bluuebunny/crossref_metadata_2025_split huggingface dataset:
Angiopoietin-Like Protein 3 Directly Regulates HDL Metabolism and Function
Authors: YANG LONGYAN , WANG YAN , FU YING , LANG JIANAN , ZHAO DONG , FENG YINGMEI 
Published: June 2018

Background: Angiopoietin-like protein 3 (ANGPTL3) is produced by hepatocytes. Once secreted, it inhibits endothelial lipase activity and regulates angiogenesis. We previously reported the positive association between serum ANGPTL3 and HDL function in nondiabetic participants. Hereby, we investigated whether ANGPTL3 directly modulates HDL function.
Methods: HDLs were isolated from plasma. ANGPTL3 in HDLs was studied by western blot and ELISA. Cholesterol efflux to HDLs was analyzed in macrophages preloaded with fluorescent cholesterol. Recombinant human ANGPTL3 was subjected to endothelial cells treated with TNF-α and ICAM-1 expression was analyzed by FACS. Similar experiments were repeated in db mice injected with AAV encoding human ANGPTL3 cDNA or shRNA.
Results: ANGPTL3 was present in human HDLs, which were lower in T2DM patients than controls (p=0.04). ANGPLT3 in HDLs was positively associated with cholesterol efflux in nondiabetic controls (r=0.33, p=0.044) but not in T2DM patients (r=0.05, p=0.77). Recombinant ANGPTL3 reduced ICAM-1 expression in endothelial cells exposed to TNF-α (p=0.0001). Similarly, ANGPTL3 levels in HDLs were lower in db mice at 18 weeks old than 8 weeks old, which was accompanied with reduced cholesterol reflux to HDLs and rendered inhibition of ICAM-1 expression in endothelial cells (p&lt;0.for all). Following AAV-mediated ANGPTL3 cDNA transfer, ANGTL3 levels were increased in HDLs of db mice, which increased cholesterol efflux and decreased ICAM-1 expression compared with db mice with vector transfer. Vice versa, decreased ANGPTL3 levels in HDLs by AAV-mediated shRNA transfer abrogated HDL function mentioned above (p&lt;0.for both). When placed on high fat diet for 10 weeks, atherosclerotic plaque was larger in db mice with ANGPTL3 shRNA transfer than other gene transferred groups (p&lt;0.05).
Conclusion: ANGPTL3 is a HDL component and direct regulates HDL function. Decrease of ANGPTL3 expression may reduce HDL function and accelerate atherosclerosis in T2DM.

Disclosure
L. Yang: None. Y. Wang: None. Y. Fu: None. J. Lang: None. D. Zhao: None. Y. Feng: None.
Unaltered Fatty Acid Uptake, Utilization, and Mitochondrial Respiration in Right Atrial Appendage of Type 2 Diabetic Human Heart
Authors: RJ NANDINI , RAJI SR , PILLAI VIVEK V. , K. JAYAKUMAR , GOPALA SRINIVAS 
Published: June 2018

Previous studies on diabetic human heart have shown decreased utilization of fatty acid (FA)/carbohydrate substrates. We hypothesized that increased mitochondrial dysfunction with concomitant decrease in fatty acid utilization would be found in diabetic hearts of patients from the Indian subcontinent that would explain their increased propensity of cardiovascular complications. We have compared mitochondrial respiration in atrial appendage tissue from nondiabetic and diabetic human subjects undergoing elective coronary artery bypass graft (CABG) surgery using high-resolution respirometry with FA and carbohydrate substrate combinations. In the presence of FA, diabetic mitochondria showed unimpaired complex I and electron transferring flavoprotein (ETF) mediated respiration while significantly lower oxygen consumption was noted when succinate was added, indicating the possible derangement of complex II respiration. Unlike other human studies, we report no significant reduction in FA- mediated mitochondrial respiration. However, the carbohydrate protocol indicated impairment of complex I mediated respiration. There was no significant change in the expression of OXPHOS proteins. Unchanged levels of FA uptake proteins like CD36 and FABP, FA oxidation enzyme, long chain acyl CoA deydrogenase (LCAD), regulators of FA metabolism like sirtuins and nuclear receptors, PPARα and transcription coactivators, PGC1α/β were observed in diabetic heart. The acetylation status of mitochondrial specific proteins involved in fatty acid oxidation (acetylated LCAD and PGC1α/β) also showed no significant changes. Diabetic patients showed equal expression of the antioxidant enzymes and other markers of oxidative stress. The unimpaired FA uptake, oxidation and mitochondrial respiration indicates absence of overt mitochondrial dysfunction in type 2 diabetic human heart.

Disclosure
N. Rj: None. R. Sr: None. V.V. Pillai: None. J. K.: None. S. Gopala: None.
Adipocyte Insulin Resistance Index in Youth along the Span of Glycemia from Normal Glucose Tolerance (NGT) to Impaired Glucose Tolerance (IGT) to Type 2 Diabetes (T2D)
Authors: YOUNG KIM JOON , BACHA FIDA , TFAYLI HALA , MICHALISZYN SARA , ARSLANIAN SILVA A. 
Published: June 2018

One of the pathophysiological components of T2D is adipocyte insulin resistance. We demonstrated diminished insulin suppression of lipolysis, using the hyperinsulinemic-euglycemic clamp combined with [2H5]glycerol tracer, in obese IGT vs. NGT youth (Diabetes 66: 2017). Herein we examined a surrogate index of adipose tissue insulin resistance (AT-IR= fasting insulin x FFA) to test the hypothesis that AT-IR increases from normal weight (NW) to obese NGT to IGT to T2D. A total of 2youth (70 M/135 F; Tanner IV-V) had body composition, visceral adipose tissue (VAT), fasting glucose, insulin and free fatty acids (FFA), and AT-IR evaluated. Despite hyperinsulinemia in obese IGT youth, fasting FFA was higher compared with NW and obese NGT peers (Table). AT-IR was 2.2 fold higher in obese NGT, 4.3 fold higher in IGT and 4.6 fold higher in T2D compared with NW before and after adjusting for sex, Tanner stage, BMI and VAT.
In conclusion, the surrogate index of AT-IR reflects pathophysiological alterations in adipose tissue insulin sensitivity showing progressive increase in AT-IR in youth from normal weight to obese, and from NGT to IGT to T2D. This AT-IR, derived from fasting blood samples, could be used in epidemiological, observational and/or interventional studies investigating changes in adipocyte insulin sensitivity in obese youth with IGT and T2D.
Variables, mean ± SEMNW (n=49)Obese-NGT (n=89)Obese-IGT (n=38)Obese-T2D (n=29)P, ANCOVAAge (years)14.4 ± 0.314.6 ± 0.214.9 ± 0.415.2 ± 0.3NSBMI (kg/m2)20.6 ± 0.333.9 ± 0.736.8 ± 1.036.8 ± 1.0&lt;0.0001Visceral adipose tissue (cm2)24.4 ± 2.260.8 ± 4.185.1 ± 5.183.6 ± 7.7&lt;0.0001Fasting glucose (mg/dL)95.1 ± 0.895.4 ± 0.696.8 ± 1.2121.5 ± 4.8&lt;0.0001Fasting insulin (µU/mL)16.2 ± 0.831.3 ± 1.550.4 ± 4.957.6 ± 9.6&lt;0.0001Fasting FFA (mmol/L)0.25 ± 0.020.28 ± 0.010.35 ± 0.020.32 ± 0.020.001AT-IR (µU/mL x mmol/L)4.± 0.388.98 ± 0.6917.51 ± 1.9918.59 ± 3.00&lt;0.0001

Disclosure
J. Kim: None. F. Bacha: Research Support; Self; AstraZeneca, JAEB Center For Health Research, National Institutes of Health, Pediatric Diabetes Consortium. H. Tfayli: None. S. Michaliszyn: None. S.A. Arslanian: None.
The Role of Exosomes in Improvement of Insulin Sensitivity in Obese Adolescents following Bariatric Surgery
Authors: KIM AHLEE , MURAKAMI KAZUTOSHI , BORRA VISHNUPRIYA J. , DOLAN LAWRENCE M. , SHAH AMY , NAKAMURA TAKAHISA 
Published: June 2018

Background: Exosomes, a type of extracellular vesicle, are a novel mode of tissue-to-tissue communication. Recent work suggests a role of exosomes in the development of obesity-related metabolic disease, such as insulin resistance or type 2 diabetes. With bariatric surgery, individuals undergo significant weight reduction and dramatic metabolic improvements. We hypothesize that exosomes mediate the metabolic improvements following bariatric surgery.
Methods: We performed comprehensive exosome analyses, including measuring size and serum concentration of exosomes, and evaluating exosomal microRNAs expression pattern in 30 teenagers who underwent sleeve gastrectomy (age=16.7± 0.4 years; gender=26 females, 4 males; race= 19 Caucasians, 11 African Americans). Individuals who had ever been diagnosed with diabetes were excluded from the study.
Results: We observed a significant reduction in serum exosome concentration (pre-op= 4.47x108± 6.28X107particles/mL; post-op=2.56x108± 2.44X107particles/mL, p=0.01), and a drastic shift of exosomal RNA expression pattern 1 month after bariatric surgery in obese adolescents, in concurrent with a modest initial weight loss (Pre-op weight=138.6± 5.3kg, Post-op weight=123.3± 5.0kg).
Conclusion: Drastic changes in exosome profile were observed 1 month after bariatric surgery in severely obese adolescents. It is interesting that the most significant change happens in the first month after the surgery with a modest initial weight reduction, indicating the presence of molecular processes responsible for the improvements in metabolic condition following bariatric surgery, independent of weight loss. These findings suggest that the exosomes play a key role in the profound metabolic improvements following bariatric surgery, and serve as a novel biomarker or a therapeutic target for metabolic diseases.

Disclosure
A. Kim: None. K. Murakami: None. V.J. Borra: None. L.M. Dolan: None. A. Shah: None. T. Nakamura: None.
Serum Exosomal Proteins—A New Component of Intercellular Communication in Metabolism
Authors: BRANDAO BRUNA B. , ALTINDIS EMRAH , GARCIA MARTIN RUBEN , KAHN C. RONALD 
Published: June 2018

Adipose tissue is an important endocrine organ; both excess or deficiency of adipose is associated with metabolic syndrome. MicroRNAs (miRNAs) play a fundamental role in regulating adipocyte function and metabolism. Recently, we showed that a large fraction of circulating miRNAs comes from exosomes released by adipose tissue and that mice with an adipose-specific knockout of the miRNA-processing enzyme Dicer (ADicerKO) exhibit lipodystrophy and metabolic syndrome. This is due, in part, to a loss of multiple circulating exosomal microRNAs and their effects on gene expression in liver and other tissues. In this study, we explored the role of exosomal proteins in metabolism by comparing the serum exosomal proteome of wild type (WT) and AdicerKO mice. To this end, we isolated serum exosomes from WT and KO mice and performed quantitative proteomics by LC-MS. A total of 277 exosomal proteins were identified, of which 12 were significantly downregulated and 16 were upregulated by ≥1.5 in AdicerKO mice. Among these were two important adipokines. Thus, the insulin sensitizer adiponectin was downregulated in exosomes, while the insulin resistance-associated adipokine retinol-binding protein-4 (Rbp4) was upregulated. Transthyretin, which binds to and extends Rbp4 half-life, was also increased in serum exosomes from AdicerKO mice. Additionally, serum amyloids A-1 and A-4, serum amyloid component P, haptoglobin and ceruloplasmin, which are adipose and/or liver-specific in origin and often altered in insulin resistant states, were down-regulated in the exosomes of knockout mice.
In summary, serum exosomes contain multiple proteins which can modulate insulin sensitivity or insulin resistance. Induction of lipodystrophy by KO of Dicer in adipose markedly alters the circulating exosomal proteome due to loss of fat or the secondary hepatosteatosis this produces. These exosomal proteins provide potential new signals in the crosstalk between fat, liver and other tissues in response to metabolic disease.

Disclosure
B.B. Brandao: None. E. Altindis: None. R. Garcia Martin: None. C. Kahn: Advisory Panel; Self; CohBar, ERX Therapeutics, AntriaBio, Inc.. Board Member; Self; Kaleio Biosciences.
NAD-Mediated Metabolic Reprogramming Epigenetically Regulates Gene Expression to Promote Preadipocyte Differentiation
Authors: OKABE KEISUKE , USUI ISAO , NAWAZ ALLAH , FUJISAKA SHIHO , KADO TOMONOBU , IGARASHI YOSHIKO , YAGI KUNIMASA , TOBE KAZUYUKI , NAKAGAWA TAKASHI 
Published: June 2018

During cell differentiation, intracellular energetic pathways are drastically reorganized. Although this alteration had been considered as a passive process to adapt to environmental change during differentiation, recent studies suggested that the metabolic alteration rather actively regulates the differentiation process. It is known that the dynamic metabolic reprogramming occurs during differentiation of preadipocytes, however its implication in adipogenesis is unknown. In this study, we employed mass spectrometry-based metabolomics and investigated the metabolic change during differentiation of 3T3-L1 preadipocytes. We found that the level of nicotinamide adenine dinucleotide (NAD), a cofactor mediating redox reaction and protein modification, was significantly increased during the differentiation. Consistently Nampt, a rate-limiting enzyme of NAD synthesis, was also upregulated in the early phase of adipogenesis. Further, we found that pharmacological or genetic inhibition of Nampt reduced NAD synthesis and repressed the metabolic reprogramming during adipogenesis. Notably, inhibition of Nampt blocked the gene expression of Pparg and impeded the preadipocyte differentiation. The effect of Nampt inhibition was cancelled by the supplementation of nicotinamide mononucleotide, a precursor of NAD. Our metabolomic analysis also revealed that TCA cycle intermediate, α-ketoglutarate (αKG) was upregulated during the differentiation and Nampt inhibition disturbed the rise of αKG. Interestingly, αKG is known as a cofactor of the demethylation of histones. The ChIP assay revealed that αKG mediated the demethylation of H3K9me3 on Pparg promoter region and promote the gene expression of Pparg during adipogenesis. This process was inhibited by Nampt inhibitor treatment, and was reversed by the supplementation of αKG. Altogether, our data indicated that Nampt-mediated NAD synthesis is necessary for differentiation of preadipocyte.

Disclosure
K. Okabe: None. I. Usui: None. A. Nawaz: Research Support; Spouse/Partner; Kobayashi Foundation, Kobayashi Foundation, Kobayashi Foundation. S. Fujisaka: Research Support; Self; Mochida Pharmaceutical Co., Ltd., Eli Lilly and Company, MSD K.K., Toyama First Bank. T. Kado: None. Y. Igarashi: None. K. Yagi: None. K. Tobe: Research Support; Self; Bristol-Myers Squibb Company, Takeda Pharmaceutical Company, Teijin Pharma Limited, Japan Diabetes Society, Eli Lilly and Company, MSD K.K., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Pfizer Inc., Astellas Parma Inc, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Company, Limited, Novo Nordisk Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Tsumura & Co., Ono Pharmaceutical Co., Ltd., Novartis Pharma K.K., Sumitomo Dainippon Pharma Co. T. Nakagawa: None.
Effects of High BMI on Synaptic Function and Metabolic Connectivity in the Brain—Evidence of Gender Difference
Authors: SALA ARIANNA , MALPETTI MAURA , FERRULLI ANNA , GIANOLLI LUIGI , LUZI LIVIO , PERANI DANIELA 
Published: June 2018

Several studies reported a significant association with obesity and cognitive deficits in aging, especially for executive, attention and memory domains. The neural effects of obesity and the correlated cognitive dysfunction have yet to be elucidated. We retrospectively collected a large cohort of healthy elderlies (N=222; age=74.03±5.88y; M/F=112/105; BMI range=19.21-38.79), from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. All subjects underwent in vivo positron emission tomography with 18F-Fluorodeoxyglucose (FDG), thus we were able to evaluate the correlation between BMI, synaptic function and metabolic connectivity in the whole brain and within the resting-state neural networks, crucially considering the effect of gender. We found a significant positive correlation between BMI levels and brain metabolism in female group only (R=.435; P&lt;0.001), with high BMI associated with increased glucose consumption in the orbitofrontal cortex. Whole brain connectivity analysis revealed an altered pattern in frontal regions in females with high BMI, namely a decreased connectivity between orbitofrontal regions and high-order prefrontal cortex, and an abnormally elevated connectivity with nucleus accumbens. The connectivity analysis of the resting-state brain networks confirmed that in elderly females with high BMI, the core of vulnerability is within the frontal regions, with impaired connectivity in executive and salience networks. In contrast, elderly males with high BMI showed loss of long-distance connections between frontal and parietal cortices, invariantly across attentional, executive and posterior default mode networks. Our findings support a strong detrimental effect of high BMI levels on brain metabolism and neural connectivity in healthy aging, with gender differences. Notably, high BMI in females affects the executive and reward systems. This evidence brings to considerations for medical practice and health policy.

Disclosure
A. Sala: None. M. Malpetti: None. A. Ferrulli: None. L. Gianolli: None. L. Luzi: Speaker's Bureau; Self; A. Menarini Diagnostics, AstraZeneca, Eli Lilly and Company. Research Support; Self; Gelesis. Consultant; Self; McKinsey & Company. Speaker's Bureau; Self; Menarini Group, Merck Sharp & Dohme Corp.. Research Support; Self; Novartis AG. Speaker's Bureau; Self; Novo Nordisk A/S. Research Support; Self; Sunstar Foundation. Speaker's Bureau; Self; Smith & Nephew. D. Perani: None.
GIP Signaling Integrates with Insulin Signaling to Regulate Glucose and Lipid Metabolism in Human Adipocytes
Authors: REGMI AJIT , THOMAS MELISSA K. , MICHAEL M. DODSON , ROELL WILLIAM C. 
Published: June 2018

Recent studies suggest that activation of GIP (glucose-dependent insulinotropic peptide) receptor in conjunction with GLP-1 and/or glucagon receptors reduces adiposity and body weight in mice. Incretin actions of GIP on pancreatic beta cells are well characterized, but functions of GIP on adipose tissue are incompletely understood. Using differentiated human adipocytes we investigated GIP regulation of carbohydrate and lipid metabolism in the context of insulin signaling. GIP dose-dependently stimulated lipolysis without affecting ATGL or HSL lipolytic enzyme mRNA expression. Insulin dose-dependently suppressed lipolysis, and addition of GIP attenuated insulin effects on lipolysis without affecting Akt phosphorylation at Thr308or Ser473. Insulin administration increased lipogenesis, but GIP, in the presence or absence of insulin, had little effect on lipogenesis in [14C]glucose incorporation assays. GIP increased glucose utilization in adipocytes, as measured by depletion of glucose in culture media over a 24 hour period. Notably GIP dose-dependently enhanced insulin-stimulated glucose uptake ([14C]-2-deoxyglucose), but GIP alone did not appreciably regulate acute glucose uptake. We propose a new mechanistic model in which GIP signaling integrates with insulin signaling to regulate glucose and lipid metabolism. In the presence of low plasma insulin levels resembling a fasting state, GIP can increase lipolysis to mobilize nutrients from adipocytes. When insulin levels rise in a fed state, GIP can increase insulin-mediated glucose uptake in adipocytes to augment efficiency of energy storage. Further elucidation of the integration of insulin and GIP signaling will be needed to support efforts to counteract dysregulated nutrient metabolism in obesity and diabetes.

Disclosure
A. Regmi: Employee; Self; Eli Lilly and Company. M.K. Thomas: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. M. Michael: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. Employee; Spouse/Partner; Eli Lilly and Company. Stock/Shareholder; Spouse/Partner; Eli Lilly and Company. W.C. Roell: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company.
An Action in the Hypothalamic Arcuate Nucleus Is Sufficient to Explain the Sustained Remission of Diabetes Induced by Central Administration of Fibroblast Growth Factor-1 (FGF-1)
Authors: BROWN JENNY M. , SCARLETT JARRAD , MATSEN MILES E. , SECHER ANNA , JORGENSEN RASMUS , MORTON GREGORY J. , SCHWARTZ MICHAEL W. 
Published: June 2018

Our recent finding that a single intracerebroventricular (icv) injection of FGF-1 elicits sustained diabetes remission in rodent models of type 2 diabetes supports a growing consensus that the brain is a key target for diabetes drug development. The current work was undertaken to pinpoint the brain area responsible for this action of FGF-1. To this end, we considered the following preliminary findings: 1) both FGF Receptor 1 and integrin receptor αvβ3 (known to be involved in sustained FGF-1 signaling) are concentrated in the hypothalamic arcuate nucleus (ARC), 2) neuronal activation and sustained induction of the MAP Kinase / ERK pathway occurs in this brain area following icv FGF-1 injection, and 3) labeled FGF-1 is concentrated in this area following icv injection. We therefore hypothesized that in rodent models of T2D, an action in the ARC (a brain area known to participate in glucose homeostasis) mediates the sustained diabetes remission elicited by icv FGF-1 injection. To test this hypothesis, we investigated whether a single microinjection of a low dose of FGF-1 into the ARC (0.3 µg bilaterally, for a total of 0.6 µg) can mimic the response elicited by icv injection of a higher dose (3.0 µg). We report that in Zucker Diabetic Fatty rats, a single microinjection of FGF-1 bilaterally into the ARC (via an indwelling dual guide cannula) induced remission of hyperglycemia lasting &gt;3 week, whereas intra-arcuate microinjection of saline vehicle was without effect (P&lt;0.vs. Veh). Since icv injection of the same FGF-1 dose (0.6 µg) had no significant effect on glycemia, sustained diabetes remission induced by intra-ARC microinjection of FGF-1 cannot be explained by leakage into ventricular cerebrospinal fluid. We conclude that an action in the ARC is sufficient to explain the effect of FGF-1 to induce sustained diabetes remission.

Disclosure
J.M. Brown: None. J. Scarlett: None. M.E. Matsen: None. A. Secher: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. Employee; Spouse/Partner; Gubra. R. Jorgensen: Employee; Self; Novo Nordisk Inc.. G.J. Morton: None. M.W. Schwartz: Consultant; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S.
Correlates of Hypoglycemia among Youth with Type 1 Diabetes (T1D) and Suboptimal Glycemic Control
Authors: KAHKOSKA ANNA R. , CRANDELL JAMIE , DRISCOLL KIMBERLY A. , KOSOROK MICHAEL R. , MAAHS DAVID M. , MAYER-DAVIS ELIZABETH J. 
Published: June 2018

Hypoglycemia is a major challenge of T1D. We examined the prevalence and correlates of hypoglycemia assessed by 7-day blinded continuous glucose monitoring at baseline among 233 youth with hemoglobin A1c (HbA1c) of 8-13% per inclusion criteria in the Flexible Lifestyles Empowering Change trial. The sample was 76.1% non-Hispanic white and 49.8% female with mean age 14.9±1.1 years and mean T1D duration 6.4±3.7 years. Mean HbA1c was 9.6±1.2%. Over 7-days, 85.4% of youth experienced hypoglycemia (i.e., time ≤70 mg/dL and &gt;54 mg/dL; an average of 32.5±37.3 min/day). 62.7% of youth experienced clinically serious hypoglycemia (i.e., time ≤54 mg/dL; an average of 24.5±40.5 min/day). Duration of hypoglycemia was inversely associated with HbA1c (Figure). In logistic regression modeling, sex, race/ethnicity, T1D duration, body mass index z-score (BMIz), fear of hypoglycemia (from the Hypoglycemia Fear Survey) and diabetes adherence (from the Diabetes Self-Management Profile-Self Report) were not associated with hypoglycemia. Youth with higher HbA1c were less likely to experience hypoglycemia (for a 1% higher HbA1c, odds ratio (OR) for clinical hypoglycemia: 0.52, (95% CI 0.39, 0.69); OR for clinically serious hypoglycemia: 0.58 (95% CI 0.43, 0.77)). The data suggest that hypoglycemia is common among youth with elevated HbA1c and and guidance to limit hypoglycemia should be part of care in these patients.

Disclosure
A.R. Kahkoska: None. J. Crandell: None. K.A. Driscoll: None. M.R. Kosorok: None. D.M. Maahs: Advisory Panel; Self; Insulet Corporation. Consultant; Self; Abbott. Research Support; Self; Medtronic, Bigfoot Biomedical, Dexcom, Inc., Insulet Corporation, Roche Diabetes Care Health and Digital Solutions. E.J. Mayer-Davis: None.