bluuebunny/crossref_metadata_2025 huggingface dataset:
280-OR: Metabolomic Signatures of Excess Fetal Growth in Pregnancies Complicated by Type 1 Diabetes (T1D)
Authors: ISGANAITIS ELVIRA M. , WOLFS DANIELLE , O'CONNELL JULIANNE C. , HANSBURY GEORGIA A. , WOLPOWITZ SHIRA , CLISH CLARY B. , JAMES-TODD TAMARRA , BROWN FLORENCE M.
Published: June 2023

Background: In pregnancies complicated by T1D, glycemic control is only moderately associated with excess fetal growth, suggesting that nutrients other than glucose may be involved. Aims: We analyzed associations between metabolites in maternal and newborn plasma, and fetal growth patterns, in T1D pregnancies.

Methods: We obtained maternal plasma samples in the 2nd and 3rd trimester and at delivery, and cord blood samples immediately after delivery, in 22 mother/infant dyads. We used an untargeted metabolomic platform (Broad Institute) and calculated correlation coefficients between individual metabolites and newborn growth percentiles adjusted for gestational age, sex, parity, and ethnicity (GROW percentile). We used a false discovery rate threshold of FDR<0.2. Large for gestational age (LGA) was defined as GROW percentile ≥90 and appropriate for gestational age (AGA) as between the 10th and 90th percentiles.

Results: Forty-five percent of newborns were classified as LGA. Maternal age, BMI, diabetes duration, insulin dose and pump use did not differ between LGA vs. AGA. We identified stronger associations between GROW percentiles and metabolites in cord blood than with metabolites in maternal plasma during the 2nd or 3rd trimester. In cord blood, 29 metabolites were associated with GROW percentile (FDR<0.2). For 51 metabolites, the ratio between abundance in cord blood to abundance in maternal blood at delivery was associated with the GROW percentile (FDR <0.2). Many of the top-ranking metabolites positively associated with infant growth were long-chain glycerophosphocholines (e.g., LPC(20:3) β 0.035, p=0.0002, FDR 0.01; LPC(22:5) β 0.033, p=0.0008, FDR 0.03).

Conclusion: Glycerophospholipids in cord blood were associated with excess fetal growth in T1D pregnancies, suggesting alterations in lipid metabolism. We also report associations between fetal growth and ratios of metabolites in cord blood to maternal blood, suggesting differences in placental transport.

Disclosure

E.M.Isganaitis: None. D.Wolfs: None. J.C.O'connell: None. G.A.Hansbury: None. S.Wolpowitz: None. C.B.Clish: None. T.James-todd: None. F.M.Brown: Other Relationship; Dexcom, Inc.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (P30DK036836, P30DK057521); Broad Institute
284-OR: An Alternative Downstream Translational Start Site in PPARG Produces a Novel Protein That Rescues Loss-of-Function Mutations in Humans
Authors: MENDEZ LARA KAREN , DU XIAOMI , GLASS KIMBERLY , HERNANDEZ RUBEN , DE ARRUDA SALDANHA CAMILA , HEINZ SVEN , MAJITHIA AMIT R.
Published: June 2023

PPARG is the target of thiazolidinediones (TZD) and plays a central role in glucose and lipid metabolism. Loss-of-function (LOF) mutations in PPARG increase the risk of type 2 diabetes (T2D) and cause Mendelian lipodystrophy. In population-scale sequencing studies, we identified protein-truncating variants in PPARG expected to cause lipodystrophy, but surprisingly showing no burden of metabolic disease in their human carriers. To further understand this finding, we use CRISPR/CAS9 to systematically target deletions to every exon of PPARG revealing that mutations causing deleterious frameshifts in exons 1 and 2 resulted in cells with intact PPARG responses. We subsequently constructed a library of PPARG transgenes encoding termination sequences at every possible codon (1-505) in the PPARG2 cDNA and tested them for transactivation function. We found that PPARG transgenes encoding termination sequences prior to codon 135 (c.ATG402-404) corresponding to exon 2 in the genomic DNA (chr3:12381414 Hg38) retained transactivation activity. We hypothesized that c.ATG402-404 served as an alternative translational start site that generates a PPARG isoform lacking the N-terminus but retaining DNA-binding, ligand-binding, and transactivation properties. Indeed, cells engineered to disrupt PPARG prior to chr3:12381414 retained TZD responsiveness and produced a 40 kDa protein recognized by antibodies targeting the C-terminus but not the N-terminus of PPARG. Analysis of the global transcriptional activity of the PPARG p.M135-505 compared to full-length PPARG revealed that p.M135-505 produced a similar TZD-induced upregulation of known PPARG targets and gene sets. In summary, PPARG p.M135-505 is a truncated but fully functional protein that responds to PPARG agonists and may rescue disruptive mutations that would otherwise cause lipodystrophy.

Disclosure

K.Mendez lara: None. X.Du: None. K.Glass: None. R.Hernandez: None. C.De arruda saldanha: None. S.Heinz: Research Support; Hologic Inc., Stock/Shareholder; Leash Laboratories. A.R.Majithia: None.

Funding

National Institutes of Health (RDK01DK123422)
288-LB: CHIP Haplodeficiency Exacerbates Experimental Type 1 Diabetes via the Regulation of DNA Damage Response and Apoptosis
Authors: HWANG HWANG AE-RANG
Published: June 2023

Type 1 diabetes is a disease characterized by hyperglycemia resulting from defects in insulin secretion. Streptozotocin (STZ)-induced pancreatic β-cell damage is commonly used as causing hyperglycemia of type 1 diabetes model. It has been established that the carboxyl terminus of heat shock protein 70-interacting protein (CHIP) contributes to the pathogeneses of diabetic complications. However, the mechanisms linking type 1 diabetes and CHIP-dependent antidiabetic signaling pathway remain to be addressed. Here we utilized STZ-induced murine model of type 1 diabetes to examine DNA damage responses (DDR) during pancreatic β-cell apoptosis. This study was undertaken to explore the mechanism whereby CHIP instigates pancreatic β-cell apoptosis via DDR-dependent signaling pathway. Wild type and CHIP haplodeficient mice were i.p. injected with 50 or 100 mg/kg STZ in order to induce experimental mouse model of type I diabetes. STZ-induced hyperglycemia, glucose intolerance, and inflammatory responses were exacerbated in CHIP haplodeficient mice compared to Wild type. In addition, immunoblotting data revealed that depletion of CHIP with siRNA against rat stub1 enhanced STZ-induced apoptosis and DDR pathway in INS-1 cells, a rat insulinoma cell line. Notably, CHIP inhibition deteriorates STZ-induced cell cycle arrest and oxidative stress in INS-1 cells. In addition to in vitro study, immunohistochemical and immunoblotting study showed that CHIP haplodeficiency exacerbates DDR in pancreas from an experimental mouse model of type I diabetes. These results suggest that CHIP protects against STZ-induced pancreatic β-cell apoptosis and hyperglycemia by interrupting the DDR-mediated apoptotic pathway. Key words: diabetes, CHIP, DNA damage response, apoptosis, β-cell

Disclosure

A. Hwang: None.
292-OR: High-Fat Diets Containing Sucrose and Fructose, but Not Glucose, Induce Obesity and Hepatic Insulin Resistance via Accumulation of Diacylglycerols
Authors: PARK SE-HYUNG , FADHUL TAGHREED I. , RONALD KAHN C. , SOFTIC SAMIR
Published: June 2023

Diets high in sugar and fat promote the development of obesity and metabolic complications, while high-sugar, low-fat or high-fat, sugar-free (ketogenic) diets do not. We assessed the importance of sugar in a commonly used 60% high-fat diet (HFD), which contains 6.7% of calories from sucrose. The sucrose content was replaced either with an equal amount of fructose (HFD+RF) or glucose (HFD+RG) and all other components of the diet were identical. After 12 weeks on the diets, the mice on HFD and HFD+RF diets gained more weight, developed hepatic steatosis, glucose intolerance and insulin resistance, compared to the mice on normal chow or HFD+RG diets. A relatively small (6.7%) amount of sucrose or fructose, but not glucose, in a HFD was sufficient to increase the fructolysis (KHK-C, ALDO B and TKFC) and de novo lipogenesis (ME1, ACLY, ACC1, FASN, SCD1) pathways by WB. Metabolomics analysis revealed higher hepatic diacylglycerol (DAG) content in HFD and HFD+RF groups, while HFD+RG group had elevated hepatic triacylglycerol content. Proteomics analysis quantified 3058 unique proteins, 736 of which were significantly different between the mice on chow and HFD. Replacing sucrose with fructose altered only 2 proteins, while replacing sucrose with fructose significantly changed 196 proteins in the liver. Reactome pathway analysis showed that the most altered processes mediate lipid biosynthesis and metabolism. In conclusion, HFDs containing sucrose or fructose but not glucose increase the fructolysis pathway and lead to hepatic DAG accumulation and insulin resistance. Thus, a relatively small amount of fructose, regardless of its source, is sufficient to alter metabolic outcomes in mice consuming a HFD.

Disclosure

S.Park: None. T.I.Fadhul: None. C.Kahn: None. S.Softic: Research Support; Alnylam Pharmaceuticals, Inc.
293-OR: Macrophage-Derived Interleukin-12 Regulates Obesity-Mediated Insulin Resistance in the Liver
Authors: FRIEDLINE RANDALL H. , ALBUSHARIF MAHAA , KIM ALLISON M. , KIM LAUREN H. , BAEZ TORRES NATALIE M. , TAUER LAUREN A. , HU XIAODI , KIM JASON K.
Published: June 2023

Inflammation and insulin resistance play a major role in nonalcoholic fatty liver disease (NAFLD), and IL-12, a pro-inflammatory cytokine primarily secreted by macrophages, is elevated in obesity. Here, we examined the effects of acute treatment with IL-12 in vivo on glucose metabolism in male C57BL/6J mice. Mouse recombinant IL-12 (0.25 μg/hour) or saline (control) was infused for 4 hours, followed by insulin clamps in mice (n=5/group). Glucose infusion rates during clamps were significantly reduced in IL-12-treated mice, resulting in a 34% decrease compared to controls (Fig. 1-2). Basal hepatic glucose production (HGP) did not differ, but clamp HGP was significantly increased in IL-12-treated mice (Fig. 3). As a result, IL-12 treatment caused a 43% decrease in hepatic insulin action compared to controls (Fig. 4). These IL-12 effects were associated with a 4-fold increase in STAT4 tyrosine-phosphorylation (0.071±0.026 vs. 0.018±0.004 in controls) and a 47% decrease in IRS1 protein levels (0.264±0.044 vs. 0.496±0.112 in controls) in the liver. Attenuated liver IL-12 level was further associated with improved hepatic insulin action in diet-induced obese mice with conditional loss of IFNγ signaling in myeloid cells. CONCLUSION: Our findings identify IL-12 as a novel cytokine regulating obesity-mediated insulin resistance and inflammation in the liver and a potential therapeutic target to treat NAFLD.

Disclosure

R.H.Friedline: None. M.Albusharif: None. A.M.Kim: None. L.H.Kim: None. N.M.Baez torres: None. L.A.Tauer: None. X.Hu: None. J.K.Kim: None.

Funding

National Institutes of Health (5U2CDK093000)
294-LB: Altered a-Cell Phenotype in Pancreata Is Associated with Increased Peri-islet Collagen Ceposition
Authors: KATTNER NICOLE , RICHARDSON SARAH , AL-SELWI YARA , TINIAKOS DINA , SHAW JAMES A.
Published: June 2023

Cystic fibrosis (CF)-related diabetes (CFRD) affects up to 50% of adults with CF, adding to treatment burden and impacting overall wellbeing. Major changes are observed in pancreas morphology with acinar tissue replaced by fibrosis and/or fat. Islets are still present even in advanced disease and may cluster together. It is believed CFRD is caused by impaired insulin secretion and loss of β-cell mass, however, detailed pathogenesis remains unknown. We investigated post-mortem pancreatic tissue from 19 donors with CF (age range: premature-27 years) and 10 donors without CF (6-65 years). CF pattern of injury (fibrotic/lipoatrophic) was assessed by routine histology. Sirius Red/Fast Green stain was used to assess fibrosis. Artificial intelligence analysis was performed to quantify intra-islet and peri-islet collagen distribution in 16 cases (7 CF, 9 control). Triple immunofluorescence staining for insulin, glucagon, and vimentin followed by confocal microscopy was used to image up to 50 islets per donor. Glucagon and vimentin-positive (glu/vim+) α-cells were observed in both CF and non-CF pancreata (mean (range) 32 (0-90)% of islets). The presence of this altered α-cell phenotype positively correlated with age in all donors (R=0.41, p<0.05). Presence of glu/vim+ α-cells correlated with peri-islet collagen density in analysed CF and control cases (glu/vim+ islets 44 (0-82)%) (R=0.60, p<0.05). In control pancreata alone glu/vim+ cells were seen in 1-82% (mean 41%) islets and correlated positively with intra-islet collagen density (R=0.76, p<0.05). Interestingly, two CF cases with confirmed diabetes showed low prevalence of this altered phenotype (2% of islets) with 13 vs 40% fibrosis in the whole section. Our data provide further evidence for exocrine-endocrine signalling in the human pancreas and suggest that presence of vimentin-expressing α-cells may be driven by increased collagen deposition in the islet microenvironment during aging and in CFRD pathogenesis.

Disclosure

N. Kattner: None. S. Richardson: None. Y. Al-selwi: None. D. Tiniakos: None. J. A. Shaw: Advisory Panel; Betalin Therapeutics, Provention Bio, Inc., Consultant; Mogrify.

Funding

Cystic Fibrosis Trust (SRC019)
296-LB: Loss of SERCA2 Induces Mitochondrial Dysfunction, Increases ß-Cell Senescence, and Accelerates Type 1 Diabetes Development
Authors: WEAVER STACI A. , BONE ROBERT N. , ACRI DOMINIC J. , KIM JUNGSU , KONO TATSUYOSHI , DAHL RUSSELL , EIZIRIK DECIO L. , SYED FAROOQ , EVANS-MOLINA CARMELLA
Published: June 2023

Type 1 diabetes (T1D) results from immune-mediated destruction of pancreatic β-cells. Senescence and activation of a senescence-associated secretory phenotype (SASP) in β-cells may contribute to T1D pathogenesis; however, the mechanisms responsible for this phenotype are not well understood. We hypothesized that loss of endoplasmic reticulum (ER) Ca2+ induces mitochondrial dysfunction and drives the development of β-cell senescence during T1D. To test this hypothesis, we generated sarco/ER Ca2+-ATPase 2 (SERCA2) haploinsufficient mice on the NOD background (NOD-S2+/-). NOD-S2+/- mice displayed accelerated T1D onset compared to NOD-WT mice (14 wks vs 18 wks; p≤ 0.0001 female and 21 wks vs 24.5 wks male; p<0.05). As expected, basal ER Ca2+ levels were reduced in NOD-S2+/- islets, but basal mitochondrial Ca2+ levels were elevated compared to NOD-WT islets. Basal cytoplasmic Ca2+ levels remained unchanged. Single cell RNA sequencing showed an increase in immune cell markers in the NOD-S2+/- islets at 6 wks of age, with signatures of ER stress and mitochondrial dysfunction at both 6 and 10 wks of age. Islets from prediabetic female NOD-S2+/- mice showed decreased glucose-stimulated O2 consumption, reduced ATP production, and decreased mitochondrial membrane potential. Additionally, protein expression of ATP synthase and Complex III was decreased in female NOD-S2+/- islets, but mitochondrial content was unchanged. There was an increased expression of multiple markers of senescence and SASP in NOD-S2+/- islets between 6 and 12 wks of age compared to NOD-WT islets. Lastly, in vivo allosteric activation of SERCA decreased insulitis and delayed diabetes onset in WT NOD mice. Our results show that SERCA2 deficiency leads to mitochondrial dysfunction, β-cell senescence, and accelerated T1D development. In future studies, we will test whether senolytic agents can delay diabetes onset and rescue mitochondrial health in models of T1D and SERCA2 deficiency.

Disclosure

S. A. Weaver: Employee; Eli Lilly and Company. R. N. Bone: None. D. J. Acri: None. J. Kim: None. T. Kono: None. R. Dahl: None. D. L. Eizirik: None. F. Syed: 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.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (F31DK134168, R01DK093954, R01DK127308, R01DK127236, UC4DK104166, U01DK127786); U.S. Department of Veterans Affairs (I01BX001733, 2I01BX001733-05); JDRF (3-PDF-2017-385-A-N, 3-IND-2022-1235-I-X); National Center for Advancing Translational Sciences (UL1TR002529)
297-LB: Dorzagliatin, a Glucokinase Activator, Repairs Defective Islet Function in High-Fat Diet-Induced Diabetic Mice
Authors: HAN DONGNA , MENG SHI , ZHOU XUE , LI RUYUE , LI CHANGHONG
Published: June 2023

The DREAM study showed long-term benefits for glucose control in newly diagnosed type 2 diabetes (T2D) patients even after withdrawal of dorzagliatin treatment, a newly approved glucokinase activator for T2D treatment, who were considered to be in the remission for diabetes. The purpose of the current study is to examine the mechanisms of dorzagliatin-induced diabetes remission by evaluating the changes in islet function over time after a period of administering dorzagliatin in high-fat diet (HFD) induced obesity and diabetes mouse models. Diabetes mice were generated after 7 months of HFD, then received dorzagliatin or vehicle controls via oral gavage once a day for 19 days (8 days of 30 mg/Kg and 11 days of 15 mg/Kg). After drug withdrawal, one group of mice remained in HFD and another group changed to a normal diet. Islets were then isolated at different time points after drug withdrawal, and the serum and liver were collected for evaluation. The glucose ramp-stimulated insulin secretion (GSIS) was evaluated in islet perifusion. Gene expression was measured by qPCR in islets and by RNA-seq in the liver. Compared to normal mouse islets, HFD-induced diabetic islets in vehicle groups have impaired GSIS with about 40% reduction in maximum insulin secretion. In contrast, GSIS was fully recovered to the levels of normal islets in 10, 18 and 38 days after dorzagliatin withdrawal, but returned to defective GSIS levels after 45 days of drug discontinuation. In addition, islet GSIS can be fully recovered after 80 days of diet change.

In conclusion, the defective GSIS in HFD-induced diabetes mouse islets is reversible and can be fully restored by dorzagliatin even after a long period of drug withdrawal while still remaining in HFD. The mechanisms are likely due to increased glucokinase gene expression caused by a short treatment of dorzagliatin. Diet change alone can recover islet function but requires weight reduction and a longer duration.

Disclosure

D. Han: Employee; Nanjing AscendRare Pharmaceutical Technology. S. Meng: Employee; Nanjing AscendRare Pharmaceutical Technology. X. Zhou: Employee; Nanjing AscendRare Pharmaceutical Technology. R. Li: Employee; Nanjing AscendRare Pharmaceutical Technology. C. Li: Employee; Hua Medicine, Nanjing AscendRare Pharmaceutical Technology.
323-OR: Association of Silent Myocardial Infarction with Cardiac Autonomic Neuropathy among Asymptomatic Patients with Type 2 Diabetes
Authors: FU YIMAN , WU LIN , YANG YI , QIN BAODING , LUO QINWEN , CHEN YANMING , ZHU YANHUA
Published: June 2023

Background: Silent myocardial infarction (SMI) is a severe cardiovascular disease among patients with DM. Nowadays, the mechanism of SMI is not clear, but diabetic cardiac autonomic neuropathy (CAN) is assumed to be the most probable reason. However, whether SMI is associated with CAN remains controversial. Therefore, we aimed to evaluate the relationship between SMI and CAN in asymptomatic patients with T2DM.

Methods: This is a hospital-based observational study. 4055 T2DM patients who were screened for CAN by Holter monitoring were investigated. Q-waves SMI was detected by ECG. The sensitivity and specificity of ECG-detected SMI by computed tomography-coronary angiography (CTA).

Results: A total of 4055 patients were screened. At last, we included 1015 patients with T2DM. In the included population, 508 cases (50%) had CAN. Patients with CAN were more likely to be older and have higher levels of TC, LDL-c, Cr, UA, and Hcy (p<0.05). A total of 466 cases of SMI were detected by ECG, and the prevalence of SMI was 45.9% in 1015 patients. Compared with T2DM patients without CAN, patients with CAN had a higher prevalence of SMI (73.4% vs 26.6%, p<0.001). Multivariate logistic regression analysis confirmed that concomitant CAN was an independent predictor of the risk of SMI in T2DM patients (OR=7.53, 95%CI:2.98-19.02, p<0.001). Among the 133 patients who underwent coronary CTA, 55 (41.0%) cases had SMI, and 36 of them had Q-waves on ECG. The sensitivity and specificity of SMI detected by ECG were 65.5% and 91.0%, respectively. In 133 T2DM patients, patients with CAN also had a higher risk of occurring SMI than those without CAN (65.5% vs 34.5%, p<0.001).

Conclusion: In asymptomatic T2DM patients, the occurrence of SMI was independently associated with CAN. Therefore, we should pay attention to the possibility of SMI in asymptomatic T2DM patients clinically. In particular, the monitoring should be strengthened when patients combined with diabetic CAN.

Disclosure

Y.Fu: None. L.Wu: None. Y.Yang: None. B.Qin: None. Q.Luo: None. Y.Chen: None. Y.Zhu: None.
325-OR: Glucagon-Like Peptide 1 Receptor Agonists Preserved Vascular Endothelial Junction through Inhibition of STING Signaling–Elicited Inflammation in Diabetic Retinopathy
Authors: HE XUEMIN , WEN SIYING , TANG XIXIANG , WEN ZHEYAO , ZHANG RUI , LI SHASHA , GAO RONG , ZHU YANHUA , LU YAN , SHI GUOJUN , CHEN YANMING
Published: June 2023

Background: Glucagon like-peptide 1 receptor agonists (GLP-1 RAs) are protective to macrovascular diseases and nephropathy in diabetic patients; however, their role in diabetic retinopathy (DR) are still debatable. This study aimed to address the effect of GLP-1 RAs on endothelial junction and inflammation in DR.

Methods: GLP-1 RAs were injected to db/db mice, then retinal inflammation and vascular changes were determined by RNA-sequencing analysis, immunostaining, fluorescein fundus imaging and Optical coherence tomography. Cross-sectional study of 1626 type 2 diabetic patients was performed.

Findings: GLP-1R was majorly detected in retinal vessels, which was down-regulated by diabetes. GLP-1 RAs significantly rescued diabetes-induced retinal thinning and vascular tortuosity, likely through altered the expression profiles of junction- and mitochondria-related genes, which was confirmed by exedin-4 treatment in vitro. Stimulator of interferon genes (STING) was most abundant in the endothelial cells from fibrovascular membranes, which was positively correlated with the levels of angiogenic factors and inflammatory factors in endothelial cells from retinas with retinopathy and fibrovascular membranes. Further analysis showed prominent inhibition by GLP-1 RAs on STING activation in db/db retinas. Cross-sectional study further showed decreased DR incidence by GLP-1 RAs.

Conclusions: Activation of the STING pathway induced inflammatory factors while suppressed junctional proteins in endothelial cells of DR. GLP-1 RAs ameliorated diabetes-elicited vascular damages through inhibition of the STING pathway.

Disclosure

X.He: None. G.Shi: None. Y.Chen: None. S.Wen: None. X.Tang: None. Z.Wen: None. R.Zhang: None. S.Li: None. R.Gao: None. Y.Zhu: None. Y.Lu: None.

Funding

National Natural Science Foundation of China (82000782, 82270886, 82070811); Third Affiliated Hospital of Sun Yat-sen University (2020G2RPYQN11); China International Medical Foundation (2018-N-01); Science and Technology Plan Project of Guangzhou City (202007040003)
335-OR: Participant Engagement and Weight Loss in the National Diabetes Prevention Program before and during COVID
Authors: SAN DIEGO EMILY , CHICHMARENKO MARIYA , SORIANO EMILY , SPIERLING BAGSIC SAMANTHA R. , ORENDAIN NATALIA , FORTMANN ADDIE L. , RUIZ MONICA , PHILIS-TSIMIKAS ATHENA
Published: June 2023

The CDC’s National Diabetes Prevention Program (NDPP) aims to prevent or delay type 2 diabetes (T2D) through lifestyle change and weight loss. Due to challenges implementing in-person programs during the COVID-19 pandemic, many CDC-recognized organizations transitioned to offer the NDPP virtually. This analysis used NDPP data collected as part of routine care at Scripps Health, a large, non-profit health system in San Diego, CA. There were 273 individuals who participated in the NDPP before COVID (in-person sessions; October 2016 - January 2020) and 73 during COVID (virtual sessions; August 2020 - June 2021). Participants who attended virtually and in-person were, on average, 59.59±12.71 and 59.90±13.93 years old, and the majority were women (69% and 83%), White (65% and 45%), married (81% and 62%), and college graduates (66% and 44%), respectively. Chi-square, Fisher’s exact, and unpaired t-tests examined differences between the in-person vs. virtual cohorts. Compared to in-person, virtual participants consisted of significantly more men (31% vs. 17%, p= .01), but fewer Hispanics (14% vs. 43%, p< .01), Spanish-speakers (1% vs. 17%, p < .05), individuals with less than high school education (0% vs. 18%, p < .05), and individuals with household income of less than $24,000 (1% vs. 17%, p < .05). While the number of core sessions attended was not significantly different (M=20.19 vs. M=18.82; p> .05), average percent weight loss was significantly lower for individuals in the virtual sessions than in the in-person sessions (M=3.35 vs. M=4.50; p= .05). Although the NDPP has continued to reach participants despite the pandemic’s challenges, participation by racial and ethnic minority and socioeconomically disadvantaged individuals declined when the program transitioned to virtual delivery. More research is needed to examine patient-centered approaches to improve outcomes and engage underserved communities that are disproportionately affected by prediabetes and T2D.

Disclosure

E.San diego: None. M.Chichmarenko: None. E.Soriano: None. S.R.Spierling bagsic: None. N.Orendain: None. A.L.Fortmann: Employee; Dexcom, Inc. M.Ruiz: None. A.Philis-tsimikas: Advisory Panel; Dexcom, Inc., Novo Nordisk A/S, Sanofi, Other Relationship; Medtronic, Research Support; Novo Nordisk A/S, Lilly, Viking Therapeutics, NIH - National Institutes of Health.

Funding

National Institutes of Health (UL1TR002550, KL2TR002552)
338-OR: Increased Glucose Time in Range following Active vs. Sedentary Days in Newly Diagnosed Youth with T1D—4T Exercise Results
Authors: ZAHARIEVA DESSI P. , RITTER VICTOR , RIDDELL MICHAEL , ADDALA ANANTA , BISHOP FRANZISKA K. , PRAHALAD PRIYA , DESAI MANISHA , HOOD KOREY K. , SCHEINKER DAVID , MAAHS DAVID M.
Published: June 2023

The 4T Exercise Study started newly diagnosed youth with T1D on CGM and physical activity (PA) trackers ~1-month post diagnosis. We examined real-world PA patterns and glycemia in youth with T1D during the first year post diagnosis. A physically active day was identified as ≥10 mins of continuous moderate-to-vigorous intensity PA, with moderate-intensity (MOD) defined as 3-6 metabolic equivalents (METS) and high-intensity (HIE) as >6 METS. All other days were deemed as sedentary (SED) days. CGM data 24h after exercise were used to compute percent time below range (TBR; <70 and TBR2; <54 mg/dL), time in range (TIR; 70-180 mg/dL), and time above range (TAR; >180 and TAR2; >250 mg/dL). A total of 45 youth (age: 13 [IQR 12, 15] years, 38% female, 40% non-Hispanic White, 76% private insurance) wore activity trackers 13 [IQR: 8, 16] hours daily. Compared to SED days, higher intensity PA levels were associated with higher TIR (70% SED vs 72% with MOD, P=0.2; 76% with HIE, P=0.001) and lower TAR (28% SED vs 24% with MOD, P=0.08; 21% with HIE, P<0.001), but no difference in TBR (2.8% SED vs 3.6% following MOD, P=0.2; 3.7% following HIE, P=0.14). Overall, higher levels of PA in youth with new onset T1D was associated with over an hour of increased TIR per day, without significant increases in TBR. Exercise education soon after diagnosis is an opportunity to improve care and establish safe and healthy PA habits.

Disclosure

D.P.Zaharieva: Advisory Panel; Dexcom, Inc., Research Support; Hemsley Charitable Trust, International Society for Pediatric and Adolescent Diabetes, Insulet Corporation, Speaker's Bureau; American Diabetes Association, Ascensia Diabetes Care, Medtronic. D.M.Maahs: Advisory Panel; Medtronic, LifeScan Diabetes Institute, MannKind Corporation, Consultant; Abbott, Research Support; Dexcom, Inc. V.Ritter: None. M.Riddell: Advisory Panel; Zealand Pharma A/S, Zucara Therapeutics, Indigo Diabetes, Consultant; Lilly Diabetes, Eli Lilly and Company, Jaeb Center for Health Research, Speaker's Bureau; Dexcom, Inc., Novo Nordisk, Sanofi, Stock/Shareholder; Supersapiens, Zucara Therapeutics. A.Addala: None. F.K.Bishop: None. P.Prahalad: None. M.Desai: None. K.K.Hood: Consultant; Cecelia Health. D.Scheinker: None.

Funding

National Institutes of Health (P30DK116074); Stanford Diabetes Research Center (R18DK122422 to D.M.M.); Dexcom, Inc.; Lucile Packard Children’s Hospital Auxiliaries Endowment; The Leona M. and Harry B. Helmsley Charitable Trust (G-2002-0425); Internationa
348-OR: Differentiation of Adult Islet Cell Precursors into ß- and α-like Cells for Islet Transplantation
Authors: DARDEN CARLY , KUNCHA JAYACHANDRA , MATTKE JORDAN D. , NAZIRUDDIN BASHOO , LAWRENCE MICHAEL C.
Published: June 2023

Advances in protocols to convert human embryonic and inducible pluripotent stem cells (hESCs and iPSCs) into pancreatic β cells has allowed us to generate islet cell organoids in culture for potential use in islet cell transplantation. Here, we demonstrate that dedifferentiated β cells and/or NGN-/RGS16+ islet cell precursors (ICPs) can be harvested from adult pancreatic tissue and converted into β- and α-like cells. In this study, we used ICPs derived from COBE bag pancreatic tissue remnants from organ donors to produce islet cell organoids capable of releasing both insulin and glucagon in response to high (16.7 mM) and low (2.8 mM) glucose conditions, respectively. These organoids displayed zinc-containing granule staining by dithizone and exhibited GSIS with stimulation indices comparable to human islets. ICPs produced genetic profiles similar to hESC-derived endocrine progenitor cells at stages 5-7 (S5-7). Using small molecule ISX9 and GSK/DYRK inhibitors GNF and harmine to induce and activate calcineurin (CN)/NFAT signaling, we were able to expand and differentiate ICPs into β- and α-like cells. CN/NFAT upregulated genes that promote cell cycle and proliferation (S5) and islet cell differentiation genes (S5-7). Islet cell type fate and function could be modulated by hedgehog/GLI signaling. Whereas introduction of sonic hedgehog (Shh) inhibitor SANT-1 at S5 favored production of β-like cells, Shh signaling agonists promoted differentiation to α-like cells up to S7. Overall, these results indicate that adult ICPs can be harvested from donor tissue and expanded for differentiation into functional β- and α-like cells. The capability to expand and differentiate adult ICPs could potentially provide an unlimited supply of islet organoid tissue for islet cell transplantation.

Disclosure

C.Darden: None. J.Kuncha: None. J.D.Mattke: None. B.Naziruddin: None. M.C.Lawrence: None.

Funding

Baylor Scott & White Health
35-LB: The Impact of the COVID-19 Pandemic on A1C Reductions in Patients with Diabetes Mellitus Who Attended an ADA-Recognized DSMES Program
Authors: STONEKING KENT B. , LATIF KASHIF , MOORE MARIAN , WHITE HANNAH
Published: June 2023

AM Diabetes Centers of America, an independent endocrinology practice in Bartlett, Tennessee, offers a diabetes self-management, education, and support (DSMES) program that has been recognized by the American Diabetes Association (ADA) since 2010. The program typically serves 450-500 participants per year, all from the Memphis/Mid-South area. Per ADA requirements, participants’ pre- and post-program attendance glycated hemoglobin (A1C), weight, blood pressure, and lipids, are reported annually. Of these, A1C was observed as a key metric indicating blood glucose control. Data sets from ADA Chronicle Diabetes were analyzed quantitatively to compare program attendance and A1C reductions between 2013-2019 and the pandemic peak in 2020-2021. From 2013-2018, program attendance grew at an average rate of 26% per year. Attendance dropped by 30% in 2019, but average A1C reduction among participants in 2019 was 0.8%, and average A1C reduction for all participants in 2013-2019 was 0.64% (SD=0.346; p=0.003). In 2020-2021, attendance dropped by an average of 30% per year, and average A1C reduction was only 0.45% (SD=0.05; p=0.035). In the first post-pandemic year, program attendance rebounded by 18% and average A1C reduction was 1.1%. Because a direct correlation exists between waning program attendance and reduced impact upon participants’ A1C levels during COVID-19, and because these trends reversed as soon as pandemic restrictions were lifted, it may be reasonably ascertained that the mandated restrictions on in-person meetings and outside activities were key factors in producing these results.

Disclosure

K. B. Stoneking: None. K. Latif: None. M. Moore: None. H. White: None.
351-OR: Two Different Ways to Replace Beta-Cell Mass after Partial Pancreatectomy
Authors: JOON KIM BYUNG , PARK HEEKYOUNG , SHIN JUN-SEOP , KIM KWANG-WON
Published: June 2023

Treatment of diabetes in which beta cell mass is reduced is islet transplantation (IT), which replaces beta cells, and insulin therapy, which rests beta cells. Although both methods show significant results in preventing the progression of diabetes, it is controversial whether the two treatments work through the same mechanism. To evaluate this hypothesis, insulin injection or IT was performed on mice that had undergone 50% partial pancreatectomy, and the IPGTT and histological changes of the remnant pancreas were examined. In the IPGTT conducted after IT or insulin treatment after pancreatectomy for 7 days, the blood glucose profile of the IT mice was similar to that of normal, but the insulin-treated mice showed a significantly higher blood glucose level than normal. In histology of the remnant pancreas in the insulin-treated group, alpha cells increases, and the alpha/beta ratio was significantly higher than in the normal or IT group. There was no difference in islet proliferation or apoptosis in the insulin-treated group, but PDX-1 expression was significantly higher in alpha cells of the insulin-treated group. In conclusion, insulin or IT as a treatment method to replace beta cells is known in a similar way. But, IT is a more physiological method than insulin treatment, and it needs to be worked more detail whether notable increases of alpha cell mass in the remnant pancreas due to insulin treatment is a short-term or a continuous change.

Disclosure

B.Kim: None. H.Park: None. J.Shin: None. K.Kim: None.
363-OR: Brown Adipose Tissue m6A mRNA Methylation Regulates Systemic Insulin Sensitivity via a Prostaglandin Interorgan Axis
Authors: XIAO LING , DE JESUS DARIO F. , JU CHENG-WEI , WEI JIANGBO , HU JIANG , TSUJI TADATAKA , CERO CHERYL , KAMINSKA DOROTA , CYPESS AARON M. , PIHLAJAMAKI JUSSI , TSENG YU-HUA , KULKARNI ROHIT
Published: June 2023

Brown adipose tissue (BAT) has the capacity to regulate peripheral insulin sensitivity via the secretion of signaling lipids. N6-methyladenosine (m6A) is among the most prevalent and abundant post-transcriptional RNA modifications in eukaryotes. Recently, m6A has been shown to regulate islet and hepatic metabolism as well as BAT adipogenesis and energy expenditure. Here, we demonstrate that deficiency of m6A methyltransferase-like 14 (M14) in BAT positively regulates BAT-secretory function to improve systemic insulin sensitivity through inter-organ communication. Using lipidomic approaches, we identified prostaglandin E2 (PGE2) and prostaglandin F2a (PGF2a) as M14KOBAT-secreted insulin sensitizers. Notably, circulatory PGE2 and PGF2a showed significant inverse correlation with HOMA-IR in humans. Furthermore, in vivo administration of PGE2 and PGF2a in HFD-induced insulin resistant obese mice recapitulated the phenotypes of M14KO mice. Exogenous PGE2 or PGF2a significantly improved insulin stimulated-pAKT by suppressing expression of specific phosphatases in human hepatocyte cell line. Mechanistically, M14-mediated m6A installation destabilizes transcripts encoding PGE2 and PGF2a synthases in brown adipocytes in an YTHDF2/3-dependent manner. Collectively, these results unveil a new mechanism by which m6A-facilitated BAT-secretory function enables the regulation of whole body insulin sensitivity.

Disclosure

L.Xiao: None. J.Pihlajamaki: None. Y.Tseng: Consultant; Cellarity, LyGenesis. R.Kulkarni: Advisory Panel; Novo Nordisk, Inversago, Biomea Fusion, Inc., REDD Pharma, Research Support; Inversago. D.F.De jesus: None. C.Ju: None. J.Wei: None. J.Hu: None. T.Tsuji: None. C.Cero: None. D.Kaminska: None. A.M.Cypess: None.
365-OR: A Machine-Learning Approach to Estimate Insulin Resistance from Untargeted Metabolomics Data
Authors: ALLRED NICHOLETTE , HSU FANG-CHI , CHEN SHYH-HUEI , NG MAGGIE , GOODARZI MARK O. , ROTTER JEROME I. , WAGENKNECHT LYNNE E. , BANCKS MICHAEL , BERGMAN RICHARD N. , BOWDEN DONALD W.
Published: June 2023

Insulin resistance (IR) is constantly invoked as a contributor to numerous common diseases, e.g. diabetes, cardiovascular disease and Alzheimer’s disease; however, with the exception of a narrow segment of diabetes-related studies, IR is infrequently measured and rarely measured well. Our goal was to develop IR estimation models for the dynamic measure of insulin sensitivity (SI) and the basal measure of homeostatic model assessment of IR (HOMAIR) from metabolomics data combined with minimal clinical data, e.g. age, sex, BMI. Least Absolute Shrinkage and Selection Operator (LASSO) and Elastic Net regression were used to build estimation models using 1274 metabolites, prioritized by trait associations and collected in the Insulin Resistance Atherosclerosis Family Study (IRASFS). Three metabolite transformations were implemented (inverse normal transformation, standardization, and Box Cox transformation) to account for distributional differences and tested to optimize estimation. The analysis was performed in one Mexican American (MA) recruitment site (San Luis Valley, CO (SLV), N=450) and tested in another MA recruitment site (San Antonio, TX (SA), N=473). In addition, the two MA recruitment sites were combined and estimation models tested in the African American recruitment site (AA; Los Angeles, California, N=495) to assess generalizability. Estimated SI was correlated with empiric SI in the SA (r2=0.77) and AA (r2=0.74) testing datasets. Further, we tested estimated SI for association with BMI, low-density lipoprotein cholesterol and triglycerides with results consistent with those observed for empiric SI. The same framework was used to estimate HOMAIR, and yielded similar results. In summary, we have developed methods for estimating multiple measures of IR from a single blood sample. This approach will greatly expand our ability to provide meaningful insight into the role of IR in disease, supporting the potential for application to a wide-range of biomedical studies.

Disclosure

N.Allred: None. D.W.Bowden: None. F.Hsu: None. S.Chen: None. M.Ng: None. M.O.Goodarzi: Advisory Panel; Nestlé Health Science, Other Relationship; Nestlé Health Science. J.I.Rotter: None. L.E.Wagenknecht: None. M.Bancks: None. R.N.Bergman: Consultant; Lilly, ReCor Medical, Inc., Research Support; AstraZeneca.

Funding

National Institutes of Health (DK118062)
366-OR: Regulation of Metabolite Pools Influences Adipocyte Differentiation and Antioxidant Capacity
Authors: FELIX JESSICA B. , SAHA PRADIP , COX AARON , SHARP ROBERT A. , MASSCHELIN PETER M. , HARTIG SEAN M.
Published: June 2023

Obesity and related metabolic disorders, such as insulin resistance and type 2 diabetes (T2D), affect over 40% of U.S. adults and increase the risk of death from cardiovascular disease. Understanding the mechanisms connecting obesity, T2D, and defective adipocyte function bring us closer to developing therapeutic strategies. We discovered expression of the enzyme aspartoacylase (ASPA) in white adipose tissue (WAT) correlates with adipocyte function and insulin sensitivity in mice and people. In the brain, ASPA contributes to the acetate pool necessary for lipid synthesis, and ASPA deficiency causes progressive myelin degeneration and death at a young age. We also observed abundant ASPA expression in WAT at significantly higher levels than whole brain. Aspa is induced during adipocyte differentiation in vitro along with known adipogenic markers. These observations led us to hypothesize that ASPA and its metabolite byproducts regulate adipocyte differentiation and systemic energy balance. When assessing the in vivo effects of Aspa deficiency, Aspa-/- mice accumulated less body mass than Aspa+/+ when fed normal chow diet for 12 weeks. Morphometric tissue analyses indicated Aspa-/- mice maintain smaller adipocytes, corresponding with lower WAT mass at necropsy. Glucose tracing experiments suggested Aspa knockout cells exhibit greater pyruvate carboxylase (PC) anaplerosis that feeds amino acid pools for glutathione synthesis. Mass spectrometry data also indicated higher PC anaplerosis in the adipose tissues of Aspa knockout mice. Persistent and prolonged oxidative stress hinders adipocyte function and insulin sensitivity, while PC activity supports antioxidant capacity. In line with this, Aspa knockout cells showed increased expression of proteins that sustain antioxidant activities. In summary, our studies establish a new role for ASPA outside the brain that contributes to redox activities in adipocytes.

Disclosure

J.B.Felix: None. P.Saha: None. A.Cox: None. R.A.Sharp: None. P.M.Masschelin: None. S.M.Hartig: None.

Funding

American Diabetes Association (1-18-IBS-105 to S.M.H.); National Institutes of Health (F31DK130596, R01DK114356)
369-OR: Continued Weight Loss with Semaglutide Once-Weekly in Patients without Type 2 Diabetes and Postbariatric Treatment Failure
Authors: LAUTENBACH ANNE , WAGNER JONAS , STOLL FABIAN D. , ABERLE JENS
Published: June 2023

Purpose: Recently, we published promising retrospective 6-months follow-up data on the effectiveness of semaglutide 0.5mg once-weekly in patients with weight regain (WR) or insufficient weight loss (IWL) following bariatric metabolic surgery (BS). Therefore, we aimed to investigate whether weight loss was sustained over a 12-months period with semaglutide in patients without type 2 diabetes (T2D) with WR or IWL.

Materials and Methods: Postbariatric patients without T2D with WR or IWL (n=29) were included in the analysis. The primary endpoint was weight loss 12 months after initiation of adjunct treatment. Secondary endpoints included change in BMI, HbA1c, lipid profile, hs-CRP and liver enzymes.

Results: Total weight loss during semaglutide treatment added up to 14.7±8.9% (mean±SD, p<0.001) after 12 months. Categorical weight loss was >5% in 89.7% of patients, >10% in 62.1% of patients, >15% in 34.5% of patients, >20% in 24.1% of patients and >25% in 17.2% of patients. Among patients with prediabetes at baseline (n=6), 12-months treatment led to normoglycemia in all patients (p<0.05).

Conclusion: Treatment options to manage postbariatric treatment failure are scarce, weight loss medications are not approved for use in the postbariatric patient population. Our results imply a clear benefit of adjunct treatment with semaglutide in postbariatric patients.

Disclosure

A.Lautenbach: Other Relationship; Novo Nordisk, Lilly. J.Wagner: None. F.D.Stoll: None. J.Aberle: Advisory Panel; Novo Nordisk, Speaker's Bureau; Novo Nordisk.
371-OR: Mortality in the Swedish Obese Subjects Study over up to 30 Years in Relation to Two-Year Diabetes Remission after Bariatric Surgery or Usual Care
Authors: SJÖHOLM KAJSA , ANDERSSON ASSARSSON JOHANNA C. , TAUBE MAGDALENA , CARLSSON EKANDER LENA
Published: June 2023

Introduction: Patients with obesity and concomitant type 2 diabetes (T2D) have reduced life expectancy, which may to some extent be explained by an increased risk of developing vascular diseases and cancer. Remission of T2D is known to reduce the risk of diabetes-related diseases. Here, we examined whether 2-year diabetes remission after bariatric surgery or usual care is associated with long-term mortality in patients from the Swedish Obese Subjects (SOS) study.

Methods: This report includes 586 patients with obesity and baseline T2D; 338 underwent bariatric surgery and 248 obtained usual obesity care, median follow up was 26 years. The Swedish Cause of Death Register, case sheets and autopsy reports were assessed to determine the direct cause of death. Analyses were adjusted for preselected risk factors (age, sex, BMI and smoking at baseline, and year of inclusion in the study).

Results: Overall, 284 patients were in remission at the 2-year examination whereas 302 were not. During follow-up, mortality rates were 16.6 deaths per 1000 person-years (95% CI:13.7-20.1) in the remission subgroup and 26.0 deaths per 1000 person-years (95% CI:22.2-30.4) in the non-remission subgroup (adjusted hazard ratio (AdjHR) 0.59, 95% CI:0.46-0.77, p<0.001). Specifically, cardiovascular mortality was decreased in the remission subgroup (Adj sub-HR 0.53, 95% CI:0.35-0.81, p=0.003). Moreover, 2-year remission was associated with reduced mortality after both surgery and usual care (AdjHR 0.57 (95% CI:0.39-0.83), p=0.003 and AdjHR 0.53 (95% CI:0.32-0.90), p=0.018, respectively).

Conclusions: Remission of T2D after bariatric surgery or usual obesity care is associated with reduced long-term mortality, mainly due to decreased cardiovascular death.

Disclosure

K.Sjöholm: None. J.C.Andersson assarsson: None. M.Taube: None. L.Carlsson ekander: None.

Funding

Swedish Research Council; Swedish State; Swedish Heart and Lung Foundation; Swedish Diabetes Foundation; Adlerbert Research Foundation
380-P: Towards Prevention of Nonsevere Hypoglycemia in Type 1 Diabetes with Oral Glucose at a Higher Blood Glucose Threshold—The REVERSIBLE Trial
Authors: CHENG RAN , TALEB NADINE , WU ZEKAI , MESSIER VIRGINIE , RABASA-LHORET RÉMI
Published: June 2023

Background: Current guidelines recommend initiating the treatment of non-severe (NS) hypoglycemia with 15g of carbohydrates (CHO) at 15 minutes intervals when blood glucose (BG) reaches <72 mg/dl. Despite this recommendation, NS hypoglycemia management remains challenging for people living with type 1 diabetes (pwT1D) and more optimal treatment strategies are required. We aim to assess the efficacy of 15g of CHO at higher treatment thresholds.

Methods: The REVERSIBLE Trial is an open-label, randomized, three interventions x three periods cross-over study. Following inpatient insulin-induced decrease in BG, 16g of oral carbohydrates is administered at a plasma glucose threshold of <72 mg/dl, ≤81 mg/dl or ≤90 mg/dl. The primary outcome is the time (in minutes) spent in hypoglycemia (<72 mg/dl) after the initial correction.

Results: Participants (n=29) characteristics are 52% male, 46.8±16.3 years old, BMI of 26.4±3.9 kg/m2, diabetes duration of 26.2±15.9 years, A1c of 53.4±15.5 mmol/mol and 62% insulin pump users. When comparing <72 mg/dl (control) to ≤81 mg/dl and ≤90 mg/dl treatment thresholds, 100% vs. 86% (p=0.1201) vs. 34% (p<0.0001) of participants had hypoglycemia. These hypoglycemic events lasted 26.0±12.6 vs. 17.9±14.7 (p=0.026) vs. 7.1±11.8 (p=0.002) minutes, with a blood glucose nadir of 56.5±9.9 vs. 63.5±7.9 (p=0.008) vs. 73.4±9.7 mg/dl (p=0.002) respectively. In the control group, 69% of participants required more than one treatment to reach or maintain normoglycemia (≥ 72 mg/dl) compared to 52% in the ≤81 mg/dl group and 31% in the ≤90 mg/dl group with no significant rebound hyperglycemia (>180mg/dl) within the first hour.

Conclusion: Compared with <72 mg/dl, consuming 16g of oral carbohydrates at ≤81 mg/dl and ≤90 mg/dl shortened the time spent in hypoglycemia, lessened the glucose nadir and reduced the need for repetitive treatments. For some NS episodes, pwT1D could benefit from CHO intake at a higher BG threshold.

Disclosure

R.Cheng: None. N.Taleb: Consultant; Viatris Inc. Z.Wu: Other Relationship; Eli Lilly and Company. V.Messier: None. R.Rabasa-lhoret: Consultant; Dexcom, Inc., Abbott, Janssen Pharmaceuticals, Inc., Novo Nordisk Canada Inc., Sanofi, Lilly, Tandem Diabetes Care, Inc., Insulet Corporation.

Funding

JDRF (4-SRA-2018-651-Q-R); Canadian Institutes of Health Research (JT1-157204)