bluuebunny/crossref_metadata_2025_split huggingface dataset:
291-LB: Possible Alpha-Cell Regeneration from Mucin-Producing Ducts in Zinc-Binding Site-Mutated CRY1-Expressing Diabetic Mice
Authors: OKANO SATOSHI , YASUI AKIRA , KANNO SHIN-ICHIRO , SASAKI YU , SATOH KENNICHI , IGARASHI MASAHIKO , NAKAJIMA OSAMU 
Published: June 2023

C414A-CRY1 transgenic mice (TG) show the symptoms of diabetes due to cellular senescence-like phenotypes in their β-cells as we have reported at ADA Scientific Sessions in 2015. Due to the cellular phenotypes, structural remodeling in islets of TG progresses with age (S. Okano et al., ADA 2016-2022): the increase of the population ratios of α-cell to β-cell and of δ-cell to β-cell as well as the occurrence of fibrillation, angiogenesis and also the generation of mucin-producing intra-islet ductal cells (IIDCs) were observed. Contrary to normal ductal cells, IIDCs only weakly react with DBA lectin, indicating unique characters different from normal ductal cells (ADA 2019). Also, we have shown the results suggesting that δ-cells may play some role as the source for β-cells to supply new β-cells in TG (ADA 2022). To examine the possible roles of IIDCs to maintain of the amount of pancreatic endocrine cells under hyperglycemia for prolonged period in TG, in this study, we conducted detailed immune-staining experiments which focused on fully developed IIDCs, not small ones that still not fully developed. We distinguished IIDCs from normal ducts, PanINs as well as PDGs as the measure of the reactivity to DBA-lectin. Chromogranin A-positive cells were observed in IIDCs, but not in normal ducts, PanINs and PDGs. Then we examined IIDCs with anti-hormone antibodies. In the region of developed IIDCs, cytokeratin 17/19 and glucagon double-positive cells were predominantly observed. Only small portion of somatostatin-positive cells were clearly located adjacent to IIDCs. Cluster of β-cells were located apart from IIDCs. In addition, scrutinized observations suggested the delamination of glucagon-positive cells from the ductal epithelium of the IIDCs. Taken together, these results strongly suggest the possible neogenesis of endocrine cells in IIDCs, that is, IIDCs and their lining cells play roles as the source for endocrine cells, particularly for α, and also for δ cells.

Disclosure
S. Okano: None. A. Yasui: None. S. Kanno: None. Y. Sasaki: None. K. Satoh: None. M. Igarashi: None. O. Nakajima: None.

Funding
Grants-in-Aid for Scientific Research (19K07498); Tohoku University Institute of Development, Aging and Cancer
292-LB: Cholesterol Accumulation in Islets Exacerbates Insulin Secretory Defects in a Model of Mild ß-Cell Dysfunction
Authors: AKTER REHANA , BARROW BREANNE , HULL-MEICHLE REBECCA L. , ZRAIKA SAKENEH , KAHN STEVEN E. 
Published: June 2023

Hypercholesterolemia is common in diabetes. We sought to determine whether cholesterol (Chol) can exacerbate impaired insulin secretion in islets from a mouse model of mild β-cell dysfunction. To induce β-cell dysfunction, C57BL/6J male mice were treated with low-dose (30 mg/kg, i.p.) streptozotocin (STZ) or vehicle (VEH) once daily on 3 consecutive days. Mice were then fed a 9% fat diet for 4 weeks, after which islets were isolated and cultured for 24 h ± Chol prior to endpoint measures. After 4 weeks, body weight (STZ 28.9±1.0 vs VEH 29.1±1.1 g) and fed glucose (STZ 191.2±11.0 vs VEH 177.8±8.2 mg/dl) did not differ. When cultured with 0 mM Chol, isolated islets from STZ-treated mice showed reduced glucose (20 mM)-stimulated insulin secretion (GSIS: 973.9±191.7 vs 1714.8±384.6 pM, n=5, p&lt;0.05) and a trend for lower insulin content (180.6±18.2 vs 230.4±22.9 nM, n=5, p=0.06), compared to islets from VEH-treated mice. Having established STZ-induced β-cell dysfunction, islets from STZ-treated mice were cultured ± 0.5 mM Chol, then Chol content and GSIS measured. Culture in 0.5 mM (vs 0 mM) Chol resulted in increased islet Chol content (58.9 ± 4.3 vs 17.6 ± 3.0 µg/mg protein; n=3, p&lt;0.01). A trend for increased basal insulin secretion (2.8 mM glucose: 185.8±64.7 vs 32.8±3.5 pM, n=5, p=0.09) and reduced GSIS (305.3±60.3 vs 973.9±191.7 pM, n=5, p&lt;0.05) were observed in islets cultured with 0.5 mM Chol. Insulin content was also reduced (125.8±10.8 vs 180.6±18.2 nM, n=5, p&lt;0.01) with 0.5 mM Chol culture. In sum, we have developed a STZ-based, euglycemic mouse model of subclinical β-cell dysfunction. Chol treatment of islets from these mice exacerbates β-cell dysfunction, in keeping with a deleterious effect of Chol. This model now provides the ability to determine whether hypercholesterolemia in vivo results in further impairment of β-cell dysfunction and the development of hyperglycemia, an observation that would be relevant to the progression of prediabetes to diabetes and diabetes per se.

Disclosure
R. Akter: None. B. Barrow: None. R. L. Hull-meichle: Employee; Veterans Administration, Research Support; Casma Therapeutics, Cystic Fibrosis Foundation, NIH - National Institutes of Health, Veterans Administration. S. Zraika: None. S. E. Kahn: Advisory Panel; Anji Pharmaceuticals, Bayer Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Merck & Co., Inc., Other Relationship; Novo Nordisk.

Funding
U.S. Department of Veterans Affairs (I01BX001060); National Institutes of Health (P30DK017047); Diabetes Research Connection (46)
293-LB: Dorzagliatin, a Glucokinase Activator, Restores Glucose-Sensing in Type 2 Diabetic Human Islets
Authors: ROMAN JEFFEREY , ZHU QIUSHA , YUAN YUE , LI CHANGHONG , CHEN LI , DOLIBA NICOLAI M. 
Published: June 2023

Introduction: Glucokinase (GK) has been considered a drug target for type 2 diabetes (T2D) to restore glucose sensing in beta cells. However, GK activators such as MK-0941 have had limited clinical success, causing hypoglycemia and other serious adverse events in terminated clinical trials. In contrast, the novel GK activator dorzagliatin, an approved therapy for T2D, showed sustained reduction in HbA1c in T2D patients and no serious adverse events. The purpose of the current study is to compare the effects of dorzagliatin with other GK activators, including MK-0941, on GK enzyme kinetics and the function of islets from T2D donors.
Methods: Insulin secretion was assessed in islets from 8 T2D donors and 38 controls obtained through the Integrated Islet Distribution Program. Both glucose step and glucose ramp perifusion protocols were used to assess glucose-stimulated insulin secretion (GSIS). GK-GK activator binding was performed using molecular dynamics analysis. Publicly available data from the Human Pancreas Analysis Program were also used.
Results: Unlike MK-0941 which strongly activates GK enzyme even at very low glucose levels, dorzagliatin activation of GK is glucose dose-dependent. This can be explained by molecular dynamics analysis showing dorzagliatin binds to GK with less affinity than MK-0941. T2D islets showed a right-shifted glucose threshold for GSIS and/or a reduction in the maximal rate of GSIS (Vmax) compared to controls in response to high glucose and IBMX, and dorzagliatin recovers both the threshold and Vmax. In contrast, MK-0941 induces a rapid and transient insulin spike at very low glucose concentrations but has a reduced response to high glucose.
Conclusion: In isolated T2D islets, dorzagliatin recovers both the normal glucose threshold and Vmax and has a wider dose range compared to MK-0941. These findings may explain why MK-0941 causes hypoglycemia whereas dorzagliatin improves blood glucose without any serious adverse events in T2D patients.

Disclosure
J. Roman: None. Q. Zhu: Employee; Nanjing AscendRare Pharmaceutical Technology. Y. Yuan: Employee; Nanjing AscendRare Pharmaceutical Technology. C. Li: Employee; Hua Medicine, Nanjing AscendRare Pharmaceutical Technology. L. Chen: Employee; Hua Medicine. N. M. Doliba: None.
297-OR: Systematic Review of Immune Interventions Trials in Recent Onset Type 1 and Effect on HbA1c
Authors: POZZILLI PAOLO , FALLUCCA SARA , PIERALICE SILVIA , MARELLI MARTA , MANCINI LORENZO 
Published: June 2023

There has been no meta-analysis that addressed the essential issue of efficacy of immunomodulatory agents on HbA1c in patients with recent onset type 1 diabetes (T1D). The aim of this study was to conduct a systematic review and meta-analysis to estimate the treatment effect of different immunotherapeutic strategies vs. placebo on HbA1c in subjects with T1D over the first 2 years of disease. We searched PubMed and Clinicaltrials.gov from 1990 until November 2022 to identify randomized clinical trials (RCTs) and observational investigations that compared the efficacy of immunomodulatory agents in adult and children with recent onset T1D. The study included 35 trials with a total of 2987 participants, 2086 in the treatment groups and 901 in the control groups. We extracted information about year of publication, study and exposure duration, immunotherapy type, no. patients, age, sex, weight, and BMI. HbA1c was evaluated at baseline, and at 3, 6, 9, 12 and 24 months. Funnel plots with confidence regions were used to explore small-study and publication biases. A random-effects model to pool effect sizes Knapp-Hartung adjustments was used to calculate confidence intervals. The evaluation outlined a significantly higher HbA1c in the treatment group at baseline (MD = 0.26 %, 95% confidence interval (CI) 0.0025 to 0.51). Heterogeneity was detected (I2 = 67%; p&lt;0.01; prediction interval -0.71 to 1.23). Small trials with higher HbA1c in the treatment group seem to be underrepresented, however, most of the studies provided non-significant results. In analysis at 12 months (12 trials) results showed a significantly higher HbA1c in the treatment group (MD = 0.13 %, 95% confidence interval (CI) 0.09 to 0.16). This result is almost driven by one study. Results of the metanalysis indicate that overall, in the first 2 years of the disease and irrespective of the immunointervention agent tested, no effect on HbA1c levels could be detected vs. placebo. A few exceptions were observed in the data analysis with some agents.

Disclosure
P.Pozzilli: None. S.Fallucca: Consultant; Dompé. S.Pieralice: None. M.Marelli: Employee; Dompé. L.Mancini: None.
3-OR: Severe Hypoglycemia among Older Adults with Diabetes (iNPHORM, USA)
Authors: RATZKI-LEEWING ALEXANDRIA , BLACK JASON E. , ZOU GUANGYONG , RYAN BRIDGET L. , HARRIS STEWART B. 
Published: June 2023

Despite an aging US diabetes population, little is known about the real-world frequency of iatrogenic severe hypoglycemia (SH) among older adults. We analyzed iNPHORM data to address this gap. People ≥60-year-old with T1DM or T2DM on insulin and/or secretagogues were recruited from a probability-based internet panel. Data on SH were obtained via a screener, baseline, and 12 monthly follow-ups. Crude SH incidence rates (IRs) and proportions (IPs) were calculated overall, and by diabetes type, medication type, and mode of SH recovery. N=307 were analyzed (T1DM: 8.5%; age: 67.5 [SD:5.5] years; male: 54.1%; retention rate: 81.8%). Among T2DM respondents, 39.9% used insulin without secretagogues, 50.2% secretagogues without insulin, and 10.0% insulin and secretagogues. The overall IP of SH was 19.9 (95%CI: 15.8-24.7)%, and the IR was 0.89 (95%CI: 0.62-1.27) events per person-year (EPPY). People with T1DM had a higher total IP (42.3 [95%CI: 25.5-61.1]%) and IR (2.07 [95%CI: 0.98-4.38] EPPY) than those with T2DM (IP: 17.8 [95%CI: 13.8-22.7]%; IR: 0.78 [95%CI: 0.52-1.15] EPPY), including insulin without secretagogue users (1.09 [95%CI: 0.66-1.80] vs. 0.61 [95%CI: 0.26 to 1.45] [insulin with secretagogues] and 0.50 [95%CI: 0.23 to 1.05] [secretagogues without insulin] EPPY). Emergency care and hospitalization constituted 3.6% (T1DM: 0%; T2DM: 6.7%) and 1.8% (T1DM: 0%; T2DM: 2.2%) of SH (n=224), respectively. Paramedical/hospital-based SH was more common in T2DM (0.06 [95%CI: 0.02-0.19]) than T1DM (0 EPPY) with IRs highest among insulin without secretagogue users (0.11 [95%CI: 0.03-0.47] EPPY). This is the first US prospective study on SH frequency in older adults with diabetes. Most (96.4%) events occurred at-home, underscoring the need for self-reported SH capture. Overall IPs and IRs were greater in T1DM than T2DM; but those with T2DM had more healthcare-based events. To mitigate undue health and economic costs, it is imperative clinicians remain vigilant to preventing SH in this vulnerable and growing population.

Disclosure
A.Ratzki-leewing: Consultant; Novo Nordisk, Eli Lilly and Company, Research Support; Sanofi. J.E.Black: None. G.Zou: None. B.L.Ryan: None. S.B.Harris: Advisory Panel; Bayer Inc., AstraZeneca, Eli Lilly and Company, Dexcom, Inc., Novo Nordisk A/S, Novo Nordisk Canada Inc., Sanofi, Consultant; Abbott Diabetes, Janssen Pharmaceuticals, Inc., Other Relationship; American Diabetes Association, Research Support; Abvance Therapeutics, Canadian Institutes of Health Research.

Funding
Sanofi Global
300-OR: Stage Transitions in Preclinical Type 1 Diabetes—Protective Effect of IA2 Variant Autoantibody Positivity
Authors: BEAM CRAIG , PIETROPAOLO SUSAN , ACEVEDO-CALADO MARIA J. , HERMAN MARK A. , REDONDO MARIA J. , PIETROPAOLO MASSIMO 
Published: June 2023

We previously demonstrated that the IA2 variant (IA2var) autoantibody (AA) is associated with enhanced prediction of type 1 diabetes (T1D) in at-risk individuals but its effect on progression through preclinical T1D stages is unknown. We aimed to assess the influence of IA2var AA on rates and risks of transitions from Stage 1 (multiple AA positive, no dysglycemia) to Stage 2 (multiple AA positive, dysglycemia) and to Stage 3 (clinical T1D). Participants in the Diabetes Prevention Trial (DPT-1) with Stage 1 or Stage 2 T1D at baseline and having ≥2 glucose tolerance tests during follow-up were selected (N=175). Standard AA (GAD65, ICA, ICA512 and insulin AA) were considered as biomarkers in addition to IA2var. Data analysis used Markov transition models. The estimated 12-month probability of transition from Stage 1 to 3 (N=89) was 13.8% (95% CI: 9.7%, 18.8%) and from Stage 2 to 3 (N=86) it was 41.3% (30.6%, 52.6%). IA2var AA, sex, age and were statistically significant risk factors for the Stage 2 to 3 transition (Table 1, B). Importantly, IA2var AA (the only significantly influential AA) was associated with a reduction in the risk of transition from Stage 2 to 3. In sum, male sex, older age and positive IA2var AA significantly decreased the risk of transition from Stage 2 to Stage 3 T1D. This information has important implications for the selection of candidates for T1D prevention in clinical and research practices.

Disclosure
C.Beam: None. S.Pietropaolo: None. M.J.Acevedo-calado: None. M.A.Herman: Research Support; Eli Lilly and Company. M.J.Redondo: None. M.Pietropaolo: None.

Funding
National Institutes of Health (2R01DK053456-19A1); Robert and Janice McNair Foundation
305-OR: Short-Term Hyperglycemia Impacts Mouse Skeletal Muscle in a Sex-Specific Manner
Authors: HULETT NICHOLAS A. , KNAUB LESLIE , POTT GREGORY , RAMIREZ DAVID , JOHNSTON ASPEN , SCALZO REBECCA L. , REUSCH JANE E.B. 
Published: June 2023

Cardiorespiratory Fitness (CRF) a universal predictor of cardiovascular and all-cause mortality, is lower in people with diabetes. Skeletal muscle is a key determinant of CRF, in particular mitochondrial content, function and oxygen extraction. Hyperglycemia is implicated in the dysfunction of microvascular blood flow. Our previous work demonstrated lower mitochondrial density/fiber and capillary mean flow velocity (MFV) with 4 weeks of hyperglycemia in males and females. Treadmill running resulted in greater capillary MFV and mitochondrial density in only hyperglycemic females. We hypothesize that along with alterations in mitochondrial density and blood flow, there is a disruption in skeletal muscle mitochondrial function with hyperglycemia, and that these parameters will respond to nitrite (NO2-) treatment in a sex-specific manner. We used a model of short-term hyperglycemia with tamoxifen inducible β-cell deletion of glucokinase. Two weeks after induction, blood flow in the gastrocnemius (gastroc) was measured using intravital microscopy, and the gastroc was collected from male (M) and female (F) mice with blood glucose &gt;400mg/dl (HG) and euglycemic controls (EG). A subset of mice received NO2- treatment for 1-2 weeks prior to gastroc measurements. Immunofluorescence imaging of gastroc were analyzed for expression of COX1 (mitochondrial marker), Dystrophin (muscle fiber sarcolemma boundary), and CD31 (capillary marker). Mitochondrial respiration was measured in gastroc fibers using Oroboros O2k. Mitochondrial respiration was lower in HG compared to EG (p&lt;0.0009), but only respiration in M appeared to respond to NO2- treatment (p=0.0252). No difference was observed in mitochondrial density in EG versus HG. Capillary MFV was greater with HG and mitigated by NO2-treatment. NO2- targets mitochondrial function by improving capillary blood flow, but only in males. Our combined data sets suggest HG-associated mitochondrial defects need to be treated in a sex-specific manner.

Disclosure
N.A.Hulett: None. L.Knaub: None. G.Pott: None. D.Ramirez: None. A.Johnston: None. R.L.Scalzo: None. J.E.B.Reusch: Advisory Panel; Medtronic.

Funding
U.S. Department of Veterans Affairs (BX002046, CX001532); National Institutes of Health (P30DK116073, 5T32AG000279-20)
313-OR: The Efficacy and Safety of Glucagon-Like-Peptide-1 Agonists in Patients with Familial Partial Lipodystrophy
Authors: IMAM SALMAN K. , FOSS-FREITAS MARIA C. , MERAL RASIMCAN , ORAL ELIF A. , DILL GOMES ANABELA , GRISSI FATIHA 
Published: June 2023

Familial partial lipodystrophy (FPLD) syndromes are a rare group of conditions with abnormal fat distribution and deposition of fat in ectopic tissues such as liver and muscle, leading to challenging metabolic abnormalities. Glucagon-like peptide-1 receptor agonists (GLP1R-A) are used for management of other metabolic dysfunction, but their efficacy in FPLD syndromes is not known. In this retrospective EMR review, we evaluate the effect of GLP1R-A for DM management in patients with FPLD for whom there are no approved treatments in the US. We collected data from 17 patients with FPLD (age 58 ± 12; 76.47 % females) and 17 patients with type 2 DM (age 58 ± 13; 71% females) before and 6 months after starting GLP1R-A. Only cases where the sole change was the addition of GLP1R-A were included in the analyses. Reduction in weight (p=0.002), BMI (p=0.001), HbA1c (p=0.02), and fasting glucose (p=0.04) (Figure 1A-D) were observed in patients with FPLD. Only the change in triglycerides after six months of treatment was greater in patients with FPLD compared to patients with DM (p=0.02, 95%CI: 13.6 to 215.8) (Figure 1E). Overall, there were no differences in changes in other parameters, and no serious events were reported. However, we observed acute pancreatitis in two cases with FPLD with longer therapy. Our study demonstrates the relative safety and effectiveness of GLP1R-A in patients with FPLD for the first time.

Disclosure
S.K.Imam: None. M.C.Foss-freitas: None. R.Meral: 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. A.Dill gomes: None. F.Grissi: None.
314-OR: The Triglyceride–Glucose Index May be a Surrogate for Both Insulin Resistance and Atherogenic Lipid Profile in Africans
Authors: WORTHY CHARLITA , DE DIEU GATETE JEAN , HURSTON JAMAIICA , SCHENK BLAYNE R. , MABUNDO LILIAN , DUBOSE CHRISTOPHER , JAGANNATHAN RAM , SUMNER ANNE E. 
Published: June 2023

As the insulin assay is expensive and often unavailable in low income countries, the triglyceride-glucose index (TyG) is undergoing global evaluation as both a surrogate marker of insulin resistance (IR) and predictor of cardiovascular disease (CVD). Yet the value of the TyG in African-born populations is uncertain. Therefore, in 555 African-born Blacks currently living in the Washington, DC area (Age: 39±0.4y (mean±SE), Male: 65% (358/555), BMI: 27.7±0.2 kg/m2) we determined: 1) ability of TyG to predict the presence of IR; and 2) correlations between TyG and four lipid parameters, specifically HDL-C and LDL-C, LDL-particle size and LDL-number. Fasting lipid profiles and OGTT were performed. IR was defined by the lowest quartile of the Matsuda Index (≤2.85). Ability of TyG to predict IR was assessed with AUC-ROC curve. Pearson correlations were performed between the lipids and both TyG and Matsuda Index. Diabetes, prediabetes and normal glucose tolerance occurred in 7% (37/555), 31% (173/555) and 62% (345/555) resp. AUC-ROC for the prediction of IR by TyG was 0.75±0.02. Correlations between the lipids and both TyG and Matsuda Index were highly significant (Table). But correlations with each lipid were stronger with TyG than Matsuda Index. Overall, TyG is marker of IR in Africans and may be better than Matsuda Index in predicting CVD because of stronger correlations with atherogenic lipids.

Disclosure
C.Worthy: None. J.Gatete: None. J.Hurston: None. B.R.Schenk: None. L.Mabundo: None. C.Dubose: None. R.Jagannathan: None. A.E.Sumner: None.