bluuebunny/crossref_metadata_2025_split huggingface dataset:
2007-P: Weight Change and Intentionality of Weight Loss Relate to Mortality Risk in the Postintervention (Years 8-16) Phase of Look AHEAD
Authors: WING RENA R. , CLARK JEANNE , ESPELAND MARK , HILL JAMES O. , JEFFERY ROBERT W. , JOHNSON KAREN C. , KNOWLER WILLIAM C. , NEIBERG REBECCA H. , OLSON KAYLONI , PI-SUNYER XAVIER , STEINBERG HELMUT O. , WYATT HOLLY 
Published: June 2020

The health effects of weight loss in older individuals with diabetes is unclear, perhaps related to intentionality of the weight loss. Look AHEAD (LA) is a randomized trial comparing intensive lifestyle intervention for intentional weight loss with diabetes support and education (control) in 5145 individuals (age 45-76 at baseline) with overweight/obesity and type 2 diabetes. We examined the association of weight change trajectories post-intervention (i.e., yrs 8 to 16; M± SD percent weight change= -3.10% ±10.1), and concurrent risk of mortality by comparing weight gainers (N=226), maintainers (N=1459), modest losers (N=2206), and steep losers (N=415). Both weight loss groups were older, more likely to be in DSE, and lost less weight in yrs 1-8. In Cox proportional hazards regression models, adjusted for sex, race, baseline obesity, age, and treatment, mortality risk among the 4 weight change categories differed significantly (p&lt;0.0001). Relative to maintainers, the hazard ratio for death was non-significantly lower in gainers (HR= .58, 95%CI 0.30,1.11) but significantly higher in modest losers (HR=1.49, 95%CI 1.20,1.36) and steep losers (HR=1.87, 95%CI 1.39,2.53). Adjusting for weight change baseline to year 8 did not alter the associations. Subsequent analyses examined the difference in the hazard ratios for death in those who reported having lost &gt;10 lb over 2 most recent 6-month assessments intentionally, unintentionally, or through the combination (intentional + unintentional), relative to maintainers (no weight loss&gt;10 lb). Adjusted analyses showed that the HR for mortality was significantly greater in both the unintentional (HR=3.26, 95%CI 2.35,5.01) and the combination (HR=2.63, 95%CI 1.28,5.39), but not different in the intentional weight loss group (HR=1.05, 95%CI 0.61,1.81) relative to maintainers. These data suggest that unintentional weight loss is associated with increased risk of mortality in older individuals with diabetes.

Disclosure
R.R. Wing: None. J. Clark: None. M. Espeland: Other Relationship; Self; Boehringer Ingelheim International GmbH, Ironwood Pharmaceuticals. J.O. Hill: Stock/Shareholder; Self; Gelesis, Shakabuku LLC. R.W. Jeffery: None. K.C. Johnson: None. W.C. Knowler: None. R.H. Neiberg: None. K. Olson: None. H.O. Steinberg: None. H. Wyatt: Research Support; Self; National Cattleman’s Association, Novo Nordisk Inc. Stock/Shareholder; Self; Shakabuku LLC. Other Relationship; Self; FoodMinds.

Funding
National Institutes of Health
201-LB: NKG2D Signaling within Pancreatic Islets Reduces NOD Diabetes and Is Associated with CD8+ Central Memory T-Cell Generation
Authors: TREMBATH ANDREW , SHARMA NEEKUN , GERLING IVAN C. , MATHEWS CLAYTON E. , MARKIEWICZ MARY A. 
Published: June 2020

Type 1 diabetes is an autoimmune disease in which the pancreatic β islet cells are destroyed. The main drivers of type 1 diabetes are islet-specific T cells. These cells must escape a myriad of tolerance mechanisms that control their activation in healthy individuals. Understanding these mechanisms is critical to developing better strategies to inhibit the disease. One pathway implicated in this process is NKG2D signaling. However, the importance of NKG2D to diabetes pathogenesis is unclear owing to conflicting results from studies in which NKG2D signaling was inhibited globally. Our previous studies indicate that these inconsistent findings are due to differential effects of NKG2D signaling in response to islet antigen and the microbiota. Therefore, new experimental approaches are required to determine the roles of NKG2D during diabetes development. To this end, we generated two novel mouse models. These are transgenic NOD mice that have enhanced NKG2D ligand expression in β cells (RIP-RAE1ε mice), and NOD mice lacking expression of the NKG2D ligand endogenously expressed in islets, H60a. We found that the RIP-RAE1ε mice and H60a-deficient mice had decreased and increased diabetes, respectively. These data demonstrate that increasing NKG2D signaling within the pancreas protects, whereas eliminating NKG2D signaling enhances, NOD diabetes. Further, we show that the NKG2D-mediated protection is associated with an increase in CD8+ central memory T cells (Tcm) in vivo, which correlates with NKG2D signaling-induced generation of both mouse and human CD8+ central memory T cells in vitro, and that CD8+ Tcm protect against diabetes in the NOD.SCID adoptive transfer model. Taken together, these data indicate that NKG2D signaling protects against diabetes by enhancing the generation of a protective CD8+ Tcm population.

Disclosure
A. Trembath: None. N. Sharma: None. I.C. Gerling: None. C.E. Mathews: None. M.A. Markiewicz: Consultant; Self; Johnson & Johnson.

Funding
American Diabetes Association (1-12-JF-41 to M.A.M.); National Institutes of Health (P30GM103326, P30CA168524, UC4DK104167, UC4DK104155, U54HD090216, P30DK020579, P30GM122731); JDRF (5-SRA-2018-557-Q-R, 17-2012-595); The Leona M. and Harry B. Helmsley Charitable Trust (2018PG-T1D053); American Association of Immunologists
201-OR: Automated Insulin Delivery (AID) System Performance with and without Meal Announcement: Effect of Meal Macronutrient Content
Authors: BARTEE AMY , BRAZG RONALD L. , KATZ MICHELLE , LALONDE AMY , WOLPERT HOWARD , JONES RICHARD 
Published: June 2020

Missed meal boluses contribute to suboptimal glucose control. There has been limited evaluation of missed boluses for complex or high glycemic index meals while on hybrid closed loop AID systems. Ten subjects with type 1 diabetes (50% male), age 52±10 y, A1C 7.1±0.9%, insulin requirement 0.5±0.2 U/kg/day, used the Lilly investigational AID system (model predictive control algorithm) during a 48 h inpatient observation with 6 meals. For each subject, the 2 breakfast (pancake; [60 g carbohydrate (CHO), 15±4 g fat]) and 2 dinner (pizza; [53±3 g CHO, 20±1 g fat]) meals were identical, and were consumed with or without a pre-meal insulin bolus. Lunch meals were subject-selected (44±16 g CHO, 7±5 g fat), and appropriate pre-meal boluses were administered. Time-in-range (TIR, 70-180 mg/dL) overnight was 99.2±9.5% and following the lunches was 82.1±26.4%. In contrast, TIR following pancake and pizza challenges with bolus were 56.0±34.4% and 65.8±29.6%, and without bolus were 17.8±5.1% and 36.5±25.2%, respectively. Incremental area under the curve (0-2 h) following the pancake meal was larger than the pizza meal within both the bolused and non-bolused scenarios (Table). This study highlights the importance of structured, but varied meal challenge tests in the evaluation of AID system performance. Meal macronutrient content affects AID performance in bolused and non-bolused scenarios.

Disclosure
A. Bartee: None. R.L. Brazg: None. M. Katz: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. A. LaLonde: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. H. Wolpert: Employee; Self; Eli Lilly and Company. R. Jones: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company.
202-LB: Diabetes-Induced Modulation of a Specialized Macrophage Implicated in Bone and Nerve Repair
Authors: SALISBURY ELIZABETH A. , MEJIA JULIO A. , GUGALA ZBIGNIEW , DAVIS ALAN R. , OLMSTED-DAVIS ELIZABETH 
Published: June 2020

Altered inflammatory responses are associated with impaired bone and nerve healing in diabetes. However, the detailed mechanisms of these responses and their contribution to neuropathy and poor fracture healing remain unclear. We previously identified a cell population expressing factors associated with brown adipocytes (uncoupling proteins and the β3-adrenergic receptor (ADRβ3)), which is activated by neuroinflammation and contributes to de novo bone formation. Single cell RNA-sequencing revealed these cells are macrophages. In this study, we investigated the role of this newly identified macrophage population during bone formation in wild type and diabetic mice. De novo bone formation was induced by intramuscular delivery of cells producing bone morphogenetic protein 2. After four days, ADRβ3+ cells were isolated by FACS to evaluate expression of different macrophage markers and macrophage polarization by qPCR. These cells expressed a unique set of markers similar to CNS macrophages, including TMEM119. Polarization assays to induce either a pro-inflammatory (M1) or reparative (M2) macrophage phenotype revealed these cells possess plasticity but are distinct from bone marrow-derived macrophages and microglia. In vivo addition of LPS to promote M1 polarization during de novo bone formation led to a reduction in bone volume. When a unicortical fracture was introduced to the femur, ADRβ3+ macrophages were observed within the fracture callus after seven days, indicating a role for these cells in the reparative process. Analysis of de novo bone formation and fracture in C57BL/6- ob/ob mice showed reduced numbers of ADRβ3+ macrophages. Initial histological analysis of human nerves indicates expansion of these ADRβ3+ cells in type 2 diabetes. These data suggest alterations to a novel macrophage population with reparative potential in diabetes. Further characterization of these cells may provide new approaches to direct their action for desired bone and nerve repair.

Disclosure
E.A. Salisbury: None. J.A. Mejia: None. Z. Gugala: None. A.R. Davis: None. E. Olmsted-Davis: None.

Funding
National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01R066556); U.S. Department of Defense (W81XWH-16-1-0649, W81XWH-17-1-0628)
202-OR: Basal Insulin Digital Titration App vs. Enhanced Paper Titration Tool: A Randomized Control Study
Authors: PHILIS-TSIMIKAS ATHENA , FORTMANN ADDIE L. , BASTIAN ALESSANDRA , KANCHI ARATI , ABAD RICARDO , SHENG TONG , PARKS LINDA , GREENFIELD MICHAEL , CLEMENTS MARK A. 
Published: June 2020

Self-adjusting insulin is challenging for people with type 2 diabetes (PWT2D). Mobile health technologies (mHealth) can help PWT2D track blood glucose more easily, but it remains unclear whether an mHealth-enabled digital therapeutic tool can effectively support basal insulin (BI) titration in a large multispecialty health care setting. We randomized 242 PWT2D on BI (baseline HbA1c 7.5% - 12.5%) to use either an app-based self-titration tool [Mobile Insulin Dosing System (MIDS)] or an enhanced paper titration tool based on a stepped algorithm with diabetes educator support (control) for 16 weeks. Cohort characteristics for the intent to treat sample (MIDS n = 117; control n = 120) were: median age 61 years [IQR: 53 - 69], 41.7% female, 75.9% non-Hispanic White, 11.4% new to insulin, median duration of diabetes 11 years [IQR: 7 - 18], and median baseline HbA1c of 8.7% [IQR: 8.0 - 9.6]. Improvements in HbA1c (-1.3% [IQR: -2.2 - -.5] and -1.2% [IQR: -1.9 - -.5]; both Ps &lt; .05) with increased median insulin dose (+8 IU [IQR: 2 - 22] and +10 IU [IQR: 2 - 25.5]; both Ps &lt; .05) and no change in hypoglycemia were observed at 16 weeks in both the MIDS and control groups, respectively. No differences in HbA1c (P = .48) or insulin dose change (P = .34) were observed between the groups. Among SMBG readings recorded during the study, the mean proportion of readings between 70-180 mg/dL (76.8% ± 22.0; 70.0% ± 26.7; p&lt;0.05) and &gt;250 mg/dL (4.9% ± 9.2; 9.2% ± 18.4; p&lt;0.05) both favored the MIDS group. The use of MIDS and the enhanced paper-based tool for BI self-titration both resulted in higher insulin dose and significantly improved glycemic control among PWT2D who were relatively uncontrolled despite most already being treated with insulin. An mHealth-enabled digital therapeutic tool such as MIDS may offer an effective alternative option for PWT2D and their HCPs for titrating BI to non-mHealth approaches; future RCTs will more clearly elucidate the efficacy of MIDS compared to usual care.

Disclosure
A. Philis-Tsimikas: Advisory Panel; Self; Lilly Diabetes, Medtronic, Novo Nordisk A/S, Sanofi. Employee; Spouse/Partner; Ionis Pharmaceuticals, Inc. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Dexcom, Inc., Lilly Diabetes, Medtronic, Novo Nordisk A/S, Sanofi. A.L. Fortmann: None. A. Bastian: None. A. Kanchi: Employee; Self; Glooko, Inc. Stock/Shareholder; Self; Glooko, Inc. R. Abad: Employee; Self; Glooko, Inc. T. Sheng: Employee; Self; Glooko, Inc. L. Parks: Employee; Self; Glooko, Inc. M. Greenfield: Consultant; Self; Glooko, Inc. M.A. Clements: Consultant; Self; Glooko, Inc. Other Relationship; Self; Glooko, Inc.
2027-P: A Retrospective Study of Weight and Metabolic Changes in Patients with Obesity (BMI≥30 Kg/m2) after Endoscopic Sleeve Gastroplasty (ESG) or Laparoscopic Sleeve Gastrectomy (LSG)
Authors: BENIAS PETROS , VEGESNA ANIL K. , LEUNG TUNG MING , ZISKOVICH KARINA , INLALL DAMIAN , PORETSKY LEONID , MILLER LARRY S. 
Published: June 2020

Weight reduction in obese individuals lowers comorbidities. LSG is the most common bariatric procedure in use today, but there is a need for less invasive approach. ESG, a novel incisionless, minimally invasive procedure, involves endoscopic plication of the greater curvature of the stomach reducing its length and width. We compared weight and metabolic changes associated with these procedures. A single center retrospective study was performed of consecutive patients that underwent LSG or ESG. SAS and multivariate mixed model were used to determine percentage change of total body weight (TBW), BMI, BSA (body surface area), HbA1c and total cholesterol level (TC). 25 patients were recruited (11[44%] had LSG and 14[56%] had ESG). The average age of LSG group was 47±3.9 and ESG group was 39±4.2 years. There was no statistical difference in the age, gender, or race between the groups. 29% of LSG patients and 10% of ESG patients had diabetes. Results are in the Table; * indicates significant differences between the groups.
Conclusions: In this limited retrospective study, patients who underwent LSG had a higher % reduction in TBW, BMI and BSA than those who underwent ESG. There was no statistical difference between the groups in the HbA1c or TC change. These preliminary data should be confirmed in larger prospective randomized trials.

Disclosure
P. Benias: Consultant; Self; Apollo EndoSurgery. A.K. Vegesna: None. T. Leung: None. K. Ziskovich: None. D. Inlall: None. L. Poretsky: None. L.S. Miller: None.

Funding
New York State Department of Health
2029-P: Role of Adipose Tissue Macrophage–Derived F13A1 in Regulating Preadipocyte Hyperplasia during Obesity
Authors: ELIZONDO DIANA M. , GELETKA LYNN M. , FLESHER CARMEN G. , LUMENG CAREY N. 
Published: June 2020

The epidemic of DM has increased in the last decades and is the leading cause of decreased life expectancy. AT adapts to nutrient excess by balancing hypertrophy and hyperplasia that contribute to AT expansion. Unhealthy AT expansion seen in a person with diabetes is characterized by decreased preadipocyte (PA) content, and increased adipocyte size. AT macrophages (ATM) contribute to unhealthy AT expansion by blocking adipogenesis, promoting adipocyte hypertrophy, fibrosis and insulin resistance (IR). Many of the cellular and molecular mechanisms by which adipocyte numbers and size is regulated by ATMs in vivo are still unknown, especially in human obesity. This study focused on the hypotheses that ATM expression of F13A1, a tissue transglutaminase enzyme shown to regulate fibrin networks during tissue growth: 1) modulates abundance of preadipocyte (PA) populations during obesity and DM states, and 2) contributes to adipocyte hypertrophic states and potential metabolic dysfunction. The premise for these studies was based on evidence that F13A1 is increased in Visceral AT (VAT) of DM individuals compared to non-DM and that it is produced by a tissue remodeling ATM subset increased in DM. We utilized nondiabetic (NDM) and DM human secondary PA treated with F13A1 and assessed the following: 1) F13A1 expression requirement for the inhibition of healthy PA expansion in obesity, and 2) the mechanisms by which its function leads to arrested proliferation. Results showed that F13A1 impairs PA proliferation through its exerted effects on PA ECM fibronectin crosslink leading to: 1) downregulation of downstream gene proliferative signaling pathways and 2) defaulted adipocyte differentiation with hypertrophic profiles as an antagonistic response to decreased proliferation. These studies have advanced our understanding of ATM-derived F13A1 as a potential immunotherapeutic target to improve AT function.

Disclosure
D.M. Elizondo: None. L.M. Geletka: None. C.G. Flesher: None. C.N. Lumeng: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (T32DK101357)
204-LB: The In Vitro Characteristics of Human Islet Cells from Diverse Donors, Coaggregated with Human Mesenchymal Stromal Cells to form “Neo-islets”, Are Consistently Identical: Relevance to Clinical Trials in Diabetic Subjects
Authors: GOOCH ANNA , CHOWDHURY SABIHA S. , ZHANG PING , HU ZHUMA , WESTENFELDER CHRISTOF 
Published: June 2020

We reported that allogeneic “Neo-Islets” (NIs), organoids composed of ~ equal numbers of Mesenchymal Stromal Cells and culture expanded Islet Cells (ICs) do, when given i.p., omentally engraft and permanently restore euglycemia in auto-immune diabetic NOD mice, i.e., without the use of either encapsulation devices or antirejection drugs. Similarly, spontaneously diabetic pet dogs treated with allogeneic canine NIs (cNIs) significantly improve glycemia with ~ 50% reduction in insulin needs (&gt; 2 years), and this without immune response. In preparation for a Phase I Clinical Trial we tested whether human ICs in NIs (hNIs) are biologically comparable to canine Islet Cells (cICs) and cNIs, i.e., cells from a larger diabetes model. In our preclinical mouse and dog studies, insulin and other islet hormone gene expression levels were used as indicators of ICs in NIs to adequately re-differentiate into insulin and islet-specific endocrine cells when implanted i.p., thereby resulting in physiological control of T1DM.Human islet cells from 6 donors of different demographics were cultured, passaged to P4, and their growth rates, insulin and other islet-associated endocrine genes’ expression levels, secretion of insulin in response to glucose stimulation (GSIS), and NI formation abilities were compared.
Results: (1) hICs and hNIs show comparable gene expression profiles to those of cICs and cNIs, and hNIs show identical GSIS responses to those of cNIs. (2) Insulin gene expression profiles of hICs are stable as a function of population doublings and independent of donor diversity.
In conclusion, these data indicate that donor variability does not appear to be a significant factor in this NI technology, facilitating our IND work and further demonstrating hNIs’ translational potential in a planned Clinical Trial in subjects with T1DM.

Disclosure
A. Gooch: Employee; Self; SymbioCellTech. S.S. Chowdhury: Employee; Self; SymbioCellTech. P. Zhang: Employee; Self; SymbioCellTech. Z. Hu: Employee; Self; SymbioCellTech. C. Westenfelder: Consultant; Self; SymbioCellTech.
2044-P: Loss of CB1R Protects against Streptozotocin-Induced ß-Cell Dysfunction in Mice
Authors: ASEER KANIKKAI RAJA , O’CONNELL JENNIFER F. , EGAN JOSEPHINE M. 
Published: June 2020

Approximately 1.25 million Americans have type 1 diabetes mellitus (T1DM), resulting from autoimmune β-cell destruction: there is no known way to prevent such destruction of β-cells. We have already reported that activation of cannabinoid 1 receptor (CB1R) contributes to the pathogenesis of pancreatic β-cell dysfunction during high fat feeding. To uncover if CB1R signaling might influence toxin-induced β-cell injury, we induced β-cell destruction in wild type mice (WT: n=8) and in mice in which CB1R was genetically nullified in β-cells only (β-CB1R-/-: n=8) in adulthood by five daily injections of streptozotocin (STZ; 50 mg/kg intraperitoneally [IP]), a toxin selective for β-cells. We found that β-CB1R-/- mice had random blood glucose (BG) levels in the range of 137-220 mg/dL throughout the study period (28 days following STZ) as well as preserved insulin secretion with superior glucose tolerance after a glucose challenge (2g/kg) at day 8, 15 or 27, relative to their WT littermates (random BG 500-600 mg/dL). CB1R-deficient β-cells exhibited significant increases in autophagy flux following STZ. We determined that mice or β-cells lacking CB1R had reduced mTOR activation and increased nuclear translocation of TFEB, a key prerequisite for lysosome biogenesis and autophagy. Importantly, we found that CB1R deletion protected against oxidative stress, endoplasmic reticulum stress, and prevented the induction of apoptosis by STZ. These anti-stress functions were accompanied by increased phosphorylation of AKT (ser) 473 and ERK1/2 in β-cells, which reveals a previously unrecognized route for mTOR/AKT axis to regulate autophagy that coordinately is permissive to β-cell survival. We conclude that CB1R nullification confers resistance to pancreatic β-cell dysfunction by upregulating autophagy and subsequently antagonizing the decline in lysosomal activity. Altogether, we propose that CB1R is a potential therapeutic target during the honeymoon phase of T1DM.

Disclosure
K. Aseer: None. J.F. O’Connell: None. J.M. Egan: None.
2056-P: In Vivo Human Islet Compensation and Dysfunction to Diet-Induced Obesity: A Phase 0 Preclinical Model
Authors: KERR-CONTE JULIE A. , THEVENET JULIEN , PASQUETTI GIANNI , PETIT PAULINE , CLABAUT CLARA , GMYR VALERY , BONNER CAROLINE , GARGANI SOFIA , PATTOU FRANCOIS 
Published: June 2020

A translational discrepancy exists between animal models used for diabetes research and diabetes in man, thus human relevant models must become a priority. We showed that collectively human islet grafts from 26 donors statistically significantly adapted their function and endocrine and β-cell mass to HFD (high fat diet) in vivo in 233 RAG2KO mice. Human islet compensation occurs at 6 weeks and metabolic dysfunction upon chronic ≥10 weeks HFD. Herein, gene expression studies (GeneChip® Human Gene 2.0 ST Arrays) identified molecular pathways involved. Indeed, human islets compensate to HFD by upregulating hormones, transcription factors, antioxidants, and unfolded protein response genes, and then become dysfunctional at 10 wks -by downregulating these genes. Herein we show Krebs cycle and Mitochondrial electron transport chain was targeted with a transient increase at 6wk and then a drop-in expression at 10 wks; whereas uncouplinggene expression UCP2 and 3 increased. Glycolysis remained upregulated. Explanations for expanded islet and beta mass in HFD (vs. CTL) may be found in cell cycle heatmap. Lastly, a marker of activated stellate cells TAGLN, and matrix genes rose during islet dysfunction (fibrosis?).
Conclusion: This human-based model system progressively depicts defects identified in human pre and T2DM that could serve as a “phase 0” in vivo model to test new targets and develop effective therapies in man.

Disclosure
J.A. Kerr-Conte: None. J. Thevenet: None. G. Pasquetti: None. P. Petit: None. C. Clabaut: None. V. Gmyr: None. C. Bonner: None. S. Gargani: None. F. Pattou: None.

Funding
JDRF; Programme d’investissements d’avenir; LabEx; European Genomic Institute for Diabetes (ANR-10-LABX-46)