Browsing by Author "Greenawald, Mark H."
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- Insulin resistance is associated with epigenetic and genetic regulation of mitochondrial DNA in obese humansZheng, Louise D.; Linarelli, Leah E.; Liu, Longhua; Wall, Sarah S.; Greenawald, Mark H.; Seidel, Richard W.; Estabrooks, Paul A.; Almeida, Fabio A.; Cheng, Zhiyong (2015-06-10)Background Mitochondrial alterations have been observed in subjects with metabolic disorders such as obesity and diabetes. Studies on animal models and cell cultures suggest aberrant glucose and lipid levels, and impaired insulin signaling might lead to mitochondrial changes. However, the molecular mechanism underlying mitochondrial aberrance remains largely unexplored in human subjects. Results Here we show that the mitochondrial DNA copy number (mtDNAn) was significantly reduced (6.9-fold lower, p < 0.001) in the leukocytes from obese humans (BMI >30). The reduction of mtDNAn was strongly associated with insulin resistance (HOMA-IR: −0.703, p < 0.05; fasting insulin level: −0.015, p < 0.05); by contrast, the correlation between fasting glucose or lipid levels and mtDNAn was not significant. Epigenetic study of the displacement loop (D-loop) region of mitochondrial genome, which controls the replication and transcription of the mitochondrial DNA as well as organization of the mitochondrial nucleoid, revealed a dramatic increase of DNA methylation in obese (5.2-fold higher vs. lean subjects, p < 0.05) and insulin-resistant (4.6-fold higher vs. insulin-sensitive subjects, p < 0.05) individuals. Conclusions The reduction of mtDNAn in obese human subjects is associated with insulin resistance and may arise from increased D-loop methylation, suggesting an insulin signaling-epigenetic-genetic axis in mitochondrial regulation.
- Mitochondrial Epigenetic Changes Link to Increased Diabetes Risk and Early-Stage Prediabetes IndicatorZheng, Louise D.; Linarelli, Leah E.; Brooke, Joseph; Smith, Cayleen M.; Wall, Sarah S.; Greenawald, Mark H.; Seidel, Richard W.; Estabrooks, Paul A.; Almeida, Fabio A.; Cheng, Zhiyong (Hindawi, 2016-04-26)Type 2 diabetes (T2D) is characterized by mitochondrial derangement and oxidative stress. With no known cure for T2D, it is critical to identify mitochondrial biomarkers for early diagnosis of prediabetes and disease prevention. Here we examined 87 participants on the diagnosis power of fasting glucose (FG) and hemoglobin A1c levels and investigated their interactions with mitochondrial DNA methylation. FG and A1c led to discordant diagnostic results irrespective of increased body mass index (BMI), underscoring the need of new biomarkers for prediabetes diagnosis. Mitochondrial DNA methylation levels were not correlated with late-stage (impaired FG or A1c) but significantly with early-stage (impaired insulin sensitivity) events. Quartiles of BMI suggested that mitochondrial DNA methylation increased drastically from Q1 (20 < BMI < 24.9, lean) to Q2 (30 < BMI < 34.9, obese), but marginally from Q2 to Q3 (35 < BMI < 39.9, severely obese) and from Q3 to Q4 (BMI > 40, morbidly obese). A significant change was also observed from Q1 to Q2 inHOMA insulin sensitivity but not in A1c or FG. Thus, mitochondrial epigenetic changes link to increased diabetes risk and the indicator of early-stage prediabetes. Further larger-scale studies to examine the potential of mitochondrial epigenetic marker in prediabetes diagnosis will be of critical importance for T2D prevention.
- Pragmatic Implementation Trials: Understanding the Integrated Research-Practice Partnership Approach to Lifestyle Obesity Management Across a Transforming Health SystemJohnson, Sarah Elizabeth (Virginia Tech, 2017-01-10)Obesity, a condition of excess body fat, is one of the most complex problems facing health systems. Lifestyle management programs that combine diet, physical activity, and intensive behavioral therapy have been shown by research to support a degree of weight loss that produces health benefits (i.e., at least a 3-5% initial body weight). However, it has been difficult for research-developed programs to be delivered in typical practice to have a meaningful impact. Integrated research-practice partnerships that involve the coming together of academic researchers, health system administrators, and program delivery staff may help overcome this gap, especially during this transformational time in the healthcare sector. This dissertation aimed to develop an understanding of how using the integrated research-practice approach would facilitate and sustain evidence-based lifestyle management strategies across a health system to treat obesity among patients and employees. An integrated research-practice partnership with Carilion Clinic, a health system in western Virginia, served as an example for the study. From 2013-2016, the Carilion Clinic integrated research-practice partnership conducted a series of trials testing different strategies for delivering weight loss and weight loss maintenance support. An evaluation guided by the RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) framework was conducted to describe implementation processes and outcomes for each strategy. Lessons learned from the evaluation support the value of the integrated-research practice partnership approach as a solution for overcoming gaps in obesity care. A shared priority perspective between research and practice was identified as the powerful process for supporting facilitation and sustainability of strategies. In addition, findings from the evaluation produced evidence to inform the future development of a system for Carilion Clinic to help patients and employees lose weight and keep it off through lifestyle management.