bluuebunny/crossref_metadata_2025_split huggingface dataset:
735-P: Effects of Insulin Degludec in Patients with Diabetes Using Continuous Glucose Monitoring: A Scoping Review
Authors: WANG CHAOFAN , XU WEN , YANG XUBIN , YAN JINHUA , YANG DAIZHI , YAO BIN , WENG JIANPING 
Published: June 2021

Background: The ultra-long-acting insulin degludec (Deg) was reported to have more stable glucose lowering effect with lower risk of hypoglycemia. This review aimed to summarize data on efficacy and safety of Deg in patients with T1DM or T2DM using continuous glucose monitoring (CGM).
Methods: A systematic literature search of studies on Deg in PubMed, EMBASE and Web of Science was performed for articles published before January 2021. Studies reporting data on the efficacy and safety of Deg in patients with diabetes using CGM were included.
Results: Thirteen studies with CGM data in 262 patients with T1DM or T2DM were included. The studies were conducted in Japan (11 studies) and Italy (2 studies). Eleven studies focused on patients with T1D (n=208) and two studies on T2D (n=54). The studies compared Deg with insulin glargine 100U/mL (n=130), insulin glargine 300U/mL (n=100), or insulin detemir (n=32). Regarding the study design, six studies were cross-over and seven studies were switching from other basal insulin to Deg. The sample sizes ranged from 7 to 46. The duration of Deg treatment varied between 3 days to 24 weeks. Three studies reported significant improvement of within-day or between-day glycemic variability by Deg, while the other ten studies revealed no difference in glycemic variability. The glucose lowering effect of Deg was comparable to other basal insulin in eleven studies, while two studies found that Deg could further improve glycemic control. Total daily insulin dose reduced in seven studies switching to Deg, while the insulin dose remained unchanged in six studies. In two studies, Deg reduced hypoglycemia when compared with glargine 100U/mL or detemir, which was not observed in other eight studies. However, three studies showed higher percentage time of hypoglycemia with Deg than glargine 300U/mL.
Conclusion: Deg leads to similarly effective, stable and safe glycemic control with comparable insulin dose requirement to other basal insulin on the current evidence.

Disclosure
C. Wang: None. W. Xu: None. X. Yang: None. J. Yan: None. D. Yang: None. B. Yao: None. J. Weng: None.

Funding
Johnson & Johnson Medical Devices Companies; Novo Nordisk (to J.W.)
754-P: SerpinB1 Delays T1D Progression and Improves Glucose Homeostasis in NOD Mice
Authors: BASILE GIORGIO , KIM HYUNKI , XIAO LING , HU JIANG , WANG HUAFANG , PEMBERTON PHILIP , KULKARNI ROHIT 
Published: June 2021

T1D occurs when the functional β-cell mass is reduced by an autoimmune cell-mediated attack. As recently reported, inducing β-cell proliferation during early life results in an almost complete resolution of T1D in rodents. SerpinB1 (sB1), a protease inhibitor, has been shown to promote β-cell proliferation by inhibiting pancreatic elastase, and to regulate specific pro-inflammatory cells, e.g., Th17 cells via blockade of cathepsin proteases. Previous studies have demonstrated beneficial effects of alpha-1-antitrypsin (AAT), another elastase inhibitor similar to sB1, in the progression of T1D in rodents and humans. Here, we tested the effects of sB1 in 1) delaying T1D onset, and 2) improving glucose homeostasis in female NOD mice, by inducing β-cell growth and suppressing autoimmunity. To examine the role of sB1 in T1D development (Study 1) we injected 4-week-old NOD mice daily with vehicle or recombinant mouse serpinb1a (rmsb1a) at different doses, intradermally for 28 weeks. Strikingly, the percentage of diabetes-free animals was higher in the rmsb1a groups compared to the non-injected group. Interestingly, islet infiltration scores were lower in rmsb1a mice compared to the vehicle-injected animals. In addition, β-cell proliferation levels were significantly higher in rmsb1a-treated mice compared to the vehicle group (~3-fold, P&lt;0.05). Finally, rmsb1a treated mice displayed a higher proportion of CD4+FoxP3+ cells and a lower count of Th17 cells compared to the vehicle group. In Study 2, diabetic NOD female mice were injected daily with either vehicle, rmsb1a or rmsb1a+AAT, intradermally for 10 weeks. We observed that glycemic levels were lower in rmsb1a and rmsb1a+AAT treated animals compared to vehicle and CTRL mice. Taken together, the beneficial effects of rmsb1a in delaying the onset and preventing progression of T1D by expanding β-cell numbers and increasing immune cell tolerance, point to the protease inhibitor as a potential therapeutic to limit hyperglycemia in T1D patients.

Disclosure
G. Basile: None. H. Kim: None. L. Xiao: None. J. Hu: None. H. Wang: None. P. Pemberton: Employee; Self; Serplus Technology LLC, Stock/Shareholder; Self; Redd Pharmaceuticals. R. Kulkarni: None.

Funding
National Institutes of Health (R41DK115326, R01DK103215)
755-P: A 26-Week Carcinogenicity Study with the Novel Glucagon Analog Dasiglucagon in CByB6F1-Tg(HRAS)2Jic Mice
Authors: ELANDER MIKAEL , FROUD ADAM 
Published: June 2021

Carcinogenicity testing is a regulatory requirement for new pharmaceuticals indicated for chronic diseases. Historically, carcinogenicity testing has been done in 2-year “lifelong” studies in rats and mice. The challenges with these studies in terms of a high false-positive rate and a high background tumor incidence in control animals have led to the development of an alternative transgenic mouse model. The rasH2 mouse is a hemizygous transgenic mouse carrying the human c-Ha-ras gene with its own promoter/enhancer elements, which induces high enhancer activity. The advantages offered by rasH2 mice are the low rate of spontaneous background findings and a lower false-positive rate with a comparable ability to predict known human carcinogens as the 2-year bioassays. We undertook the current carcinogenicity study to assess the novel glucagon analog, dasiglucagon, in the rasH2 mouse model. Four groups of 25 male and female CByB6F1-g(HRAS)2Jic mice received once-daily subcutaneous administration of the vehicle (25 mM sodium phosphate buffer, 17 mg/mL propylene glycol, pH 6.5) or dasiglucagon at 1, 5, and 20 mg/kg. The high dose was selected to result in exposure at least 25 times higher than the relevant clinical exposure. A positive control group received a single intraperitoneal injection of N-methyl-N-nitrosourea. Dasiglucagon at doses up to 20 mg/kg/day to transgenic CByB6F1-Tg(HRAS)2Jic mice for 26 weeks did not result in any neoplastic changes to demonstrate that dasiglucagon was not carcinogenic in the transgenic CByB6F1-Tg(HRAS)2Jic mouse model. Neoplastic findings in stomach of positive control animals demonstrated the functionality of the transgene and the suitability of the batch of transgenic animals. The data provide additional confidence that dasiglucagon has an acceptable profile for use in the treatment of humans.

Disclosure
M. Elander: None. A. Froud: None.
760-P: Allogeneic "Neo-Islets," Organoids Composed of Cultured Pancreatic Islet and Mesenchymal Stromal Cells from Diverse Donors, Afford a Marked Increase in the Global Availability of a Curative, Novel, Anti-Rejection-Drug-Independent Biotherapy of T1DM
Authors: WESTENFELDER CHRISTOF , CHOWDHURY SABIHA S. , GOOCH ANNA 
Published: June 2021

The scarcity of suitable pancreas/islet donors, the life-long need for potentially toxic anti-rejection drugs for transplants and certain biotherapies, and failure of some immune-isolating encapsulation devices collectively warrant the urgent development of novel therapies for T1DM that significantly expand the donor pool without reliance on anti-rejection drugs. Allogeneic, i.p.-administered “Neo-Islets” (NIs) are potentially such a therapy. We previously reported that the use of NIs reestablished permanent normoglycemia in autoimmune diabetic NOD mice without immunosuppression. Our FDA-guided pilot study (INAD 012-0776) in insulin dependent, spontaneously diabetic pet dogs showed similar, durable responses, also without immunosuppression. Scoring systems have improved allotransplantation outcomes while their use may actually waste potentially valuable cells for novel diabetes therapies such as NIs.
In preparation for a Phase 1 clinical trial with NIs, we examined whether human “non-clinical grade” islets from diverse, nondiabetic human and canine donors (n=6-8 each) could be processed to generate fully functioning NIs. Islet gene expression profiles (insulin, others) in both species closely correlate with population doublings and GSIS responses. Human-NIs establish normoglycemia in STZ diabetic NOD/SCID mice. Based on these results, an estimated 600 therapeutic doses can be generated from a single islet donor.
Conclusion: human-NIs created from diverse, “non-clinical grade” donors have the potential to greatly expand patient access to this curative therapy, facilitated by biotherapy-specific adjustments in the current scoring systems.

Disclosure
C. Westenfelder: Consultant; Self; SymbioCellTech. S. S. Chowdhury: Employee; Self; SymbioCellTech. A. Gooch: Employee; Self; SymbioCellTech.
77-OR: Circulating MicroRNAs Predict Glycemic Improvement and Response to a Behavioral Intervention
Authors: FLOWERS ELENA , ALLEN ISABEL D. , KANAYA ALKA M. , AOUIZERAT BRADLEY 
Published: June 2021

Introduction: MicroRNAs (miRs) may be important regulators of risk for type 2 diabetes (T2D). The purpose of this study was to assess whether circulating miRs predicted glycemic improvement and responses to a behavioral intervention over 12 months.
Methods: The study included 82 participants from a previously completed trial (PRYSMS study) that tested the effect of restorative yoga vs. stretching among overweight and inactive individuals with prediabetes and the metabolic syndrome, which found significant improvements in fasting blood glucose (FBG) after 12 months of yoga intervention. Circulating miRs were measured using flow cytometry. Linear models were used to determine the optimal sets of miR predictors.
Results: Subsets of miRs were significant predictors of FBG (R2=0.754, p&lt;0.001) and change in FBG over 12 months (R2=0.731, p&lt;0.001) in the overall sample. Three miRs (let-7c, miR-363, miR-374b) were significant among the control group only for both FBG outcomes. There was no significant interaction by intervention group. Among the identified miRs, several have previously been associated with risk for T2D and related complications.
Conclusions: This is one of the first studies to use a longitudinal design to assess whether miRs predict changes in FBG over time. Exploration of the function of the identified miRs may provide new insights about the etiology of T2D and responses to behavioral risk reduction interventions.

Disclosure
E. Flowers: None. I. D. Allen: None. A. M. Kanaya: None. B. Aouizerat: None.

Funding
National Center for Advancing Translational Sciences (KL2TR000143); National Center for Complementary and Alternative Medicine (R01AT004569); National Institute of Diabetes and Digestive and Kidney Diseases (R21DK117346); National Heart, Lung, and Blood Institute (2K24HL112827)
772-P: Portability of Nasal Glucagon for the Rescue of Severe Hypoglycemia: Stability and Performance Evaluation across a Broad Range of Temperatures
Authors: PACK BRIAN W. , MELNICK JASON , BREEN CHRISTOPHER , ALLEN ROSS 
Published: June 2021

Background and Aims: Nasal glucagon is a ready-to-use, drug-device combination therapy for the treatment of severe hypoglycemia. Portability is key, as nasal glucagon should be carried by persons with diabetes at all times. In designing for portability, the medication must allow for exposure to a broad range of temperatures without significant adverse effect on product quality/performance. In this study, we evaluated the stability and performance of nasal glucagon at temperatures ranging from -20 to +30 °C (-4 to +86 °F) in order to mimic real world situations.
Methods: Testing focused on characterization of drug product (glucagon amount) and combination product performance (consistent delivery to nasal cavity). Critical quality elements, including chemical purity and content, particle size, actuation force, delivered dose, shot weight, spray pattern and plume geometry, were evaluated after being exposed to temperatures from -20 and +30 °C, a range broader than a typically controlled room temperature product [i.e., Store at Controlled Room Temperature, 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F)], such as glucagon for injection.
Results: All testing demonstrated that 100% of critical quality elements were satisfied. Nasal glucagon could be exposed to frozen (-20 °C), refrigerated (2 to 8°C), and up to 30 °C conditions for the 2-year shelf life. The degradation of glucagon followed Arrhenius kinetics (i.e., slower degradation rates at lower temperatures). Temperature cycling studies showed no significant changes in the chemical/product performance attributes.
Conclusions: These analyses indicate no adverse impact to nasal glucagon from the chemical and physical perspective when exposed to frozen, refrigerated, and up to 30 °C conditions. The stability across a broad range of temperatures facilitates the portability of nasal glucagon as a rescue medication for severe hypoglycemia.

Disclosure
B. W. Pack: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. J. Melnick: Employee; Self; Eli Lilly and Company, Employee; Spouse/Partner; Eli Lilly and Company. C. Breen: Employee; Self; Eli Lilly and Company. R. Allen: Employee; Self; Eli Lilly and Company.

Funding
Eli Lilly and Company
774-P: Hereditary Renal Glycosuria, Diabetes, and Responses to SGLT2 Inhibitor
Authors: REN QIAN , GONG SIQIAN , HAN XUEYAO , JI LINONG 
Published: June 2021

Aims: To present the clinical features of two rare cases with hereditary renal glycosuria and diabetes, and summarize the previously reported SLC5A2 mutations and the related phenotypes.
Methods: The two patients were followed up for 7 and 3 years respectively, and detailed clinical characteristics were collected. SLC5A2 and HNF1A gene were sequenced. We used flash glucose monitoring system to record the variation of glucose with and without SGLT2 inhibitor treatment. Then we retrieved all the literature from Pubmed and analyzed SLC5A2 gene mutations and the phenotypes.
Results: During regular long-time follow up, the two patients both had frequent un-proportional renal glycosuria in the morning even when their fasting serum glucose was only slightly increased above the normal range. A novel rare mutation V359G and a pathogenic rare mutation ivs7+5G&gt;A in SLC5A2 gene were found in Case 1 and Case 2 respectively. In Case 1, the 24h glycosuria was 2.2g/d, and increased to 103g/day after dapaglifozin treatment. The average glucose (6.33±1.56 vs. 6.28±1.74mmol/L, P=0.663), and Time in Range (TIR) (95% vs. 93%) were not significantly different in metformin and dapaglifozin treatment respectively. In Case 2, the 24h glycosuria was 121.4g/d and increased to 185.8g/day after dapaglifozin add-on treatment, with a further reduction of average glucose (9.11±2.63 vs. 7.54±2.39mmol/L, P&lt;0.001), and better TIR 70% vs. 84%. We reviewed 139 cases with hereditary renal glycosuria and SLC5A2 gene mutation. The quantity of urine glucose was highest in patients with homozygous mutation (64.0(36.6-89.6)g/24h) compared with compound heterozygous (25.9(14.4-41.2)g/24h) and heterozygous(3.45(1.41-7.50)g/24h) (P&lt;0.001).
Conclusions: Genetic renal glycosuria could not be translated into protecting individuals completely from developing diabetes. The response of these patients suggested that even in diabetic patients with decreased renal glucose threshold, SGLT2 inhibitor could also be effective.

Disclosure
Q. Ren: None. S. Gong: None. X. Han: None. L. Ji: None.

Funding
National Key Research and Development Program of China (2016YFC1304901); Beijing Municipal Commission of Science and Technology (Z141100007414002, D131100005313008)
78-OR: Aß Classification in Children with New-Onset Diabetes
Authors: TOSUR MUSTAFA , DEEN SAIMA , UYSAL SERIFE , ASTUDILLO MARCELA , JAHOOR FAROOK , REDONDO MARIA J. , BALASUBRAMANYAM ASHOK 
Published: June 2021

The current binary classification (T1D vs. T2D) is inadequate to comprehensively dissect the heterogeneity of pediatric diabetes. The Aβ classification system, based on presence of islet autoimmunity (A+ or A-) and beta-cell functional reserve (β+ or β-), has been validated to define distinct phenotypic forms of Ketosis-Prone Diabetes in adults. Here, we aimed to study the utility of the Aβ classification system in children with new-onset diabetes. “A+” was defined as presence of ≥1 islet autoantibodies (GAD65, ICA512, insulin and ZnT8 autoantibodies) and “β+” as random C-peptide level ≥0.6 ng/mL at diagnosis. We compared the clinical characteristics at diabetes onset between the groups. The study cohort (n=67) was 46% female, 33% non-Hispanic white, 43% Hispanic, 21% non-Hispanic black and 3% Other. Mean age was 11.2 years and mean BMI was 59.3%ile. Aβ classification at diagnosis defined the following groups: A+β- (43%), A+β+ (24%) and A-β+ (33%). There were no A-β- patients. Median C-peptide levels in the three groups were 0.3, 0.7 and 3.3 ng/mL, respectively. Mean BMI %iles were 34.4 in A+β-, 53.1 in A+β+, and 96.4 in A-β+ group (p&lt;0.001). A-β+ group were older (14 y/o) compared to A+β- (8.9 y/o) and A+β+ (11.7 y/o) (p&lt;0.001). Diabetic ketoacidosis at diabetes onset was most frequent in A+β- (69%), intermediate in A+β+ (44%) and least in A-β+ (18%) (p&lt;0.01). Hispanic ethnicity was more common in A-β+ (64%) compared to A+β+ (44%) and A+β- (28%) (p=0.03). There were no significant differences in sex, mean HbA1c and daily insulin dose per kg at diabetes diagnosis between the groups. The Aβ classification system provides more pathophysiologic insight and discrimination of characteristics than the current classification system. The A-β- group, which we previously reported to be 2.6% of a large pediatric diabetes cohort, was not represented in this smaller study. If prospective follow-up confirms distinct natural histories for these groups, the Aβ classification will be useful in clinical practice and for the design of intervention trials.

Disclosure
M. Tosur: Advisory Panel; Self; Provention Bio, Inc. S. Deen: None. S. Uysal: None. M. Astudillo: None. F. Jahoor: None. M. J. Redondo: Advisory Panel; Self; Provention Bio, Inc. A. Balasubramanyam: None.

Funding
Texas Children’s Hospital
79-LB: Pharmacokinetics and Pharmacodynamics of Avexitide (Exendin 9-39) in Neonates and Infants with Congenital Hyperinsulinism
Authors: CRAIG COLLEEN , DE LEON DIVA D. 
Published: June 2021

Congenital hyperinsulinism (HI) is an ultra-rare pediatric disease with high unmet medical need. Avexitide, a first-in-class GLP-1 receptor antagonist, has been shown to reduce hyperinsulinemic hypoglycemia in children and adolescents with HI. Among neonates, maintenance of euglycemia often depends on high glucose infusion rates (GIR) by central lines. Those whose GIR exceeds 10 mg/kg/min frequently require subtotal pancreatectomy, leading to prolonged hospitalization, life-threatening complications, and induction of insulin-dependent diabetes. In this Phase 2 trial, 13 neonates and infants ages 11 days to 5 months with diazoxide-unresponsive HI were randomized to single ascending doses of avexitide and placebo by continuous IV infusion for up to 12 hours on two days in crossover design. Plasma glucose was monitored with GIR adjusted to maintain euglycemia. The primary endpoint was GIR. Relationships between avexitide exposure and absolute difference in GIR during avexitide vs. placebo were evaluated. A pharmacokinetic (PK) simulation of avexitide following subcutaneous (SC) injection in neonates was performed based on a modified PopPK model previously established with inclusion of weight-based allometric scaling. Relative to placebo, avexitide significantly reduced GIR when evaluated across dose levels (p=0.0087) with dose-dependent improvements observed. On average, avexitide infused at 100, 200 and 1000 pmol/kg/min demonstrated 1.3 (15%), 2.9 (24%), and 4.3 (56%) mg/kg/min reductions in GIR relative to placebo and entirely abolished glucose requirements in 50% of patients at the top dose. PK/PD analysis demonstrated an exposure-response relationship best described by an Emax model. PK simulation indicated that avexitide dosed by SC injection may achieve adequate steady-state exposure to lower GIR requirements. Subcutaneous avexitide may represent a promising therapeutic approach for treatment of neonates and infants with HI.

Disclosure
C. Craig: Consultant; Self; Eiger BioPharmaceuticals. D. D. De leon: Advisory Panel; Self; Zealand Pharma A/S, Consultant; Self; Hanmi Pharmaceutical, Heptares Therapeutics, Poxel SA, Soleno Therapeutics, Inc., Employee; Spouse/Partner; Merck & Co., Inc., Research Support; Self; Crinetics Pharmaceuticals, Tiburio, Zealand Pharma A/S.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (1R56DK083670); Clifford and Katherine Goldsmith Foundation; National Center for Research Resources (UL1RR024134); Eiger BioPharmaceuticals
79-OR: Butyrate Producing Bacteria and Insulin Homeostasis: The Microbiome and Insulin Longitudinal Evaluation Study (MILES)
Authors: CUI JINRUI , ZHU TIANTIAN , JENSEN ELIZABETH T. , CRAGO OSA L. , RAMESH GAUTAM , SANDOW KEVIN ALBERT M. , CHEN YII-DER IDA , ROTTER JEROME I. , PETROSINO JOSEPH , GOODARZI MARK O. 
Published: June 2021

Several studies have compared the stool microbiomes of people with and without type 2 diabetes (T2D), from which a pattern of depletion of butyrate producing taxa in T2D has emerged. Seventeen taxa encompass ~85% of the total butyrate producing potential in humans (mSystems 2017;2:e00130). The goal of MILES is to elucidate the effect of diet and gut microbiota on the components of insulin homeostasis (insulin sensitivity, secretion, clearance) whose dysfunction underlies T2D. MILES consists of 224 non-Hispanic Whites and 129 African Americans (mean age 59, 62% female), all of whom have completed an oral glucose tolerance test from which insulin homeostasis traits were calculated. Stool microbiome was assessed by whole metagenome shotgun sequencing (10 Gb depth), with taxonomic profiling using MetaPhlAn3. Spearman correlation was used to assess associations between the 17 dominant butyrate producing taxa (8 genera, 9 species) and insulin sensitivity, insulin secretion, disposition index (product of insulin sensitivity and insulin secretion), and insulin clearance. The Wilcoxon test was used to associate taxa with dysglycemia (prediabetes plus diabetes, 46% of cohort). Genera Coprococcus was associated with higher insulin sensitivity (ρ=0.16, P=0.003) and disposition index (ρ=0.14, P=0.009) and a lower rate of dysglycemia. Flavonifractor was associated with lower insulin sensitivity (ρ=-0.17, P=0.002) and a higher rate of dysglycemia. Eubacterium hallii was associated with insulin sensitivity (ρ=0.12, P=0.02). Analysis of 27 species from the 8 genera revealed additional associations with insulin sensitivity and disposition index, most of which displayed positive associations with these traits. These data suggest that improved insulin sensitivity and improved insulin secretion response to insulin sensitivity (i.e., disposition index) are key mechanisms whereby butyrate producing bacteria may exert metabolic protection against T2D.

Disclosure
J. Cui: None. M. O. Goodarzi: None. T. Zhu: None. E. T. Jensen: None. O. L. Crago: None. G. Ramesh: None. K. M. Sandow: None. Y. Chen: None. J. I. Rotter: None. J. Petrosino: None.

Funding
National Institutes of Health (R01DK109588)