bluuebunny/crossref_metadata_2025 huggingface dataset:
1462-P: ASCL1—A Potentially Novel Type 1 Diabetes Gene
Authors: LAVELLE KRISTEN C. , YANG KATHERINE , WANG JUEHU , CHAMBERLAIN CHESTER , GERMAN MICHAEL
Published: June 2023

Background: New insights into type 1 diabetes (T1D) have recently come from studies of rare monogenic forms of the disease. Uncovering the genes that drive these monogenic forms can reveal mechanisms and druggable pathways in affected families that may be extended to the general T1D population. We have identified one such candidate gene: Achaete-scute complex 1 (ASCL1). ASCL1 encodes a basic helix-loop-helix (bHLH) transcription factor and is well-known for its role in neurogenesis, however it is less understood how this gene may impact immune tolerance. Recent studies have demonstrated that ASCL1 and its targets are expressed in medullary thymic epithelial cells (mTECs), which are key players in the removal of autoreactive T cells from the thymus.

Methods: Whole exome sequencing (WES) was performed on individuals from our monogenic T1D registry and functional studies were performed in a human cell line using lentiviral vectors and bulk RNAseq.

Results: We identified a novel coding mutation in the bHLH transcription factor ASCL1 in siblings with suspected monogenic T1D. WES revealed a heterozygous coding variant in ASCL1 that was predicted to be both deleterious and rare. This caused an amino acid substitution within the transcriptional activation domain of the ASCL1 protein. RNAseq analysis showed a broad reduction in the activation of gene targets in cells expressing the ASCL1 patient mutation.

Conclusion: ASCL1 may play a role in central tolerance and be a new candidate gene for T1D.

Disclosure

K.C.Lavelle: None. K.Yang: None. J.Wang: None. C.Chamberlain: None. M.German: Advisory Panel; Encellin, Inc., Stock/Shareholder; ViaCyte, Inc.

Funding

The Leona M. and Harry B. Helmsley Charitable Trust; Larry L. Hillblom Foundation; Nora Eccles Treadwell Foundation; National Institute of Diabetes and Digestive and Kidney Diseases
1463-P: Heterozygous Variant in NFKB1 Presenting with Autoantibody-Negative (AbNeg) Insulin-Dependent Diabetes (IDDM)
Authors: REDONDO MARIA J. , LIU PENGFEI , ALKANAQ AHMED N. , TOSUR MUSTAFA , RAM NALINI , KREIENKAMP RAYMOND J. , ORAL ELIF A. , PIHOKER CATHERINE , POSEY JENNIFER , BALASUBRAMANYAM ASHOK
Published: June 2023

Due to its uncertain etiology and clinical management, AbNeg IDDM is a phenotype of interest for the NIH-funded Rare and Atypical Diabetes Network (RADIANT), which aims to identify and characterize people with unknown forms of diabetes (DM). We report a case of childhood-onset AbNeg IDDM found to have a likely pathogenic variant in NFKB1. A 17-year-old female presented with DM at age 7 with A1c 10.8%; random C-peptide 0.21 ng/ml; no diabetic ketoacidosis; negative GAD65, insulin, IA-2 and ZnT8 Ab; normal BMI%ile; no signs of insulin resistance; and negative genetic testing for monogenic DM. She has required continuous insulin therapy. Past medical history: IgA deficiency, vitamin D deficiency, orthostatic intolerance, neurocardiogenic pre-syncope and chronic migraine. Family history: Autoimmune adult-onset DM and hypothyroidism in mother, frequent upper respiratory infections in sisters, Addison’s disease in maternal grandfather, hemochromatosis in paternal grandmother and pericarditis at age 30 in paternal grandfather. Physical exam: Unremarkable. RADIANT Labs: Undetectable serum C-peptide. Negative Ab. Whole genome sequencing: Heterozygous likely pathogenic variant in NFKB1 impacting the canonical splice acceptor sequence (NM_003998.4:c.1753-1G>C). This is a case of youth-onset AbNeg IDDM found to have a likely pathogenic variant in NFKB1. Heterozygous loss-of-function variants in NFKB1 are associated with Common Variable Immunodeficiency (CVID) type 12 (OMIM #616576), characterized by incomplete penetrance and variable expressivity of immunodeficiency and autoimmunity, including features of IDDM. Immune dysregulation may explain lack of classic Ab. There are no prior reports of CVID first ascertained through a DM phenotype. Thus, this case represents a phenotype expansion of NFKB1-associated disease, and contributes to our understanding of the heterogeneity of AbNeg IDDM. Genetic testing of first-degree relatives is underway.

Disclosure

M.J.Redondo: None. A.Balasubramanyam: None. P.Liu: Other Relationship; Baylor Genetics. A.N.Alkanaq: None. M.Tosur: Advisory Panel; Provention Bio, Inc. N.Ram: None. R.J.Kreienkamp: None. E.A.Oral: Advisory Panel; Amryt Pharma Plc, Regeneron, Rejuvenate Bio, Third Rock Ventures, Consultant; Amryt Pharma Plc, Ionis Pharmaceuticals, Regeneron, Other Relationship; Amryt Pharma Plc, Research Support; Amryt Pharma Plc, Novo Nordisk, Fractyl Health, Inc., Ionis Pharmaceuticals, Regeneron, GI Dynamics, Rejuvenate Bio. C.Pihoker: None. J.Posey: None.

Funding

National Institutes of Health (U54DK118638)
147-OR: Revisiting the Impact of Opioid Receptor Blockade on Hypoglycemia-Associated Autonomic Failure (HAAF)
Authors: BOYLE CAROLINE E. , MATHIAS PRIYANKA M. , FABIOLA NOGUEIRA CORDEIRO MONICA , MANAVALAN ANJALI , CAREY MICHELLE , JIANG NANCY , SANDU OANA , GABRIELY ILAN , ZHANG KEHAO , HAWKINS MEREDITH , LONTCHI YIMAGOU ERIC , ALEKSIC SANDRA
Published: June 2023

HAAF, which has been defined as >20% reduction in average epinephrine (Epi) levels following recurrent hypoglycemia (PMID: 28911152), complicates insulin therapy in T1D. We previously showed that activation of opioid receptors induces HAAF, while intravenous (IV) administration of the opioid receptor antagonist naloxone prevents HAAF. Because of its wide clinical use and possible direct CNS effects, we examined the effects of intranasal naloxone (IN) on hypoglycemia and HAAF.

Seventeen (15M, age 43.8±8.7) healthy adults were enrolled in a randomized, placebo-controlled, cross-over, double-blinded study in which they underwent three hyperinsulinemic hypoglycemic clamp studies (duration 2h, glucose nadir 54 mg/dL), with administration of IN (4mg) or placebo during the first two clamps. Two subjects were excluded for lack of Epi response to hypoglycemia. Nine of the remaining 15 subjects developed HAAF, confirming inter-individual variability in susceptibility to HAAF (PMID: 32915987, 35475026).

Among the 15 subjects included in the analysis, Epi levels trended downward between the 1st and 3rd clamps in placebo studies (mean ± SEM: 677 ± 114 vs. 512 ± 78 pg/mL, p=0.054), whereas Epi levels remained stable in IN studies (1st vs. 3rd: 519 ± 70 vs. 487 ± 77 pg/mL, p= 0.69). Among the 9 subjects who developed HAAF, Epi levels during the 1st clamp were significantly lower with IN vs. placebo (493 ± 102 vs. 858 ± 161 pg/mL, p=0.03), but there was no further reduction in Epi with IN (1st vs. 3rd: 493±102 vs. 539±101 pg/ml, p=0.67).

In summary, these studies suggest differential effects of intranasal naloxone on initial vs. repeated hypoglycemic episodes. Specifically, IN may be effective in preventing Epi blunting during repeated exposure to hypoglycemia. In subjects susceptible to HAAF, IN may paradoxically blunt the Epi response to initial hypoglycemic exposure. Future studies should investigate the clinical significance of initial vs. ongoing epinephrine responses to hypoglycemia.

Disclosure

C.E.Boyle: None. M.Hawkins: None. E.Lontchi yimagou: Employee; Sanofi. S.Aleksic: None. P.M.Mathias: None. M.Nogueira cordeiro: None. A.Manavalan: None. M.Carey: None. N.Jiang: None. O.Sandu: None. I.Gabriely: None. K.Zhang: None.

Funding

National Institutes of Health (R01DK079974)
1475-P: Novel Mutations in the Wolframin Gene with Diabetes—A Case Series of a Potential Addition to the Monogenic Diabetes Profile
Authors: YIN ZACHARY , NOOR ABDULLAH A. , ROMO KARINA G. , BHAMRE SNEHA , GABRIEL MARY , PULISETTY TANAYA , SHU SHARON , UWAIFO GABRIEL I.
Published: June 2023

Monogenic DM (MGDM) is a heterogeneous group of disorders caused by single gene mutations resulting in variable clinical phenotypes of diabetes mellitus (DM). While maturity onset diabetes of the young (MODY) remains the most known group, it is now recognized that there are other single gene defects associated with DM. Current MODY classification details 14 distinct genetic types which are mostly autosomal dominant (AD). We present a case series of 4 African-American (AA) men with novel mutations of the Wolframin (WS1) gene and type 2 DM (T2DM) phenotype.

Patient 1 is a 54-yr-old AA man with presumed T2DM. Given his lack of family DM history, short DM duration, late onset and rapid renal functional decline, the possibility of atypical DM was considered. Genetic testing showed a heterozygous mutation of the WFS1 (wolframin gene); c.169 G>A, p.Ala57Thr. He had no other features of Wolfram’s syndrome; DIDMOAD (diabetes insipidus, DM, optic atrophy + deafness).

Pts 2-4 are all family members. Pt 2 is a 65-yr-old AA man with new onset DKA and presumed T2DM. Given his initial DKA presentation, non-obese phenotype and absent family DM history, full phenotyping was done and genetic testing revealed a heterozygous mutation of the WFS1 gene; c.2385 G>C, p.Glu795Asp. He had no other features of DIDMOAD. Neither of his parents had DM and nor does his wife. He has 3 children (two sons and a daughter). Both sons (Pts 3-4), aged 41 and 36 yrs, have DM and both have the same WFS1 mutation. Both sons were diagnosed with DM before their father. The familial distribution suggests possible AD transmission.

WFS1 mutations have a broad spectrum of phenotypes and inheritance patterns. Our case series with unique WFS1 mutations suggests a possible MGDM syndrome in subjects with heterozygous WFS1 mutations without DIDMOAD. Further functional analyses of WFS1 mutations associated with DM without DIDMOAD are needed to better understand their DM pathophysiology and inform best management strategies.

Disclosure

Z.Yin: None. A.A.Noor: None. K.G.Romo: None. S.Bhamre: None. M.Gabriel: None. T.Pulisetty: None. S.Shu: None. G.I.Uwaifo: None.
1476-P: Genetic Relationships between Puberty Onset and Type 2 Diabetes
Authors: RAMIREZ-LUZURIAGA MARIA J. , KOBES SAYUKO , WEDEKIND LAUREN E. , HSUEH WEN-CHI , BAIER LESLIE , HANSON ROBERT L.
Published: June 2023

Early puberty onset is a risk factor for type 2 diabetes (T2D). In this study we aimed to determine whether these phenotypes are associated via genetic variation that contributes to both T2D and puberty onset. We, thus, investigated the associations of a polygenic score (PS) for T2D and a PS for age of menarche (AAM) with parameters of adolescent growth and T2D status in an Indigenous population from the Southwestern US with a high T2D prevalence. Genotypic and clinical data were obtained from a longitudinal study. Two key parameters of the adolescent growth spurt, including age at take-off (ATO) and age at peak velocity (APV), were derived from the Preece-Baines growth model, a parametric growth curve for longitudinal height data. PSs were constructed using imputed genotypes, where variants for the T2D-PS (n=289) and the AAM-PS (n= 275) were selected from genome-wide significant variants in European meta-analyses (DIAGRAM Consortium and Reprogen Consortium, respectively). Associations between PS and T2D status (N=7659) were adjusted for age, sex, birth year and the first 5 genetic PCs. Associations with ATO and APV (N=787) were adjusted for birth year, sex, maternal diabetes and the first 5 genetic principal components (PCs). Associations were calculated using linear mixed models, accounting for genetic relationships. The T2D-PS had a significant, positive association with T2D (OR=1.47 per SD [95% CI 1.38, 1.57]; p=4.05×10−30). We found no association of the T2D-PS with ATO (p=0.11) nor APV (p=0.20). Conversely, genetically-predicted later puberty onset (AAM-PS) had a significant, inverse association with T2D (OR=0.92 per SD [95% CI 0.86, 0.98]; p=0.0194). The AAM-PS also associated with ATO (r=0.11, p=0.0013) and APV (r=0.13, p=1.8×10−04). Our results suggest that many variants that associate with AAM and T2D in large European cohorts also affect these traits in this Indigenous population. They also support the notion that variants that associate with early puberty onset also confer susceptibility to T2D.

Disclosure

M.J.Ramirez-luzuriaga: None. S.Kobes: None. L.E.Wedekind: None. W.Hsueh: None. L.Baier: None. R.L.Hanson: None.
1478-P: Polygenic Risk Score Predicts Incident Cardiovascular Disease in People with Diabetes at Borderline or Intermediate 10-Year ASCVD Risk
Authors: CHOI JAEWON , LEE HYUNSUK , LEE JUNESEONG S. , RHEE TAE-MIN , SOO PARK KYONG , HEON KWAK SOO
Published: June 2023

People with type 2 diabetes (T2D) and 10-year atherosclerotic cardiovascular disease (ASCVD) of 20% or higher are recommended for intense lipid management. However, the role of genetic predisposition to ASCVD on determining the intensity of statin therapy in patients with T2D at borderline (5-7.5%) or intermediate (7.5-20%) risk for incident ASCVD is unclear. We aimed to investigate the utility of polygenic risk score (PRS) in predicting incident ASCVD in people with T2D at borderline and intermediate risk from UK Biobank. We calculated 10-year ASCVD risk using pooled cohort risk equations and PRS for coronary artery disease by Bayesian regression (PRS-CS) in participants of UK Biobank. We performed time-to-event analysis for incident ASCVD and assessed improvement of C-statistic when PRS was added to 10-year ASCVD risk. In addition, risk of ASCVD was estimated for those who were in the top 20 percentile of PRS compared to the remainders. During a median follow-up of 9 years, the incidence of ASCVD in people with T2D was 5.9% and 8.6% in borderline (N=2511) and intermediate (N=8292) group, respectively. The normalized mean PRS for those who developed ASCVD was higher in each group: 0.20±0.96 vs −0.02±1.01 in borderline and 0.20±1.02 vs −0.02±0.99 in intermediate group (all P<0.01). Adding PRS to 10-year ASCVD risk improved the C statistic from 0.51 (95% CI 0.46-0.55) to 0.57 (0.52-0.62) in borderline and from 0.55 (0.53-0.57) to 0.58 (0.56-0.60) in intermediate group. Standardized PRS was associated with incident ASCVD in each group: HR 1.22 (CI 1.05-1.45, P<0.05) and 1.24 (1.15-1.34, P<0.001). Moreover, those who were in the top 20 percentile had increased risk of ASCVD: HR 1.63 (1.14-2.33, P<0.01) and 1.43 (1.21-1.70, P<0.001), respectively. In conclusion, genetic information in people with T2D at borderline and intermediate ASCVD risk could be used to identify those who are at higher risk for incident ASCVD and require high intensity statin treatment.

Disclosure

J.Choi: None. H.Lee: None. J.S.Lee: None. T.Rhee: None. K.Park: None. S.Kwak: None.

Funding

National Human Genome Research Institute (FAIN U01HG011723)
1481-P: Islet Cell Autoantibody Formation and Its Effect on Insulin Requirement after Total Pancreatectomy with Islet Autotransplantation (TPIAT)
Authors: LAVIK ANDREW R. , LOWE COLLEEN M.O. , TELLEZ SIOBHAN E. , HORNUNG LINDSEY , HEINZMAN CHRISTIE , NATHAN JAIMIE D. , ABU-EL-HAIJA MAISAM , ELDER DEBORAH A.
Published: June 2023

Introduction: Long term insulin requirements following TPIAT range from insulin independence to full (high) dose daily insulin (>0.5 units/kg/day). Markers of islet cell autoimmunity are used in children to predict type 1 diabetes risk. However, no studies have explored whether an association exists between islet cell autoimmunity and insulin requirement following TPIAT in children. We hypothesized that children with islet cell autoantibody formation were more likely to have a persistent insulin requirement following TPIAT.

Methods: All children who underwent TPIAT between 2015 and 2021 at our institution were eligible for inclusion. Islet cell autoimmunity was defined as positive islet cell autoantibody screen for one or more of the following types of autoantibodies: Glutamic Acid Decarboxylase (GAD), Islet Antigen-2 (IA-2), Insulin (IAA), or Zinc Transporter 8 (ZnT8). Patients were screened prior to TPIAT and every six months following TPIAT for up to three years. In all, 73 patients were included in the analysis. Total daily insulin dose was determined for each patient at each time interval. Chi-square or Fisher’s exact tests were used to compare proportions.

Results: Of patients with 12-month data (n=38), 47% of islet cell autoantibody negative patients were off insulin vs 26% of antibody positive patients (p=0.19). This trend was significant at 18, 24, and 36 months after TPIAT. At 18 months, 90% (9/10) of antibody negative patients were off insulin vs 29% (4/14) of antibody positive patients (p=0.005). At 24 months, 73% (8/11) of antibody negative patients were off insulin vs 23% (3/13) of antibody positive patients (p=0.04). At 36 months, 100% (8/8) of antibody negative patients were off insulin compared to 0% (0/9) of antibody positive patients (p<0.0001).

Conclusions: The presence of pancreatic islet cell antibodies was associated with persistent insulin requirement after TPIAT.

Disclosure

A.R.Lavik: None. C.M.O.Lowe: None. S.E.Tellez: None. L.Hornung: None. C.Heinzman: None. J.D.Nathan: None. M.Abu-el-haija: None. D.A.Elder: None.
1486-P: Effects of the COVID-19 Booster Vaccine on Glycemia and Insulin Resistance in People with Type 1 Diabetes—A Prospective Pilot Study
Authors: ZILBERMINT MIHAIL , MOTEVALLI MAHSA , BATTY KRISTINE , VENNER-WALCOTT JEMILA , EDWARDS ALEXIS , BURLEY TANYA , JACKSON KEITH , AKHTAR MAHRUKH , DEMIDOWICH ANDREW
Published: June 2023

Background: Inflammation is well-known to worsen glycemia in people with type 1 diabetes (T1D). COVID-19 vaccines are vital for protection against SARS-CoV-2 infection, but by necessity trigger an acute immune response. Case reports have described hyperglycemic crises shortly after a booster dose. However, effects of COVID-19 vaccines on glycemic control in T1D is poorly understood.

Methods: This was a prospective cohort study of adults with T1D receiving a COVID-19 booster dose. At the baseline visit a blinded Dexcom G6 Pro CGM was placed, subjects received COVID-19 booster vaccine 3-4 days later, and returned 6 days post-vaccination to have the CGM removed. Primary outcome was change in mean daily glucose level from baseline. Secondary outcomes included total daily insulin dose (TDI), total daily insulin resistance (TDIR = mean glucose * TDI), and time in range (TIR = %glucose readings between 70-180mg/dL). Data were transformed as necessary to maintain normality.

Results: We enrolled 20 adults with T1D; one subject was excluded for nonadherence with study procedures. Baseline characteristics included (mean±SD) age: 48.9±19.4y, sex: 68.4%F, BMI: 29.6±6.2kg/m2, A1c: 7.0±1.0%. 42% received a Moderna and 58% Pfizer-BioNTech booster. Mean glucose on Day#2 post-vaccination was significantly greater than baseline (165.1±27.4 vs 154.5±30.2 mg/dL, p=0.04), as was TDIR (7970±4113 vs 7036±3999; p=0.02). No other days had significant differences in glycemic metrics as compared to baseline. There were no differences in any outcome metrics between booster vaccine manufacturers.

Conclusions: These results suggest that adults with T1D may experience transient glycemic elevations after receiving a COVID-19 booster. Clinicians may need to warn people with T1D to be more vigilant with glucose testing and insulin dosing temporarily after vaccination. Larger studies are warranted to corroborate these findings.

Disclosure

M.Zilbermint: Consultant; EMD Serono, Other Relationship; American Association of Clinical Endocrinologists. M.Motevalli: None. K.Batty: None. J.Venner-walcott: None. A.Edwards: None. T.Burley: None. K.Jackson: None. M.Akhtar: None. A.Demidowich: Research Support; Dexcom, Inc.

Funding

Dexcom, Inc. (IIS-2021-136)
1493-P: Immune-Mediated Diabetes Mellitus—A Rare Complication of Nivolumab Therapy
Authors: IQBAL SHUMAILA M. , HOUSTON CAROLINE
Published: June 2023

Background: Immune mediated diabetes mellitus (DM) is a rare complication of immune checkpoint inhibitor (ICI) therapy, with an incidence of less than 1%. We present a case of immune-mediated DM with nivolumab therapy presenting as diabetic ketoacidosis (DKA).

Case: A 74-year-old Caucasian male with no history of DM or autoimmune disease was diagnosed with stage III metastatic melanoma and started on treatment with nivolumab, an ICI. He tolerated treatment well and had no evidence of endocrine dysfunction on routine laboratory monitoring. Shortly after completing his 14th cycle of nivolumab therapy, he presented to the emergency department with a one-week history of fatigue, poor appetite, polydipsia, and polyuria. He was found to have DKA with serum blood glucose 446 mg/dL, anion gap 20 mEq/L, serum bicarbonate 14 mEq/L, arterial pH 7.23, and 4+ urine ketones. His hemoglobin A1c was 7.3%, increased from 5.4% one year earlier. He was treated with intravenous insulin then transitioned to basal-bolus subcutaneous insulin therapy, which was continued at discharge. Evaluation in the outpatient setting revealed no measurable GAD65 antibodies or anti-insulin antibodies, but his serum c-peptide was found to be <0.10 ng/mL with corresponding serum blood glucose level 214 mg/dl. This supported a diagnosis of endocrine pancreatic insufficiency, in his case likely immune mediated due to nivolumab therapy. He completed an additional 6 cycles of nivolumab with no further complications. Meanwhile his DM became well-controlled with subcutaneous insulin injections, and he was eventually transitioned to insulin pump therapy.

Discussion: ICIs such as nivolumab are known to cause multiple autoimmune complications that can appear at any point during treatment. The underlying mechanisms of beta cell immunotoxicity are incompletely understood, but progression to insulin-dependency appears to be rapid. It is important to recognize new or worsening DM early to avoid life-threatening complications such as DKA.

Disclosure

S.M.Iqbal: None. C.Houston: None.
1495-P: Bionic Pancreas-3D Bioprinting of Pancreatic Tissue Petals—Results of Transplantation in Large Animals
Authors: KLAK MARTA , BERMAN ANDRZEJ , JANOWSKA OLIWIA , DOMANSKI SYLWESTER , SZKOPEK DOMINIKA , ROSZKOWICZ-OSTROWSKA KATARZYNA I. , KONDEJ AGATA , WOLINSKI JAROSLAW , WSZOLA MICHAL
Published: June 2023

The first milestone of a new therapy for the treatment of T1D is the development of 3D bioprinted petals consisting of: pancreatic islets and biomaterials. The aim of the study was to demonstrate the functionality of pancreatic islets in in vivo studies on large animals.

Material and Methods: Domestic pigs were the research model. The animals were divided into 4 groups:(1)healthy pigs (Control; n=3);(2) animals with T1D after pancreatectomy, treated with insulin (T1D;n=3);(3) animals after pancreatectomy and autotransplantation of pancreatic islets to the liver (LIVER; n=3);(4) animals with T1D after pancreatectomy, which were autotransplanted with bionic petals (3D-PETALS; n=3). The effectiveness of the transplantation (TX) was assessed by the concentration of glucose, insulin intake and C-peptide. The observation lasted 1 month.

Results: The results showed that in the LIVER group, insulin intake within 3 weeks decreased by 71% compared to the demand before TX. Whereas 1 month after TX, the demand was lower by 62%. The 3D-PETALS group showed that the insulin intake in 3 weeks after TX decreased by 65%, and within a month decreased by 84%. In the 4th week after TX, the insulin intake average in the T1D group was 8.17U, while in the LIVER group=2.44U and in the 3D-PETALS group=1.06U. Islet TX significantly reduced insulin intake (T1D vs LIVER; p=0.0001 and T1D vs 3D-PETALS; p<0.0001). Glucose measurement showed significant changes. After 1 month of follow-up, glucose levels were significantly lower in the LIVER vs T1D (265.8mg% vs 310.2mg%; p<0.0001) and 3D-PETALS & T1D (198.3mg% vs 310.2mg%; p=0.0354). Most importantly, glycemic levels were also significantly lower between the LIVER & 3D PETALS groups (265.8mg% vs 198.3mg%; p=0.0021). The concentration of C-peptide during the study was 0.14ng/ml.

Conclusion: Bioprinted petals with dECM-based bioink significantly reduces diabetic parameters. Thus, it seems to be an effective therapy for people with T1D.

Disclosure

M.Klak: Employee; Polbionica Sp. z o.o., Stock/Shareholder; Polbionica Sp. z o.o. A.Berman: Board Member; Polbionica Ltd., Stock/Shareholder; Polbionica Ltd. O.Janowska: Employee; POLBIONICA Sp. z o.o. S.Domanski: Employee; Polbionica. D.Szkopek: None. K.I.Roszkowicz-ostrowska: None. A.Kondej: None. J.Wolinski: None. M.Wszola: Board Member; Polbionica Ltd., Stock/Shareholder; Polbionica Ltd.
1501-P: Deletion of miR-494 Induces Adipocyte Browning and Slows Aging in Mice
Authors: SUGAWARA LUCIA , MORINO KATSUTARO , IWASAKI HIROTAKA , IDA SHOGO , YANAGIMACHI TSUYOSHI , LEMECHA MENGISTU , MAEGAWA HIROSHI , FUJITA YUKIHIRO , KUME SHINJI
Published: June 2023

Adipocyte browning is a potent therapeutic strategy for obesity and metabolic disorders. We previously reported that miR-494 served as a negative regulator of mitochondrial biogenesis during browning in cultured adipocytes. However, the in vivo evidence has not been provided. In this study, we examined the role of miR-494 in adipocyte browning and aging using miR-494 knockout (KO) mice.

KO mice were generated using CRISPR/Cas9 system. KO mice had equivalent energy expenditure, physical activity, food intake and body weight compared to wild-type (WT) mice; had lower resting respiratory quotient (0.95±0.006 vs 0.91±0.004), less visceral fat (16.3±1.08 vs 13.4±0.96 g/kg body weight) and 3.7-fold increased expression of Ucp1 in subcutaneous fat. In addition, KO mice showed cold tolerance during 3 hours exposure to 4ºC and increased oxygen consumption than WT mice after administration of a β3 agonist in thermoneutral condition, indicating an increase in non-shivering thermogenesis. In adipose tissues of KO mice, increased expression of Pgc-1α, a target gene of miR-494, and tendency to increase in mitochondrial DNA were observed. Primary adipocytes derived from KO mice showed enhanced mitochondrial respiration driven by fatty acids as determined by extracellular flux analysis. Finally, KO mice showed an extended median lifespan 29% relative to WT mice (from 113.7 to 146.7 weeks). Aged KO mice (≥ 2 years old) showed reduced age-related changes, such as hair graying and low physical activity.

In conclusion, deletion of miR-494 demonstrated increased adipocyte browning and survival advantage in mice. Although there are numerous studies that focused on promoting adipocyte browning, its long-term effect has not been well evaluated. Thus, our data showing the association among miR-494, adipocyte browning and longevity provide a novel insight into adipocyte biology and aging study. The gene sequence of miR-494 and its binding site to Pgc-1α are conserved from mice to humans; it is expected to be applied to human research.

Disclosure

L.Sugawara: None. K.Morino: Research Support; AstraZeneca, Astellas Pharma Inc., Sanwa Kagaku Kenkyusho, Ono Pharmaceutical Co., Ltd. H.Iwasaki: None. S.Ida: None. T.Yanagimachi: None. M.Lemecha: None. H.Maegawa: None. Y.Fujita: Research Support; Terumo Corporation, Boehringer Ingelheim Japan, Inc., Japan Society for the Promotion of Science, Mitsubishi Tanabe Pharma Corporation, Sumitomo Dainippon Pharma Co., Ltd. S.Kume: Research Support; Boehringer Ingelheim International GmbH, Japan Society for the Promotion of Science.

Funding

Grants-in-Aid for Scientific Research (22K08650)
1510-P: Lipid-Induced Renal Cortical Insulin Resistance Perturbs Gluconeogenic and Oxidative Metabolism via an sn-1,2-diacylglycerol-PKCe-Insulin Receptor Kinase Axis In Vivo
Authors: HUBBARD BRANDON T. , GASPAR RAFAEL C. , ZHANG DONGYAN , KAHN MARIO , NASIRI ALI , SHULMAN GERALD I.
Published: June 2023

Recently, our group demonstrated that 3-week high fat diet feeding (HFD) impairs insulin signaling in the renal cortex at the level of the insulin receptor kinase (IRK). Specifically, IRKY1162 and AKTS473 phosphorylation were reduced by ~50% during hyperinsulinemic-euglycemic clamp (HEC); however, it is unknown how renal cortical insulin resistance (IR) may affect gluconeogenic (GNG) and oxidative metabolism. To address this, here we measure renal cortical GNG fluxes in vivo using Q-Flux. In regular chow (RC) fed mice, hyperinsulinemia significantly suppressed mitochondrial pyruvate carboxylase (PC), as PC flux relative to α-ketoglutarate dehydrogenase flux (VPC/VOGDH) was 1.25 under basal conditions, but decreased by ~50%, to 0.57 during HEC. Similarly, PEPCK flux relative OGDH flux (VPEPCK/VOGDH) was reduced by ~60% during HEC. In contrast, insulin failed to suppress both PC and PEPCK fluxes with HFD. Using a [13C6]glucose tracer, we also find insulin-stimulated mitochondrial pyruvate oxidation to be impaired by ~30% with HFD. Mechanistically, we previously found HFD led to a 2-fold increase in plasma membrane (PM) sn-1,2-diacylglycerol (DAG) and a 4-fold increase in Protein Kinase Cε (PKCε) translocation, suggesting renal cortical IR may be mediated by an sn-1,2-DAG-PKCε-IRK axis. We further interrogated this possibility here by assessing inhibitory phosphorylation at IRKT1150, the key target of PKCε, finding a 42% increase with HFD. In addition, IRKT1150A knockin mice, whose IRK cannot be phosphorylated by PKCε, were protected from HFD-induced signaling and pyruvate oxidation defects.

Conclusion: HFD inhibits renal cortical insulin signaling at the level of the IRK, which is associated with perturbed mitochondrial GNG and oxidative metabolism. IRKT1150A mice are protected from HFD-induced defects, indicating a PM sn-1,2-DAG-PKCε-pIRKT1150 mechanism for lipid-induced renal cortical IR.

Disclosure

B.T.Hubbard: None. R.C.Gaspar: None. D.Zhang: None. M.Kahn: None. A.Nasiri: Other Relationship; Medtronic. G.I.Shulman: Consultant; Novo Nordisk, DiCerna Pharmaceuticals, Inc., Bayer Consumer Care AG, Kriya Therapeutics, Arrowhead Pharmaceuticals, Inc., ESPERION Therapeutics, Inc., Other Relationship; AstraZeneca, Merck & Co., Inc., Janssen Research & Development, LLC, iMetabolic Biopharma Corporation, Maze Therapeutics, 89bio, Inc., Equator Therapeutics, Inc., Generian Pharmaceuticals, Fortress Biotech, Inc., OrsoBio, Aro Biotherapeutics Company, Stock/Shareholder; Levels Health, Inc.
1517-P: Interactive Calculator to Estimate Insulin Sensitivity (IS) in Type 1 Diabetes
Authors: JANUSZEWSKI ANDRZEJ S. , NIEDZWIECKI PAWEL , SACHITHANANDAN NIRUPA , WARD GLENN M. , O'NEAL DAVID N. , ZOZULINSKA-ZIOLKIEWICZ DOROTA , URUSKA ALEKSANDRA , JENKINS ALICIA
Published: June 2023

Introduction: Euglycemic hyperinsulinemic clamps, although costly, time- and labor-intensive, are “gold standard” in measuring insulin sensitivity (IS). Several formulae to estimate IS in people with Type 1 diabetes (T1D) exist (DOI: 10.1007/978-3-030-81303-1_18-1), using various routine and research assays, and with wide ranging IS results.

Aim: To develop a free online tool to estimate IS using different metrics and existent formulae and compare estimated IS with measured glucose disposal rate (GDR) from 104 clamp studies.

Methods: We prepared an online tool for calculating IS using 17 formulae. Suitable formula(e) are suggested based on available (clinical and research) data. We also compare calculated IS with measured IS (GDR) from clamp studies in 104 adults with T1D (mean±SD) age 34±7 yrs, T1D duration 10±4 yrs, HbA1c 7.7±1.5%, 33 with microvascular complications). Logistic regression was used to infer probability of calculated IS being below GDR=4.45 mg/kg/min or above GDR=6.5 mg/kg/min, which represent respectively the median and 75th percentile of measured GDR values.

Results: A calculator is available at www.bit.ly/estimated-GDR and an example result in the Figure 1. Estimated IS varied widely, but results interpretation is generally consistent.

Conclusion: We developed an interactive tool to estimate IS in T1D for clinical and research use.

Disclosure

A.S.Januszewski: None. P.Niedzwiecki: None. N.Sachithanandan: None. G.M.Ward: None. D.N.O'neal: None. D.Zozulinska-ziolkiewicz: Advisory Panel; Abbott, Lilly, Lilly, Novo Nordisk, Medtronic, Speaker's Bureau; Abbott, Ascensia Diabetes Care, Novo Nordisk, Medtronic, Boehringer-Ingelheim, AstraZeneca. A.Uruska: Other Relationship; Lilly, Boehringer-Ingelheim, AstraZeneca, Ascensia Diabetes Care, Sanofi. A.Jenkins: Advisory Panel; Insulet Corporation, Board Member; Insulin for Life, Research Support; Abbott Diabetes, Medtronic, Hemsley Charitable Trust, Juvenile Diabetes Research Foundation (JDRF), National Institutes of Health.
1523-P: A Leptin-Mediated Interoceptive Network between the Brain and Brown Adipose Tissue
Authors: MUNOZ MARCOS D. , YANG XIAOHUA , TORRES IRIZARRY VALERIA C. , LUO PEI , CARRILLO-SÁENZ LESLIE , ANTONY NIMISHA , WEE LIEW CHONG , XU PINGWEN
Published: June 2023

Obesity is attributed to chronic disruption in energy homeostasis. This phenomenon is controlled by systemic and local signals such as leptin, a nutrient-sensitive signal secreted primarily by the white adipose tissue (WAT). Previously, interscapular brown adipose tissue (iBAT) has been shown to express undetectable or very low levels of leptin. Unexpectedly, in this study, we observed that iBAT leptin expression displayed a distinct circadian pattern and fluctuated with nutritional and ambient temperature. These observations suggest a vital role of iBAT leptin in the regulation of energy homeostasis. To explore this idea, we performed gain and loss of function experiments by overexpressing (LEPOE) or knocking down (LEPKD) leptin selectively in UCP1+ cells of iBAT, respectively. We found that LEPOE reduced food intake while LEPKD increased it in normal and fasting-induced feeding conditions. Notably, LEPOE/LEPKD selectively increased/decreased the mRNA expression of leptin in the iBAT without affecting circulating leptin levels, indicating a possible paracrine role of iBAT leptin. In supporting this point of view, we found that the leptin receptor is highly expressed in the iBAT-associated sensory nerve (iBAT-SN). Moreover, iBAT-specific leptin infusion activated leptin signaling in the iBAT-SN and subsequently stimulated proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus. Conversely, chemical ablation of iBAT-SN increased food intake and blunted hypothalamic POMC activation induced by iBAT-specific leptin infusion. These findings indicate that iBAT possesses a structural and functional basis for paracrine leptin signaling via iBAT-SN, which cross-talks with POMC neurons to modulate energy homeostasis. Our results support an unappreciated metabolic role of iBAT leptin in energy homeostasis.

Disclosure

M.D.Munoz: None. X.Yang: None. V.C.Torres irizarry: None. P.Luo: None. L.Carrillo-sáenz: None. N.Antony: None. C.Liew: None. P.Xu: None.

Funding

National Institutes of Health (R01DK123098); U.S. Department of Defense (W81XWH-19-PRMRP-DA); Diabetes Research and Training Center (DK020595)
1528-P: Hypothalamic SEL1L-HRD1 ER–Associated Degradation Is Indispensable for Leptin Signaling in Diet-Induced Obesity by Degrading Misfolded Leptin Receptor
Authors: MAO HANCHENG , QI LING
Published: June 2023

It has been reported that endoplasmic reticulum (ER) stress, also known as unfolded protein response (UPR), is a contributor to the development of diet-induced leptin resistance in central nervous system. However, the evidence for this model remains circumstantial and controversial. Moreover, the importance of ER homeostasis in leptin signaling remains unexplored. Interestingly, our data suggested that neither acute nor chronic HFD feeding triggers any overt UPR in vivo though with the presence of the central and peripheral pathogenesis. Rather, we found that the SEL1L-HRD1 protein complex of ER-associated protein degradation (ERAD) - the principal protein degradation and quality control mechanism - in hypothalamic POMC neurons is indispensable for leptin signaling in diet-induced obesity. We found that SEL1L-HRD1 ERAD, ubiquitously expressed in hypothalamic neurons, can be transiently induced by acute HFD. Notably the deficiency of SEL1L-HRD1 ERAD in POMC neurons leads to striking hypothalamic leptin resistance, concomitant hyperphagia and diet-induced obesity and pathogenesis in mice of both sexes. Mechanistically, our data show that in ER, SEL1L-HRD1 interacts with leptin receptors long isoform (LepRb) and mediates the degradation of LepRb. The lack of SEL1L-HRD1 impairs the clearance of misfolded LepRb that forms high molecular aggregates. Further, the SEL1L-HRD1 deficient cells exhibit significantly less membrane display of lepRb. Hence, we hypothesize that leptin receptor is an endogenous substrate candidate of SEL1L-HRD1 ERAD and that SEL1L-HRD1 ERAD is required for the maturation of nascent leptin receptor in the ER in response to leptin signaling. Overall, this study challenges the current dogma by demonstrating a key role of hypothalamic SEL1L-HRD1 ERAD, not UPR, in the pathogenesis of diet-induced obesity and leptin resistance.

Disclosure

H.Mao: None. L.Qi: None.
153-LB: Early Impact of a Hybrid Chronic Care Model on A1C Levels among Underserved Patients with Diabetes in Primary Care
Authors: LEE JOYCE Y. , NGUYEN JENNY T. , SEO MINJONG , NGUYEN TAN , PATEL NISA , RODRIGUEZ VANESSA , MAYORGA JOSE
Published: June 2023

Underserved populations are at higher risk of developing diabetes-related complications. This study aimed to evaluate changes in A1c among undeserved patients who received care through a hybrid Chronic Care Model (h-CCM).

This was a retrospective observational study conducted in two satellite clinics of a federally qualified health center. h-CCM was delivered collaboratively via in-person and telehealth visits conducted by family physicians, nurse practitioners and clinical pharmacists. Baseline sociodemographic of patients >40 years old with diabetes who received care through h-CCM for ≥ 3 months between Oct 2020 and Nov 2022 were included. Patients with any missing data were excluded. Descriptive analysis and paired t-test were used accordingly.

A total of 104 (53.0%) patients were analyzed. The average age was 60.7± 9.8 years with the majority being Hispanic (72.1%), female (57.7%) and with a mean h-CCM visits of 2.2± 1.8 over 3 months. The average ASCVD risk at baseline was 20.0± 16.6% with hypertension (88.5%) being the most common comorbidity. Average A1c decreased from 9.4± 2.1% at baseline to 8.7±1.9 at 3 months (-0.7%, p <0.001) with improvements observed in all levels of baseline A1c (p<0.001, Figure 1).

h-CMM was effective in achieving timely A1c reduction among underserved patients with diabetes. Greater improvements were observed in patients with higher baseline A1c.

Disclosure

J. Y. Lee: None. J. T. Nguyen: None. M. Seo: None. T. Nguyen: None. N. Patel: None. V. Rodriguez: None. J. Mayorga: None.
1537-P: Regulation of Energy Balance by a Gut–Brain Axis Mediated by SCFAs and FFA2/3 in the Brain
Authors: YANG XIAOHUA , LUO PEI , FENG BING , YE HUI , ANTONY NIMISHA , CARRILLO-SÁENZ LESLIE , TORRES IRIZARRY VALERIA C. , LAYDEN BRIAN T. , HE YANLIN , XU PINGWEN
Published: June 2023

Short-chain fatty acids (SCFAs) derived from gut microbiota fermentation have been shown to generate beneficial metabolic effects on energy and glucose homeostasis by binding with free fatty acid receptors 2 (FFA2) and 3 (FFA3). Accumulating evidence indicates that the gut microbiota/SCFAs interact with the central nervous system (CNS) to regulate central metabolic function. Interestingly, we found that a single bolus intracerebroventricular (ICV) injection of acetate (ACE), propionate (PRO), or butyrate (BUT) dose-dependently inhibited food intake in an FFA2/3-dependent manner. Notably, both in situ hybridization and RNAscope analysis showed that FFA3 but not FFA2 was expressed in the cerebellar granule neurons, which was inhibited by PRO or FFA3-selective agonists in a Gi/o-dependent mechanism. We also showed that high-fat diet (HFD)-induced hypothalamic inflammation is diminished by dietary fiber supplementation, which is associated with increased circulating SCFAs. Notably, these anti-inflammatory effects of dietary fiber supplementation were partially attenuated in FFA2/3 double-knockout mice, suggesting a beneficial effect of FFA2/3 on hypothalamic inflammation. Taking all these together, our results suggest a model that SCFAs act on the brain to regulate energy homeostasis and hypothalamic inflammation.

Disclosure

X.Yang: None. P.Xu: None. P.Luo: None. B.Feng: None. H.Ye: None. N.Antony: None. L.Carrillo-sáenz: None. V.C.Torres irizarry: None. B.T.Layden: Consultant; Bayer Inc. Y.He: None.

Funding

National Institutes of Health (R01DK123098, P30DK020595 to P.X.), (P20GM135002, R01DK129548 to Y.H.), (T32AA026577 to V.C.T.I.); American Heart Association (915789 to V.C.T.I.), (20POST35120600 to Y.H.); U.S. Department of Defense (W81XWH-20-1-0075 to P.X
154-LB: HEDIS Glycemic Goals Achieved by Control-IQ Technology Users across All Payer Types
Authors: PATEL BIMAL V. , ALENCAR GABRIEL , WANG SHARON M. , LEAS SCOTT , MESSER LAUREL H. , PINSKER JORDAN E.
Published: June 2023

Background: The t:slim X2 with Control-IQ technology (“Control-IQ”) is an advanced hybrid closed-looped system. This analysis evaluated glycemic outcomes in Control-IQ users by payer type using Healthcare Effectiveness Data and Information Set (HEDIS) quality thresholds. HEDIS is used by >90% of health plans to measure performance and includes a metric to identify A1c control (<8.0%) and poor control (>9.0%). Glucose management indicator (GMI) is a recognized surrogate for A1c when sufficient data are provided (≥14 days, 70% CGM use).

Methods: We retrospectively analyzed glycemic data for individuals with type 1 diabetes from 1/1/20 to 3/4/23 who used Control-IQ for ≥1 year (with ≥70% of CGM use in final 3 months) and had a recorded baseline A1c prior to Control-IQ initiation. Results were stratified by payer type, prior therapy, and baseline A1c. GMI was calculated for last 3 months and compared to baseline A1c.

Results: Analysis included 20,319 users, with 42% (n= 8,493) on multiple daily injections (MDI) and 58% (n=11,826) on pump therapy at baseline. Control-IQ use significantly improved glycemic outcomes and mean HEDIS thresholds were achieved for all payer types and strata (table).

Conclusion: Control-IQ use improved HEDIS A1c (GMI) outcomes across all payer types, with the largest glycemic improvement seen in those with the highest A1c at baseline and for prior MDI users.

Disclosure

B. V. Patel: Employee; Tandem Diabetes Care, Inc. Stock/Shareholder; Tandem Diabetes Care, Inc. G. Alencar: Employee; Tandem Diabetes Care, Inc. S. M. Wang: Employee; Tandem Diabetes Care, Inc. Stock/Shareholder; Tandem Diabetes Care, Inc. S. Leas: Employee; Tandem Diabetes Care, Inc. L. H. Messer: Employee; Tandem Diabetes Care, Inc. Consultant; Dexcom, Inc. Advisory Panel; Lilly. Consultant; Capillary Biomedical, Inc. Research Support; Beta Bionics, Inc., Medtronic, Insulet Corporation. J. E. Pinsker: Employee; Tandem Diabetes Care, Inc.
1543-P: The Effect of Insulin Resistance on Brain Glucose Uptake—A Systematic Review and Meta-analysis
Authors: JENSEN NICOLE J. , PORSE ANE J. , SPEYER HELENE , KROGH JESPER , GEJL MICHAEL , GJEDDE ALBERT H. , RUNGBY JØRGEN
Published: June 2023

Objective: We investigated the association between peripheral insulin resistance (IR) and brain glucose uptake (BGU) and further determined if testing condition (fasting vs. hyperinsulinemic-euglycemic clamp) was a moderator of the association.

Methods: A systematic search was conducted in PubMed, Embase, Cochrane Library, and Web of Science, studies assessing an association between measures of or clinical proxies for IR (e.g. diabetes and obesity) and BGU were included. Effect sizes were standardized and transformed into correlation coefficients and a random effect meta-analysis performed. Further, a subgroup analysis on testing condition was conducted.

Results: Twenty-one studies (n = 3,620) were included in the meta-analysis. The pooled correlation (-0.13 [95% CI: -0.37; 0.12], p=0.3) showed a substantial heterogeneity (I2 = 98%). Subgroup analysis revealed that IR negatively correlated with BGU when subjects were examined at fasting conditions (-0.42 [95% CI: -0.59; -0.21], I2 = 99%) and positively correlated when subjects were examined during a hyperinsulinemic-euglycemic clamp (0.53 [ 0.38; 0.66], I2 = 47%)(figure 1). Test condition significantly moderated the association (p <0.01) and explained 55% of the heterogeneity.

Conclusion: Across the studies IR results in abnormal BGU in both fasting and hyperinsulinemic states, clamp conditions reverse the low BGU in IR.

Disclosure

N.J.Jensen: None. A.J.Porse: None. H.Speyer: None. J.Krogh: None. M.Gejl: None. A.H.Gjedde: None. J.Rungby: Advisory Panel; Abbott, Consultant; Novo Nordisk, Speaker's Bureau; Boehringer-Ingelheim, AstraZeneca.
155-LB: Econsults—An Innovative Model for Diabetes Specialty Care Delivery
Authors: KARSLIOGLU-FRENCH ESRA , ZUPA MARGARET , QUAYTMAN JACOB
Published: June 2023

Background: More than 10% of the US population has diabetes. However, a national shortage of endocrinologists limits access to diabetes specialty care, creating a delay of several weeks to months for a new patient appointment in endocrine clinic. Econsults, which are asynchronous provider-to-provider communications embedded in the electronic medical record, are a relatively new pathway to seek consultation from specialists. The most common reason for endocrine econsult is uncontrolled diabetes. However, there is little evidence on effectiveness of econsults in improving diabetes control.

Methods: We completed a retrospective chart review of all endocrine econsults that were completed for adults with diabetes within a large integrated health system in 2022. We compared HbA1c values before and 3, 6, 12 months after econsult to assess glycemic change. We also analyzed how many econsults were followed by an endocrinology office visit.

Results: Of 212 diabetes econsults completed in 2022, 8% (16/212) were for type 1 DM, and 92% (196/212) were for type 2 DM management. Follow-up HbA1c values were available in 189 patients. Eighty-eight percent (166/189) of patients had improvement in HbA1c 12 months following econsult. Only 15% (32/212) of all econsults were followed by a video or in-person visit with an endocrinologist, while 85% (180/212) did not require a follow-up endocrine appointment. Of the patients who only received econsult, mean HbA1c improved from 9.9% at baseline to 7.4% at 12 months (p<0.05). Of the 31 patients with type 2 DM who required a follow-up appointment with endocrinologist, mean HbA1c improved from 10.4% at baseline to 7.1% post-visit (p<0.05). Of note, 6 patients were diagnosed with new-onset type 1 DM during econsult process and were triaged to an immediate video visit to start appropriate insulin treatment and prevent DKA.

Conclusion: Econsult is an efficient and effective model which can expand access to diabetes specialty care for patients with uncontrolled diabetes.

Disclosure

E. Karslioglu-French: Research Support; Abbott. M. Zupa: None. J. Quaytman: None.

Funding

Pittsburgh Foundation Grant (MR2022-128717)