bluuebunny/crossref_metadata_2025 huggingface dataset:
21-PUB: Meaningful Improvements in Treatment Satisfaction with Gla-300 in Insulin-Naïve PwT2D—A Post Hoc Analysis of Real-World ATOS PRO Study
Authors: HARRIS STEWART B. , KHAN NIAZ , TIROSH AMIR , KESAVADEV JOTHYDEV , VARGAS-URICOECHEA HERNANDO , ROBOREL DE CLIMENS AUDE , BAGHOUS HOUSSEM , SNOEK FRANK J. , MABUNAY MARIA AILEEN N. , GRULOVIC NATASA , CORP DIT GENTI VALERIE , MSIHID JEROME , GALSTYAN GAGIK R.
Published: June 2024

Introduction: Initiating Gla-300 has shown to improve treatment satisfaction in PwT2D in RCT and real-world studies. ATOS, a 12-month prospective observational global study showed that initiating Gla-300 in insulin-naïve PwT2D resulted in improved glycemic control and low hypoglycemia rates.

Methods: This post-hoc analysis evaluated meaningful improvements in Diabetes Treatment Satisfaction Questionnaire status (DTSQs) scores with glycemic parameters. Data was collected at baseline, months 3, 6 and 12, and based on distribution-based method (0.5 SD of baseline DTSQs score) for meaningfulness, percentage of responders was determined.

Results: Total, 3801 participants completed the questionnaire. At baseline, mean ± SD age was 57.7 ± 10.5 years, duration of diabetes was 10.2 ± 6.2 years and DTSQs total treatment satisfaction score 21.7 ± 7.4. Percentages of responders (improvement in DTSQs total score ≥4 points) were 60.2% at month 3 and 75.2% at month 12. A decrease in perceived frequency of hyper/hypoglycemia and higher reduction in mean HbA1c and FPG from baseline to month 12 were also observed for responders vs. non-responders (Table).

Conclusion: The majority of insulin naïve PwT2D initiating Gla-300 reported meaningful increase in treatment satisfaction and decrease in perceived frequency of hyper/hypoglycemia, associated with decreased HbA1c.

Disclosure

S.B. Harris: Consultant; Abbott. Research Support; Boehringer-Ingelheim. Consultant; Dexcom, Inc. Advisory Panel; Eli Lilly and Company. Consultant; Eli Lilly and Company, Novo Nordisk, Sanofi. Research Support; Novartis AG. Consultant; Bayer Inc. N. Khan: None. A. Tirosh: Advisory Panel; Novo Nordisk. Speaker's Bureau; Eli Lilly and Company. Advisory Panel; Sanofi, GlaxoSmithKline plc, Medtronic. Consultant; Radella Pharmaceuticals. J. Kesavadev: None. H. Vargas-Uricoechea: Speaker's Bureau; Abbott, Sanofi-Aventis U.S. A. Roborel de Climens: Stock/Shareholder; Sanofi. H. Baghous: Other Relationship; Sanofi, Novo Nordisk. F.J. Snoek: Advisory Panel; Abbott, Sanofi, Eli Lilly and Company, Roche Diabetes Care. M.N. Mabunay: None. N. Grulovic: Employee; Sanofi. V. Corp dit Genti: Employee; Sanofi. J. Msihid: Employee; Sanofi. Stock/Shareholder; Sanofi. G.R. Galstyan: None.

Funding

Sanofi
210-OR: ADA Presidents' Select Abstract: Discovering Stimulatory State-Specific Type 2 Diabetes GWAS Mechanisms with Single-Cell Multiomics on iPSC-Derived Fibro-adipogenic Progenitor Cell Villages
Authors: VENTRESCA CHRISTA , VARSHNEY ARUSHI , ORCHARD PETER , TSAN YAO-CHANG , MONTEIRO DA ROCHA ANDRE , LAAKSO MARKKU , TUOMILEHTO JAAKKO , LAKKA TIMO A. , MOHLKE KAREN L. , BOEHNKE MICHAEL , SCOTT LAURA , KOISTINEN HEIKKI A. , COLLINS FRANCIS S. , HERRON TODD J. , BIELAS STEPHANIE , PARKER STEPHEN
Published: June 2024

Variants at type 2 diabetes (T2D) and related trait genome wide association study (GWAS) signals may impact T2D risk via skeletal muscle, a primary insulin responsive tissue. We previously generated in vivo single nucleus (sn-)multi-omics (RNA+ATAC) profiling of 286 skeletal muscle biopsies from the FUSION Tissue Biopsy Study and found that a subset of GWAS signals colocalize with cell-type specific e/caQTL active in fibro-adipogenic progenitors (FAPs). In a subset of 50 of these individuals, we derived induced pluripotent stem cell (iPSC) lines from fibroblasts. We hypothesize that FAPs can be differentiated from iPSC lines to investigate the impact of FAP-specific molecular mechanisms on T2D risk and T2D-related traits. Here, we demonstrate that FAPs can be derived from iPSC lines for deep molecular phenotyping. These iPSC-derived FAPs display FAP morphology, expression of FAP marker genes, and loss of expression of pluripotency markers. Over the course of the differentiation, PODXL, a pluripotency marker, drops from 99.1% of cells expressing this down to 0.19%, based on flow cytometry analysis. Meanwhile, expression of NT5E, a FAP marker, increases from 0.095% of cells up to 98.9%. We performed a time course analysis with 10 independent iPSC lines, all multiplexed into a cell village, to explore the trajectory from iPSCs to FAPs. A logistic regression between cell type specific chromatin accessibility peaks of the iPSC-FAPs and skeletal muscle cell types reveals the chromatin accessibility profile of iPSC-FAPs to be very similar to in vivo FAPs, indicating that the differentiated FAPs can be used as a model system to characterize FAPs. We are currently upscaling the experiment to 40 iPSC-derived FAP samples to investigate stimulatory state specific genetic regulatory effects (e/caQTL) within T2D pathways. We will validate our results by performing CRISPRi knockdown and CRISPRa activation on a subset of nominated loci.

Disclosure

C. Ventresca: None. A. Varshney: None. P. Orchard: None. Y. Tsan: None. A. Monteiro da rocha: None. M. Laakso: None. J. Tuomilehto: Stock/Shareholder; Orion Pharma, Aktivolabs, Digostics. T.A. Lakka: None. K.L. Mohlke: None. M. Boehnke: None. L. Scott: None. H.A. Koistinen: Other Relationship; AstraZeneca, Novo Nordisk. F.S. Collins: None. T.J. Herron: None. S. Bielas: None. S. Parker: Research Support; Pfizer Inc.

Funding

National Institutes of Health (1F31DK135342-01A1); National Institutes of Health (R01DK117960); University of Michigan (UM1DK126185)
2101-LB: Restoring ß-Cell Mass and Identity in KATP-Induced Neonatal Diabetes—The Synergy of Autophagy and Intermittent Fasting
Authors: CASTELBLANCO ESMERALDA , REMEDI MARIA S. , RAMIREZ SOTERO IRVING
Published: June 2024

Pancreatic β-cell dysfunction is central to diabetes pathogenesis. Autophagy, which degrades damaged organelles and proteins, has emerged as a key player in β-cell function, but its role in preserving β-cell mass and identity remains poorly understood. Here, we investigated the interplay between autophagy and β-cell identity in the tamoxifen-inducible KATP gain-of-function (GOF) mouse model of neonatal diabetes. As expected due to the expression of overactive channels, non-obese KATP-GOF mice developed severe diabetes due to a lack of insulin secretion. As diabetes progressed, they showed increased β-cell endoplasmic reticulum (ER) stress and a decline in β-cell mass and identity, accompanied by dysregulated autophagy with impaired autophagic flux and autophagosome accumulation. KATP-GOF mice showed altered liver architecture with hepatocytes containing lipid droplets, but no changes in liver autophagy markers were observed. Strikingly, KATP-GOF mice exposed to alternate-day intermittent fasting (IF) showed improved glycemic control and glucose tolerance, mitigation of β-cell ER stress and mitochondrial abnormalities, and restored β-cell mass and identity. IF KATP-GOF mice demonstrated normalization of β-cell autophagic flux and reduction of autophagosome accumulation, accompanied by restored liver architecture and enhanced expression of genes involved in gluconeogenesis and lipolysis. These studies demonstrate, for the first time, impaired autophagy in non-obese KATP-induced diabetes and suggest that IF preserved β-cell identity via improved autophagy in the absence of body-weight loss or insulin secretion, implying similar mechanisms occurring in different forms of diabetes. These findings not only increase our understanding of the mechanisms underlying β-cell demise in diabetes but also offer insights into therapeutic strategies aimed at preserving functional β-cell mass.

Disclosure

E. Castelblanco: None. M.S. Remedi: None. I. Ramirez Sotero: None.

Funding

National Institutes of Health (R01DK123163)
2102-LB: Dysregulation of Cholesterol Homeostasis Is an Early Signal of Beta-Cell Proteotoxicity Characteristic of Type 2 Diabetes
Authors: GURLO TATYANA , LIU RUOSHUI , YANG XIA , BLENCOWE MONTGOMERY , BUTLER PETER C.
Published: June 2024

Type 2 diabetes (T2D) is a common metabolic disease due to insufficient insulin secretion by pancreatic beta cells in the context of insulin resistance. Islet molecular pathology reveals a role for protein misfolding in beta cell dysfunction and loss with islet amyloid derived from islet amyloid polypeptide (IAPP), a protein co-expressed and co-secreted with insulin. The most toxic form of misfolded IAPP is intracellular membrane disruptive toxic oligomers present in beta cells in T2D and in beta cells of mice transgenic for human IAPP (hIAPP). Prior work revealed a high degree of overlap of transcriptional changes in islets from T2D and pre-diabetic 9-10-week-old mice transgenic for hIAPP with most changes being pro-survival adaptations and therefore of limited therapeutic guidance. The aim of the study was to investigate islets from hIAPP transgenic mice at an earlier age (6 weeks) to screen for potential mediators of hIAPP toxicity that precede predominance of pro-survival signaling. Islets from 6-week-old hIAPP mice and wild-type mice were subjected to bulk RNA sequencing analysis followed by differential expression analysis, and then compared to prediabetic 9-10 weeks-old mouse islets. Analysis of intracellular lipid distribution in islets was performed in pancreas sections and isolated islets. hIAPP misfolding induced early suppression of cholesterol synthesis and trafficking along with aberrant intra-beta cell cholesterol and lipid deposits. The abnormality in lipid homeostasis mediated by hIAPP misfolding align with comparable lipid deposits present in beta cells in T2D and increased vulnerability to develop T2D in individuals taking medications that suppress cholesterol synthesis.

Disclosure

T. Gurlo: None. R. Liu: None. X. Yang: None. M. Blencowe: None. P.C. Butler: Consultant; Vertex Pharmaceuticals Incorporated.

Funding

Larry L. Hillblom Foundation (2014-D-001-NET, 2021-D-004-SUP)
223-OR: Characterization of Regenerative Adult Islet Progenitor Cells from Human Pancreatic Tissue
Authors: DARDEN CARLY , KUNCHA JAYACHANDRA , MATTKE JORDAN D. , LAWRENCE MICHAEL C. , NAZIRUDDIN BASHOO
Published: June 2024

Introduction & Objective: To identify and characterize expandable islet progenitor cells in human pancreatic tissue capable of regenerating islet organoids in vitro and in vivo.

Methods: Single cell RNA-sequencing was performed on dissociated pancreatic tissue from normal human pancreas and pancreatitis to identify islet progenitor cell populations, gene signatures, and unique markers expressed in vitro and in vivo. Islet progenitors were validated by QPCR and flow cytometry. Islet progenitor cells were isolated by flow-sorting and expanded to produce functional islet-like organoids. Undifferentiated islet progenitor cells and differentiated islet-like organoids were transplanted into STZ-induced diabetic nude mice to assess islet function. Grafts and native pancreas were assessed for expression of islet organoids.

Results: A total of 9807 cells were analyzed and multiple cell types were identified and matched to pancreatic cell subtypes, including activated stellate cells (86%), ductal cell (9.2%), beta cell (3.8%), and alpha cell (0.5%). Human islet progenitors were identified expressing stem-cell marker Procr, immature beta-cell marker CD9, and islet endocrine progenitor marker RGS16. These Procr+, CD9+, RGS16+ cells also expressed ductal epithelial, stellate, and mesenchymal cell markers indicative of epithelial-mesenchymal transition. Undifferentiated islet progenitor cells could migrate to the damaged mouse pancreas to produce human islet organoids in vivo within 28 days post-transplantation. Islet progenitor cells could be differentiated to produce and release insulin and glucagon in vitro and restore islet cell function in vivo.

Conclusion: Procr+, CD9+, RGS16+ islet progenitor cells expanded from human pancreatic tissue retain regenerative properties to produce functional islet cell organoids in vitro and in vivo for potential use in islet cell replacement therapy or strategies to regenerate islet cells in the native pancreas.

Disclosure

C. Darden: None. J. Kuncha: None. J.D. Mattke: None. M.C. Lawrence: None. B. Naziruddin: None.
241-OR: Health-Related Quality of Life and Burden of Type 1 Diabetes and Severe Hypoglycemia in Adult Continuous Glucose Monitor Users
Authors: BOATENG-KUFFOUR ADRIANA , CALLAHAN PATRICK , CHANDARANA KEVAL , BARRY DIANNE , CHEN LIANG , KELLY CAITLIN S. , NGUYEN HUYEN , CHAPMAN KATHERINE S.M. , CORNELIUS EMILEE M. , WOLF WENDY , POLONSKY WILLIAM H.
Published: June 2024

Introduction & Objective: Continuous glucose monitors (CGM) help manage glycemic control, but severe hypoglycemic events (SHE) remain challenging for adults with T1D. SHE may also reduce health-related quality of life (HRQoL) and increase humanistic and economic burden. Published literature on HRQoL in adult CGM users with T1D is limited.

Methods: Adult (≥18 years) CGM users from the T1D Exchange Registry completed an online self-report survey with SHE experiences, impaired awareness of hypoglycemia (IAH, Modified Gold Score), and patient-reported outcome measures (PROM). SHE cohorts were created based on SHE frequency in the past 12 months and presence/absence of IAH: problematic SHE, single SHE/no IAH, undetermined IAH, and no SHE (defined in the Table). Descriptive results (mean, SD) of PROM are reported overall and by SHE cohort.

Results: Overall, participants (N=1,847) were 45.9 years old, had T1D for 29 years (SD 15.1), and reported 1.8 SHE (SD 13.3) in the past year. Variability in patient-reported burden and HRQoL impairment was observed across cohorts. The problematic SHE cohort reported the highest mean burden and impairment (Table).

Conclusion: Despite advanced diabetes technology utilization, individuals with T1D and SHE experience substantial negative impacts of HRQoL, highlighting the significant unmet need in this patient population.

Disclosure

A. Boateng-Kuffour: Employee; Vertex Pharmaceuticals Incorporated. P. Callahan: Employee; Vertex Pharmaceuticals Incorporated. K. Chandarana: Employee; Vertex Pharmaceuticals Incorporated. Stock/Shareholder; Vertex Pharmaceuticals Incorporated, Novo Nordisk, Eli Lilly and Company. D. Barry: Employee; Vertex Pharmaceuticals Incorporated. L. Chen: None. C.S. Kelly: None. H. Nguyen: None. K.S.M. Chapman: None. E.M. Cornelius: None. W. Wolf: None. W.H. Polonsky: Research Support; Abbott Diagnostics, Dexcom, Inc. Consultant; Eli Lilly and Company, Sanofi. Advisory Panel; embecta. Consultant; Vertex Pharmaceuticals Incorporated. Advisory Panel; 9am Health.

Funding

Vertex Pharmaceuticals Incorporated
247-OR: Blood Monocyte Phenotype Predicts Cardiovascular Risk in Type 2 Diabetes
Authors: VENTECLEF NICOLAS , JULLA JEAN-BAPTISTE , GAUTIER JEAN-FRANÇOIS , POTIER LOUIS
Published: June 2024

Background: Diabetes is a major risk factor for atherosclerotic cardiovascular diseases with a 2-fold higher risk of cardiovascular events in people with diabetes compared with those without. Circulating monocytes are inflammatory effector cells involved in both type 2 diabetes (T2D) and atherogenesis.

Methods: We investigated the relationship between circulating monocytes and cardiovascular risk progression in people with T2D, using phenotypic, transcriptomic, and metabolomic analyses. cardiovascular risk progression was estimated with coronary artery calcium score in a cohort of 672 people with T2D.

Results: Coronary artery calcium score was positively correlated with blood monocyte count and frequency of the classical monocyte subtype. Unsupervised k-means clustering based on monocyte subtype profiles revealed 3 main endotypes of people with T2D at varying risk of cardiovascular events. These observations were confirmed in a validation cohort of 279 T2D participants. The predictive association between monocyte count and major adverse cardiovascular events was validated through an independent prospective cohort of 757 patients with T2D. Integration of monocyte transcriptome analyses and plasma metabolomes showed a disruption of mitochondrial pathways (tricarboxylic acid cycle, oxidative phosphorylation pathway) that underlined a proatherogenic phenotype.

Conclusions: In this study, we provide evidence that frequency and monocyte phenotypic profile are closely linked to cardiovascular risk in patients with T2D. The assessment of monocyte frequency and count is a valuable predictive marker for risk of cardiovascular events in patients with T2D.

Disclosure

N. Venteclef: None. J. Julla: Speaker's Bureau; Lilly Diabetes, Novo Nordisk. Board Member; Sanofi. J. Gautier: Board Member; Sanofi. Other Relationship; Sanofi. Speaker's Bureau; AstraZeneca, Novo Nordisk. Research Support; Novo Nordisk. Advisory Panel; Pfizer Inc. L. Potier: Research Support; Abbott. Consultant; AstraZeneca, Bayer Inc., Eli Lilly and Company, Novo Nordisk, Sanofi, Boehringer-Ingelheim.
25-OR: Two Weeks of Exercise Alters Neuronal Extracellular Vesicle Insulin Signaling in Adults with Prediabetes
Authors: MALIN STEVEN K. , BATTILLO DANIEL J. , CHAUDHRY BILAL A. , BEERI MICHAL S. , DELGADO-PERAZA FRANCHESKA , KAPOGIANNIS DIMITRIOS
Published: June 2024

Introduction & Objective: Prediabetes raises Alzheimer’s Disease and Related Dementia (ADRD) risk. While exercise may lower ADRD risk, it is unclear if it does so by raising brain insulin sensitivity and/or brain derived neurotrophic growth factor (BDNF). We hypothesized that short-term exercise would raise brain insulin signaling and BDNF from neuronal extracellular vesicles (nEVs) in adults with prediabetes.

Methods: Twenty-one adults (18F, 60.0±8.6 y; 33.5±1.1 kg/m2) with prediabetes (75g OGTT, ADA criteria) were randomized to 12 supervised work-matched continuous (n=13, 70% HRpeak) or interval (n=8, 90% and 50% HRpeak for 3 min each) sessions over 2-wks for 60 min/d. Aerobic fitness (VO2peak) and body weight were assessed. After an overnight fast, whole-body glucose tolerance (total area under the curve, tAUC) and insulin resistance (glucose x insulin tAUC) were determined from a 120min 75g OGTT. nEVs were measured at 0- and 60min of the OGTT to depict phosphorylated insulin signaling (i.e. p-IRS-1, total/pAkt, pERK1/2, pJNK1/2 and pp38) and pro-BNDF. OGTT stimulated effects were calculated from protein differences (i.e. 60-0min).

Results: Adults were collapsed into a single group as exercise intensity did not affect measures. Exercise raised VO2peak (+1.4±2.0 ml/kg/min, P<0.01) and decreased weight (-0.4±0.9 kg, P=0.04) as well as whole-body glucose tAUC120min (P=0.02) and insulin resistance (P=0.01). Training lowered fasting pro-BDNF (704.1±1019.0 vs. 414.5±533.5 pg/ml, P=0.04), and increased OGTT-stimulated tAkt (-51.8±147.2 vs. 95±204.5 a.u., P=0.01), which was paralleled by reduced pAkt/total-Akt at 60min of the OGTT (1.3±0.2 vs. 1.2±0.1 a.u., P=0.04). No other insulin protein was impacted by exercise.

Conclusion: Two weeks of exercise altered brain insulin signaling responses to the OGTT and lowered pro-BNDF in adults with prediabetes. Further work is needed to assess if exercise-induced brain insulin sensitivity contributes to ADRD risk reduction.

Disclosure

S.K. Malin: None. D.J. Battillo: None. B.A. Chaudhry: None. M.S. Beeri: None. F. Delgado-Peraza: None. D. Kapogiannis: None.

Funding

National Institutes of Health (RO1-HL130296)
253-OR: Exploring Incorporation of Type 1 Diabetes into Identity and Perceptions of Diabetes Technologies in Adolescents and Young Adults (AYAs)
Authors: COMMISSARIAT PERSIS V. , SCHNEIDER-UTAKA AIKA K. , MORRISSEY BRENDEN , TINSLEY LIANE J. , HANES SARAH , HOOD KOREY K. , LAFFEL LORI M.
Published: June 2024

Objective: AYAs with T1D have endorsed physical, emotional, and social barriers to device use that suggest devices may negatively impact one’s identity. We examined associations between AYAs’ incorporation of T1D into identity and perceptions of diabetes technologies.

Methods: AYAs with T1D (ages 14-25 yrs, T1D ≥1 yr, eligibility A1c 7-13%) were recruited at 2 sites. AYAs completed the ADAPT (Accepting Diabetes and Personal Treatment) survey with 3 factors measuring incorporation of T1D into identity as well as validated surveys of diabetes technology attitudes and glucose monitoring satisfaction. See table for survey information.

Results: Participants were 191 AYAs (age 19.8±3.4 yrs, T1D duration 11.4±5.4 yrs, 49% male, 89% White, 86% on pump, 98% on CGM, 77% on AID, A1c 8.0±1.2%). Greater overall identity incorporation was related to lower A1c and higher % TIR (p’s <0.01). Greater overall incorporation was also related to more positive attitudes toward technology, less behavioral and emotional burden of glucose monitoring, greater feelings of freedom and device trust, and greater satisfaction with glucose monitoring (p’s <0.01). See table for details on ADAPT factors.

Conclusion: Greater incorporation of T1D into identity was associated with better glycemia and more positive perceptions of diabetes technologies reducing burden and increasing flexibility in daily life.

Disclosure

P.V. Commissariat: None. A.K. Schneider-Utaka: None. B. Morrissey: None. L.J. Tinsley: None. S. Hanes: None. K.K. Hood: Consultant; Cecelia Health, Sanofi. L.M. Laffel: Consultant; Dexcom, Inc. Advisory Panel; Medscape, Medtronic, Vertex Pharmaceuticals Incorporated. Consultant; Novo Nordisk. Advisory Panel; Lilly Diabetes, Provention Bio, Inc., Sanofi-Aventis U.S., Janssen Pharmaceuticals, Inc., MannKind Corporation.

Funding

National Institutes of Health (R01DK129479)
256-OR: Understanding Parent and Youth Diabetes Device Satisfaction
Authors: WONG JESSIE J. , FLORES HALEY M. , HANES SARAH , NGO JESSICA , HOOD KOREY K.
Published: June 2024

Aim: As youth increasingly adopt diabetes technologies, little is known about device satisfaction. This study sought to understand factors associated with youth and parent diabetes device satisfaction.

Methods: A sample of 157 youth ages 12-19 (Mage=14.7, SD=1.89; 46% female) and their parents enrolled in an RCT provided glycemic and survey data, including single-item ratings of diabetes device satisfaction. Chi-square and t-tests evaluated baseline correlates of satisfaction.

Results: Most youth (57%) endorsed being “very satisfied” with their devices compared to 35% of parents. Only 25% of parent-youth dyads were both “very satisfied.” Most very satisfied youth were male. While youth satisfaction was unrelated to glycemic outcomes, high satisfaction was related to less diabetes distress, better diabetes-related quality of life, better parent-child relationships, and less non-supportive diabetes involvement by parents. Parent satisfaction was related to lower A1c, lower youth diabetes distress, and higher parent diabetes-related quality of life.

Conclusions: Our results highlight key similarities and differences between youth and parents’ device satisfaction. While both parent and youth satisfaction were correlated with youth diabetes distress, parent satisfaction was linked with A1c while youth satisfaction correlated with parent-youth diabetes dynamics. Addressing these areas may promote ongoing device use.

Disclosure

J.J. Wong: None. H.M. Flores: None. S. Hanes: None. J. Ngo: None. K.K. Hood: Consultant; Cecelia Health, Sanofi.

Funding

National Institute of Health (K23-DK121771)
266-OR: Retatrutide, an Agonist of GIP, GLP-1, and Glucagon Receptors, Improves Markers of Pancreatic Beta-Cell Function and Insulin Sensitivity
Authors: ROSENSTOCK JULIO , COSKUN TAMER , HARTMAN MARK L. , LOU JITONG , WU QIWEI , DU YU , GURBUZ SIREL , MATHER KIEREN J. , MILICEVIC ZVONKO , THOMAS MELISSA K.
Published: June 2024

Retatrutide (RETA), an agonist of GIP, GLP-1 and glucagon receptors, significantly reduced HbA1c up to 2.2% in T2D and body weight up to 17% in T2D at wk 36 and 24% in obesity without T2D (OB) at wk 48 in Ph2 trials. To explore mechanisms by which RETA improved glycemic control, we assessed markers of beta-cell function and insulin sensitivity. Mixed models for repeated measures evaluated fasting biomarkers from two Ph2 double-blind randomized placebo-controlled trials: in T2D (281 subjects, 36-wks) and in OB (338 subjects, 48-wks). Homeostatic model assessment (HOMA2)-IR index (insulin), a measure of insulin resistance, decreased over time from baseline with RETA 12 mg reaching reductions of 39% in T2D at 36 wks and 52% in OB at 48 wks. Adiponectin, a marker of insulin sensitivity, increased with RETA from baseline up to 52% in T2D and up to 70% in OB, (p<0.001). HOMA2-B index (C-peptide), a marker of beta-cell function, rapidly increased with RETA up to 88% from baseline in T2D but did not significantly increase in OB. Proinsulin and proinsulin/C-peptide ratios, measures of beta-cell stress and dysfunction, decreased from baseline with RETA, by up to 71% and 62%, respectively, in T2D (p<0.001). In conclusion, RETA improved markers of beta-cell function in T2D and markers of insulin sensitivity in T2D and OB.

Disclosure

J. Rosenstock: Research Support; Biomea Fusion, Inc. Other Relationship; Lilly Diabetes. Research Support; Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Corcept Therapeutics. Other Relationship; Novo Nordisk. Research Support; Pfizer Inc. Other Relationship; Sanofi, Boehringer-Ingelheim. Research Support; Shionogi & Co., Ltd. Other Relationship; Structure Therapeutics, Inc. Advisory Panel; Terns Pharmaceuticals, Zealand Pharma A/S. Other Relationship; Applied Therapeutics, Hanmi Pharm. Co., Ltd., Oramed Pharmaceuticals. Advisory Panel; Scholar Rock. T. Coskun: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. M.L. Hartman: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. J. Lou: None. Q. Wu: None. Y. Du: None. S. Gurbuz: Employee; Eli Lilly and Company. K.J. Mather: Employee; Eli Lilly and Company. Z. Milicevic: Employee; Eli Lilly and Company. M.K. Thomas: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company.

Funding

Eli Lilly and Company
269-OR: Glucose Control in Free-Life under Hybrid Closed-Loop 6 and 12 Months after Initiation from a Nationwide Survey
Authors: RIVELINE JEAN-PIERRE , JULLA JEAN-BAPTISTE , JOUBERT MICHAEL , LABLANCHE SANDRINE , RENARD ERIC , GAUTIER JEAN-FRANÇOIS
Published: June 2024

The effectiveness of the Hybrid Closed Loop (HCL) system has been demonstrated in randomized controlled studies. This extensive national study was conducted to assess the initiation process, follow-up modalities, and the metabolic effectiveness of HCL during real-life use, following six and twelve months of continuous usage.

Methods: All adult patients who began HCL therapy between January 1st and December 31st, 2022, were included from 48 centers, irrespective of the specific HCL model employed. Clinical, continuous glucose monitoring (CGM), and HbA1c data were gathered at the initiation of HCL therapy and subsequently every 6 months. We also documented the approach healthcare professionals took when educating patients during follow-up. In this report, we present the 6-month and 12-month follow-up results for adult patients in the study.

Results: A total of 2156 adults patients were included; baseline characteristics are presented in Table 1. Metabolic evolution at 6 months ((n=1993) and at 12 months (n=1143) are presented in Table 2. At 12 months, 3.2% have stopped the HCL.

Conclusions: HCL has shown remarkable effectiveness in real-life scenarios, enabling the achievement of time in range goals and a significant reduction in severe hypoglycemic events after a 12-month follow-up. Only a small number of patients discontinued the use of HCL.

Disclosure

J. Riveline: Board Member; Abbott, Novo Nordisk A/S, Sanofi, Eli Lilly and Company, Medtronic, Dexcom, Inc., Insulet Corporation, Air Liquide, AstraZeneca. J. Julla: Speaker's Bureau; Lilly Diabetes, Novo Nordisk. Board Member; Sanofi. M. Joubert: Consultant; Abbott, Medtronic, Dexcom, Inc. S. Lablanche: None. E. Renard: None. J. Gautier: Board Member; Sanofi. Other Relationship; Sanofi. Speaker's Bureau; AstraZeneca, Novo Nordisk. Research Support; Novo Nordisk. Advisory Panel; Pfizer Inc.
279-OR: FBLN7 in Pre-adipocytes Promotes Adipose Tissue Fibrosis and Disrupts Metabolic Homeostasis in Obesity
Authors: YU HAIRONG , YAN JING , HU CHENG
Published: June 2024

Fibrosis, resulting from excess extracellular matrix deposition, is a feature of adipose tissue (AT) dysfunction and obesity-related insulin resistance. However, the precise mechanisms underlying AT fibrosis in obesity remain unclear. In this study, through scRNA-seq data we discovered Fibulin7 (FBLN7), a recently identified member of fibulin family, as a promoter of AT fibrosis. The precise role of FBLN7 in AT remains unknown. We showed that the loss and gain of function of FBLN7 in pre-adipocytes inhibits and promotes, respectively, TGFβ-induced fibrogenic responses. In vivo, genetic ablation of FBLN7 in adipocyte precursors, and treatment with FBLN7-neutralizing antibody dramatically alleviated AT fibrosis-inflammation state and improved systemic metabolic health. Mechanically, FBLN7 bound to thrombospondin-1 (TSP1) through its EGF-like calcium-binding domain, activated TGFBR1/TGFβ/Smad signaling via TSP1. Furthermore, in obese humans, FBLN7 levels were upregulated in both visceral fat and systemic circulation and correlated with clinical metabolic traits. And we also revealed that variant p.V99E was associated with improved metabolic performance in humans and inhibited TSP1/TGFBR1/TGFβ/Smad axis in cells. Conclusively, our findings imply that FBLN7 produced by pre-adipocytes is a potential biomarker of AT fibrosis and may represent a therapeutic target for AT fibrosis.

Disclosure

H. Yu: None. J. Yan: None. C. Hu: None.
281-OR: Pyruvate Carboxylase Flux Is Increased in the Type 1 Diabetic Exocrine Pancreas
Authors: RUSHIN ANNA , GRAHAM DALTON S. , HARDIN CALLIE , MERRITT MATTHEW
Published: June 2024

The exocrine pancreas displays structural and functional abnormalities in type 1 diabetes, such as acinar atrophy and fibrosis. Metabolic dysfunction may occur alongside these changes. Real-time exocrine pancreatic metabolism was investigated using nuclear magnetic resonance (NMR) and hyperpolarized (HP) pyruvate. This work used the hyperglycemic NOD.Rag1-/-.AI4α/β mouse model of T1D (n=4), normoglycemic NOD.Rag1-/-.AI4α/β mice (n=3) to model the pre-T1D state, and the NOD.Rag1-/- control (n=3). NMR spectra were collected at 14 T after injection of 4 mM HP [1-13C] pyruvate into the common bile duct, and 13C signals from several central carbon metabolites were detected. Pancreata from diabetic mice produced significantly more (p<0.05) fumarate and aspartate compared to control mice, indicating increased pyruvate carboxylase flux. Alanine to lactate and bicarbonate to lactate ratios were significantly altered in pre-diabetic and diabetic mice compared to the control, indicating a detectable shift in tissue redox balance prior to altered glycemia. Separately, immunofluorescence imaging of pancreas slices revealed pyruvate carboxylase levels were increased in T1D mice. Ultimately, these results indicate that the diabetic pancreas displays increased pyruvate carboxylase (PC) flux and altered redox balance, thus providing unique insights into uncharacterized metabolic shifts in the exocrine pancreas in T1D.

Disclosure

A. Rushin: None. D.S. Graham: None. C. Hardin: None. M. Merritt: None.

Funding

National Institutes of Health (T32 DK10876); National Science Foundation (DMR-1644779)
289-OR: Autophagy Promotes Islet α-Cell Function by Maintaining ER Proteostasis and Glucagon Production
Authors: ZHU WENZHEN , PAN LINXIU , CHIARA RUSSO ANNA , RAY ROHIT , PEDERSON BRENT , SHRESTHA NEHA , QI LING , REINERT RACHEL B.
Published: June 2024

Introduction & Objective: Islet α cells have traditionally been maligned for contributing to hyperglycemia in diabetes but are increasingly recognized for their potential to promote β cell mass and function. The cellular mechanisms regulating proglucagon production and its subsequent processing into glucagon and/or glucagon-like peptide 1 (GLP-1) in α cells are incompletely understood. Autophagy, the process of recycling cellular components by lysosomal degradation, is essential for insulin production and β cell survival.

Methods: To investigate the role of autophagy in α cells, we deleted the key autophagosome protein Atg7 using the Cre-lox system in mice or CRISPR in αTC cells.

Results: Atg7 Δ Gcg mice showed normal growth and oral glucose tolerance into adulthood but had impaired glucagon secretion following hypoglycemia by two months of age. Islet α cells in Atg7 Δ Gcg mice became hypertrophic and vacuolated with age, but survived without a substantial decline in mass. Instead, pancreatic glucagon content was reduced in Atg7 Δ Gcg mice (42.2 +/- 7.3 vs. 75.3 +/- 9.1 ng/g). Electron microscopy revealed α cells with fewer glucagon granules and dilated endoplasmic reticulum (ER), and increased expression of the ER chaperone BiP was confirmed in αTCΔAtg7 cells. This was associated with a decrease in the proglucagon processing hormone PC2, possibly limiting production of mature glucagon. Interestingly, total pancreatic GLP-1 content was increased in Atg7 Δ Gcg mice (1351 +/- 114 vs. 891 +/- 75 pg/g) without changes in serum GLP-1 levels. Using the GLP-1 receptor antagonist exendin(9-39), we observed a similar impairment in oral glucose tolerance in Atg7 Δ Gcg mice and littermate controls.

Conclusion: These data show that autophagy promotes classic α cell function by maintaining ER proteostasis and glucagon production. However, defective α cell autophagy does not entirely disrupt proglucagon-mediated signaling in vivo and may promote α cell GLP-1 production.

Disclosure

W. Zhu: None. L. Pan: None. A. Russo: None. R. Ray: None. B. Pederson: None. N. Shrestha: Employee; Regeneron Pharmaceuticals Inc. L. Qi: None. R.B. Reinert: None.

Funding

National Institutes of Health (K08DK129719, T32DK007245)
29-OR: Analysis of Fib-4 Index Changes in Adults with Type 2 Diabetes in an Effective Comprehensive Diabetes Care Program
Authors: SILVA-TINOCO RUBÉN , RIVAS-ALARCÓN ALINNE , DELATORRE-SALDAÑA VIRIDIANA , GALINDEZ-FUENTES ANA , MÁRQUEZ-GUILLÉN ERNESTO , SANTOS-LÓPEZ FRANCISCO , AMAYA DAVID , CASTRO ELIZABETH , MUNGUÍA BERENICE , LÓPEZ NARAI , GUZMAN-OLVERA EILEEN B. , CUATECONTZI-XOCHITIOTZI TERESA
Published: June 2024

Introduction: The Fib-4 index (FIB4) is recommended for screening liver fibrosis (LF) risk in adults with T2D. Recent evidence suggests that dynamic changes (increases/decreases) in FIB4 overtime may be linked to subsequent risk of liver events and diabetes-related complications. We explored the change in FIB4 among adults with T2D engaged in a quality improvement initiative within primary care-the DIABEMPIC program.

Methods: This quasi-experimental, single group pre/post-intervention design encompassed participants undergoing a 5-month multicomponent comprehensive care program. Designed to improve diabetes care goals, the program featured therapeutic diabetes education and interdisciplinary care, emphasizing intensive lifestyle modification and treatment intensification. No liver fibrosis-modifying drugs were used.

Results: The observed prevalence of indeterminate/high risk (FIB4 ≥ 1.3; IHR) for LF was 27%. Baseline characteristics and changes (Δ) in participants, stratified by baseline LF risk status, are detailed in Table 1. The Δ in FIB4 in the overall participants was -0.11 ± 0.5 (p = 0.004), while in the IHR group the Δ observed was -0.5 ± 0.77 (p < 0.001). At follow-up, 35 subjects (46%) moved from the IHR to the low-risk status.

Conclusions: This study underscore that intensive comprehensive care schemes within adults with T2D can mitigate the risk of LF, as measured through FIB4.

Disclosure

R. Silva-Tinoco: None. A. Rivas-Alarcón: None. V. delaTorre-Saldaña: None. A. Galindez-Fuentes: None. E. Márquez-Guillén: None. F. Santos-López: None. D. Amaya: None. E. Castro: None. B. Munguía: None. N. López: None. E.B. Guzman-Olvera: None. T. Cuatecontzi-Xochitiotzi: None.
290-OR: Acetylation Induces a SUMOylation–Phosphorylation Switch to Enhance MafA Transactivation
Authors: CHIRIKJIAN MARGOT , LIANG JIANI Z. , BARTOLOMÉ ALBERTO , SONI RAJESH , STEIN ROLAND , PAJVANI UPTAL
Published: June 2024

MAF bZIP transcription factor A (MafA) transactivates multiple genes involved in β-cell maturity function. MafA transactivation is increased by recruitment and binding of multiple lysine acetyltransferases, Kat2b and CBP, but mechanisms underlying this phenomenon are unclear. We performed a LC-MS/MS screen and validation experiments that revealed that Kat2b and CBP increased MafA acetylation at lysines (K) 32, 33 and 255. To understand functional consequences of MafA acetylation, we mutated all three to glutamine (3KQ) or arginine (3KR) to mimic constitutively acetylated and deacetylated MafA, respectively, and performed luciferase assays with these mimetics that showed increased transactivation ability at the insulin promoter by 3KQ, independent of stability, DNA binding or MafA localization. Intriguingly, 3KQ MafA also showed retarded mobility on SDS-PAGE, suggesting that acetylation induced another post-translational modification (PTM). In a second LC-MS/MS screen followed by alanine scanning, we identified that acetylation increased MafA phosphorylation at serine (S) 14. Thus, S14A mutation attenuated the effects of acetylation. Simultaneously, MafA acetylation at K32 prevents SUMOylation at the same site; thus, inhibition of SUMOylation increased MafA acetylation and activity. Overall, our findings suggest that acetylation induces a novel PTM switch in MafA - enhancing S14 phosphorylation and blocking K32 SUMOylation, to potentiate transactivation at target promoters.

Disclosure

M. Chirikjian: None. J.Z. Liang: None. A. Bartolomé: None. R. Soni: None. R. Stein: None. U. Pajvani: None.
30-PUB: Difference in Glycemic Control between Ipragliflozin (Ipra) and Sitagliptin (Sita) according to Fatty Liver Index (FLI)—Post Hoc Analysis of the Results of the Niigata Ipragliflozin and Sitagliptin with Metformin (NISM) Study
Authors: KITAZAWA MASARU , SONE HIROHITO , FUJIHARA KAZUYA , YAMADA TAKAHO , MATSUBAYASHI YASUHIRO , ISHIZAWA MASAHIRO , SUZUKI HIROSHI , YAMAMOTO MASAHIKO , YAMADA MAYUKO H. , HATTA MARIKO
Published: June 2024

Fatty liver (FL) is a major complication of type 2 diabetes mellitus and has adverse effects on glycemic control. Although there are many reports on drug selection to improve FL (e.g., SGLT2 inhibitors), reports on drug selection considering the effects of the presence or degree of FL on glycemic control are scarce. To address this issue, we performed a post-hoc analysis of the results of the NISM study, a 52-week randomized controlled trial comparing the efficacy of Ipra and Sita. Included were 90 participants (58.9% male; 44 using Ipra; 46 using Sita). Mean age was 59.3 y and mean HbA1c 7.5%, BMI 26.6 kg/m2, ALT 30.7 U/L and FLI 51.1. Participants were stratified into low FLI (n=44, FLI <51.0) and high FLI (n=46, FLI ≥51.0) groups. In the low FLI group, HbA1c improved significantly with Sita compared with Ipra (Ipra 0.37 vs. Sita -0.68, p = 0.04). On the other hand, in the high FLI group, HbA1c improved significantly with Ipra compared with Sita (Ipra -0.63 vs. Sita -0.14, p = 0.04). There was no difference in changes in the FLI in the low FLI group (-8.1 vs. -2.7, p = 0.051), but in the high FLI group, FLI improved significantly (-13.5 vs. -0.8, p <0.001) with Ipra compared with Sita. The FLI is effective in drug selection for type 2 diabetes.

Disclosure

M. Kitazawa: None. H. Sone: Research Support; Novo Nordisk, Astellas Pharma Inc., Kowa Company, Ltd., Kyowa Kirin Co., Ltd., Eisai Inc., Sumitomo Dainippon Pharma Co., Ltd. K. Fujihara: None. T. Yamada: None. Y. Matsubayashi: None. M. Ishizawa: None. H. Suzuki: None. M. Yamamoto: None. M.H. Yamada: None. M. Hatta: None.

Funding

This study was funded by Astellas Pharma Inc. The company was not involved in study design, patient selection, data aggregation/analysis, interpretation of results, or preparation of the manuscript.
320-OR: Pyruvate Kinase M2 (PKM2) Activation in the Podocyte Prevented Subset Differentiation of Glomerular Cells Induced by Diabetes
Authors: FU JIALIN , LI QIAN , PARK KYOUNGMIN , SHINJO TAKANORI , HUANG QIAN , WU I-HSIEN , KING GEORGE L.
Published: June 2024

Pyruvate kinase M2 (PKM2) activation in the glomeruli has been reported as a potential protective factor against diabetic nephropathy (DN). We have previously found that systemic or local activation of PKM2 in the podocyte could reversed mitochondrial dysfunction, glomerular metabolism and pathology in diabetic mice, partially via its regulation of paracrine action of vascular endothelial growth factor (VEGF) against the toxicity of hyperglycemia. To further investigate the protective function of PKM2 in glomerular cell differentiation and gene expressions induced by diabetes, unbiased single-cell RNA sequencing (scRNA-seq) was performed using glomerular cells from mice with PKM2-specific overexpression in podocytes (PPKM2Tg) or WT mice, with or without 7 months of diabetes. High-qualitied glomerular cells (N=87,283) were isolated and sequenced, with > 98% from glomeruli, including 43% endothelial cells (EC), 31% podocytes, 14% mesangial cells (MC), 2% of parietal epithelial cells (PEC), 8% immune cells (macrophages, B cells, T cells, NK cells and neutrophils). Diabetes increased macrophage and B cell numbers from 2.2% to 4.8% and 0.35% to 1%, respectively. Although diabetes or PKM2 overexpression did not change the percentage of EC, MC and podocytes, phenotype switch occurred within subsets of these cells. Diabetes increased podocyte subsets enriched for stressed proteins, while decreased subsets enriched for ECM production and CDC42 GTPase cycle, which were involved in cytoskeleton and foot process formation. These phenotype switches induced by diabetes were reversed in PPKM2Tg mice. Further, MC subset with high expression of mitochondrial electron transport chain and TCA cycle, and EC subset with anti-inflammatory phenotype were reduced by diabetes and restored in PPKM2Tg mice. Thus, PKM2 overexpression in the podocyte changed the energy metabolism and differentiation of subsets of podocyte, MC and EC to protect from DN.

Disclosure

J. Fu: None. Q. Li: None. K. Park: None. T. Shinjo: None. Q. Huang: None. I. Wu: None. G.L. King: None.
321-OR: Haptoglobin (Hp) Levels and Phenotype Are Unrelated to Severe Retinopathy in Type 2 Diabetes, but Lower Hp Reductions by Fenofibrate Are Associated with Greater Retinopathy Benefit—A FIELD Trial Study
Authors: LEUNG ONG KWOK , JANUSZEWSKI ANDRZEJ S. , FRANCIS HABIB , MANGANI ABUBAKAR SIDDIQ O. , O'CONNELL RACHEL L. , JENKINS ALICIA , KEECH ANTHONY C.
Published: June 2024

Background: The abundant plasma protein Hp has anti-oxidant and anti-inflammatory effects. Its genotype/phenotype modulates chronic diabetes complication risk and fenofibrate benefit on coronary artery and kidney disease in type 2 diabetes (T2D). It is unknown whether Hp phenotype and level are associated with risk of sight-threatening diabetic retinopathy (STDR) and fenofibrate benefit. Fenofibrate reduced STDR risk by 31% in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial.

Methods: Hp phenotype and level were measured in 8047 FIELD subjects at baseline and randomization (after a 16-week run-in with fenofibrate in the last 6-weeks).

Results: There were 307 on-trial STDR events over 5 years. Hp phenotype and baseline levels were not related to STDR risk. Fenofibrate benefit on STDR risk appeared greater for the Hp 2-1/2-2 phenotypes, but p for heterogeneity was >0.05 (Table 1). During run-in fenofibrate reduced Hp level by 20.7%, p<0.001. Fenofibrate benefit was greatest in those with the lowest tertile of baseline Hp levels as well as among those in whom Hp levels decreased least with treatment.

Conclusion: Whilst baseline Hp levels and phenotype are not strongly related to STDR risk in T2D Hp levels and phenotype identify subjects more likely to benefit from fenofibrate.

Disclosure

K. Ong: None. A.S. Januszewski: None. H. Francis: None. A.O. Mangani: None. R.L. O'Connell: None. A. Jenkins: Research Support; Abbott, Viatris Inc. Advisory Panel; Abbott. Research Support; Medtronic. Board Member; Insulin for Life. Research Support; Leona M. and Harry B. Helmsley Charitable Trust, Juvenile Diabetes Research Foundation (JDRF), Jaeb Center for Health Research, National Institutes of Health, National Health and Medical Research Council Australia. A.C. Keech: Research Support; Abbott, Amgen Inc., Bayer Inc., Kowa Company, Ltd., Mylan. Speaker's Bureau; Novartis Pharmaceuticals Corporation. Research Support; Novartis Pharmaceuticals Corporation, Sanofi, Viatris Inc.

Funding

Laboratoires Fournier, Dijon, France and the National Health and Medical Research Council of Australia (NHMRC) (457103, 1024105, 1037786, 1105467)
325-OR: Enhancing Physical Activity Engagement among Individuals with Type 1 Diabetes—Exploring Perceived Barriers in the Era of New Technologies
Authors: GUÉDET CAPUCINE , TAGOUGUI SEMAH , MESSIER VIRGINIE , BOUDREAU VALERIE , BRAZEAU ANNE-SOPHIE , RABASA-LHORET RÉMI P.R.
Published: June 2024

Background: Physical activity benefits people with type 1 diabetes (PwT1D); however, PwT1D appear less active than their nondiabetic peers. This study seeks to investigate the potential of diabetes technologies in mitigating perceived barriers to physical activity in type 1 diabetes (T1D).

Methods: A cross-sectional study with participants from the BETTER registry (age> 14 years) who completed BAPAD-1 (Barriers to Physical Activity in T1D) questionnaire. A significant barrier is defined by score > 5 to BAPAD-1 items. Four groups were defined according to the participants' treatment and blood glucose monitoring mode: Multiple daily injections (MDI) without continuous glucose monitoring (CGM), MDI with CGM, pump with CGM, and those using an automated insulin delivery system (AID).

Results: Among 1019 eligible participants, the main perceived barrier is the fear of hypoglycemia. The mean BAPAD-1 score is similar for all groups. A higher proportion of individuals using AID systems reported significant barriers for items fear of hypoglycemia and loss of control over their diabetes compared to the No-CGM-MDI (+20% both), CGM-MDI (+7% and +10%), and CGM+Pump (+9% and +7%).

Conclusion: Barriers to physical activity for PwT1D are not reduced by diabetes technologies. Some barriers are even perceived as more important for people using CGM, pump, and AID systems.

Disclosure

C. Guédet: None. S. Tagougui: None. V. Messier: None. V. Boudreau: None. A. Brazeau: Other Relationship; Dexcom, Inc. Research Support; Canadian Institutes of Health Research, Juvenile Diabetes Research Foundation (JDRF), Diabète québec, Fonds de recherche du Québec en Santé. R.P.R. Rabasa-Lhoret: Other Relationship; Abbott, AstraZeneca, Bayer Inc., Boehringer-Ingelheim, Dexcom, Inc. Research Support; Diabetes Canada. Other Relationship; Eli Lilly and Company. Research Support; Cystic Fibrosis Canada, Canadian Institutes of Health Research, FFRD - Fondation Francophone pour la Recherche du Diabète. Other Relationship; Janssen Pharmaceuticals, Inc. Research Support; Juvenile Diabetes Research Foundation (JDRF). Other Relationship; Novo Nordisk, GlaxoSmithKline plc. Consultant; HLS Therapeutics Inc., Insulet Corporation. Speaker's Bureau; CPD Networks. Other Relationship; Medtronic. Consultant; Pfizer Inc. Speaker's Bureau; Tandem Diabetes Care, Inc. Other Relationship; Sanofi. Speaker's Bureau; Vertex Pharmaceuticals Incorporated. Research Support; SFD - Société Francophone du Diabète.