bluuebunny/crossref_metadata_2025 huggingface dataset:
1433-P: Relationships between HbA1c Levels and Diabetes Management Practices—NHANES Data, 2007–2018
Authors: YOUNG CLIPPER F. , MYUNG CHERRY
Published: June 2023

Objective: To evaluate the relationships between HbA1c levels and the recommended diabetes management practices captured in the National Health and Nutrition Examination Survey (NHAHES) datasets between 2007 and 2018 in adults with diabetes.

Methods: This study utilized a cross-sectional approach. Logistic regression models were created, adjusting for covariates while examining the relationships between diabetes management practices and HbA1c levels.

Results: The study included 4,623 individuals with an average age of 62 years (SD 0.19). Of these individuals, 33.8% were non-Hispanic Whites, 26.9% non-Hispanic Blacks, 17.4% Mexican Americans, 10.7% other Hispanics, and 11.3% other races. The following table summarizes these relationships' odds ratios, 95% confidence intervals, and p-values.

Conclusion: From 2007 to 2018, participants who saw a diabetes specialist once or less per month were less likely to have a lower A1c level (< 9%). Those who reported checking their feet, reducing fat/calories in their diet, and taking Insulin were significantly more likely to have a lower A1c level than their counterparts. These significant findings confirm the importance of the recommended diabetes management (e.g., nutrition and medication) at the national level, reinforcing the ongoing large-scale public health campaigns that are warranted to support the existing messages to patients with diabetes.

Disclosure

C.F.Young: Other Relationship; Abbott Diabetes. C.Myung: None.
1435-P: Therapeutic Patterns at Three-Year Follow-up in LANDMARC—Longitudinal Nationwide Study on Real-World Outcomes of Type 2 Diabetes in India
Authors: THACKER HEMANT , DAS ASHOK K. , JOSHI SHASHANK R. , MITHAL AMBRISH , KALRA SANJAY , GOPALAKRISHNAN UNNIKRISHNAN AMBIKA , PRASANNA KUMAR K.M. , SETHI BIPIN , CHOWDHURY SUBHANKAR , SUGUMARAN AMARNATH , SATPATHY ASHWINI , GADEKAR ARVIND , MENON SHALINI K. , NEOGI RENUKA , CHODANKAR DEEPA , TRIVEDI CHIRAG , KUMAR WANGNOO SUBHASH , ZARGAR ABDUL H. , RAIS NADEEM
Published: June 2023

Therapy patterns across various subgroups were examined at the end of third year (yr) in LANDMARC, a prospective observational study (CTRI/2017/05/008452), that included participants with T2D on ≥2 antihyperglycemic medications. Of 6222 evaluable participants (mean baseline values - age: 52.1 yrs, T2D duration: 8.6 yrs and A1C: 8.05%), 5273 completed 3-yr follow-up visit. Therapeutic management was at the discretion of the treating physician. At the end of the third yr, the proportion of participants taking insulin + OAD increased (baseline: 23.95%; 3-yrs: 34.86%); while those taking only OADs decreased (baseline: 74.51%; 3-yrs: 63.30%). Among injectable glucose-lowering drugs, there was an increase in basal, prandial and premix insulin. Biguanides and sulfonylureas were the most commonly used OAD classes, the highest increase in OAD addition was seen for DPP4 inhibitors (baseline: 3043/6222, 48.91%; 3-yrs: 3287/5264, 62.44%) followed by SGLT2 inhibitors (baseline: 654/6222, 10.51%; 3-yrs: 1231/5264, 23.39%). Overall, glycemic parameters improved in the insulin subgroup compared to the insulin naïve subgroup (p<0.0001). No difference in change of glycemic parameters was noted in those on basal vs. premix insulin (Table). Overall, 3-yr data indicate that timely intensification of therapy may play an important role in improving glycemic parameters.

Disclosure

H.Thacker: None. A.Sugumaran: Employee; Sanofi. A.Satpathy: Employee; Sanofi. A.Gadekar: Employee; Sanofi. S.K.Menon: Employee; Sanofi. R.Neogi: Employee; Sanofi. D.Chodankar: Employee; Sanofi. C.Trivedi: None. S.Wangnoo: None. A.H.Zargar: None. N.Rais: Advisory Panel; Bayer Consumer Care AG, Board Member; Abbott, Biocon. A.K.Das: n/a. S.R.Joshi: Advisory Panel; Biocon, Zydus Cadila, Torrent Pharmaceuticals Ltd, Franco India, Consultant; Glenmark Pharmaceuticals, Twin Health, Speaker's Bureau; Abbott Nutrition, Sanofi, Abbott, Novo Nordisk, Lupin Pharmaceuticals, Inc. A.Mithal: Advisory Panel; Eris Lifesciences Ltd., Consultant; Glenmark Pharmaceuticals, Lupin Pharmaceuticals, Inc., USV Private Limited, Research Support; Sanofi, Speaker's Bureau; Novo Nordisk, Boehringer-Ingelheim, AstraZeneca, Sun Pharmaceutical Industries Ltd., Novartis. S.Kalra: Speaker's Bureau; Abbott, Bayer Inc., Novo Nordisk, Sanofi. A.Unnikrishnan: Speaker's Bureau; Sanofi, AstraZeneca, Boehringer-Ingelheim, Intas Pharmaceuticals Ltd. K.Kumar: None. B.Sethi: None. S.Chowdhury: None.

Funding

Sanofi India
1438-P: Diabetes after Cardiac Transplant with Low-Dose Everolimus and Tacrolimus
Authors: RAVEN LISA M. , MUIR CHRISTOPHER A. , POULIOPOULOS JIM , MACDONALD PETER S. , JABBOUR ANDREW , GREENFIELD JERRY
Published: June 2023

Background: Although modern immunosuppressants improve survival post-transplant, they are associated with long-term metabolic complications, such as post-transplant diabetes mellitus (PTDM). Calcineurin inhibitor-sparing regimens using everolimus attenuate some complications such as left ventricular hypertrophy. However, the metabolic effects of everolimus following transplant are less clear.

Aims: To compare incidence of diabetes in heart transplant recipients exposed to low-dose everolimus and tacrolimus versus standard-dose tacrolimus.

Methods: Post-hoc analysis in participants of a randomised open-label clinical trial of low-dose everolimus and tacrolimus versus standard-dose tacrolimus in heart transplant recipients.

Results: There were 39 participants in the trial, mean follow up was 6.4 ± 1.5 years. There was a high rate of pre-existing diabetes (26%) and newly-diagnosed PTDM (36%) during follow-up (Figure 1). Half the patients who developed PTDM in the everolimus-tacrolimus group (n=4/8) ceased diabetes medications during follow-up, which was not observed in patients on standard tacrolimus (n=0/6).

Conclusion: This study suggests that treatment with everolimus may improve PTDM outcomes relative to treatment with standard doses of calcineurin inhibitor. These findings should be further studied in prospective randomised trials.

Disclosure

L.M.Raven: None. C.A.Muir: None. J.Pouliopoulos: None. P.S.Macdonald: Advisory Panel; AstraZeneca, Boehringer Ingelheim Inc., Other Relationship; Novartis. A.Jabbour: None. J.Greenfield: None.
144-OR: Norepinephrine Mediates Severe Hypoglycemia–Induced Fatal Heart Block in Rats
Authors: NUIBE EMILY H. , CHAMBERS MATT , RENO-BERNSTEIN CANDACE M.
Published: June 2023

Severe hypoglycemia can lead to fatal cardiac arrhythmias, specifically 3rd degree heart block. During hypoglycemia, the brain senses low glucose and activates the sympathetic nervous system leading to epinephrine and norepinephrine secretion. It is hypothesized that norepinephrine increases severe hypoglycemia induced fatal cardiac arrhythmias. To test this hypothesis, nondiabetic Sprague Dawley rats underwent hyperinsulinemic/severe hypoglycemic (10-15 mg/dl) clamps for 3 hours with continuous electrocardiogram recording. Rats were continuously infused with either 1) brain norepinephrine (ICV; n =15), 2) brain control (ICV aCSF; n = 11), 3) IV norepinephrine nerve terminal blocker (reserpine; n = 7), or 4) IV control (DMSO/saline; n = 6). Severe hypoglycemia induced mortality was increased to 40% with brain norepinephrine infusion compared to 27% in aCSF. Similarly, heart block was increased to 40% with brain norepinephrine infusion compared to 25% in aCSF (p < 0.05). Blockade of norepinephrine completely prevented mortality and heart block during severe hypoglycemia compared to 17% and 25% (p < 0.05), respectively, in controls.

In summary, norepinephrine increases while blockade of norepinephrine prevents fatal heart block during severe hypoglycemia. Drugs that target norepinephrine action may have therapeutic potential in people with diabetes at risk for severe hypoglycemia.

Disclosure

E.H. Nuibe: None. M. Chambers: None. C.M. Reno-Bernstein: None.

Funding

National Institutes of Health (1R56HL160835-01); University of Utah
1440-P: Single Islet Antigen 2 Antibody–Positive (IA2A Ab+) Children Exhibit Significant Metabolic Abnormalities and 5-Year Type 1 Diabetes (T1D) Risk
Authors: SIMS EMILY K. , CUTHBERTSON DAVID D. , BOSI EMANUELE , EVANS-MOLINA CARMELLA , REDONDO MARIA J. , NATHAN BRANDON M. , ISMAIL HEBA M. , JACOBSEN LAURA M. , SOSENKO JAY
Published: June 2023

Current T1D staging defines multiple Ab+ as the start of T1D (Stage 1 or 2 depending on presence of dysglycemia). However, single Ab+ individuals are considered low-risk and are typically not considered for inclusion in prevention trials. We hypothesized that single IA2A+ children exhibit metabolic compromise with appreciable Stage 3 (clinical diabetes) risk. To test this, we evaluated 2163 confirmed single Ab+ children (IA2A, glutamic acid decarboxylase [GADA], or insulin [IAA]) with available OGTT data in the TrialNet natural history study. With and without age and BMI adjustment (Table), IA2A+ children had higher area under the curve (AUC) glucose, lower AUC C-peptide, and higher diabetes risk indices (Diabetes Prevention Trial Type 1 Risk Score [DPTRS] and Index60). Cox regression demonstrated that IA2A+ children were most likely to have progressed to Stage 3 (50.9% vs. 12.0% or 9.6% over 5 years). Of single Ab+ children who did not progress to Stage 3, GADA+ most frequently progressed to multiple Ab+ (34.0% over 5 years). In conclusion, amongst single Ab+ children, IA2A+ children have greater metabolic dysfunction and rates of progression to Stage 3. These findings suggest that single IA2A+ children exhibit substantial T1D risk, should also be considered as having Stage 1 T1D, and be considered for eligibility in prevention studies.

Disclosure

E.K.Sims: Speaker's Bureau; Medscape, American Diabetes Association. D.D.Cuthbertson: None. E.Bosi: None. C.Evans-molina: Advisory Panel; Provention Bio, Inc., DiogenX, Avotres Inc., Neurodon, MaiCell Therapeutics, Other Relationship; Isla Technology, Bristol-Myers Squibb Company, Nimbus Therapeutics, Research Support; Lilly, Astellas Pharma Inc. M.J.Redondo: None. B.M.Nathan: None. H.M.Ismail: Consultant; Rise Therapeutics. L.M.Jacobsen: None. J.Sosenko: None.
1449-P: Machine Learning Reveals Metabolic Signatures in Patients with Type 1 Diabetes
Authors: ZHU JIANGYU , ZHAO MINZHE , ZHENG XUEYING , LUO SIHUI , DING YU , WENG JIANPING
Published: June 2023

Background: Metabolic dysbiosis has been linked to the development of type 1 diabetes. However, there are few studies reflecting the metabolic signatures in patients with type 1 diabetes based on machine learning. Therefore, we aim to investigate the serum metabolic alterations and signatures in patients with type 1 diabetes.

Methods: We recruited 29 type 1 diabetes patients and 29 healthy controls with matching age, sex and ethnicity. Serum metabolites were analyzed using liquid chromatograph-mass spectrometry (LC-MS). Four machine-learning approaches (Logistic Regression, Support Vector Machine, Gaussian Naive Bayes, and Random Forest) were used to screen potential T1D-related biomarkers.

Results: Between the T1D group and the control group, 150 different metabolites were identified. These metabolites were significantly enriched in three metabolic pathways (P<0.05), purine metabolism, ketone body synthesis and degradation, and methyl butyrate metabolism. We combined comprehensive analysis and four machine-learning algorithmsto screen for biomarkers associated with type 1 diabetes. The top 20 metabolites coincided with 150 metabolites identified by LC-MS. In addition, three metabolites were identified as T1D diagnostic biomarkers, including docosahexaenoic acid, estrane and inosine. The combination of these metabolites also accurately diagnosis type 1 diabetes.

Conclusions: In this study, purine metabolism, synthesis and degradation of ketone bodies, and impaired methyl butyrate metabolism were identified as metabolic disturbance associated with type 1 diabetes. These biomarkers by using machine-learning approaches may have important clinical significance in the diagnosis of type 1 diabetes and in the follow of responses to therapeutic interventions.

Disclosure

J.Zhu: None. M.Zhao: None. X.Zheng: None. S.Luo: None. Y.Ding: None. J.Weng: None.
1455-P: Developing Computable Phenotypes (CPs) for Identifying Children, Adolescents, and Young Adults with Diabetes Using Electronic Health Records in the DiCAYA Network
Authors: SHAO HUI , GUO YI , BIAN JIANG , LI PIAOPIAO , DABELEA DANA , CONWAY REBECCA B. , CRUME TESSA L. , SCHWARTZ BRIAN S. , HIRSCH ANNEMARIE G. , DIXON BRIAN E. , LUSTIGOVA EVA , ROSENMAN MARC , ZHONG VICTOR W. , CONDERINO SARAH , DIVERS JASMIN , THORPE LORNA , LIESE ANGELA D. , RUDISILL CAROLINE , OBEID JIHAD S. , PAVKOV MEDA E. , IMPERATORE GIUSEPPINA , EWING JOSEPH A.
Published: June 2023

The DiCAYA Network, which is funded by the CDC and NIDDK, is working to create a nationwide electronic health record-based diabetes surveillance system. The feasibility and performance of existing diabetes computable phenotypes in this system were unknown, as they had only been tested in individual health systems. This study aimed to develop a DiCAYA-wide EHR-based computable phenotype (CP) to identify prevalent cases of diabetes by type. We conducted network-wide chart reviews for 1830 youth (age < 18y) and 1830 young adults (age 18 - <45y) among individuals with possible diabetes, identified as those with any potential indication of diabetes in the EHR (any diabetes-related diagnosis, medication, or abnormal lab test). We assessed the performance of the DiCAYA CP (two outpatient diagnoses or one inpatient diagnosis by type) for identifying diabetes and diabetes type in children and young adults in the reviewed sample, using chart review as the gold standard. (Table 1). We developed a highly accurate EHR-based CP for diabetes in children and young adults based on EHR data from the DiCAYA network. Our results support the feasibility of deploying a unified CP across a nationwide EHR network for diabetes surveillance, with consistently high accuracy across the participating sites.

Disclosure

H.Shao: Consultant; Lilly Diabetes. B.E.Dixon: Consultant; Merck & Co., Inc. E.Lustigova: None. M.Rosenman: None. V.W.Zhong: None. S.Conderino: None. J.Divers: None. L.Thorpe: None. A.D.Liese: None. C.Rudisill: Stock/Shareholder; Pfizer Inc., Viatris Inc., Teladoc Health, Catalent. J.S.Obeid: None. Y.Guo: None. M.E.Pavkov: None. G.Imperatore: None. J.A.Ewing: None. J.Bian: None. P.Li: None. D.Dabelea: None. R.B.Conway: None. T.L.Crume: None. B.S.Schwartz: None. A.G.Hirsch: None.

Funding

Centers for Disease Control and Prevention (U18DP006512)
146-OR: Causative Role of Hypothalamic Ventromedial Glucose-Inhibited Neurons in Impaired Counterregulatory Responses to Hypoglycemia
Authors: COPPERI FRANCESCA , SHEN XIAOTIAN , DIANO SABRINA
Published: June 2023

The development of impaired counterregulatory responses (CRR) after recurrent hypoglycemia (RH) is one of the most life-threatening and debilitating aspects of Type 1 Diabetes (T1D). Numerous scientific evidence points to the ventromedial nucleus of the hypothalamus (VMH) glucose-inhibited (GI) neurons as major players in the development of impaired CRR. However, there is no current evidence of a causative role of VMH GI neurons in impaired CRR. In this study, we used a protocol in which mice were injected with insulin (2.5 U/kg, i.p.) for 4 consecutive days. These mice displayed impaired CRR after 2-deoxy-D-glucose (2-DG) administration (200 mg/kg, i.p. injected on the 5th day) with blunted levels of circulating glucose, corticosterone, and epinephrine in comparison to mice with intact CRR after 2-DG administration. Using a TRAP2:tdTomato mouse model, we labeled (tdTomato) GI neurons by injecting 4-hydroxytamoxifen after 2-DG administration. Four weeks later, the mice were injected with either insulin or vehicle for 4 days followed by 2-DG administration, of which the brains were then immunostained and analyzed for cFos in the VMH. We observed a significant decrease in double-labeled tdTomato/cFos cells in mice with impaired CRR compared to the controls, thus suggesting an altered VMH GI neuronal activation following insulin-induced RH. In support of this, chemogenetic activation of VMH GI neurons in mice with impaired CRR significantly increased blood glucose levels following 2-DG administration compared to mice with impaired CRR. Overall, our data provide evidence for a direct and causal involvement of VMH GI neurons in the development of impaired CRR following RH.

Disclosure

F.Copperi: None. X.Shen: None. S.Diano: None.

Funding

Naomi Berrie Diabetes Center; National Institute of Diabetes and Digestive and Kidney Diseases (DK107293)
1466-P: Genome-Wide Association Studies in the GRADE Study Identify Genetic Variation Influencing the Response to Pharmacotherapy for Type 2 Diabetes
Authors: LI JOSEPHINE H. , SZCZERBINSKI LUKASZ , LIU HAIYIN , TRIPPUTI MARK , KRETOWSKI ADAM , KAHN STEVEN E. , LACHIN JOHN M. , YOUNES NAJI , MERCADER JOSEP M. , FLOREZ JOSE C.
Published: June 2023

Treatment selection for type 2 diabetes (T2D) is largely driven by guidelines based on population-level clinical data and does not incorporate genetics into decision making. To address this gap, we conducted genome-wide association studies in GRADE, a randomized trial comparing the metabolic effects of glargine, glimepiride, liraglutide, or sitagliptin, when added to metformin over a mean follow-up of 5 years. 4,689 participants with T2D from diverse ancestries underwent genome-wide genotyping with the Illumina Infinium GSA 3.0 array, and high-quality imputation was performed with the TOPMed reference panel. We defined cases as meeting the two outcome criteria (primary: HbA1c ≥7%; secondary: HbA1c ≥7.5%) after 1 or 4 years of treatment. Whole-genome logistic regression using an additive model tested for case-control associations for each treatment. Results were filtered to minor allele frequency >0.005 and imputation R2 ≥0.80. We identified four loci associated with glargine response and one with sitagliptin response at standard genome-wide significance (p<5.0×10−8). For glargine, rs116991960 proximal to the RPSAP52 pseudogene region was associated with increased risk of the primary outcome at year 1 (p=2.6×10−8). Interestingly, RPSAP52 interacts with the RNA binding protein IGF2BP2, and genetic variation in IGF2BP2 has been associated with increased T2D risk. Moreover, rs142895019, located in ITPK1, was associated with the secondary outcome for sitagliptin at year 1 (p=9.4×10−9). In a separate Cox proportional hazards survival analysis, C-allele carriers of rs142895019 had an increased risk of treatment failure on sitagliptin (HR 3.6, p=1.0×10−7). In summary, we identified new genetic loci that may be associated with glycemic response in a multi-ancestry clinical trial of common glucose-lowering medications for T2D. These findings require independent validation but have potential utility in guiding therapy selection.

Disclosure

J.H. Li: None. L. Szczerbinski: None. H. Liu: None. M. Tripputi: None. A. Kretowski: None. S.E. Kahn: Advisory Panel; Anji Pharmaceuticals, Bayer Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Merck & Co., Inc. Other Relationship; Novo Nordisk. J.M. Lachin: None. N. Younes: None. J.M. Mercader: None. J.C. Florez: Consultant; AstraZeneca. Other Relationship; AstraZeneca, Merck & Co., Inc. Consultant; Novo Nordisk.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (U01DK098246, U34DK088043, R01DK123019)
1467-P: Type 2 Diabetes Polygenic Score Predicts the Risk of Glucocorticoid-Induced Hyperglycemia in Patients without Diabetes
Authors: DEUTSCH AARON J. , SCHROEDER PHILIP H. , MANDLA RAVI , ERENLER FEYZA , MERCADER JOSEP M. , UDLER MIRIAM , FLOREZ JOSE C. , BRENNER LAURA
Published: June 2023

Introduction: Glucocorticoids are commonly prescribed medications with a known side effect of hyperglycemia due to their effect on glucose metabolism. However, only 10-50% of patients receiving glucocorticoids develop overt hyperglycemia. It is unknown whether patients with increased genetic risk for type 2 diabetes (T2D) are predisposed to develop hyperglycemia after glucocorticoid treatment.

Methods: We accessed electronic health records and genetic data in the Mass General Brigham Biobank. We examined patients with no diagnosis of diabetes or prediabetes who received a glucocorticoid dose equivalent to 10 mg of prednisone or more, and who had glucose levels checked within 7 days of glucocorticoid administration. Hyperglycemia was defined as fasting blood glucose ≥126 mg/dL or random blood glucose ≥200 mg/dL. A T2D global extended polygenic score was constructed through a meta-analysis of T2D genome-wide association studies in the Million Veteran Program, DIAMANTE, and FinnGen. We performed logistic regression to analyze the association between the polygenic score and hyperglycemia, controlling for age, gender, BMI, baseline creatinine, glucocorticoid dose and duration, and the first 10 principal components of genetic ancestry.

Results: Out of 552 patients who received glucocorticoids, 216 developed hyperglycemia and 336 did not. The T2D polygenic score was significantly associated with glucocorticoid-induced hyperglycemia (p = 0.032, OR = 1.5 per standard deviation of the polygenic score). Other significant covariates included baseline creatinine (p = 8.0 × 10−4, OR = 2.2 per mg/dL of creatinine) and glucocorticoid dose (p = 9.5 × 10−5, OR = 1.01 per 10 mg of prednisone).

Conclusions: Patients carrying a higher burden of genetic variants that confer risk for T2D have an increased risk of hyperglycemia after receiving glucocorticoids. This finding offers a mechanism for risk stratification as part of a precision approach to medical treatment.

Disclosure

A.J.Deutsch: None. P.H.Schroeder: None. R.Mandla: None. F.Erenler: None. J.M.Mercader: None. M.Udler: None. J.C.Florez: Consultant; AstraZeneca, Novo Nordisk, Other Relationship; AstraZeneca, Merck & Co., Inc. L.Brenner: None.

Funding

National Institutes of Health (T32DK007028)
1474-P: Identification and Management of MODY2 Pregnancy Patients
Authors: LIU LIMEI , JIANG YANYAN , CHEN YATING , LIU CHANWEI , LI TIANTIAN
Published: June 2023

Precise differentiation of glucokinase (GCK) monogenic diabetes, MODY2, from gestational diabetes mellitus (GDM) is critical for accurate management of the pregnancy outcome. We screened MODY2 complicating pregnancies in Chinese GDM patients, explored the pathogenesis of novel GCK mutations, and evaluated the patients’ pregnancy outcome and management. The GCK gene from 411 GDM patients was screened with PCR-direct sequencing and multiplex ligation-dependent probe amplification (MLPA) and 15 GCK mutations were identified. We also retrospectively analyzed a total of 65 pregnancies from 21 MODY2 families, wherein 41 were from 15 maternal families and 24 were from six paternal families. Bioinformatic analysis and biochemical functional study were conducted to identify novel GCK mutations. In total, we identified 21 GCK mutations: 15 from the 411 GDM patients and six from 24 fathers. Of the Asp78Asn (GAC → AAC), Met87Arg (ATG → AGG), Leu451Val (CTT → GTT), Leu451Pro (CTG → CCG) and 1019 + 20G > A mutations, five, i.e., were novel and deleterious, with markedly decreased enzyme activity and thermal stability. The unaffected offspring of GCK mutation affected mothers were heavier than affected offspring (p<0.001). Of 21 insulin-treated affected mothers, 10 had maternal hypoglycemia (47.6%) and seven had perinatal complications (33.3%), and the affected offspring of the insulin-treated affected mothers had significantly lower birth weights than that of the 20 diet-control affected mothers (p=0.031). In this study, the prevalence of MODY2 complicating pregnancy in Chinese GDM patients was 3.6% (15/411). The defective GCK may contribute to the hyperglycemia in MODY2. Insulin therapy is not beneficial for MODY2 complicating pregnancy and therefore should not be recommended.

Disclosure

L.Liu: None. Y.Jiang: None. Y.Chen: None. C.Liu: None. T.Li: None.

Funding

National Natural Science Foundation of China (81970686, 81770791, 81471012, 82070823, 81270876); Interdisciplinary Program of Shanghai Jiao Tong University (YG2019ZDA08); Shanghai Leading Talent (SLJ15055); National Institutes of Health (SC1DK104821); Tobacco-Related Disease Research Program (T31IR1603)
1477-P: Improved Diabetes Risk Prediction Using Ancestry-Specific Polygenic Score—Results from the Asian Indian Diabetic Heart Study/Sikh Diabetes Study
Authors: TUNG GURLEEN K. , ROUT MADHUSMITA , SANGHERA DHARAMBIR K.
Published: June 2023

Background: Genome-wide polygenic risk scores (PRS) have shown high specificity and sensitivity in predicting type 2 diabetes (T2D) risk in Europeans. However, PRS-driven information on other ethnic groups is sparse, including Asian Indians (AI), who have a heightened risk for T2D. We examined the predictive efficacy of ancestry-derived (PRSAI) and European-derived (PRSEU) with a clinical risk score (CRS) of T2D.

Methods: Weighted PRSs were computed using 2921 variants (common and rare) from (Punjabi/Sikh) genome-wide association studies and 432 variants from European meta-analyses studies in 4,602 individuals (2,574 cases and 2,028 controls) of the Asian Indian Diabetes Heart Study/Sikh Diabetes Study. Both Ancestry-specific PRSAI and European PRSEU were validated on 9372 UK Biobank South Asian individuals (1943 cases/7429 controls).

Results: Ancestry-specific PRSAI showed 36.2% improved efficacy than PRSEU in Punjabi Asian Indians. Similarly, Ancestry-specific PRSAI was 18.6% superior to PRSEU in Asian Indians from UKBB based on Nagelkerke’s R2. Sensitivity analysis explained enhanced sensitivity (area under the curve-AUC) of ancestry-specific PRS over PRSEU in predicting T2D risk.

Conclusions: Our data suggest expanding genetic studies in diverse ethnic groups to exploit the full potential of PRS to improve health outcomes. More genetic evaluations, specifically in understudied/underrepresented populations, would help increase the transferability of genome-wide polygenic scores across racial and ethnic groups to make their integration into clinical practice easier.

Disclosure

G.K.Tung: None. M.Rout: None. D.K.Sanghera: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK082766, R01DK118427); Presbyterian Health Foundation
148-LB: Glycemic Outcomes of Telemedicine Endocrinology Care for Adults with T2D
Authors: ZUPA MARGARET , ROTHENBERGER SCOTT D. , LIN JONATHAN Y. , ROSLAND ANN-MARIE
Published: June 2023

Current specialty care for T2D via telemedicine may not be as effective for patients with clinical complexity given barriers to delivery of key care elements, such blood glucose data sharing and involvement of multidisciplinary teams. In this retrospective cohort study, adults who had a telemedicine endocrinology visit for T2D in a large health system from May-October 2020 were followed through May 2022 to assess follow-up care modality and HbA1c change. Patients were assigned to telemedicine (n=1,182, baseline HbA1c 7.6%) and in-person (n=1,049, baseline HbA1c 7.4%) cohorts based on follow-up care modality. Multivariable regression models estimated the association of baseline insulin regimen and key comorbidities (macrovascular disease and psychological conditions) with HbA1c change over 12 months in each cohort. Patients who used multiple daily injections (MDI) had less HbA1c improvement at 12 months vs those not on insulin in both cohorts, and HbA1c change was significantly worse for patients on MDI who used only telemedicine (HbA1c change telemedicine-only 0.77% higher, 95% CI 0.59-0.94; HbA1c change in-person 0.52% higher, 0.34-0.70, p<0.001 for both; see figure). Key comorbidities were not associated with HbA1c change in either cohort. These results indicate that patients in endocrinology care who use complex insulin regimens may need additional support to achieve HbA1c improvement, especially with telemedicine.

Disclosure

M. Zupa: None. S. D. Rothenberger: None. J. Y. Lin: None. A. Rosland: None.

Funding

National Center for Advancing Translational Sciences (KL2TR001856)
1482-P: Neutrophil Inflammasome Is Activated in Diabetes and Contributes to the Exacerbated NETosis
Authors: DE WANG LIANG , DALAN RINKOO , LING WONG SIU
Published: June 2023

Activation of the NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome has recently been implicated in driving the pathogenesis of diabetic complications. While diabetes is known to increase NETosis propensity, little is known whether neutrophil NLRP3 mediates NETosis in diabetes, and if organelles that govern metabolic homeostasis contribute to aberrant activation of NLRP3. In this study, we sought to examine if neutrophil NLRP3 is activated in diabetes, and if key metabolic organelles are involved in the activation of NLRP3, resulting in NETosis upregulation. We found that pre-treatment of blood neutrophils isolated from mice and humans with diabetes using MCC-950, a potent and specific NLRP3 inhibitor, normalized NET formation to levels similar to those of neutrophils isolated from healthy mice and humans. Similar to blood neutrophils, HL-60-derived neutrophils primed in high glucose also showed reduced NETosis when pre-treated with MCC-950. Notably, compared to their normoglycemic counterparts, neutrophils isolated from mice and humans with diabetes exhibited increased speck formation of the inflammasome adaptor protein, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) even at baseline, indicative of heightened NLRP3 activation in diabetes. In mouse neutrophils, confocal microscopy revealed that oxidized DNA release into the cytoplasm is a prerequisite for ASC speck formation, which co-localized with mitochondria. In addition, MCC-950 yielded no further reduction in NET formation when HL-60-derived neutrophils were pre-treated with tauroursodeoxycholic acid, an alleviator of endoplasmic reticulum (ER) stress. In summary, our findings suggest that mitochondria and ER stress may synergize in the activation of neutrophil NLRP3 that exacerbates NETosis in diabetes. Therapeutics that aim at intercepting the pathway may alleviate NET-mediated chronic inflammation in diabetes.

Disclosure

L.Wang: None. R.Dalan: None. S.Wong: None.

Funding

Nanyang Assistant Professorship; Singapore Ministry of Education Academic Research Fund Tier 1 (RG25/20); Nanyang President's Graduate Scholarship
1483-P: Distinct Immune Features in the Partial Remission Phase of Type 1 Diabetes Identified by Single-Cell RNA Sequencing and Functional Analysis
Authors: LI XIA , ZHONG TING , LI XINYU , KANG LEI , TANG RONG
Published: June 2023

Type 1 diabetes (T1D) patients might experience a transient partial remission (PR) stage. However, the immunological mechanisms responsible for the PR stage still need to be elucidated. Here, we have applied single-cell RNA sequencing to delineate the immune underpinnings of peripheral immune cells among healthy individuals, new-onset T1D patients, and T1D patients in the PR phase. Combined with cohort validation and functional assays, the expansion of TIGIT+ CCR7− Tregs as well as the decrease of CD226+ CCR7− CD8+ T cells helps to maintain a window in which to transit the immune balance in the remission stage via the TGF-β signal. These findings, especially the identified cell subsets may provide novel mechanism for future therapeutic interventions.

Disclosure

X.Li: None. T.Zhong: None. X.Li: None. L.Kang: None. R.Tang: None.
1487-P: Inosine Monophosphate Preferentially Regulates Myeloid Progenitor Differentiation toward Neutrophil Production in Diabetes
Authors: DONG YUAN , YAN CEN , ZHANG YEUJIE , YANG XUANYI , FENG YINGMEI
Published: June 2023

Previous studies described hyperglycemia-induced myelopoiesis and atherosclerotic progression in mice with type I diabetes. By targeted metabolomics, we reported the increase of inosine monophosphate (IMP) in granulocyte/monocyte progenitors (GMP) in db/db mice. Moreover, IMP treatment stimulated GMP proliferation, resulting in skewed myelopoiesis and enhanced acute pancreatitis progression. However, how IMP modulates granulocyte production is not known. To investigate that, equal amount of FACS-sorted GMP of wild-type mice were cultivated with PBS or 15 mM IMP for 5 days in vitro. FACS analysis revealed that the absolute number of neutrophils was 1.7-fold higher but the number of CD11b+ monocytes was 3.2-fold lower in IMP group compared to control (p<0.05 for both). Thereafter, FACS-sorted GMP treated with or without IMP for 3 days were harvested for single cell RNA sequencing. When classified by marker gene expression, 19 clusters representing 7 cell types were identified including neutrophils, monocytes, GMP, intermediate GMP/neutrophils, basophils, Megakaryocyte erythroid progenitors/megakaryocytes (MEP/Mgk), and platelets. The proportions of neutrophils and MEP/Mgk increased 1.3-, and 1.6-fold in IMP-treated GMP cells compared with controls (p=0.059 for neutrophils; p=0.032 for MEP/Mgk). Nevertheless, the percentage of other cell populations were comparable between two groups (p≥0.08 for all). Furthermore, cycling neutrophils in cluster 3 was 1.4-fold increase in IMP-treated GMP cells compared with controls (p=0.04). Accordingly, GO analysis and Gene set enrichment analysis illustrated that genes involved in cell cycles was enriched in cycling neutrophil clusters. In conclusion, our data demonstrated that IMP preferentially regulated GMP proliferation and differentiation toward neutrophil production, which provides new insights on the crosstalk between skewed metabolites and inflammation in diabetes.

Disclosure

Y.Dong: None. C.Yan: None. Y.Zhang: None. X.Yang: None. Y.Feng: None.

Funding

National Natural Science Foundation of China (81670765, 82070841)
1488-P: Reduced iPLA2b Expression in T-Lymphocytes Decreases Proinflammatory Eicosanoid Production and Cytokine Secretion Delaying Type 1 Diabetes Development in NOD Mice
Authors: WHITE TAYLEUR , RAMANADHAM SASANKA , DILORENZO TERESA P. , CHALFANT CHARLES E.
Published: June 2023

Type 1 diabetes (T1D) is characterized by the destruction of insulin-producing pancreatic islet β-cells, but the causes of this process remain unclear. We find that Ca2+-independent phospholipase A2β (iPLA2β), which hydrolyzes membrane phospholipids at the sn-2 substituent to yield iPLA2β-derived lipids (iDLs), is induced under a diabetic milieu and mitigation of iPLA2β activity attenuates β-cell death. Several iDLs are pro-inflammatory and have been studied in different diseases but are not understood in diabetes. We investigated the role of immune-cell iDLs by utilizing T-cell adoptive transfer. Isolated CD4+/8+ T-cells from splenocytes prepared from donor female NOD and NOD. iPLA2β+/− (HET) mice, were transferred i.p. to NOD.scid recipient mice. We observed T1D onset for all T-cell recipient groups between 10-12 weeks of age. However, reduction of iPLA2β in CD4/8 T-cells delayed 50% incidence by 10 weeks in NOD4/HET8-recipient mice and HET4/NOD8 T-cell recipients compared to “matched” T-cell recipients. Furthermore, reduced insulitis and increased β-cell preservation was detected in HET4/NOD8-recipients compared to NOD4/8 recipients. The immune cell composition between our genotypes revealed no difference suggesting iDL signaling contributes to the observed incidence. Lipidomic analyses revealed a decrease in pro-inflammatory eicosanoids (PGs, DHETs and HETEs) in nondiabetic recipient mice, compared to diabetic counterparts. In addition, by targeting select eicosanoid signaling (PGE2 and DHET) utilizing chemical inhibitors (i.e., Grapiprant (EP4 receptor antagonist) and EC5026 (soluble epoxide hydrolase inhibitor)), we observed decreased IFN-γ production by Th1 helper cells in HET donors compared to NOD. These findings suggest that iPLA2β in T-cells is a critical contributor to the production of pro-inflammatory iDLs and could be a potential target in reducing T1D development.

Disclosure

T. White: None. S. Ramanadham: None. T.P. DiLorenzo: None. C.E. Chalfant: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK069455); National Institute of Allergy and Infectious Diseases (R21AI146743, R21AI169214); JDRF (2-SRA-2022-1210-S-B); University of Alabama at Birmingham (5T32GM8111-34)
1496-P: Resatorvid, an Inhibitor of Toll-Like Receptor-4, Protects Allogenic Islets from Inflammatory and Immune Response
Authors: MATTKE JORDAN D. , NAZIRUDDIN BASHOO , KANE BOB
Published: June 2023

Purpose: Loss of islet mass by instant blood mediated inflammatory reaction (IBMIR) and immunological rejection are major hurdles currently facing the field of islet transplantation. Toll-like receptor 4 (TLR4) plays a central role in inflammation and shaping adaptive immune response. We investigated the protective effects of resatorvid (TAK-242) using in vitro models of islet transplantation.

Methods: Soluble TAK-242 or TAK-242 conjugated to the surface of islets utilizing copper-free click chemistry with a cleavable chemical linker were used. Islets were mixed with allogenic blood for a period of 3 hours and plasma levels of miRNA-375 and miRNA-200c were analyzed by RT-qPCR. Allogenic peripheral blood mononuclear cells were cultured with islets. T cell and monocyte activation were monitored by flow cytometry. Cytokine and miRNA levels in culture supernatant were measured by Luminex assay and RT-qPCR respectively.

Results: The presence of TAK-242 in soluble form as well as released by cleavable linker from islet surface significantly reduced the release of miRNA-375 (p<0.01) and miRNA-200c (p<0.01) indicating less islet damage. In allogenic co-culture of islets and PBMCs, TAK-242 inhibited the expression of CD69 in T cells as well as decreased (p<0.05) the expression of CD86 and CD80 in monocytes. The production of cytokines IL-1β (p<0.001), IL-6 (p=0.01), IL-8 (p<0.05), IP10 (p<0.05), MCP-1 (p<0.001) and TNFα (p=0.005) in culture supernatant was decreased in the presence of soluble TAK-242 as well as TAK-242 released from islet surfaces.

Conclusions: Inhibition of TLR4 using small molecule, TAK-242, protected islets from innate damage due to IBMIR as well as adaptive responses of activation of T cells and monocytes. These results validate the future study of inhibition of TLR4 using in vivo transplant model(s) to further investigate the efficacy of TLR4 inhibition to improve islet transplant survival and function.

Disclosure

J.D.Mattke: None. B.Naziruddin: None. B.Kane: None.
15-OR: The Impact of Insulin Out-of-Pocket Caps among Commercially Insured Diabetes Patients
Authors: GARABEDIAN LAURA F. , ROSS-DEGNAN DENNIS , COSTA REBECCA , ARGETSINGER STEPHANIE , ZHANG FANG , FRANK WHARAM J.
Published: June 2023

In January 2021, 8 states capped insulin out-of-pocket (OOP) costs at $25-$100 per 30-day supply. We examined the impact of these state policies on insulin OOP costs and use among commercially insured members with diabetes. Given that members in high-deductible health plans with health savings accounts (HSA) pay the full price of insulin before reaching their annual deductible, we hypothesized that these members would be the most impacted by the policies. We took advantage of a natural experiment created by state variation in policy to employ a robust quasi-experimental design. We used a pre-post with control group study design, with unadjusted difference-in-differences analysis, to evaluate changes in outcomes from 2020 (pre-policy) to 2021 (post-policy) in the 8 intervention states compared to contemporaneous changes in outcomes in 40 control states. We measured (1) insulin OOP cost per insulin user per year and (2) 30-day insulin fills per diabetes patient per year, and stratified results by HSA vs. non-HSA plans. We included 450,351 commercially insured members diagnosed with diabetes enrolled in a large, national health plan (19% were in an HSA plan). For the OOP cost analyses, we included 70,904 members with non-zero insulin costs. Among members with diabetes in HSA plans, state insulin OOP caps were associated with a $178 (95% CI: -$239, -$116) absolute and 18% (95% CI: -24%, -12%) relative reduction in annual OOP insulin costs. However, insulin fills among members with diabetes in HSA plans were unchanged (0.01 fills [95%: -0.05, 0.08]). The state policies also had no impact on annual OOP insulin costs or insulin fills for members with diabetes in non-HSA plans. State policies that capped insulin OOP costs were effective in reducing financial burden among HSA members but did not increase insulin use. Furthermore, the policies had little impact among members in plan types with lower baseline cost-sharing. These findings shed light on the potential impact of Medicare’s insulin copayment cap policy.

Disclosure

L.F.Garabedian: None. D.Ross-degnan: None. R.Costa: None. S.Argetsinger: None. F.Zhang: Other Relationship; GlaxoSmithKline plc., Pfizer Inc. J.Wharam: None.

Funding

Centers for Disease Control and Prevention (U18DP006527)
1506-P: Effect of Beta-Agonist Treatment on Selenium Metabolism in Differentiated Brown Adipocytes
Authors: SWANSON SYDONIE
Published: June 2023

Selenium (Se) is an essential trace element important to several body processes such as metabolism, thyroid function, and curbing of oxidative stress. Se is utilized as the amino acid known selenocysteine (Sec), decomposed by the enzyme selenocysteine lyase (Scly). Selenoproteins have a broad range of functions, including protecting against lipid peroxidation and apoptosis, metabolic dysregulation such as glucose intolerance, and other immune responses. In brown adipocytes, the selenoprotein glutathione peroxidase 4 (GPX4) plays a key role in lipid peroxidation which in turn allows for proper thermogenic responses triggered by adrenergic signals. GPX4 removes toxic lipid peroxides by converting them into non-toxic alcohol and water. When Se levels are insufficient in brown adipocytes, the selenoprotein GPX4 may be downregulated, leading cells to accumulate a lethal amount of lipid peroxidases and triggering ferroptosis, a type of cell death. Ferroptosis activation, in turn, negatively impact pathways dependent on adrenergic responses in brown adipocytes, such as thermogenesis activation. To determine how Se levels regulate the expression of Scly and GPX4 upon treatment with adrenergic agonist in differentiated PAZ6 brown adipocytes. Human PAZ6 pre-adipocytes were differentiated for 21 days, then treated with insufficient (20 nM), adequate (80 nM), and high sodium selenite (160 nM) levels for 48h. Differentiated brown adipocytes were also treated with 1 μM CL-316243, a β3-adrenergic receptor agonist, for 24h after selenite treatment. Cells were then harvested for qPCR and Western blot analysis. Differentiated PAZ6 cells had an increase in UCP1 expression, a marker of brown adipocytes. Upon Se treatment, both Scly and GPX4 expression were unchanged in PAZ6 cells. Treatment with β3-adrenergic receptor agonist also did not affect the expression levels of both proteins. In differentiated brown adipocytes, expression of Scly and GPX4 is not dependent on Se nor β-agonist signals.

Disclosure

S.Swanson: None.

Funding

National Institutes of Health (R01DK128390)
151-LB: Expansion of Medicaid Coverage of Continuous Glucose Monitor Reduces Health Disparity
Authors: MIYAZAKI BRIAN , ZEIER TROY , BARBER REBECCA O. , ESPINOZA JUAN C. , CHAO LILY C.
Published: June 2023

Background: Continuous glucose monitor (CGM) usage improves glycemia in people with type 1 diabetes (PWT1D) and is accepted as the standard of care. CGM utilization is lower in patients with public insurance and minorized ethnicities. In 2022, California Medicaid expanded CGM coverage to all PWT1D without requiring a minimum number of glucose tests per day. It is unknown if this policy change is sufficient to increase CGM usage. We hypothesize that Medicaid expansion narrowed but did not eliminate the disparity in CGM usage.

Methods: Data was extracted from electronic medical record of a large urban children's hospital in 2021 and 2022. CGM usage was determined based on clinician documentation or the presence of CGM downloads. We limited the data query to PWT1D who were seen at least once in the diabetes clinic each year. Chi-square and student T-tests were used to determine statistical significance (P<0.05).

Results: We included 1471 and 1355 PWT1D in 2021 and 2022, respectively. Medicaid insured 66.8% and 62.2% of the patients in 2021 and 2022, respectively. CGM usage increased 1.4-fold in the entire patient population (2021: 52.2%, 2022: 71.1%). Between 2021 and 2022, CGM usage increased 1.6-fold (39% to 63%) and 1.1-fold (77% to 85%) for those with Medicaid and private insurances, respectively. CGM usage increased in all race/ethnicities, with the largest increase seen in patients who identify as Black and Latino (2021 vs 2022: White 69% vs 83%, Latino 38% vs 60%, Black 15% to 50%, P≤ 0.0001 for all comparisons). CGM usage increased 1.3-fold (58% to 74%) in English speakers and 2.1-fold (29% to 59%) in non-English speakers.

Conclusion: Our results demonstrate that Medicaid expansion of CGM coverage increases its utilization for pediatric PWT1D. Despite increased CGM usage in marginalized community, disparity persists among patients with public insurance, minority races/ethnicities, and non-English language. Future studies are needed to identify barriers that preclude equity in technology uptake.

Disclosure

B. Miyazaki: None. T. Zeier: None. R. O. Barber: None. J. C. Espinoza: Consultant; Sanofi, Research Support; NIH - National Institutes of Health, FDA, Speaker's Bureau; Glooko, Inc. L. C. Chao: None.

Funding

U.S. Food and Drug Administration (P50FD006425 to J.C.E.)
1513-P: IAPP25 in Beta Cells and DNSP11 in Alpha Cells Inhibit IAPP37 Fibrillation
Authors: LIU QING-RONG , ZHU MIN , EGAN JOSEPHINE M.
Published: June 2023

Amyloidosis due to aggregation of mature islet amyloid polypeptide (IAPP37) in human islets causes β-cell dysfunction and there is a need to develop anti-amyloid therapeutics to protect β-cells. We used a bioinformatic approach to uncover novel human IAPP isoforms and we developed a quantitative selective reaction monitoring (SRM) proteomic assay to measure their translated peptide levels in human pancreatic islets. We used the Thioflavin T amyloid reporter assay to monitor the isoform-derived peptides for fibrillation propensity and for anti-amyloid potential to prevent aggregation of IAPP37. We uncovered hominid specific IAPP isoforms that are encoded by 4 exons instead of the conventional 3 exons: hIAPPβ, which encodes an elongated propeptide, and hIAPPγ, which is a frameshifted prepropeptide that is processed to mature IAPP25 instead of IAPP37. We found IAPP25 peptide levels to be significantly reduced in the islets of T2DM postmortem samples. We also found IAPP25, Cα-peptide (a novel short C-peptide of 19 AAs), and GDNF-derived DNSP11 present in α cells, to be nonaggregating peptides that inhibited the aggregation of IAPP37 in vitro. These novel peptides have potential to be developed as peptide based anti-amyloid therapies (This research was supported entirely by the Intramural Research Program of the NIH, National Institute on Aging).

Disclosure

Q.Liu: None. M.Zhu: None. J.M.Egan: None.

Funding

National Institute on Aging