bluuebunny/crossref_metadata_2025_split huggingface dataset:
ODP258 CRHR1 gene shows extensive linkage to major depression and type 2 diabetes in Italian families
Authors: Amin Mutaz , del Bosque-Plata Laura , Gonzalez Manuel Gea , Wu Rongling , Postolache Teodor T , Vergate Michael , Gordon Derek , Ott Jurg , Gragnoli Claudia 
Published: November 2022

Abstract

Background
Major Depressive Disorder (MDD) and Type 2 Diabetes (T2D) are heterogeneous polygenic and complex disorders and are often comorbid. This shared comorbidity can be partially explained by several genetic, environmental, and hormonal factors such as hypercortisolism in MDD and a subset of patients with T2D. CRH receptor-1 (CRHR1) dysfunction may explain the MDD- and T2D-hypercortisolism, at least in a subgroup of patients. CRHR1-variants predisposing to impaired CRHR1 dosage and/or function may lead to hypercortisolism (substrate for serotonin dysfunction and MDD), as well as hyperglycemia, insulin resistance, and increased visceral fat, all T2D-traits. We hypothesize that CRHR1-variants may impair the stress and cortisol response, conferringincreased risk for MDD, T2D, and MDD-T2D comorbidity.

Methods
Using 212 Italian families with T2D, enriched T2D-familial history, and MDD, we amplified and tested 158 CRHR1 SNPs by two-point parametric analysis for linkage and linkage-disequilibrium (LD), using the models dominant (D) and recessive (R), with complete (1) and incomplete (2) penetrance (Pseudomarker).

Results
We detected linkage to and/or LD with MDD: for 93 SNPs (D1), 57 SNPs (D2), 91 SNPs (R1), and 14 (R2); and T2D for 15 SNPs (D1), 18 SNPs (D2), twelve SNPs (R1) and ten SNPs (R2), for a total of 122 SNPs. Specific LD-blocks’ underlined each disorder without overlap. Of note, three independent SNPs were comorbid forMDD and T2D. All risk SNPs are intronic, except for one synonymous, one splice site, one missense, and one 3'UTR. In-silicoanalysis detected functional gene and tridimensional protein changes in a risk-SNP.

Conclusion
We are the first to report CRHR1 in linkage and LD with MDD and T2D in T2D-families. CRHR1contribution to MDD appears stronger thanthe contribution to T2D and may thus antecede its onset . Genetically impaired stress and cortisol response may lead to comorbid MDD-T2D, likely a molecular-clinical entity in a subset of families. Our findings should be replicated in families from other ethnic groups.
Presentation: No date and time listed
ODP632 Preadmission Use Of Antidiabetic Medications And Mortality Among Patients With Covid-19 Having Type 2 Diabetes: A Meta-analysis
Authors: Nguyen Nam Nhat , Ho Dung S , Nguyen Hung Song , Dang Ngan Ho Khanh , Li Hung-Yuan , Lin Chia-Yuan , Chiu Hsiao-Yean , Chen Yang-Ching 
Published: November 2022

Abstract

Introduction
Diabetes is an independent predictor of poor outcomes in patients with COVID-19. We compared the effects of the preadmission use of antidiabetic medications on the in-hospital mortality of patients with COVID-19 having type 2 diabetes.

Methods
A systematic search was performed until November 30, 2021. We used a random-effects meta-analysis to calculate the pooled OR (95% CI).

Results
We included 61 studies (3,061,584 individuals). We found some medications protective against COVID-related death, including metformin, GLP-1RA and SGLT-2i. DPP-4i and insulin users were more likely to die during hospitalization. SU, TZD, and AGI were mortality neutral. Metformin use was associated with better outcome in a dose-response manner.

Conclusions
Metformin, GLP-1RA, and SGLT-2i were associated with lower mortality rate in patients with COVID-19 having type 2 diabetes. DPP-4i and insulin were linked to increased mortality. SU, TZD and AGI were mortality neutral.
Presentation: No date and time listed
ODP633 Impact of Undiagnosed Diabetes on Cardiovascular Events and Clinical outcomes in Patients Hospitalized with COVID-19 Pneumonia
Authors: Krishnasamy Sathya , Sheikh Daniya , Ali T’Shura , Arnold Forest , Ramirez Julio , Furmanek Stephen , Clemons Victoria , Abdelhaleem Ahmed , Salunkhe Vidyulata , Akbar Usman Ali , Chlebowy Diane 
Published: November 2022

Abstract

Type 2 diabetes has emerged as an important risk factor for poor prognosis in hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Hyperglycemia can independently predispose the patients with SARS-CoV-2 to adverse outcomes, irrespective of the diagnosis of diabetes 1. Despite the accentuated risk, there is limited evidence about the complex interplay of undiagnosed diabetes and SARS-CoV-2 pneumonia on the clinical outcomes. We propose to investigate the cardiovascular events and clinical outcomes in patients with undiagnosed and type 2 diabetes hospitalized with SARS-CoV-2 pneumonia.

Methods
This retrospective study included patients hospitalized with SARS-CoV-2 pneumonia between March 7, 2020, through March 30, 2021. The diagnosis of SARS-CoV-2 pneumonia required a positive reverse transcriptase polymerase chain reaction (RT-PCR) for SARS-CoV-2, presence of new or worsening pulmonary infiltrates on computed tomography scan or chest X-ray, and at least one of the following: new or increased cough, a temperature of &gt;37.8 °C or dyspnea. The diagnosis of undiagnosed diabetes was determined in patients with no previous history of diabetes and glycated hemoglobin (HbA1c) ≥ 6.5% (48 mmol/mol) or an admission serum glucose ≥ 200 mg/dL (≥ 11.1 mmol/mol). The outcomes included in-hospital cardiovascular events, intensive care unit (ICU) admissions and in-hospital mortality. Logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for association of undiagnosed diabetes and type 2 diabetes for individual outcomes. Results Among the 1,645 adults hospitalized with SARS-CoV-2 pneumonia, 107 (10.8%) patients were identified with undiagnosed diabetes and 634 (39%) had established diagnosis of type 2 diabetes. Patients with undiagnosed diabetes had increased odds of developing cardiovascular events (OR: 1.73, 95% CI 1. 07, 2.80), ICU admissions (OR: 1.61, 95% CI 1.10, 2.34), and mortality (OR: 1.77, 95% CI 1. 02, 3. 07), compared to patients type 2 diabetes and no diabetes. A prior history of type 2 diabetes was not significantly associated with primary study outcomes.

Conclusions
Patients with undiagnosed diabetes hospitalized with SARS-CoV-2 pneumonia have an increased risk of developing cardiovascular complications and overall poor clinical outcomes compared to patients with type 2 diabetes and no diabetes. Implementation of healthcare-wide strategies for screening and early intervention of prediabetes and diabetes are needed to improve the disease outcomes in the current pandemic and future public health threats. References Khunti, K., et al., COVID-19, Hyperglycemia, and New-Onset Diabetes. Diabetes Care, 2021. 44(12): p. 2645-2655.
Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
OR03-1 Achievement of HbA1c &lt;6.5% without weight gain and hypoglycemia in people with type 2 diabetes treated with tirzepatide across the phase 3 SURPASS program
Authors: Allen Sheryl Elaine , Cheng Alice , Choudhary Pratik , Levine Joshua A , Ranta Kari , Thieu Vivian Thuyanh , Valderas Elisa Gomez , Lingvay Ildiko 
Published: November 2022

Abstract

Introduction
Tirzepatide, the novel dual GIP/GLP-1 receptor agonist for the treatment of type 2 diabetes, has been shown to reduce HbA1c and weight, with more patients achieving HbA1c ≤6.5%, compared to placebo and active comparators in the phase 3 SURPASS 1-5 studies. This analysis compared the percentage of patients treated with tirzepatide achieving a composite endpoint of HbA1c &lt;6.5% without weight gain and hypoglycemia in these studies.

Methods
We compared the proportion of participants achieving the composite endpoint between the tirzepatide (5, 10, or 15 mg) and respective comparator groups while patients were on treatment and without rescue medication. Missing data was imputed based on observed data in the same treatment arm from subjects who had their efficacy measure at the endpoint visit assessed after early discontinuation of study drug. End of treatment HbA1c and weight were evaluated at week 40 (SURPASS-1, 2, 5) and week 52 (SURPASS-3, 4). Weight gain was defined as a change from baseline in weight &lt;0.1 kg. Hypoglycemia included blood glucose level &lt;54 mg/dL with symptoms of hypoglycemia or severe hypoglycemia.

Results
In SURPASS-1, 2, 3, 4, and 5 significantly more patients treated with tirzepatide achieved the composite endpoint compared to placebo or comparator (P≤0.002). As a monotherapy in SURPASS-1, significantly more patients treated with tirzepatide 5mg, 10mg, 15mg achieved the composite endpoint than placebo (75%, 78%, 83%, and 5%, respectively; all P&lt;0.001). As add-on to metformin in SURPASS-2, significantly more patients treated with tirzepatide 5mg, 10mg, 15mg achieved the composite endpoint than semaglutide (67%, 77%, 83%, and 59%, respectively; P=0.002, P&lt;0.001, P&lt;0.001, respectively). When compared to basal insulin in SURPASS-3, significantly more patients treated with tirzepatide 5mg, 10mg, 15mg achieved the composite endpoint than insulin degludec (63%, 76%, 82%, and 13%, respectively; all P&lt;0.001). When added to 1-3 oral antihyperglycemics in SURPASS-4, significantly more patients treated with tirzepatide 5mg, 10mg, 15mg achieved the composite endpoint than insulin glargine (56%, 68%, 75%, and 10%, respectively; all P&lt;0.001). As an add-on to basal insulin in SURPASS-5, significantly more patients treated with tirzepatide 5mg, 10mg, 15mg achieved the composite endpoint than placebo (63%, 70%, 76%, and 8% respectively; all P&lt;0.001).

Conclusions
Significantly more patients treated with tirzepatide achieved a composite endpoint of HbA1c &lt;6.5% without weight gain or hypoglycemia than those treated with placebo, semaglutide, insulin degludec, or insulin glargine in the phase 3 SURPASS program.
Presentation: Saturday, June 11, 2022 11:30 a.m. - 11:45 a.m.
OR03-2 Phase 1, Randomized, Controlled Trial of GFB-024, a Once-Monthly CB1 Inverse Agonist, in Healthy Overweight and Obese Participants and in Participants with Type 2 Diabetes Mellitus
Authors: Bilic Sanela , Dagon Yossi , Gustafson Thomas , Johnson Leslie , Lawler John , Rudolph-Own Lori , Gaich Gregory , Tucker Edwin 
Published: November 2022

Abstract
Evidence from nonclinical studies suggests a role of cannabinoid-1 receptor (CB1) in the development of diabetic nephropathy (DN). Kidney CB1 expression is upregulated in podocytes and tubular cells in murine models of obesity and diabetes mellitus (DM). Inhibition by CB1 inverse agonists has been shown to ameliorate diabetes-induced albuminuria, inhibit kidney fibrosis and inflammation, and prevent podocyte dysfunction. Mouse models of DM have shown that genetic deletion of CB1 in podocytes or proximal tubular cells protects against glomerular and tubular dysfunction.
GFB-024 is a recombinant humanized monoclonal antibody functioning as a CB1-specific inverse agonist. Pharmacodynamic studies demonstrated that GFB-024 protects human podocytes in vitro. Targeting the CB1 pathway with GFB-024 is a potentially novel approach to protecting podocytes from injury in patients with CB1-associated DN.
In a phase 1, randomized, double-blind, placebo-controlled single ascending dose (SAD) trial, we evaluated the safety, tolerability, pharmacokinetics (PK), and immunogenicity of GFB-024 in up to 56 healthy overweight and obese (BMI 25–40 kg/m2) participants.
A total of 38 subjects have completed 5 cohorts in the SAD, receiving single doses of 5 mg to 300 mg administered subcutaneously. GFB-024 was well tolerated, and there were no dose-limiting adverse effects.
PK exposures achieved in the trial exceeded the estimated efficacious exposure, based on four different in vitro activity assays. Absorption was prolonged with flat exposure over the first 7 days, with a Tmax ranging from approximately 4-7 days. Elimination half-life was approximately 12-13 days, with exposures remaining in the estimated efficacious range at 28 days for all but the lowest dose tested.
In summary, GFB-024 was safe and well tolerated following single doses of up to 300 mg. PK analysis demonstrated potentially efficacious exposure, a prolonged absorption phase, and elimination half-life compatible with once-monthly dosing.
Presentation: Saturday, June 11, 2022 11:45 a.m. - 12:00 p.m.
OR24-3 GPR31 Mediates the Proinflammatory Reponses in the Setting of Diabetic Inflammation
Authors: Anderson Ryan , Avadhanam Sriya , Kulkarni Abhishek , Mirmira Raghavendra , Nelson Jennifer , Tersey Sarah 
Published: November 2022

Abstract
The pathogenesis of type 1 diabetes (T1D) involves the interaction of the immune system with pancreatic islets, featured by inflammation in both macrophages and β cells. The enzyme 12-lipoxygenase (12-LOX) is expressed in macrophages and β-cells, produces the eicosanoid 12(S)-HETE and promotes inflammation. GPR31 has recently been identified as a 12(S)-HETE receptor. GPR31 protein levels increase in human islets after cytokine-induced inflammation. To elucidate the role of GPR31 in the 12-LOX pathway and during diabetic inflammation, we generated Gpr31b-/- mice on the C57BL/6J background. Gpr31-/- mice are viable, with normal body weight, glucose tolerance, and β-cell mass. Upon low dose streptozotocin treatment to induce β-cell inflammation, Gpr31b-/- mice remained normoglycemic unlike wildtype littermates and maintained near normal β-cell mass. To examine GPR31 in islet inflammation, RNA sequencing was performed on isolated mouse islets treated with a cytokine cocktail (IL-1β, IFN-γ, TNF-α). Both wildtype and Gpr31b-/- islets showed expected increases in Nos2 and Il1b after cytokine treatment. By contrast, Gpr31b-/- islets, showed changes in Gene Ontology pathways related to ER stress, oxidative stress, protein targeting, and MAPK activity compared to wildtype islets after cytokine treatment. To test a role for GPR31 in macrophage function, we first interrogated its role in the generation of proinflammatory macrophages upon polarization in vitro to the M1-like state using LPS and IFN-γ; under these conditions, we found no differences between Gpr31b-/- and wildtype macrophages, as assessed by flow cytometric analysis, suggesting that GPR31 does not play a role in macrophage polarization. Next, we tested if GPR31 is required for the ability of macrophages to migrate. To do this, bone marrow derived macrophages were isolated from Gpr31b-/- and wildtype littermates and in vitro migration assays were performed using Transwell chambers. We observed a significant decrease in migration of the Gpr31b-/- macrophages compared to wildtype macrophages. Taken together, our data support the concept that GPR31 promotes proinflammatory responses in both macrophages and pancreatic islets.
Presentation: Monday, June 13, 2022 11:30 a.m. - 11:45 a.m.
OR24-4 Targeting Hyperglucagonemia Reverses Glucagon Resistance
Authors: Bernal-Mizrachi Ernesto , Kramer Nadejda Bozadjieva , Gittes George , Lubaczeuski Camila 
Published: November 2022

Abstract
Elevation of glucagon levels and increase in alpha-cell mass are associated with states of hyperglycemia in diabetes. A better understanding of the molecular mechanisms governing glucagon secretion could have major implications in understanding abnormal responses to hypoglycemia in diabetic patients and provide novel avenues for diabetes management. Stimulation of glucagon secretion in hypoglycemia, or by amino acids, induces hepatic glucose production via cellular mechanisms including suppression of glycogenesis and glycolysis and stimulation of glycogenolysis and gluconeogenesis. The close link between amino acids and the alpha-cell is highlighted by the liver–alpha-cell axis. This axis was identified by the major increase in alpha-cell hyperplasia and hyperglucagonemia in models of reduced glucagon action in hepatocytes genetically or pharmacologically by treatment with glucagon receptor antagonists, which was subsequently attributed to the dramatic rise in amino acids. Induction of mTORC1 by constitutive genetic deletion of TSC2 in alpha-cells (aTSC2KO) recapitulated the effects of chronic hyperaminoacidemia with increases in alpha-cell mass and chronic hyperglucagonemia indicating that mTORC1 mediates amino acids signals in alpha-cells. However, the effects of acute versus chronic induction of alpha-cell mTORC1 signaling on these outcomes have not been explored. Using mice with doxycycline induction of Rheb (activator of mTORC1 signaling) (aRhebTg) and inducible Cre-mediated deletion of the mTORC1 inhibitor, TSC2, in alpha-cells (iaTSC2KO), we showed that induction of hyperglucagonemia is associated with two phases: Acute phase characterized by impaired glucose tolerance because of increased gluconeogenesis and glucose output by the liver. And a chronic phase, characterized by normalization of glucose tolerance due to downregulation of the hepatic glucagon receptor (Gcgr), Pepck, and some genes involved in amino acid metabolism and urea production. Importantly, the consequences of chronic hyperglucagonemia were reversible after normalization of glucagon levels by turning off alpha-cell Rheb expression. These studies uncovered the acute versus chronic effects of hyperglucagonemia on glucose homeostasis and further demonstrate that glucagon resistance is a reversible process. These observations provide insight into the impact of glucagon in the pathogenesis of hyperglycemia and the physiological effects of administration of dual GLP1/Glucagon receptor agonists.
Presentation: Monday, June 13, 2022 11:45 a.m. - 12:00 p.m.
OR28-1 Racial and Ethnic Disparities in Diabetes Technology Use amongst Persons with Type 1 Diabetes
Authors: Alzedaneen Yazan , Bukhari Khulood , Munir Kashif , Sagar Prem Raj , Park Jeayoung 
Published: November 2022

Abstract

Objective
Despite recent advances in diabetes technology, the distribution of healthcare resources is often unequal among racial and socio-economic groups. A recent multicenter study looking at technology use amongst young adults with T1D demonstrated that socioeconomic status (SES) was not the sole driver of racial/ethnic disparities and that adjustment for income, insurance level, and health literacy did not significantly attenuate disparities. Here we present a retrospective cohort study looking at racial/ethnic disparities in insulin pump and CGM use in adults with T1D at an urban university hospital system.

Methods
We reviewed the charts of all adults aged 18 to 89 with T1D who attended the University of Maryland Center for Diabetes and Endocrinology (UMCDE) between 1/2019 and 12/2019. Age, gender, race/ethnicity, type of insurance, ZIP code, BMI, A1c, method of insulin delivery, and type of glucose monitoring device were obtained from each chart. We utilized the 2019 US Census data to determine the median income for each ZIP code. Patient charts were re-accessed in 2021 to check for changes in diabetes technology use from 1/2020 until 12/2021. Logistic regression modeling was done in PRISM to control for age, gender, race, insurance type, ZIP code, last known provider, BMI, and A1c. Hosmer-Lemeshow test was done to evaluate goodness of fit. Stratified analysis was done for potential confounders such as insurance type and income. The Breslow-Day test and Likelihood Ratio test for nested models were used to evaluate their degree and significance.

Result
A total of 532 adults were included in the study; 277 identified as non-Hispanic (NH) White, 204 identified as NH Black, 7 identified as Hispanic, and 44 identified as other racial/ethnic groups. NH White adults had a significantly higher insulin pump use when compared to NH Black (adjusted ratio 54.0% vs. 18.4%, OR 2.43 after regression, 95%CI [1.41-4.22]). Similarly, NH White adults had significantly higher CGM use when compared to NH Black (66.5% vs. 35.2%, OR 2.00 after regression, 95%CI [1.24-3.22]). Disparities between NH White and NH Black patients did not resolve throughout 2020-2021. Insurance type was a potential effect modifier for CGM prescriptions between NH White and NH Blacks (Crude OR 4.04, Commercial Strata OR 2.68, Medicaid 1.79, Medicare 2.79, Other/Self-pay 25.7, p=0.039 on Breslow-Day test). There was large heterogeneity in the rate of Pump or CGM prescriptions between providers.

Conclusion
NH White adults with T1D were significantly more likely to have been prescribed diabetes-related technologies when compared to other racial/ethnic groups, and this difference did not resolve over 2 years of follow-up. Future directions include a comprehensive survey of our population regarding patient-derived and patient-perceived factors driving disparities beyond socioeconomic status.
Presentation: Tuesday, June 14, 2022 9:45 a.m. - 10:00 a.m.
OR28-6 Combating Therapeutic Inertia: Project ECHO for Diabetes Improves Primary Care Providers’ Comfort and Use of Diabetes Medication and Technology
Authors: Ajabnoor Yasser , Aldous Annette , Bouchonville Matt , Cuttriss Nicolas , Ehrhardt Nicole , Hood Nancy , Peek Monica , Thomas Celeste , Zou Tracy 
Published: November 2022

Abstract

Background
Despite newer diabetes medications and technology being available, therapeutic inertia persists and there are more people living with "uncontrolled" diabetes than meeting A1c targets. Here we evaluate how the ECHO© model for diabetes management changed prescribing practices among participating primary care providers (PCPS).

Methodology
Three unique diabetes ECHO programs evaluated comfort or perception of prescribing practice changes for local community PCPs (n=74) in four regions (Illinois, District of Columbia, New Mexico, and Washington). One site representing two regions collected pre- and post-program participant surveys (n=45) while two sites collected post-program surveys only (n=29), in which respondents reported perceptions of changes resulting from participation in ECHO. Participants reported their use of technology (professional and personal continuous glucose monitoring (CGM) and insulin pumps) and medications (insulin and non-insulin).

Results
On a 4-point Likert scale, PCPs’ (n=45) average self-reported prescription use for newer diabetes medications with cardiovascular indications increased from 3.07 (sometimes) to 3.84 (sometimes-always).
Presentation: Tuesday, June 14, 2022 11:00 a.m. - 11:15 a.m.
PSUN171 CORRELATIONS BETWEEN SERUM AND TEAR PLASMINOGEN ACTIVATOR INHIBITOR-1 (PAI-1) AND TISSUE PLASMINOGEN ACTIVATOR (tPA) IN PATIENTS WITH DIABETIC RETINOPATHY
Authors: Jasmiad Nurbadriah , Ghani Rohana Abd , Ghani Rohana Abd 
Published: November 2022

Abstract

Introduction
Diabetic retinopathy (DR) is a leading cause of blindness and visual disability, worldwide. The aim of the study was to investigate the correlation between tears and plasma levels of activity of tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) in patients with diabetic retinopathy.

Method
Patients with T2DM and DR (n=26) were enrolled in this study. Blood and tears samples were obtained from both groups and analysed for PAI-1 and tPA activities. Anthropometric measurements were also obtained.

Results
There was no correlation between serum and tear PAI-1 levels with a Spearman's coefficient of 0.028 (p=0.928). We were also unable to detect significant correlations between serum and tear tPA levels. However, there was a significant positive correlation between levels of tears PAI-1 and BMI (r=0.555, p=0.026).

Conclusion
This present study demonstrated no significant correlations between tears and serum PAI-1 and tPA, which was most likely due to the small sample size. However, the significant correlation between tear PAI-1 levels with BMI could indicate the potential role of tear biomarkers in diabetic retinopathy in obese patients.
Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.