J. , EVERETT BRENDAN M. , D'ANDREA ELVIRA , GLYNN ROBERT , KIM SEOYOUNG C. , PATORNO ELISABETTA
Published: May 2022

The role of SGLT-2i in the primary prevention of atrial fibrillation (AF) remains unclear from clinical trials. We assessed the association of SGLT-2i use and incident AF in routine clinical practice. Using Medicare claims data 2013-2018, we identified patients with type 2 diabetes (T2D) and aged ≥66 years with no AF history (i.e., no diagnosis, procedure or medication codes suggestive of underlying AF at baseline) initiating an SGLT-2i or a comparator (a DPP-4i or a GLP-1RA) , in two pairwise comparisons (74,868 and 80,475 1:1 propensity score-matched pairs, respectively) . The primary outcome was AF hospitalization. Secondary outcomes were AF diagnosis in any care setting and AF treated with medications. We calculated hazard ratios (HRs) and rate differences (RDs, per 1000 patient-year) , in the matched groups, well-balanced across 138 baseline covariates. Over a median follow-up of approximately 6 months, the risk of AF hospitalization was lower in the SGLT-2i group than the DPP-4i group (HR, 0.82 [95%CI, 0.76-0.89]; RD, -3.7 [95%CI, -5.2, -2.2]) or the GLP-1RA group (HR, 0.90 [95%CI, 0.83-0.98]; RD, -1.8 [95%CI, -3.2, -0.3]) (Table) . Findings for secondary outcomes were consistent with the primary outcome. In routine care, SGLT-2i use was associated with a reduction in the risk of incident AF, compared to DPP-4i or GLP-1RA among older patients with T2D.

Disclosure

M.Zhuo: None. J.M.Paik: None. D.J.Wexler: Other Relationship; Elsevier, Novo Nordisk, UpToDate. B.M.Everett: Consultant; Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc., Lilly, Provention Bio, Inc., UpToDate, Other Relationship; American Heart Association, Research Support; Novo Nordisk. E.D'andrea: None. R.Glynn: None. S.C.Kim: Research Support; AbbVie Inc., Bristol-Myers Squibb Company, Pfizer Inc., Roche Pharmaceuticals. E.Patorno: Research Support; Boehringer Ingelheim International GmbH, National Institutes of Health, Patient-Centered Outcomes Research Institute.
184-OR: Antigen-Presenting Cells Can Generate Hybrid Peptides Identified in Type 1 Diabetes
Authors: KHOKHAR SHAZAD A. , LIU MI , GAGLIA JASON L.
Published: May 2022

Type 1 Diabetes (T1D) is an autoimmune disease characterized by selective loss of pancreatic β-cells. Aberrant reactivity to insulin and insulin precursor peptides has long been considered important in the pathogenesis of T1D. Recently, T cells recognizing hybrid insulin peptides (HIPs) have been described, first in a rodent model and later in human T1D. A HIP is a CD4 T-cell epitope that is formed by the post-translational fusion of two peptide fragments with at least one of the peptide fragments derived from insulin or a precursor. HIP formation can occur intra- or intermolecularly. The role of these HIPs in the pathogenesis of T1D remains unclear. Others have proposed that HIPs are formed in β-cells during crinophagy of secretory granules. As ultrastructural studies have demonstrated that β-cells can transfer secretory vesicles to local antigen presenting cells (APCs) , we hypothesized that APCs could similarly generate HIPs via protease mediated transpeptidation. To test this, we manufactured peptide-containing nanocarriers mimicking β-cell secretory vesicles to transfer selected peptides to APCs in both mouse and human in vitro systems utilizing donor APCs and CD4 TCR transgenic T cells or a CD4 transductant reporter cells respectively. Here, we demonstrate the subsets of APCs which are capable of intramolecular and intermolecular HIP formation. We further demonstrate that this formation can be blocked by proteosome inhibition. Our study identifies a novel mechanism for the generation of HIPs recognized in T1D.

Disclosure

S.A.Khokhar: None. M.Liu: None. J.L.Gaglia: Advisory Panel; Dompé, Regeneron Pharmaceuticals Inc., Consultant; Vertex Pharmaceuticals Incorporated, Research Support; Avotres Inc., Dompé, Janssen Research & Development, LLC, Provention Bio, Inc., Stock/Shareholder; Vertex Pharmaceuticals Incorporated.

Funding

National Institutes of Health 5P30DK036836JDRF 5-ECR-2016-186-A-N
186-LB: Relationship of the Diagnosis of Diabetes Mellitus (DM) and Hyperglycemia without DM Diagnosis at Hospital Admission with the Evolution of Patients Hospitalized for COVID-19 in a Private Hospital Center in Asunción-Paraguay
Authors: CANATA MARIA G. , LOGWIN SERGIO A. , BUENO COLMAN ELVIO D. , BENITEZ ALDO , FRETES ARIEL J. , BRUNSTEIN DIEZ PEREZ GERARDO , BORDON CLAUDIA , JIMENEZ JORGE T. , PALACIOS MAFALDA
Published: May 2022

Aim: To analyze the relationship between diagnosis of DM, Hyperglycemia of hospital admission and evolution of patients hospitalized for COVID-19 in the Sanatorium “Las Lomas” Asunción, Paraguay. Materials and methods: Observational, analytical, case-control, retrospective design. Total population: 304 patients. Study period: September 2020 to March 2021. Definitions: Controls (Group 1) : Demographically similar patients without diagnosis of DM or Hyperglycemia at hospital admission. Non-probabilistic sampling, consecutive cases.

Cases: adult patients ≥18 years, both sexes, hospitalized for COVID-19 with diagnosis of DM (Group 2) or Hyperglycemia at admission without prior diagnosis of DM (Group 3) Admission hyperglycemia was considered 140 mg/dl.

Results: Of the 304 patients selected: 100 were from Group 1 (G1) , 102 from Group 2 (G2) and 102 from Group 3 (G3) . The length of hospital stay was 7, 10 and 10 days, for G1, G2 and G3 respectively. Mortality was 5%, 10.7% (OR: 2.3 p: 0.12) and 11.7% (OR: 2.5 P: 0.08) for G1, G2 and G3 respectively. It was observed in G1, G2 and G3: the need for O2: 56%, 57.8% (OR: 1.07 p: 0.79) and 71.5% (OR: 2 p: 0.02) ; the use of high-flow cannula was necessary in 7%, 10,7% (OR: 1.6 p: 0.34) and 17.6% (OR: 2.8 p: 0.02) ; ICU admission in 11%, 25.4% (OR: 2.8 p: 0.007) 27.4% (OR: 3 p: 0.003) ; need for mechanical ventilation: 8%, 22.5% (OR: 3.3 p: 0.004) , 21.5% (OR: 3.1 p: 0.006) ; need for dialysis: 2%, 3.9% (OR: 2 p: 0.42) , 6.8% (OR: 3.6% p: 0.09) . The occurrence of complications: 11%, 30.3% (OR: 3.5 p: 0.000) , 34.3% (OR: 4,2 p: 0,000)

Conclusion: The need for admission to ICU, mechanical ventilation, and occurrence of complications were significantly more frequent in patients with DM than controls. Mortality was no different statistically. In patients with hyperglycemia without prior diagnosis of DM, mortality was more frequent, but without statistical significance. The rest of the variables of bad evolution except the need for dialysis were all more frequent.

Disclosure

M. G. Canata: None. S. A. Logwin: None. E. D. Bueno colman: None. A. Benitez: None. A. J. Fretes: None. G. Brunstein diez perez: None. C. Bordon: None. J. T. Jimenez: None. M. Palacios: None.
186-OR: Novel Autoantibodies to Deamidated IA2 Extracellular Domain in Type 1 Diabetes
Authors: JIA XIAOFAN , MIAO DONGMEI , ZHANG CAIGUO , MICHELS AARON W. , YU LIPING , WENZLAU JANET M.
Published: May 2022

Background: Insulinoma antigen-2 (IA2) is a major self-antigen in T1D with post translational modification (PTM) of the extracellular domain (IA2ec) by deamidation eliciting T cell responses in T1D patients. Yet the autoantibodies (Abs) to these IA2ec PTM epitopes in T1D has not been studied.

Methods: IA2ec protein containing all the four T-cell responsive deamidated Q>E epitopes (aa 198-216, 467-482, 523-536 and 545-562) was produced. Sera from 269 new onset T1D children (median age= 12.6yrs) and 3age-matched healthy children were tested for Abs to IA2ecQ>E and wide type (WT) IA2ec with radiobinding assay (RBA) .

Results: The assay cut-offs were set at the 99th percentile for both IA2ecQ>E Ab and IA2ecWT Ab. In T1D children, positivity for IA2ecQ>E Ab was 60.6% (163/269) vs. IA2ecWT Ab 19.3% (52/269, P<0.0001) . In two subgroups of T1D patients who were positive (n=157) or negative (n=112) for current Abs to IA2 intra-cellular domain (IA2ic) , the positivity of IA2ecQ>E Ab were significantly higher than IA2ecWT Ab (Fig) , 58% (91/157) vs. 15.3% (24/157, P<0.0001) and 64.3% (72/112) vs. 25% (28/112, p<0.0001) . However, the positivity of IA2ec Ab did not differ between the patients with or without IA2ic Ab.

Conclusion: IA2ecQ>E Ab was detected in a large proportion of T1D patients, independent of the prototypical IA2ic Ab. IA2ecQ>E Ab is potentially a new novel predictive and diagnostic biomarker for T1D.

Disclosure

X.Jia: None. D.Miao: None. C.Zhang: None. A.W.Michels: Employee; ImmunoMolecular Therapeutics, Stock/Shareholder; ImmunoMolecular Therapeutics. L.Yu: None. J.M.Wenzlau: None.

Funding

National Institutes of Health (R21- AI153665) National Institutes of Health (RDK032083) Diabetes Research Center (DRC) grant P30 DK116073
187-LB: Leveling Health Disparities through Digital Health—Associations between Risk for Health Inequity and Diabetes App Satisfaction, Use, and Outcomes
Authors: IMRISEK STEVEN D. , NAGRA HARPREET , HOY-ROSAS JAMILLAH R. , LEE MATTHEW , GOLDNER DAN , DACHIS JEFF , SEARS LINDSAY
Published: May 2022

Introduction: Disparities in health outcomes are well documented in the literature, with factors such as race, education and income increasing the risk of inequity. Mobile health (mHealth) may help bridge the health equity gap. This study investigates use and attitudes toward One Drop's mHealth program for type 2 diabetes (T2D) as it relates to cumulative risk for health inequity.

Methods: Members with T2D using One Drop completed a health survey in exchange for a $20 gift card. We tested relationships between cumulative risk for inequity, calculated as a count of risks related to race/ethnicity, income, education, insurance and employment, and One Drop attitudes, use and outcomes.

Results: Members (N=149) reported a median of 1 risk factor. Risk was positively associated with reported helpfulness of the One Drop app, educational topics, reminders and actual views of lessons, while negatively related to past-month glucose logging (p’s<.05) . No associations were found for helpfulness of glucose analysis or coaching, use of coaching, self-reported A1C and actual past-month blood glucose (p’s>.05) .

Discussion: Higher risk for health inequity was associated with reporting greater helpfulness of One Drop's app and the use of some of its features. Combined with the absence of an association between risk for inequity and self-reported A1C and glucose, results suggest mHealth apps may be creating equitable outcomes by providing trusted content and greater accessibility. mHealth platforms should ensure this population has access to education emphasizing regular glucose monitoring as part of diabetes self-care.

Disclosure

S. D. Imrisek: Employee; One Drop. H. Nagra: Employee; One Drop, One Drop. J. R. Hoy-rosas: None. M. Lee: Employee; One Drop. D. Goldner: Employee; One Drop. J. Dachis: Board Member; One Drop, Employee; One Drop, Stock/Shareholder; One Drop. L. Sears: Employee; One Drop.
188-LB: Deep Learning–Based Population Screening of Type 1 Diabetes and Celiac Disease Genetic Risk from Blood Spots at Birth
Authors: SHARP SETH A. , LOCKE JONATHAN M. , XU YU , FRASER DIANE P. , FERRAT LAURIC A. , WEEDON MICHAEL N. , INOUYE MICHAEL , ORAM RICHARD A. , HAGOPIAN WILLIAM
Published: May 2022

Introduction: Screening for type 1 diabetes (T1D) genetic risk in early life can prevent life threatening complications such as diabetic ketoacidosis and allow cost-effective recruitment into intervention and immunotherapy trials. Celiac disease (CD) frequently presents as a comorbidity in those with T1D and shares a strong genetic basis with T1D. Single nucleotide polymorphism (SNP) based genetic risk scores (GRS) for both T1D and CD have shown to be very predictive of future disease but are difficult to generate and typically require SNP array genotyping. We aimed to develop a combined GRS screening panel that could be genotyped from a single dried blood spot at birth.

Methods: We developed assays for proxy SNPs of common HLA-DQ haplotypes reported in previous GRS and additional loci from the most recent available genome-wide association studies (GWAS) . We used backwards stepwise regression to identify a subset of variants able to be genotyped with DNA eluted from 800 6mm dried blood spots. We developed and validated neural network models to quantify genetic risk of both T1D and CD using T1DGC and UK Celiac case-control SNP array data, validated in UK Biobank. Assays were developed with LGC Genomics and validated on 675 Seattle area samples.

Results: The complete panel consisted of 71 validated SNP assays, including 11 backup variants for key loci. We generated neural nework models which demonstrate equivalent or greater predictive power (AUC: T1D=0.914, CD=0.893) to previously published GRS yet require much less expertise to apply. We have developed an algorithm for preparation of raw genotyping data and subsequent generation of GRS requiring little expertise to apply.

Conclusion: A 71 SNP blood-spot screening panel is highly effective at screening genetic risk associated with T1D and CD at birth. Using a neural network model the panel enables widely available, easy to generate and inexpensive population screening of genetic risk for T1D and CD.

Disclosure

S. A. Sharp: None. J. M. Locke: None. Y. Xu: None. D. P. Fraser: None. L. A. Ferrat: None. M. N. Weedon: None. M. Inouye: None. R. A. Oram: Consultant; Janssen Research & Development, LLC, Research Support; Randox R & D. W. Hagopian: Research Support; Janssen Research & Development, LLC.

Funding

Diabetes UK (16/0005529) JDRF (3-SRA-2019-827-S-B)
188-OR: Metabolic Blockade of Glycolysis Can Delay the Adoptive Transfer of Type 1 Diabetes
Authors: CHAVEZ MIRANDA D. , MCDOWELL RUTH , TSE HUBERT M.
Published: May 2022

Type 1 diabetes (T1D) is a result of insulin-secreting pancreatic β-cell destruction by autoreactive CD4 and CD8 T cells. There is no cure for T1D, but determining the role of immunometabolism in promoting autoreactive CD4+ T cell effector responses may provide a novel target in delaying T1D. Systemically inhibiting glycolysis with 2-deoxyglucose (2-DG) can decrease autoreactive CD8 T cell islet infiltration. However, the effects of 2-DG on CD4 T cell diabetogenicity is unknown. Proinflammatory Th1 cells mediate β-cell destruction prefer glycolysis for maintaining effector responses, while immunosuppressive Treg cells prefer oxidative phosphorylation. We hypothesize that metabolic inhibition of glycolysis will diminish proinflammatory Th1 cell responses and delay β-cell destruction in T1D. Utilizing 2-DG, we performed an adoptive transfer of diabetogenic CD4+ T cells from NOD.BDC-2.5 or NOD.BDC-6.9 mice into NOD.scid mice. Recipient mice were systemically treated with 30 mM 2-DG in the drinking water beginning 4 days prior to adoptive transfer and monitored for hyperglycemia for 80 days post-transfer. NOD.scid mice treated with 2-DG had a significant delay in diabetes onset when transferred with either BDC-2.5 (n=14, p=0.0284) or BDC-6.9 (n=17, p=0.0249) CD4+ T cells compared to vehicle-treated groups. To define the effects of 2-DG on autoreactive CD4 T cell effector responses, NOD.BDC-6.9 splenocytes were in vitro stimulated with their cognate hybrid insulin peptide (HIP; insulin C-peptide and islet amyloid polypeptide) with or without 2-DG. Flow cytometry analysis revealed a decrease in T cell proliferation, T cell activation, and Th1 lineage commitment as shown by Ki67, CD25, and T-bet expression, respectively. Effector responses were also dampened as IFN-γ synthesis was decreased in our 2-DG treatment group compared to HIP only controls. Future studies will investigate the effects of 2-DG on CD4 T cell chemokine secretion, trafficking into the islet, and cellular metabolic profiles.

Disclosure

M.D.Chavez: None. R.Mcdowell: None. H.M.Tse: None.
198-OR: Altered Prandial Glucose Metabolism in Nondiabetic Subjects with Spinal Cord Injury Is Associated with Impaired Insulin Secretion and Clearance
Authors: TRBOVICH MICHELLE , DIMAS RUDI , SALEHI MARZIEH
Published: May 2022

Patients with spinal cord injury (SCI) develop type 2 diabetes earlier and at 2-3 times higher frequency compared to the matched able-bodied persons (AB) . The difference in glucose abnormalities among SCI and AB cohorts remains after adjusting for known risk factors for DM, such as decreased physical activity, or lower body lean mass, or larger visceral fat mass. The mechanism for this dramatic effect of SCI on glucose metabolism is unknown but is consistent with endocrine-neurological alterations after injury. We hypothesized that SCI is associated with abnormalities in prandial glucose metabolism and β-cell function. To test this hypothesis glucose, insulin, and C-peptide levels were measured during 3-hr mixed meal tolerance test in 4 non-diabetic SCI (3M/1F, ages 33-61 years) and 6 age-matched AB with normal glucose tolerance test (2M/4F, ages 37-57 years) . SCI subjects had lower BMI (p=0.05) and A1C (p<0.05) than AB (SCI vs. AB; BMI range: 19-29 vs. 25-39 kg/m2; A1C range: 5.0-5.3 vs. 5.3-5.9%) . Fasting values of glucose, insulin, C-peptide, insulin sensitivity (HOMA-IR) , and insulin clearance (CP/insulin) were similar between SCI and AB. Prandial glucose (AUCGlucose3h) and insulin (AUCInsulin3h) responses, however, were greater in SCI than AB (p<0.01) . Despite larger prandial insulinemia β-cell output (AUCC-peptide3h) did not differ among 2 groups. This was consistent with a diminished insulin clearance (Total AUCC-peptide3h / Total AUCInsulin3h) in SCI compared to AB by 3-fold (p<0.05) . Oral glucose insulin sensitivity (OGIS) was similar between 2 groups while β-cell glucose sensitivity and disposition index were smaller in SCI than AB by 2-fold (p=0.08) . These findings indicate that among subjects with normal glucose tolerance, those with SCI have larger prandial glycemic concentration despite lower BMI and A1C. This glycemic effect of SCI is associated with impaired β-cell function as well as insulin clearance.

Disclosure

M.Trbovich: None. R.Dimas: None. M.Salehi: None.
20-LB: Heart Failure Hospitalization among African American Compared with White Individuals with Type 2 Diabetes on Empagliflozin—Real-World Data
Authors: MISHRIKY BASEM M. , CUMMINGS DOYLE M. , FU YUANYUAN , HALLADAY JACQUIE , JONES WILLIAM S. , BOAN ANDREA , BERKELEY SARA JONES , PATIL SHIVAJIRAO P. , POWELL JAMES R. , ADAMS ALYSSA , IRISH WILLIAM
Published: May 2022

While African Americans (AA) were underrepresented in the SGLT2i CVOT, the results from those trials were generalized to all, regardless of race. Our goal was to evaluate the risk of heart failure hospitalization (hHF) among AA vs. White (Wh) vs. Hispanic (His) patients with type 2 diabetes (T2D) initially prescribed empagliflozin (EMPA) .

We performed a multicenter retrospective study that extracted real world data for patients with T2D from 4 institutions in North & South Carolina who were ≥ 18 years, either AA or Wh or His, & were prescribed EMPA between Aug 2014 & Dec 2019. Our 1ry outcome was time to first hHF. Cumulative probability of hHF by race was estimated using the cumulative incidence function. The association of race with risk of hHF was evaluated using multivariable Cox hazards model.

A total of 9708 patients were eligible. Of these, 8994 patients had no history of hHF prior to EMPA administration (incident cohort) . Baseline characteristics & results are summarized in Table 1. AA patients were significantly younger, predominantly female, less likely to have pre-existing cardiac conditions, & more likely to have hypertension. When adjusting for age, gender, & baseline comorbidities, there was no significant difference in the risk of hHF between AA vs. Wh or His vs Wh.

Although clinical trials often misrepresent minorities, using real world data we found no significant difference in the risk of hHF in AA or His versus Wh patients with T2D taking EMPA.

Disclosure

B. M. Mishriky: Advisory Panel; AstraZeneca, AstraZeneca, Bayer AG, Bayer AG, Other Relationship; Lilly, Research Support; Lilly. A. Adams: None. W. Irish: Consultant; Eurofins Transplant Genomics, Taleris. D. M. Cummings: None. Y. Fu: None. J. Halladay: None. W. S. Jones: Research Support; Boehringer Ingelheim International GmbH. A. Boan: None. S. Jones berkeley: None. S. P. Patil: Research Support; Novo Nordisk. J. R. Powell: None.

Funding

Brody Brothers Endowment Grant (20-0922)
200-LB: Persistent cAMP Signaling Induces Adipocyte Browning through Biphasic Transcriptional and Epigenetic Remodeling
Authors: SO JISUN , TALEB SOLAEMA , WANN JAMIE , STROBEL OLIVIA , CHEOL ROH HYUN
Published: May 2022

Beige adipocytes are inducible thermogenic cells formed in response to cold exposure and other environmental cues within white adipose tissue. Their capacity to produce heat would provide metabolic benefits against obesity and type 2 diabetes; however, the mechanisms underlying beige adipocyte recruitment, so-called adipocyte browning, induced by different stimuli remain unclear. Using our new adipocyte cell line with improved browning potentials, we compared adipocyte browning responses induced by cAMP (forskolin) versus PPARɣ activation (rosiglitazone) . Time-course RNA-seq revealed that chronic activation of cAMP but not PPARɣ resulted in a biphasic response. The cAMP signaling promoted tissue remodeling at the early phase and subsequently activated energy metabolism while inhibiting cell cycle, which resembles the kinetics of in vivo cold-induced browning. Those late-phase changes were highly correlated with those by PPARɣ activation. Consistently, the cAMP-driven effects were abolished by treatment with PPARɣ antagonists, suggesting PPARɣ as a converging point of its thermogenic actions. Assay for transposase-accessible chromatin sequencing (ATAC-seq) revealed unique dynamics of chromatin landscape distinct from transcriptional changes during cAMP-induced browning. Chromatin at early-induced genes opened acutely and stayed open until the late phase despite the rapid return of gene expression. The chromatin regions at late-induced genes also opened early, preceding transcriptional activation. Using a motif discovery method, we identified NFIL3 that was enriched in both early and late phases of cAMP-induced browning. Reduced thermogenic gene expression and mitochondrial respiration by NFIL3 knockdown suggest NFIL3 as a putative transcription factor mediating the biphasic response of adipocyte browning. These findings define new mechanisms that orchestrate transcriptional and epigenetic remodeling underlying beige adipocyte formation.

Disclosure

J. So: None. S. Taleb: None. J. Wann: None. O. Strobel: None. H. Roh: None.

Funding

American Diabetes Association (7-21-JDF-056) , National Institute of Health (DK129289)