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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]

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

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

Research has been conducted on the histidine-containing phosphotransfer (HPt) domain. The effect of the HPt YPD1 protein on the phosphostability of the response regulator domains has been investigated and the results are discussed.

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]

Objective: Obesity is a major risk factor for cardiovascular disease, metabolic syndrome, and type 2 diabetes mellitus, whereas weight loss is associated with improved health outcomes. It is therefore important to learn how adipose contraction during weight loss contributes to improved health. It was hypothesized that adipose tissue undergoing weight loss would have a unique transcriptomic profile, expressing specific genes that might improve health.Methods: This study conducted an RNA-sequencing analysis of the epididymal adipose tissue of mice fed either a high-fat diet (HFD) or a regular rodent chow diet (RD) ad libitum for 10 weeks versus a cohort of mice fed HFD for the first 5 weeks before being swapped to an RD for the remainder of the study (swapped diet [SWAP]).Results: The swapped diet resulted in weight loss, with a parallel improvement in insulin sensitivity. RNA sequencing revealed several transcriptomic signatures distinct to adipose tissue in SWAP mice, distinguished from both RD and HFD adipose tissue. The analysis found a unique upregulated mRNA that encodes a secreted lipopolysaccharide-binding glycoprotein (CRISPLD2) in adipose tissue. Whereas cellular CRISPLD2 protein levels were unchanged, plasma CRIPSLD2 levels increased in SWAP mice following weight loss and could correlate with insulin sensitivity.Conclusions: Taken together, these data demonstrate that CRISPLD2 is a circulating adipokine that may regulate adipocyte remodeling during weight loss. [ABSTRACT FROM AUTHOR]

Byline: Daryl Van Moorsel, J.A.L. Cranfield, David Sparling 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.

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]

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]

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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]

Factors influencing the development and commercialization of functional food and nutraceutical (FFN) products are explored. Count data models are developed to relate firm, market, and regulatory covariates to the number of FFN product lines firms have under development, on the market, and in total. Canadian firm-level innovation data were taken from Statistics Canada (2003) Functional Food and Nutraceutical Survey. Firms involved in product development/scale-up had more product lines in total and on the market. Firms with a strong and positive perception of the impact of regulatory reform related to generic health claims and harmonization of Canadian regulations with U.S. regulations had fewer product lines in total and on the market. Firms with more positive perceptions of the business impact of structure and function health claims had more product lines on the market. One implication of the study is the importance of developing policies and reforming regulations which better enable use of generic health claims on FFN products. Further, policies which better enable or foster development/scale-up of product lines would increase the Canadian FFN sector's ability to develop new products. [EconLit: O130, L500, Q180]. © 2008 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

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]

Focuses on the relationship between economic value added (EVA) and shareholder return and reexamines the evidence and issues surrounding the use of EVA as a tool for valuing investments. Weak correlations between EVA and shareholder value in all instances tested.

Analyzes the strategies of independent, domestically owned medium-sized processing companies in Canada. Details on the theoretical concept of a core competence; Competition for agricultural food firms; Role of internal factors in the strategies of meduimd-size food processors.

Introduces the Just-In-Time (JIT) practices in U-shaped production lines to identify efficiencies and eliminate manufacturing waste. Details on the U-line balancing problems; Model for the N U-Line Balancing with Travel (NULB-T) problem; Computational study which investigated the benefits of multiple U-lines and the effectiveness of the solution algorithms; Discussion on the study.

As part of studies to understand human pancreatic islet pathophysiology in type 1 diabetes (T1D), we discovered normal β cell mass in a 33-year-old deceased organ donor with T1D for 17 years. Further analysis revealed the donor's diabetes resulted from a causative variant in hepatic nuclear factor 1-alpha (HNF1A), associated with Maturity-onset Diabetes of the Young-3 (MODY3) (J Clin Invest 129:246, 2019), which can be treated with sulfonylureas. Review of the donor's redacted medical chart suggested a family history of diabetes consistent with the known autosomal dominant pattern of inheritance of MODY3. With this clinically-actionable information, we desired to inform the donor's family. However, de-identified samples are not considered "human subject" research by Institutional Review Boards (IRB), so the family's identity was unknown with no defined pathway for communicating these findings. Working with a Human Tissue and Organ Research Resource and an organ procurement organization, we developed a new, IRB-approved communication path between those involved in tissue collection, scientific investigation, and the donor's family and physician. This allowed targeted genetic testing of potentially affected family members, which revealed five living relatives of the donor who carried the HNF1A variant: three adults diagnosed with diabetes before the age of 25 currently treated with insulin and two children (ages 6 months and 3 years) who did not have clinical diabetes. Since none of the identified individuals were known to have MODY3, they will likely benefit from appropriate clinical care and surveillance. This experience demonstrates the need for the scientific community to develop guidelines to address handling, reporting, and use of research findings from de-identified tissue collected for research. Defining ethical avenues for donor family-investigator communications will benefit for both organ donor families and scientific research. Disclosure: D. Sparling: None. R. Haliyur: None. J. Lindner: None. L. Weber: None. A. Ramirez: None. M. Brissova: None. A.C. Powers: None. [ABSTRACT FROM AUTHOR]

Youth with type 1 diabetes (T1D) require 24/7 access to T1D management supplies. This study aims to characterize access to T1D supplies when youth are away from home. We emailed a comprehensive survey to 4756 parents of T1D Exchange participants <18 years old; 752 respondents completed the survey (83% completed by parents). Results were age-stratified: <6 (N=21), 6-12 (N=271) and 13-18 (N=459). The majority of youth carry rapid-acting insulin most of the time or always, yet the proportion decreases as age increases (Table 1). ≥80% of injection users carry an extra pen or syringe, while >55% of pump users carry an extra infusion set. Among CGM users, 100% of ≤6 years old vs. 67% of adolescents carry a receiver or phone; 33% of 13-18 years old never carry an extra sensor. 38% of youth ≤6 years old vs. 27% of teens carry blood or urine ketone testing supplies. In total, 64% reported carrying glucose tablets or gel; 87% carry another rapid acting carbohydrate. 64% of respondents carry glucagon, again decreasing across adolescence. Over 2/3 carry at least one form of T1D identification. Technology to optimize glycemic control and detect/prevent acute complications of T1D have improved. Yet, adolescents are less likely than younger T1D-affected youth, to carry supplies to detect, prevent and/or treat acute events. These findings call for novel and ongoing T1D emergency preparedness training to strike a balance between supervision and autonomy of adolescents. Disclosure: M. Quinn: None. R. Bailey: None. N.C. Foster: None. J. Simmons: None. E. Eyth: None. H. Rodriguez: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Daiichi Pharm Corp, MannKind Corporation, Medtronic MiniMed, Inc. Research Support; Spouse/Partner; Medtronic MiniMed, Inc. Research Support; Self; Takeda Pharmaceutical Company Limited. Other Relationship; Self; Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc. S. Corathers: None. C.J. Levy: Advisory Panel; Self; Novo Nordisk A/S, Sanofi. Employee; Spouse/Partner; Allergan. N.M. Sheanon: None. R.M. Wasserman: None. D. Sparling: None. D. Adkins: None. A. Albanese-O'Neill: None. D.J. DeSalvo: Consultant; Self; Dexcom, Inc., Insulet Corporation. Funding: The Leona M. and Harry B. Helmsley Charitable Trust [ABSTRACT FROM AUTHOR]

Presents a study that determined whether exercise increases the DNA-binding activity of both myocyte enhancer factor 2 (MEF2) and glucose transporter isoform 4 (GLUT4) enhancer factor (GEF) in human skeletal muscle. Findings of the study; Conclusions and significance of the study.

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]

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]

Context: Use of continuous glucose monitoring (CGM) is increasing for insulin-requiring patients with diabetes. Although data on glycemic profiles of healthy, nondiabetic individuals exist for older sensors, assessment of glycemic metrics with new-generation CGM devices is lacking., Objective: To establish reference sensor glucose ranges in healthy, nondiabetic individuals across different age groups using a current generation CGM sensor., Design: Multicenter, prospective study., Setting: Twelve centers within the T1D Exchange Clinic Network., Patients or Participants: Nonpregnant, healthy, nondiabetic children and adults (age ≥6 years) with nonobese body mass index., Intervention: Each participant wore a blinded Dexcom G6 CGM, with once-daily calibration, for up to 10 days., Main Outcome Measures: CGM metrics of mean glucose, hyperglycemia, hypoglycemia, and glycemic variability., Results: A total of 153 participants (age 7 to 80 years) were included in the analyses. Mean average glucose was 98 to 99 mg/dL (5.4 to 5.5 mmol/L) for all age groups except those over 60 years, in whom mean average glucose was 104 mg/dL (5.8 mmol/L). The median time between 70 to 140 mg/dL (3.9 to 7.8 mmol/L) was 96% (interquartile range, 93 to 98). Mean within-individual coefficient of variation was 17 ± 3%. Median time spent with glucose levels >140 mg/dL was 2.1% (30 min/d), and median time spent with glucose levels <70 mg/dL (3.9 mmol/L) was 1.1% (15 min/d)., Conclusion: By assessing across age groups in a healthy, nondiabetic population, normative sensor glucose data have been derived and will be useful as a benchmark for future research studies., (Copyright © 2019 Endocrine Society.)

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.