15 results on '"Sparling, David P."'
Search Results
2. Real-Time Continuous Glucose Monitoring Reduced Costly Diabetes-Related Events in Adolescents and Young Adults despite Lack of Short-Term Reduction in Hemoglobin A1c.
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Beck, Joni K., Allen, Rebecca A., Jeter, Kathryn M., Fisher, Rachel S., Dattilo, Taylor M., Traino, Katherine A., Anderson, Michael, Cutler, James, and Sparling, David P.
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GLYCOSYLATED hemoglobin ,HOME diagnostic tests ,BLOOD sugar monitoring ,GLYCEMIC control ,TYPE 1 diabetes ,MEDICAL care costs ,BLOOD sugar monitors ,COST control ,COST benefit analysis ,DESCRIPTIVE statistics ,INTRACLASS correlation ,HOSPITAL care ,EMERGENCY medical services ,ADVERSE health care events ,SECONDARY analysis ,TELEMEDICINE ,ADULTS ,ADOLESCENCE - Abstract
Real-time continuous glucose monitoring (rtCGM) can directly improve patient outcomes, including decreased health care system utilization and associated costs. The purpose of this study was to evaluate the clinical benefits of rtCGM use in a high-risk, under-resourced cohort of adolescents and young adults (AYA) with type 1 diabetes (T1D) who had no prior access to rtCGM. The effects of rtCGM use on hemoglobin A1c (A1c) and the frequency of health care events (i.e., diabetes-related emergency room (ER) visits, hospitalizations, emergency medical services (EMS), and after-hour emergency calls) were evaluated regarding payor costs in 33 AYA with ≥70% rtCGM use. Secondary aims included the evaluation of a phone-based pattern management intervention. The frequency of health care events decreased at 12 and 24 weeks for all participants, and there was no significant difference by treatment group. We estimated that the use of rtCGM in this cohort results in a projected annualized cost-savings of $195,943 to $294,864 or 43–65% per year based on Medicare or list pricing for rtCGM, respectively. Results also revealed improvements in A1c at 12 weeks for all study participants, but this was not maintained at 24 weeks for the phone-based pattern management intervention group. Our findings suggest that rtCGM may be an effective tool for reducing diabetes-related events and underscores the importance of access. Future studies are needed to further examine tailored interventions and support to optimize rtCGM use and glycemic health in high-risk AYA. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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3. Hyperphosphorylation of MEF2A in primary adipocytes correlates with downregulation of human GLUT4 gene promoter activity
- Author
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Sparling, David P., Griesel, Beth A., and Olson, Ann Louise
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Phosphorylation -- Research ,Fat cells -- Research ,Genetic transcription -- Research ,Biological sciences - Abstract
GLUT4 promoter activity is regulated by hormonal, metabolic, and tissue-specific controls. This complicates the study of GLUT4 gene transcription, as no cell culture model adequately recapitulates these extracellular regulators. While investigating cultured primary adipocytes as a model system for GLUT4 transcription, we observed that GLUT4 mRNA was specifically and rapidly downregulated upon tissue dispersal. Downregulation of GLUT4 mRNA was mediated in part by loss of regulatory control by the trans-acting factors that control GLUT4 transcriptional activity [the myocyte enhancer factor 2 (MEF2) transcription factor family and the GLUT4 enhancer factor] and their cognate DNA binding sites in transgenic mice. The differences in GLUT4 transcription when whole adipose tissue and cell culture model systems are compared can be correlated to a posttranslational phosphorylation of the transcription factor MEF2A. The difference in the MEF2A phosphorylation state in whole tissue vs. isolated cells may provide a further basis for the development of an in vitro system that could recapitulate fully regulated GLUT4 promoter activity. Development of an in vitro system to reconstitute GLUT4 transcriptional regulation will further efforts to discern the molecular mechanisms that underlie GLUT4 expression. glucose transporter-4 transcription; myocyte enhancer factor 2
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- 2007
4. Regulation of muscle GLUT4 enhancer factor and myocyte enhancer factor 2 by AMP-activated protein kinase
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Holmes, Burton F., Sparling, David P., Olson, Ann Louise, Winder, William W., and Dohm, G. Lynis
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Cyclic adenylic acid -- Research ,Protein kinases -- Research ,Muscles -- Research ,Dextrose -- Research ,Glucose -- Research ,Biological sciences - Abstract
As the primary glucose transporter in skeletal muscle, GLUT4 is an important factor in the regulation of blood glucose. We previously reported that stimulation of AMP-activated protein kinase (AMPK) with 5-aminoimidazole-4-carboxamide-1-[beta]-D-ribofuranoside (AICAR) increased GLUT4 expression in muscle. GLUT4 enhancer factor (GEF) and myocyte enhancer factor 2 (MEF2) have been shown to be important for normal GLUT4 expression because deletion or truncation of the consensus sequences on the promoter causes depressed GLUT4 mRNA expression. This led to the current study to investigate possible roles for GEF and MEF2 in mediating the activation of GLUT4 gene transcription in response to AMPK. Here we show that, although AMPK does not appear to phosphorylate MEF2A, AMPK directly phosphorylates the GEF protein in vitro. MEF2 and GEF are activated in response to AMPK as we observed translocation of both to the nucleus after AICAR treatment. Nuclear MEF2 protein content was increased after 2 h, and GEF protein was increased in the nucleus 1 and 2 h post-AICAR treatment. Last, GEF and MEF2 increase in binding to the GLUT4 promoter within 2 h after AICAR treatment. Thus we conclude that GEF and MEF2 mediate the AMPK-induced increase in transcription of skeletal muscle GLUT4. AMPK can phosphorylate GEF and in response to AICAR, GEF, and MEF2 translocate to the nucleus and have increased binding to the GLUT4 promoter. 5-aminoimidazole-4-carboxamide-1-[beta]-D-ribofuranoside; glutathione S-transferase; glucose transporter 4
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- 2005
5. Inhibition of γ-secretase in adipocytes leads to altered IL-6 secretion and adipose inflammation.
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Sparling, David P., McCullough, Nile, Pajvani, Utpal, and Humphrey, Mary Beth
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FAT cells , *INTERLEUKIN-6 , *TYPE 2 diabetes , *SECRETION , *ADIPOSE tissues - Abstract
Adipocyte-mediated inflammatory signalling has been proposed to alter adipose physiology in obesity and Type 2 diabetes mellitus. Novel targets for alteration of inflammatory signalling are needed to improve obesity-related outcomes. The γ-secretase enzyme complex has been suggested to play a role both in adipocyte function as well as in immune regulation. We hypothesized that adipocyte-specific γ-secretase inhibition could alter the inflammatory makeup of adipose tissue. We found that genetic blockade of γ-secretase in adipocytes leads to a decrease in EMR1 (F4/80) expression, as a marker of macrophage presence, in adipose tissue without changes in expression of markers of other inflammatory cell types. To explore the mechanism by which adipocytes can alter macrophage function in vitro, fully differentiated 3T3-L1 adipocytes were treated with a γ-secretase inhibitor in the presence of lipopolysaccharide (LPS) and transcription of IL6 and ccl2 (MCP1) were quantified. IL-6 expression and secretion were significantly inhibited by γ-secretase blockade, with little effect on MCP1. Preconditioned media from 3T3-L1 adipocytes treated with a γ-secretase inhibitor also alters macrophage activation but did not affect macrophage translocation in vitro. Therefore, γ-secretase inhibition in fully differentiated adipocytes can alter IL-6 signalling to macrophages, consistent with our hypothesis that that γ-secretase is involved in adipocyte-initiated inflammatory signalling cascades. [ABSTRACT FROM AUTHOR]
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- 2020
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6. Macrophage-Derived microRNA-155 Increases in Obesity and Influences Adipocyte Metabolism by Targeting Peroxisome Proliferator-Activated Receptor Gamma.
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Tryggestad, Jeanie B., Teague, April M., Sparling, David P., Jiang, Shaoning, and Chernausek, Steven D.
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PEROXISOME proliferator-activated receptors ,HUMAN stem cells ,MESENCHYMAL stem cells ,WESTERN immunoblotting ,BLOOD cells ,RNA metabolism ,PROTEIN metabolism ,OBESITY ,PROTEINS ,BIOCHEMISTRY ,RESEARCH ,CELL culture ,ANIMAL experimentation ,RESEARCH methodology ,MACROPHAGES ,RNA ,GENETIC disorders ,EVALUATION research ,MEDICAL cooperation ,PHENOMENOLOGY ,COMPARATIVE studies ,FAT cells ,GENES ,CELLS ,RESEARCH funding ,LIPID metabolism disorders ,MICE - Abstract
Objective: This study aimed to investigate cellular sources of microRNAs (miRNA) within adipose tissue and the impact of obesity on miRNA expression, as well as to examine targets of miRNAs.Methods: miRNA expression by quantitative polymerase chain reaction was examined in adipocytes, adipose tissue macrophages (ATM), and peripheral blood mononuclear cells from and individuals with normal weight and with obesity. Differentiated 3T3-L1 adipocytes were cocultured with macrophages, and 3T3-L1 and differentiated human mesenchymal stem cells were transfected with miR-155, with peroxisome proliferator-activated receptor gamma (PPAR-γ) and solute carrier family 2 member 4 (GLUT4) abundance measured via Western blot analysis.Results: Abundance of miR-155 and miR-210 was increased in ATM of participants with obesity by 6.7-fold and 2.9-fold (P = 0.002 and P = 0.013, respectively). miR-130b expression was increased 1.8-fold in ATM and 4.3-fold in adipocytes from participants with obesity (P = 0.007 and P = 0.02, respectively). PPARG mRNA expression decreased 32% (P = 0.044) in adipocytes from individuals with obesity. In 3T3-L1 cells exposed to macrophages, PPARG expression decreased 99.4% (P = 0.02). PPAR-γ protein content declined 75% (P = 0.001) in 3T3-L1 cells transfected with miR-155. GLUT4 protein levels were reduced by 55% (P = 0.021) in differentiated human mesenchymal stem cells exposed to miR-155.Conclusions: Adipose tissue miRNAs are influenced in a cell type-specific fashion by obesity, with macrophage miR-155 potentially impacting neighboring adipocytes. [ABSTRACT FROM AUTHOR]- Published
- 2019
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7. Diabetes Technology Use for Management of Type 1 Diabetes Is Associated With Fewer Adverse COVID-19 Outcomes: Findings From the T1D Exchange COVID-19 Surveillance Registry.
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Noor, Nudrat, Ebekozien, Osagie, Levin, Laura, Stone, Sheri, Sparling, David P., Rapaport, Robert, and Maahs, David M.
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TYPE 1 diabetes ,COVID-19 ,INSULIN pumps ,TECHNOLOGY management ,GLYCEMIC control ,DIABETES - Published
- 2021
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8. Congenital hypothyroidism and thyroid dyshormonogenesis: a case report of siblings with a newly identified mutation in thyroperoxidase.
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Sparling, David P., Fabian, Kendra, Harik, Lara, Jobanputra, Vaidehi, Anyane-Yeboa, Kwame, Oberfield, Sharon E., and Fennoy, Ilene
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Background: Thyroid dyshormonogenesis continues to be a significant cause of congenital hypothyroidism. Over time, forms of thyroid dyshormonogenesis can result in goiter, which can lead to difficult management decisions as the pathologic changes can both mimic or lead to thyroid cancer. Methods: Herein we describe the cases of two brothers diagnosed with congenital hypothyroidism, with initial findings consistent with thyroid dyshormonogenesis. One brother eventually developed multinodular goiter with complex pathology on biopsy, resulting in thyroidectomy. Results: Whole exome sequencing revealed the brothers carry a novel frameshift mutation in thyroperoxidase; the mutation, while not previously described, was likely both deleterious and pathogenic. Conlcusions: These cases highlight the complex pathology that can occur within thyroid dyshormonogenesis, with similar appearance to possible thyroid cancer, leading to complex management decisions. They also highlight the role that a genetic diagnosis can play in interpreting the impact of dyshormonogenesis on nodular thyroid development, and the need for long-term follow-up in these patients. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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9. Innovation and commercialisation in the Canadian bioproducts industry.
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Laughland, Pamela, Cranfield, John, and Sparling, David
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BIOLOGICAL products ,BIOTECHNOLOGY industries ,NEW product development ,COMMERCIALIZATION ,AGRICULTURE - Abstract
Industrial biotechnology is an emerging industry in which firms are developing novel alternatives to petroleum-based goods. Canadian-based firms have an opportunity to capitalise on the availability of biomass from Canadian agriculture and Canada's broad resource base. However, complexity of the product development process coupled with immaturity of this industry means little is currently known about these firms, their innovation activities and decision making. This study uses data from the 2003 and 2006 bioproduct development surveys to examine the Canadian bioproducts industry, focusing on factors conducive to innovative activity for bioproduct producing firms. Several factors are important in facilitating innovation, such as intellectual property, collaborations, focus on bioproducts relative to other business activities, the dominant product type and region in which the firm operates. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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10. GLUT4 Enhancer Factor (GEF) Interacts with MEF2A and HDAC5 to Regulate the GLUT4 Promoter in Adipocytes.
- Author
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Sparling, David P., Griesel, Beth A., Weems, Juston, and Olson, Ann Louise
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PROTEINS , *BIOMOLECULES , *FAT cells , *DNA , *GENES , *NUCLEIC acids , *HYPOGLYCEMIC agents , *PANCREATIC secretions , *TRANSGENIC animals - Abstract
The insulin-responsive glucose transporter, GLUT4, is regulated in various physiologic states at the transcriptional level. When expressed in transgenic mice, the human GLUT4 promoter is governed by two cis-acting sequences: an MEF2 binding domain and Domain I, that function both as positive and negative regulators depending on the physiologic state. MEF2 proteins and GLUT4 enhancer factor (GEF) are known ligands for these cis-acting elements, but their mechanism of action is unclear. To begin to understand this important process, we have characterized GEF structural domains and its interactions with the MEF2A isoform. We find that the C terminus of GEF comprises its DNA-binding domain, but does not contribute to GEF homo-oligomerization. We also have found that GEF dimerizes with increased affinity to a hypophosphorylated form of MEF2A. Furthermore, we demonstrated that MEF2A binding to its cognate binding site can increase the DNA binding activity of GEF to Domain I, suggesting a novel mechanism for MEF2A transcriptional activation. Finally, we have demonstrated that the transcriptional co-repressor HDAC5 can interact with GEF in the absence of MEF2 proteins and specifically inhibit GLUT4 promoter activity. These findings lead to the hypothesis that GEF and the MEF2 proteins form a complex on the GLUT4 promoter that allows for recruitment of transcriptional co-regulators (repressors and/or activators) to control GLUT4 promoter activity. [ABSTRACT FROM AUTHOR]
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- 2008
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11. Novel Role for an HPt Domain in Stabilizing the Phosphorylated State of a Response Regulator Domain.
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Janiak-Spens, Fabiola and Sparling, David P.
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PHOSPHOTRANSFERASES , *PHOSPHORYLATION - Abstract
Studies the novel role for a histidine-containing phosphotransfer (HPt) domain in stabilizing the phosphorylated state of a response regulator domain. Phosphorylation of response regulator domains; Half-lives of phosphorylated response regulator domains in the absence or presence of YPD1 proteins.
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- 2000
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12. mTORC1-independent Raptor prevents hepatic steatosis by stabilizing PHLPP2.
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Kim, KyeongJin, Qiang, Li, Hayden, Matthew S., Sparling, David P., Purcell, Nicole H., and Pajvani, Utpal B.
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- 2016
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13. Molecular Mechanisms Controlling the GLUT4 Promoter in Transgenic Mice.
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Sparling, David P. and Olson, Ann L.
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GLUCOSE , *INSULIN , *ADIPOSE tissues , *DIABETES , *INSULIN resistance , *TRANSCRIPTION factors , *STREPTOZOTOCIN , *TRANSGENIC mice - Abstract
Glucose import down its concentration gradient via the glucose transporter GLUT4 is one of the primary physiologic roles of the insulin-signaling cascade. Insulin sensitivity is therefore highly correlated with the levels of GLUT4 protein in adipose and muscle tissues. GLUT4 expression is known to be regulated by diverse tissue-specific, hormonal, and/or metabolic controls, and a loss of GLUT4 protein in diabetes mellitus has been correlated to a decrease in the transcriptional rate. Elucidating the molecular mechanisms that control the GLUT4 promoter could therefore aid in the search for new interventions for insulin resistance and diabetes. Our work has previously identified two of the cis-acting sites within the smallest functional GLUT4 promoter as well as the transcription factors binding those sites, namely the MEF2-family members MEF2A and MEF2D, and the GLUT4 Enhancer Factor (GEF). We have also recently identified a post-translational modification of MEF2A that correlates with a model of decreased GLUT4 promoter activity. We are examining whether an observed hyperphosphorylation event occurs within insulin-responsive tissues under the streptozotocin-induced diabetic phenotype. Interestingly, hyperphosphorylation correlates with increased cytoplasmic localization of MEF2A in transfected cells, suggesting that hyperphosphorylation regulates nuclear MEF2A concentration. Previously, we observed that MEF2A and GEF function cooperatively to regulate GLUT4 gene expression. Using a biotinylated oligonucleotide corresponding to a truncated GLUT4 promoter that MEF2A and GEF interact with their cognate binding sites cooperatively, thus providing a molecular mechanism to account for the functional cooperativity. Further examination of the regulatory elements governing GLUT4 expression in vivo and in vitro will lead to the development of an system that recapitulates all the essential molecular mechanisms that control GLUT4 promoter activity, aiding in further study of potential therapeutics. ADA-Funded Research [ABSTRACT FROM AUTHOR]
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- 2007
14. Factors affecting biotechnology innovation in Canada: analysis of the 2001 biotechnology use and development survey.
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Van Moorsel, Daryl, Cranfield, J. A. L., and Sparling, David
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TECHNOLOGICAL innovations & economics ,BIOTECHNOLOGY ,BIOTECHNOLOGY industries ,SCIENTIFIC development ,COMMERCIAL products ,COMMERCIAL law - Abstract
Advancement in biotechnology requires continued innovative activity by firms. To grow, biotechnology firms must understand the factors affecting their innovative activity. Such understanding also informs policy makers, and supports the development of policies promoting one's biotechnology sector. This study explores factors, which determine innovative activity within the Canadian biotechnology industry. Innovative activity is measured as the natural log of the number of products/processes a firm has at different stages of the innovation spectrum. A model is developed to regress this measure on several determinants of innovation. Significant drivers of innovation include: collaborative arrangements, transfer of intellectual property, firm size and age, whether the firm was in the agricultural or human health biotechnology sectors and whether the firm focused on development or commercialisation. Generally speaking, these factors all contributed to firms having more products/processes either under development, undergoing clinical trials or regulatory approval, or on the market. [ABSTRACT FROM AUTHOR]
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- 2007
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15. Adipocyte-specific blockade of gamma-secretase, but not inhibition of Notch activity, reduces adipose insulin sensitivity.
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Sparling DP, Yu J, Kim K, Zhu C, Brachs S, Birkenfeld AL, and Pajvani UB
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Objective: As the obesity pandemic continues to expand, novel molecular targets to reduce obesity-related insulin resistance and Type 2 Diabetes (T2D) continue to be needed. We have recently shown that obesity is associated with reactivated liver Notch signaling, which, in turn, increases hepatic insulin resistance, opening up therapeutic avenues for Notch inhibitors to be repurposed for T2D. Herein, we tested the systemic effects of γ-secretase inhibitors (GSIs), which prevent endogenous Notch activation, and confirmed these effects through creation and characterization of two different adipocyte-specific Notch loss-of-function mouse models through genetic ablation of the Notch transcriptional effector Rbp-Jk (A-Rbpj) and the obligate γ-secretase component Nicastrin (A-Nicastrin)., Methods: Glucose homeostasis and both local adipose and systemic insulin sensitivity were examined in GSI-treated, A-Rbpj and A-Nicastrin mice, as well as vehicle-treated or control littermates, with complementary in vitro studies in primary hepatocytes and 3T3-L1 adipocytes., Results: GSI-treatment increases hepatic insulin sensitivity in obese mice but leads to reciprocal lowering of adipose glucose disposal. While A-Rbpj mice show normal body weight, adipose development and mass and unchanged adipose insulin sensitivity as control littermates, A-Nicastrin mice are relatively insulin-resistant, mirroring the GSI effect on adipose insulin action., Conclusions: Notch signaling is dispensable for normal adipocyte function, but adipocyte-specific γ-secretase blockade reduces adipose insulin sensitivity, suggesting that specific Notch inhibitors would be preferable to GSIs for application in T2D.
- Published
- 2015
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