Dawn K Coletta

Interests

Teaching

Endocrine Physiology, Cell Biology, Molecular Basis of Diabetes and Obesity, Insulin and Glucagon Action, The Global Obesity Pandemic, Life Sciences Career Paths, Physiological Analysis of States of Health, Principles of Physiological Control, Translational Biomedical Sciences, Infrastructure in the "Genomics Age", Genomics/Epigenomics, Epigenetics of Insulin Resistance, Childhood Obesity

Research

My primary research interests are to study the genetic and epigenetics of insulin resistance, which is a characteristic feature of a number of common metabolic diseases including type 2 diabetes mellitus, obesity and the insulin resistance syndrome. The prevalence of these complex metabolic diseases is rapidly and relentlessly increasing and to prevent the epidemic rise, it is necessary to define the genetic and epigenetic defects responsible for the insulin resistance that characterizes these common diseases. My laboratory combines state of the art techniques (global epigenetic mapping, oligonucleotide-based DNA chip microarray analysis, DNA resequencing, genomewide linkage analysis, single nucleotide polymorphism association studies, linkage disequilibrium mapping and mass spectrometry proteome analyses) and in vivo methods (euglycemic hyperinsulinemic clamp, muscle biopsies, exercise training, bariatric surgery, lipid infusion, drug intervention studies) to identify and characterize genes/loci that influence this complex phenotype. Susceptibility genes/loci identified from these analyses are characterized further using assays and molecular techniques that allow for functional analysis of each candidate gene. Identification of the genes that are critical to the development of insulin resistance will provide new targets for therapeutic interventions to reverse/ameliorate the insulin resistance and thereby lead to an improvement in these common metabolic diseases.

Courses

Scholarly Contributions

Chapters

• Coletta, D. K. (2014). Genetic and Epigenetics of Type 2 Diabetes. In Genetic and Epigenetics of Type 2 Diabetes. Elsevier Inc. doi:10.1016/B978-0-12-386456-7.02002-5
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  Over the past three decades, the global prevalence of type 2 diabetes (T2D) has rapidly and relentlessly increased, and in the United States, 8.3% have T2D. In order to prevent the epidemic rise, it is necessary to define the genetic and epigenetic defects responsible for characterizing this common and complex disease. T2D is characterized by chronic hyperglycemia and arises from a combination of insulin resistance and beta-cell dysfunction. Environmental factors including physical inactivity and caloric excess play a key role in the development of the disease. However, genetic factors also contribute to the pathogenesis of T2D, and more recently, epigenetic influences such as DNA methylation, histone modifications, and microRNAs have been proposed in the pathogenesis of this complex disease. This article will provide an up-to-date review on the genetics and epigenetics of T2D.

Journals/Publications

• Muscogiuri, G., Kohler, L., Parra, O., Soltani, L., Spegman, D., Coletta, D., & Mandarino, L. (2024). Longitudinal study of the impact of the COVID-19 pandemic on diet and physical activity among Latinos of Mexican ancestry. Journal of Translational Medicine, 22(1). doi:10.1186/s12967-024-05007-y
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  Background: The COVID-19 pandemic caused societal disruption in the United States and most of the world, affecting many aspects of life, including healthcare and health-related behaviors such as diet, food security, and physical activity. Communities with economic and health disparities may have been particularly affected. This study was undertaken to determine how conditions in the early pandemic (January, 2021–February, 2022) affected Latino patients of Mexican Ancestry at high risk of type 2 diabetes mellitus who participated in El Banco por Salud biobank project in Tucson, Arizona. Methods: Baseline, prepandemic measurements were available in 17, 21, and 60 patients with normal hemoglobin A1c (HbA1c), prediabetes, and type 2 diabetes, respectively. Results: People with healthy HbA1c were significantly younger, less obese, and had higher HDL cholesterol. HbA1c was unaffected by the pandemic in any group. Triglycerides, total and HDL cholesterol levels fell in all groups during the pandemic. Physical activity levels in all groups were remarkably low, with most reporting no engagement in any voluntary physical activity. Engagement in physical activity or its enjoyment was lower in patients with diabetes and prediabetes than in younger, less obese patients. Major diet differences were between men and women and were present before the pandemic. Women consumed significantly more vegetables, fruit, and salad than men. The only pandemic-related change in diet was a drop in egg consumption, possibly explaining the fall in total cholesterol. Conclusion: Societal disruption during the COVID-19 pandemic had minimal effects on adverse health-related behaviors, cardiometabolic risk, or changes in glycemic control in a Latino community with diabetes and healthcare disparities in the Southwest US.
• Reed, B. L., Tavoian, D., Bailey, E. F., Funk, J. L., & Coletta, D. K. (2024). Inspiratory muscle strength training to improve cardiometabolic health in patients with type 2 diabetes mellitus: protocol for the diabetes inspiratory training clinical trial. Frontiers in endocrinology, 15, 1383131.
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  Type 2 diabetes mellitus (T2DM) is a complex, chronic metabolic disease that carries with it a high prevalence of comorbid conditions, making T2DM one of the leading causes of death in the U.S. Traditional lifestyle interventions (e.g., diet, exercise) can counter some adverse effects of T2DM, however, participation in these activities is low with reasons ranging from physical discomfort to lack of time. Thus, there is a critical need to develop novel management strategies that effectively reduce cardiometabolic disease risk and address barriers to adherence. High-resistance inspiratory muscle strength training (IMST) is a time-efficient and simple breathing exercise that significantly reduces systolic and diastolic BP and improves vascular endothelial function in adults with above-normal blood pressure. Herein we describe the study protocol for a randomized clinical trial to determine the effects of a 6-week IMST regimen on glycemic control and insulin sensitivity in adults with T2DM. Our primary outcome measures include fasting plasma glucose, fasting serum insulin, and insulin resistance utilizing homeostatic model assessment for insulin resistance (HOMA-IR). Secondary outcome measures include resting systolic BP and endothelium-dependent dilation. Further, we will collect plasma for exploratory proteomic analyses. This trial seeks to establish the cardiometabolic effects of 6 weeks of high-resistance IMST in patients with T2DM.
• Reed, B., Tavoian, D., Bailey, E., Funk, J., & Coletta, D. (2024). Inspiratory muscle strength training to improve cardiometabolic health in patients with type 2 diabetes mellitus: protocol for the diabetes inspiratory training clinical trial. Frontiers in Endocrinology, 15. doi:10.3389/fendo.2024.1383131
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  Type 2 diabetes mellitus (T2DM) is a complex, chronic metabolic disease that carries with it a high prevalence of comorbid conditions, making T2DM one of the leading causes of death in the U.S. Traditional lifestyle interventions (e.g., diet, exercise) can counter some adverse effects of T2DM, however, participation in these activities is low with reasons ranging from physical discomfort to lack of time. Thus, there is a critical need to develop novel management strategies that effectively reduce cardiometabolic disease risk and address barriers to adherence. High-resistance inspiratory muscle strength training (IMST) is a time-efficient and simple breathing exercise that significantly reduces systolic and diastolic BP and improves vascular endothelial function in adults with above-normal blood pressure. Herein we describe the study protocol for a randomized clinical trial to determine the effects of a 6-week IMST regimen on glycemic control and insulin sensitivity in adults with T2DM. Our primary outcome measures include fasting plasma glucose, fasting serum insulin, and insulin resistance utilizing homeostatic model assessment for insulin resistance (HOMA-IR). Secondary outcome measures include resting systolic BP and endothelium-dependent dilation. Further, we will collect plasma for exploratory proteomic analyses. This trial seeks to establish the cardiometabolic effects of 6 weeks of high-resistance IMST in patients with T2DM.
• Verde, L., Kohler, L. N., Muscogiuri, G., Parra, O., Klimentidis, Y. C., Coletta, D. K., & Mandarino, L. J. (2024). Food insecurity and its associations with cardiometabolic health in Latino individuals of Mexican ancestry. Frontiers in nutrition, 11, 1499504.
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  Latino populations, especially those of Mexican ancestry, face higher rates of both cardiometabolic diseases and food insecurity, compounding negative health outcomes. Food insecurity is associated with poor dietary choices, which not only worsen cardiometabolic health but also contribute to various health complications, making it a critical public health issue in these communities. The aim of this study was to investigate the prevalence of food insecurity and its associations with diet, cardiometabolic risk factors, and glycemic control among Latino individuals of Mexican ancestry.
• Verde, L., Kohler, L., Muscogiuri, G., Parra, O., Klimentidis, Y., Coletta, D., & Mandarino, L. (2024). Food insecurity and its associations with cardiometabolic health in Latino individuals of Mexican ancestry. Frontiers in Nutrition, 11. doi:10.3389/fnut.2024.1499504
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  Background: Latino populations, especially those of Mexican ancestry, face higher rates of both cardiometabolic diseases and food insecurity, compounding negative health outcomes. Food insecurity is associated with poor dietary choices, which not only worsen cardiometabolic health but also contribute to various health complications, making it a critical public health issue in these communities. The aim of this study was to investigate the prevalence of food insecurity and its associations with diet, cardiometabolic risk factors, and glycemic control among Latino individuals of Mexican ancestry. Methods: Cross-sectional observational study using data from the El Banco por Salud biobank. The study included 1,827 participants with a mean age of 52.5 ± 14.4 years, recruited from community-based settings. The majority were women (67.6%), obese (mean BMI 32.4 ± 7.0 kg/m2), and sedentary (43.5%). Food insecurity was assessed using the 6-item U.S. Household Food Security Module, while dietary information was obtained using the Brief Dietary Assessment Tool for Hispanics. Primary outcomes included cardiometabolic risk factors and glycemic control, specifically HbA1c levels. Results: Of 1,827 participants, 69.7% were food secure and 30.3% were food insecure. Food insecure participants had a significantly larger waist circumference (p = 0.034), consumed poorer quality diets, and had higher HbA1c levels (p = 0.043), with the association remaining significant after adjustments (p = 0.007 for age, sex, BMI, and waist circumference; p = 0.021 for additional sociodemographic factors). Conclusion: The findings reveal that food insecurity among Latino individuals of Mexican ancestry is associated with unhealthy food choices and higher HbA1c levels, exacerbating the risk of poor cardiometabolic health. This underscores an urgent need for targeted interventions to address food insecurity, ultimately promoting better metabolic health outcomes in vulnerable populations.
• Voisin, S., Seale, K., Jacques, M., Landen, S., Harvey, N., Haupt, L., Griffiths, L., Ashton, K., Coffey, V., Thompson, J., Doering, T., Lindholm, M., Walsh, C., Davison, G., Irwin, R., McBride, C., Hansson, O., Asplund, O., Heikkinen, A., , Ollikainen, M., et al. (2024). Exercise is associated with younger methylome and transcriptome profiles in human skeletal muscle. Aging Cell, 23(1). doi:10.1111/acel.13859
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  Exercise training prevents age-related decline in muscle function. Targeting epigenetic aging is a promising actionable mechanism and late-life exercise mitigates epigenetic aging in rodent muscle. Whether exercise training can decelerate, or reverse epigenetic aging in humans is unknown. Here, we performed a powerful meta-analysis of the methylome and transcriptome of an unprecedented number of human skeletal muscle samples (n = 3176). We show that: (1) individuals with higher baseline aerobic fitness have younger epigenetic and transcriptomic profiles, (2) exercise training leads to significant shifts of epigenetic and transcriptomic patterns toward a younger profile, and (3) muscle disuse “ages” the transcriptome. Higher fitness levels were associated with attenuated differential methylation and transcription during aging. Furthermore, both epigenetic and transcriptomic profiles shifted toward a younger state after exercise training interventions, while the transcriptome shifted toward an older state after forced muscle disuse. We demonstrate that exercise training targets many of the age-related transcripts and DNA methylation loci to maintain younger methylome and transcriptome profiles, specifically in genes related to muscle structure, metabolism, and mitochondrial function. Our comprehensive analysis will inform future studies aiming to identify the best combination of therapeutics and exercise regimes to optimize longevity.
• Barakati, N., Bustos, R. Z., Coletta, D. K., Langlais, P. R., Kohler, L. N., Luo, M., Funk, J. L., Willis, W. T., & Mandarino, L. J. (2023). Fuel Selection in Skeletal Muscle Exercising at Low Intensity; Reliance on Carbohydrate in Very Sedentary Individuals. Metabolic syndrome and related disorders, 21(1), 16-24.
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  Resting skeletal muscle in insulin resistance prefers to oxidize carbohydrate rather than lipid, exhibiting metabolic inflexibility. Although this is established in resting muscle, complexities involved in directly measuring fuel oxidation using indirect calorimetry across a muscle bed have limited studies of this phenomenon in working skeletal muscle. During mild exercise and at rest, whole-body indirect calorimetry imperfectly estimates muscle fuel oxidation. We provide evidence that a method termed "ΔRER" can reasonably estimate fuel oxidation in skeletal muscle activated by exercise. Completely sedentary volunteers ( = 20, age 31 ± 2 years, V̇O 24.4 ± 1.5 mL O per min/kg) underwent glucose clamps to determine insulin sensitivity and graded exercise consisting of three periods of mild steady-state cycle ergometry (15, 30, 45 watts, or 10%, 20%, and 30% of maximum power) with measurements of whole-body gas exchange. ΔRER, the RER in working muscle, was calculated as (V̇CO2 -V̇CO)/(V̇O - V̇O), from which the fraction of fuel accounted for by lipid was estimated. Lactate levels were low and stable during steady-state exercise. Muscle biopsies were used to estimate mitochondrial content. The rise of V̇O at onset of exercise followed a monoexponential function, with a time constant of 51 ± 7 sec, typical of skeletal muscle; the average O cost of work was about 12 mL O/watt/min, representing a mechanical efficiency of about 24%. At work rates of 30 or 45 watts, active muscle relied predominantly on carbohydrate, independent of insulin sensitivity within this group of very sedentary volunteers. The fraction of muscle fuel oxidation from fat was predicted by power output ( 
• Blomquist, S., Albrecht, J., Hallmark, B., Garcı́a, L., Mandarino, L. J., Coletta, D. K., & Chilton, F. H. (2023). P10-006-23 Impact of FADS and ELOVL2/5 Genetic Variation on Fatty Acid and Cardiometabolic Endpoints in Mexican American Individuals. Current Developments in Nutrition. doi:10.1016/j.cdnut.2023.101673
• Grijalva, A., Benson, D. R., Fink, J. N., Zhang, X., Coletta, D. K., Langlais, P., Pandey, A. C., Mangiola, M., Koevary, J. W., Lancaster, J. J., & Goldman, S. (2023). Abstract 17096: Immune Modulation to Treat Ischemic Heart Failure. Circulation, 148(Suppl_1). doi:10.1161/circ.148.suppl_1.17096
• Lynn, H., Sun, X., Casanova, N. G., Bime, C., Reyes Hernon, V., Lanham, C., Oita, R. C., Ramos, N., Sun, B., Coletta, D. K., Camp, S. M., Karnes, J. H., Ellis, N. A., & Garcia, J. G. (2023). Linkage of NAMPT promoter variants to eNAMPT secretion, plasma eNAMPT levels, and ARDS severity. Therapeutic advances in respiratory disease, 17, 17534666231181262.
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  eNAMPT (extracellular nicotinamide phosphoribosyltransferase), a novel DAMP and TLR4 ligand, is a druggable ARDS therapeutic target with promoter SNPs associated with ARDS severity. This study assesses the previously unknown influence of promoter SNPs on transcription, eNAMPT secretion, and ARDS severity.
• Mandarino, L. J., Willis, W. T., Funk, J. L., Langlais, P. R., Davidson, L., Galons, J., Coletta, D. K., & Zapata Bustos, R. (2023). Nonequilibrium thermodynamics and mitochondrial protein content predict insulin sensitivity and fuel selection during exercise in human skeletal muscle. Front Physiol.
• Mandarino, L. J., Willis, W. T., Funk, J. L., Luo, M., Kohler, L. N., Langlais, P. R., Coletta, D. K., Zapata Bustos, R., & Barakati, N. (2023). Fuel Selection in Skeletal Muscle Exercising at Low Intensity; Reliance on Carbohydrate in Very Sedentary Individuals. Metabolic Syndrome and Related Disorders.
• Standage-Beier, C. S., Garcia, L. A., De Filippis, E., Shaibi, G. Q., Mandarino, L. J., & Coletta, D. K. (2023). Association of Vitamin D Receptor Gene Polymorphisms with Cardiometabolic Phenotypes in Hispanics: A Life Course Approach. Nutrients, 15(9).
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  The vitamin D receptor (VDR) is vital for maintaining calcium and phosphate balance and regulating bone metabolism. Recent research has suggested that VDR also plays an essential role in metabolic diseases. Previous studies on non-Hispanic whites have shown that VDR single nucleotide polymorphisms (SNP) are associated with cardiometabolic phenotypes. However, the association between VDR SNPs and cardiometabolic traits in Hispanics remains unclear. This study investigated the association between VDR SNPs and cardiometabolic phenotypic data in self-reported Hispanics (n = 1610) from the Arizona Insulin Resistance registry and Sangre Por Salud Biobank. The study population was predominantly female (66.4%) with a mean age of 40 ± 14 years (n = 121
• Voisin, S., Seale, K., Jacques, M., Landen, S., Harvey, N. R., Haupt, L. M., Griffiths, L. R., Ashton, K. J., Coffey, V. G., Thompson, J. M., Doering, T. M., Lindholm, M. E., Walsh, C., Davison, G., Irwin, R., McBride, C., Hansson, O., Asplund, O., Heikkinen, A. E., , Piirilä, P., et al. (2023). Exercise is associated with younger methylome and transcriptome profiles in human skeletal muscle. Aging cell, 23(1), e13859.
  More info

  Exercise training prevents age-related decline in muscle function. Targeting epigenetic aging is a promising actionable mechanism and late-life exercise mitigates epigenetic aging in rodent muscle. Whether exercise training can decelerate, or reverse epigenetic aging in humans is unknown. Here, we performed a powerful meta-analysis of the methylome and transcriptome of an unprecedented number of human skeletal muscle samples (n = 3176). We show that: (1) individuals with higher baseline aerobic fitness have younger epigenetic and transcriptomic profiles, (2) exercise training leads to significant shifts of epigenetic and transcriptomic patterns toward a younger profile, and (3) muscle disuse "ages" the transcriptome. Higher fitness levels were associated with attenuated differential methylation and transcription during aging. Furthermore, both epigenetic and transcriptomic profiles shifted toward a younger state after exercise training interventions, while the transcriptome shifted toward an older state after forced muscle disuse. We demonstrate that exercise training targets many of the age-related transcripts and DNA methylation loci to maintain younger methylome and transcriptome profiles, specifically in genes related to muscle structure, metabolism, and mitochondrial function. Our comprehensive analysis will inform future studies aiming to identify the best combination of therapeutics and exercise regimes to optimize longevity.
• Wu, L., Garcia, L., Lipinski, A., Langlais, P., & Coletta, D. (2023). Identification of novel changes in skeletal muscle proteome after sildenafil treatment. Physiology, 38(S1). doi:10.1152/physiol.2023.38.s1.5731380
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  Insulin Resistance (IR) is associated with increased matrix proteins, including collagens, fibronectins, and laminins in the endomysium surrounding skeletal muscle. The increased ECM deposition in skeletal muscle IR results in ECM stiffening that decreases muscle integrity and cellular signaling. Recent evidence has shown that Sildenafil, a phosphodiesterase 5a inhibitor, improves insulin sensitivity in humans, and in high fat diet mice, reduces collagen deposition in the matrix surrounding skeletal muscle. In addition, data shows that a short-term treatment of Sildenafil for 7 days increases protein synthesis and decreases muscle fatigue in humans, which may mitigate the effects of IR. However, very few studies have examined the molecular mechanisms and metabolic signaling directly associated with Sildenafil’s influence on skeletal muscle. The aim of our study was to perform an unbiased proteomic analysis on Sildenafil’s effects on skeletal muscle in C2C12 myotubes. We hypothesized that Sildenafil would alter the abundance of proteins in metabolic pathways that are involved in communicating with the ECM. We performed a dose response (n = 3 for each dose; 0.5 μM, 1 μM, 2.5 μM, 5 μM, and 10 μM) and time response (n = 3 for each time; 30 min, 1 hour, 4 hour, 6 hour) curve. Proteomic analyses revealed that the highest number of proteins significantly changing was at 1 μM for 30 min (n = 423). Analysis of the significant proteins revealed 396 and 27 proteins that increased and decreased, respectively. KEGG analysis revealed that 20% of the total changing proteins (n = 83) were in metabolic pathways. The top 10 metabolic protein increasers, represented as a fold change of abundance compared to vehicle, were ASCL3 (1.27 ± 0.08), GT251 (1.12 ± 0.10), ODPA (1.15 ± 0.03), PCKGM (1.08 ± 0.04), PCY1A (1.23 ± 0.04), PGM1 (1.06 ± 0.04), PTG1S (1.21 ± 0.05), PYR1 (1.37 ± 0.09). SAHH (1.19 + 0.07), and THIM (1.13 ± 0.08). Of the 83 metabolic proteins, only 6 were decreasing, P5CR2 (0.78 ± 0.04), ALD1 (0.82 ± 0.11), P4K2A (0.67 ± 0.05), DGAT1 (0.27 ± 0.19), SCLY (0.77 ± 0.15), and PLCD3 (0.61 ± 0.16). The results from this preliminary study conclude that Sildenafil affects proteins involved in metabolic pathways. Further analysis will be performed to confirm the roles of these proteins in relation to ECM signaling/communication in these metabolic pathways. University of Arizona's Research, Innovation & Impact Faculty Seed Grant This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
• Zapata Bustos, R., Coletta, D. K., Galons, J. P., Davidson, L. B., Langlais, P. R., Funk, J. L., Willis, W. T., & Mandarino, L. J. (2023). Nonequilibrium thermodynamics and mitochondrial protein content predict insulin sensitivity and fuel selection during exercise in human skeletal muscle. Frontiers in physiology, 14, 1208186.
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  Many investigators have attempted to define the molecular nature of changes responsible for insulin resistance in muscle, but a molecular approach may not consider the overall physiological context of muscle. Because the energetic state of ATP (ΔG) could affect the rate of insulin-stimulated, energy-consuming processes, the present study was undertaken to determine whether the thermodynamic state of skeletal muscle can partially explain insulin sensitivity and fuel selection independently of molecular changes. P-MRS was used with glucose clamps, exercise studies, muscle biopsies and proteomics to measure insulin sensitivity, thermodynamic variables, mitochondrial protein content, and aerobic capacity in 16 volunteers. After showing calibrated P-MRS measurements conformed to a linear electrical circuit model of muscle nonequilibrium thermodynamics, we used these measurements in multiple stepwise regression against rates of insulin-stimulated glucose disposal and fuel oxidation. Multiple linear regression analyses showed 53% of the variance in insulin sensitivity was explained by 1) VO ( = 0.001) and the 2) slope of the relationship of ΔG with the rate of oxidative phosphorylation ( = 0.007). This slope represents conductance in the linear model (functional content of mitochondria). Mitochondrial protein content from proteomics was an independent predictor of fractional fat oxidation during mild exercise (R = 0.55, = 0.001). Higher mitochondrial functional content is related to the ability of skeletal muscle to maintain a greater ΔG, which may lead to faster rates of insulin-stimulated processes. Mitochondrial protein content can explain fractional fat oxidation during mild exercise.
• Barakati, N., Coletta, D. K., Funk, J. L., Mandarino, L. J., Willis, W. T., Luo, M., Kohler, L. N., Langlais, P. R., & Bustos, R. Z. (2022). Fuel Selection in Skeletal Muscle Exercising at Low Intensity; Reliance on Carbohydrate in Very Sedentary Individuals. Metabolic Syndrome and Related Disorders. doi:10.1089/met.2022.0062
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  Background: Resting skeletal muscle in insulin resistance prefers to oxidize carbohydrate rather than lipid, exhibiting metabolic inflexibility. Although this is established in resting muscle, complexities involved in directly measuring fuel oxidation using indirect calorimetry across a muscle bed have limited studies of this phenomenon in working skeletal muscle. During mild exercise and at rest, whole-body indirect calorimetry imperfectly estimates muscle fuel oxidation. We provide evidence that a method termed "ΔRER" can reasonably estimate fuel oxidation in skeletal muscle activated by exercise. Methods: Completely sedentary volunteers (n = 20, age 31 ± 2 years, V̇O2peak 24.4 ± 1.5 mL O2 per min/kg) underwent glucose clamps to determine insulin sensitivity and graded exercise consisting of three periods of mild steady-state cycle ergometry (15, 30, 45 watts, or 10%, 20%, and 30% of maximum power) with measurements of whole-body gas exchange. ΔRER, the RER in working muscle, was calculated as (V̇CO2exercise -V̇CO2rest)/(V̇O2exercise - V̇O2rest), from which the fraction of fuel accounted for by lipid was estimated. Results: Lactate levels were low and stable during steady-state exercise. Muscle biopsies were used to estimate mitochondrial content. The rise of V̇O2 at onset of exercise followed a monoexponential function, with a time constant of 51 ± 7 sec, typical of skeletal muscle; the average O2 cost of work was about 12 mL O2/watt/min, representing a mechanical efficiency of about 24%. At work rates of 30 or 45 watts, active muscle relied predominantly on carbohydrate, independent of insulin sensitivity within this group of very sedentary volunteers. Conclusions: The fraction of muscle fuel oxidation from fat was predicted by power output (P < 0.001) and citrate synthase activity (P < 0.05), indicating that low mitochondrial content may be the main driver of fuel choice in sedentary people, independent of insulin sensitivity.
• Garcia, L. A., Zapata-Bustos, R., Day, S. E., Campos, B., Hamzaoui, Y., Wu, L., Leon, A. D., Krentzel, J., Coletta, R. L., De Filippis, E., Roust, L. R., Mandarino, L. J., & Coletta, D. K. (2022). Can Exercise Training Alter Human Skeletal Muscle DNA Methylation?. Metabolites, 12(3).
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  Skeletal muscle is highly plastic and dynamically regulated by the body's physical demands. This study aimed to determine the plasticity of skeletal muscle DNA methylation in response to 8 weeks of supervised exercise training in volunteers with a range of insulin sensitivities. We studied 13 sedentary participants and performed euglycemic hyperinsulinemic clamps with basal vastus lateralis muscle biopsies and peak aerobic activity (VO2 peak) tests before and after training. We extracted DNA from the muscle biopsies and performed global methylation using Illumina's Methylation EPIC 850K BeadChip. Training significantly increased peak aerobic capacity and insulin-stimulated glucose disposal. Fasting serum insulin and insulin levels during the steady state of the clamp were significantly lower post-training. Insulin clearance rates during the clamp increased following the training. We identified 13 increased and 90 decreased differentially methylated cytosines (DMCs) in response to 8 weeks of training. Of the 13 increased DMCs, 2 were within the following genes, , and . Of the 90 decreased DMCs, 9 were within the genes , , , , , , , , and . Moreover, pathway analysis showed an enrichment in metabolic and actin-cytoskeleton pathways for the decreased DMCs, and for the increased DMCs, an enrichment in signal-dependent regulation of myogenesis, NOTCH2 activation and transmission, and SMAD2/3: SMAD4 transcriptional activity pathways. Our findings showed that 8 weeks of exercise training alters skeletal muscle DNA methylation of specific genes and pathways in people with varying degrees of insulin sensitivity.
• McGraw, M. B., Kohler, L. N., Shaibi, G. Q., Mandarino, L. J., & Coletta, D. K. (2022). A performance review of novel adiposity indices for assessing insulin resistance in a pediatric Latino population. Frontiers in pediatrics, 10, 1020901.
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  Body mass index (BMI) percentile or BMI adjusted for age and sex is the most common anthropometric index to monitor and assess obesity in children. However, the ability of BMI to accurately predict insulin resistance (IR) in youth is debated. Determining the best method to noninvasively measure IR in the pediatric population is especially important due to the growing prevalence of type 2 diabetes mellitus (T2DM), which is more likely to develop in people with IR. Therefore, this study analyzed the performance of BMI against newer anthropometric indices in assessing IR in a pediatric Latino identifying sample.
• Rautenberg, E. K., Hamzaoui, Y., & Coletta, D. K. (2022). Mini-review: Mitochondrial DNA methylation in type 2 diabetes and obesity. Frontiers in endocrinology, 13, 968268.
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  Type 2 diabetes (T2D) and obesity are two of the most challenging public health problems of our time. Therefore, understanding the molecular mechanisms that contribute to these complex metabolic disorders is essential. An underlying pathophysiological condition of T2D and obesity is insulin resistance (IR), a reduced biological response to insulin in peripheral tissues such as the liver, adipose tissue, and skeletal muscle. Many factors contribute to IR, including lifestyle variables such as a high-fat diet and physical inactivity, genetics, and impaired mitochondrial function. It is well established that impaired mitochondria structure and function occur in insulin-resistant skeletal muscle volunteers with T2D or obesity. Therefore, it could be hypothesized that the mitochondrial abnormalities are due to epigenetic regulation of mitochondrial and nuclear-encoded genes that code for mitochondrial structure and function. In this review, we describe the normal function and structure of mitochondria and highlight some of the key studies that demonstrate mitochondrial abnormalities in skeletal muscle of volunteers with T2D and obesity. Additionally, we describe epigenetic modifications in the context of IR and mitochondrial abnormalities, emphasizing mitochondria DNA (mtDNA) methylation, an emerging area of research.
• Standage-Beier, C. S., Ziller, S. G., Bakhshi, B., Parra, O. D., Mandarino, L. J., Kohler, L. N., & Coletta, D. K. (2022). Tools to Measure Health Literacy among Adult Hispanic Populations with Type 2 Diabetes Mellitus: A Review of the Literature. International journal of environmental research and public health, 19(19).
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  Health literacy (HL) is associated with short- and long-term health outcomes, and this is particularly relevant in Hispanics, who are disproportionally affected by lower HL. Hispanics have become the largest minority population in the United States. Also, Hispanics experience higher burdens of chronic diseases such as type 2 diabetes mellitus (T2DM) than non-Hispanic whites. Thus, effectively choosing culturally appropriate validated instruments that measure a marker found in health assessments should be a serious consideration. Using a systemized approach, we identified and reviewed 33 publications and found eight different HL and numeracy (separate or combined) instruments. We assessed the study designs and instrument structures to determine how HL was measured across these studies. We categorized the results into direct and indirect measurements of HL. The Test of Functional Health Literacy in Adults (TOFHLA) family of HL instruments was favored for direct measures of HL, while the Brief Health Literacy Screen (BHLS) instrument was favored for indirect measures. Despite identified trends in instruments used, more comprehensive measurement tools have been developed but not validated in Hispanic populations. In conclusion, further validation of more comprehensive HL instruments in adult Hispanic populations with T2DM could better assess HL levels and improve health promotion efforts.
• Coletta, D. K., Hlusko, L. J., Scott, G. R., Garcia, L. A., Vachon, C. M., Norman, A. D., Funk, J. L., Shaibi, G. Q., Hernandez, V., De Filippis, E., & Mandarino, L. J. (2021). Association of EDARV370A with breast density and metabolic syndrome in Latinos. PloS one, 16(10), e0258212.
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  The ectodysplasin receptor (EDAR) is a tumor necrosis factor receptor (TNF) superfamily member. A substitution in an exon of EDAR at position 370 (EDARV370A) creates a gain of function mutant present at high frequencies in Asian and Indigenous American populations but absent in others. Its frequency is intermediate in populations of Mexican ancestry. EDAR regulates the development of ectodermal tissues, including mammary ducts. Obesity and type 2 diabetes mellitus are prevalent in people with Indigenous and Latino ancestry. Latino patients also have altered prevalence and presentation of breast cancer. It is unknown whether EDARV370A might connect these phenomena. The goals of this study were to determine 1) whether EDARV370A is associated with metabolic phenotypes and 2) if there is altered breast anatomy in women carrying EDARV370A. Participants were from two Latino cohorts, the Arizona Insulin Resistance (AIR) registry and Sangre por Salud (SPS) biobank. The frequency of EDARV370A was 47% in the Latino cohorts. In the AIR registry, carriers of EDARV370A (GG homozygous) had significantly (p < 0.05) higher plasma triglycerides, VLDL, ALT, 2-hour post-challenge glucose, and a higher prevalence of prediabetes/diabetes. In a subset of the AIR registry, serum levels of ectodysplasin A2 (EDA-A2) also were associated with HbA1c and prediabetes (p < 0.05). For the SPS biobank, participants that were carriers of EDARV370A had lower breast density and higher HbA1c (both p < 0.05). The significant associations with measures of glycemia remained when the cohorts were combined. We conclude that EDARV370A is associated with characteristics of the metabolic syndrome and breast density in Latinos.
• Garcia, L. A., Day, S. E., Coletta, R. L., Campos, B., Benjamin, T. R., De Filippis, E., Madura, J. A., Mandarino, L. J., Roust, L. R., & Coletta, D. K. (2021). Weight loss after Roux-En-Y gastric bypass surgery reveals skeletal muscle DNA methylation changes. Clinical epigenetics, 13(1), 100.
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  The mechanisms of weight loss and metabolic improvements following bariatric surgery in skeletal muscle are not well known; however, epigenetic modifications are likely to contribute. The aim of our study was to investigate skeletal muscle DNA methylation after weight loss induced by Roux-en-Y gastric bypass (RYGB) surgery. Muscle biopsies were obtained basally from seven insulin-resistant obese (BMI > 40 kg/m) female subjects (45.1 ± 3.6 years) pre- and 3-month post-surgery with euglycemic hyperinsulinemic clamps to assess insulin sensitivity. Four lean (BMI 
• Hernandez, J. D., Li, T., Rau, C. M., LeSuer, W. E., Wang, P., Coletta, D. K., Madura, J. A., Jacobsen, E. A., & De Filippis, E. (2021). ω-3PUFA supplementation ameliorates adipose tissue inflammation and insulin-stimulated glucose disposal in subjects with obesity: a potential role for apolipoprotein E. International journal of obesity (2005), 45(6), 1331-1341.
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  Long chain omega-3 polyunsaturated fatty acids (ω-3PUFA) supplementation in animal models of diet-induced obesity has consistently shown to improve insulin sensitivity. The same is not always reported in human studies with insulin resistant (IR) subjects with obesity.
• Mandarino, L. J., De Filippis, E. A., Grandjean, D., Luo, M., Coletta, D. K., Langlais, P. R., Finlayson, J., & Zapata Bustos, R. (2021). Altered Transcription Factor Expression Responses to Exercise in Insulin Resistance. Frontiers in Physiology.
• Mandarino, L. J., Willis, W. T., Luo, M., Coletta, D. K., Zapata Bustos, R., Funk, J. L., Langlais, P. R., Barakati, N., & Finlayson, J. (2021). Site-specific acetylation of adenine nucleotide translocase 1 at lysine 23 in human muscle. Analytical biochemistry, 630, 114319.
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  Evidence suggests acetylation of human adenine nucleotide translocase 1 (ANT1) at lysine 23 (Lys23) reduces binding of ADP. Lys23 contributes to the positive charge that facilitates this interaction. This study was undertaken to characterize ANT1 abundance and acetylation by a novel method using small amounts of human skeletal muscle biopsies. Lysates of whole muscle or mitochondria from the same tissue were prepared from needle biopsies of vastus lateralis muscle of healthy volunteers. Lysed proteins were resolved on gels, the section containing ANT1 (surrounding 30 Kd) was excised, digested with trypsin, spiked with labeled unacetylated and acetylated synthetic standard peptides and analyzed by mass spectrometry. Natural logarithm transformation of data linearized ion intensities over a 10-fold range of peptide mass. Coefficients of variation ranged from 7 to 30% for ANT1 abundance and Lys23 acetylation. In three volunteers, ANT1 content was 8.36 ± 0.33 nmol/g wet weight muscle and 0.64 ± 0.05 nmol/mg mitochondria, so mitochondrial content was 13.3 ± 2.4 mg mitochondria per gram muscle. Acetylation of Lys23 averaged 14.3 ± 4.2% and 4.87 ± 1.84% in whole muscle and mitochondria, respectively. This assay makes it possible to assess effects of acetylation on the function of ANT1 in human muscle.
• Roe, J. D., Garcia, L. A., Klimentidis, Y. C., & Coletta, D. K. (2021). Association of PNPLA3 I148M with Liver Disease Biomarkers in Latinos. Human heredity, 86(1-4), 21-27.
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  Liver disease accounts for approximately 2 million deaths per year worldwide. The majority of liver diseases are due to complications of cirrhosis, viral hepatitis, and hepatocellular carcinoma. Increased levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) may indicate liver disease. Moreover, there are additional noninvasive liver fibrosis indices that help to estimate liver damage, including AST-to-ALT ratio, AST-to-platelet ratio index (APRI), fibrosis-4 (FIB-4) score, and nonalcoholic fatty liver disease (NAFLD) fibrosis score. The aims of the present study were to (1) perform an association analysis of the patatin-like phospholipase domain containing 3 (PNPLA3) I148M (rs738409) variant with ALT, AST, and various liver fibrosis indices, and (2) determine whether there are gender-related differences in these associations.
• Urashima, K., Miramontes, A., Garcia, L. A., & Coletta, D. K. (2021). Potential evidence for epigenetic biomarkers of metabolic syndrome in human whole blood in Latinos. PloS one, 16(10), e0259449.
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  Metabolic syndrome (MetS) is highly prevalent worldwide. In the United States, estimates show that more than 30% of the adult population has MetS. MetS consists of multiple phenotypes, including obesity, dyslipidemia, and impaired glucose tolerance. Therefore, identifying the molecular mechanisms to explain this complex disease is critical for diagnosing and treating MetS. We previously showed 70 increased genes and 20 decreased genes in whole blood in MetS participants. The present study aimed to identify blood-based DNA methylation biomarkers in non-MetS versus MetS participants. The present study analyzed whole blood DNA samples from 184 adult participants of Latino descent from the Arizona Insulin Resistance (AIR) registry. We used the National Cholesterol Education Program Adult Treatment Panel III (NCEP: ATP III) criteria to identify non-MetS (n = 110) and MetS (n = 74) participants. We performed whole blood methylation analysis on select genes: ATP Synthase, H+ Transporting mitochondrial F1 Complex, Epsilon Subunit (ATP5E), Cytochrome C Oxidase Subunit VIc (COX6C), and Ribosomal Protein L9 (RPL9). The pyrosequencing analysis was a targeted approach focusing on the promoter region of each gene that specifically captured CpG methylation sites. In MetS participants, we showed decreased methylation in two CpG sites in COX6C and three CpG sites in RPL9, all p < 0.05 using the Mann-Whitney U test. There were no ATP5E CpG sites differently methylated in the MetS participants. Furthermore, while adjusting for age, gender, and smoking status, logistic regression analysis reaffirmed the associations between MetS and mean methylation within COX6C and RPL9 (both p < 0.05). In addition, Spearman's correlation revealed a significant inverse relationship between the previously published gene expression data and methylation data for RPL9 (p < 0.05). In summary, these results highlight potential blood DNA methylation biomarkers for the MetS phenotype. However, future validation studies are warranted to strengthen our findings.
• Yang, C., Hallmark, B., Chai, J. C., O'Connor, T. D., Reynolds, L. M., Wood, A. C., Seeds, M., Chen, Y. I., Steffen, L. M., Tsai, M. Y., Kaplan, R. C., Daviglus, M. L., Mandarino, L. J., Fretts, A. M., Lemaitre, R. N., Coletta, D. K., Blomquist, S. A., Johnstone, L. M., Tontsch, C., , Qi, Q., et al. (2021). Impact of Amerind ancestry and FADS genetic variation on omega-3 deficiency and cardiometabolic traits in Hispanic populations. Communications biology, 4(1), 918.
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  Long chain polyunsaturated fatty acids (LC-PUFAs) have critical signaling roles that regulate dyslipidemia and inflammation. Genetic variation in the FADS gene cluster accounts for a large portion of interindividual differences in circulating and tissue levels of LC-PUFAs, with the genotypes most strongly predictive of low LC-PUFA levels at strikingly higher frequencies in Amerind ancestry populations. In this study, we examined relationships between genetic ancestry and FADS variation in 1102 Hispanic American participants from the Multi-Ethnic Study of Atherosclerosis. We demonstrate strong negative associations between Amerind genetic ancestry and LC-PUFA levels. The FADS rs174537 single nucleotide polymorphism (SNP) accounted for much of the AI ancestry effect on LC-PUFAs, especially for low levels of n-3 LC-PUFAs. Rs174537 was also strongly associated with several metabolic, inflammatory and anthropomorphic traits including circulating triglycerides (TGs) and E-selectin in MESA Hispanics. Our study demonstrates that Amerind ancestry provides a useful and readily available tool to identify individuals most likely to have FADS-related n-3 LC-PUFA deficiencies and associated cardiovascular risk.
• Hallmark, B., Coletta, D. K., Chilton, F. H., Yang, C., Rich, S. S., Manichaikul, A. W., Mandarino, L. J., Hallmark, B., Coletta, D. K., Chilton, F. H., & Blomquist, S. (2020). Abstract MP67: Fatty Acid Desaturase Gene-induced Omega-3 Deficiency In Amerindian-Ancestry Hispanic Populations. Circulation, 141(Suppl_1). doi:10.1161/circ.141.suppl_1.mp67
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  Hispanic populations in the US have increased risk of obesity, elevated circulating triglycerides, nonalcoholic fatty liver disease, and diabetes. Our previous studies suggest that ancestry-related differences in the frequency of variants in the fatty acid desaturase ( FADS) gene cluster in the context of the modern Western diet can lead to inadequate circulating and tissues levels of n-3 long-chain (LC-; ≥ 20 carbons) polyunsaturated fatty acids (PUFA); these deficiencies in turn have the capacity to increase metabolic disease risk. Specifically, we and others have demonstrated Amerindian (AI)-Ancestry populations have high frequencies of FADS gene variants that may lead to less efficient n-3 LC-PUFA biosynthesis. To test this hypothesis, concentrations of fatty acids, including LC-PUFAs in plasma phospholipids were analyzed in 1,102 Hispanic American participants from Multi-Ethnic Study of Atherosclerosis (MESA) cohort, which represent six Hispanic subgroups based on self-reported region of origin: Central America, South America, Mexico, Cuba, Dominican Republic, and Puerto Rico. These data revealed a striking inverse relationship between genome-wide AI-ancestry and levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Additional analyses revealed that the genotype at FADS SNP rs174537, for which the frequency of the T allele increases with AI-ancestry, could primarily explain the associations. There also was a strong association between the number of T alleles (additive model) at rs174537 and circulating triglycerides (18.5 mg/dL per T allele; P =2.0 x 10 -5 ) as well as an important marker of vascular inflammation sICAM-1 (β=12.7 ng/mL, P =0.02). We also genotyped the FADS SNP, rs174537, in a separate adult Arizona Hispanic cohort (Arizona Insulin Resistance [AIR] registry) and compared the FADS genotypic frequencies with other racial/ethnic groups. Importantly, the TT genotype associated with limited LC-PUFA biosynthesis ranges from
• Hallmark, B., Coletta, D. K., Chilton, F. H., Yang, C., Rich, S. S., Manichaikul, A. W., Mandarino, L. J., Hallmark, B., Coletta, D. K., Chilton, F. H., & Blomquist, S. (2020). Fatty Acid Desaturase Gene‐Induced Omega‐3 Deficiency in Amerindian‐Ancestry Hispanic Populations. The FASEB Journal, 34(S1), 1-1. doi:10.1096/fasebj.2020.34.s1.06389
• Rafikov, R., Coletta, D. K., Mandarino, L. J., & Rafikova, O. (2020). Pulmonary Arterial Hypertension Induces a Distinct Signature of Circulating Metabolites. Journal of clinical medicine, 9(1).
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  Pulmonary arterial hypertension (PAH) is an incurable, progressive disorder, and the early diagnosis and treatment of PAH are associated with increased survival [...].
• Coletta, D. K., Zhang, N., Shaibi, G. Q., Mandarino, L. J., Krell-roesch, J., Hentz, J. G., Geda, Y. E., Fonseca-portilla, R., Filippis, E. A., Dawit, S., Coletta, D. K., & Caselli, R. J. (2019). Brain-Derived Neurotrophic Factor and Its Associations with Metabolism and Physical Activity in a Latino Sample.. Metabolic syndrome and related disorders, 17(2), 75-80. doi:10.1089/met.2018.0028
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  Brain-derived neurotrophic factor (BDNF) is associated with body weight and other health conditions but remains understudied in the Latino population. The aim of this study was to examine the associations of BDNF serum levels with body mass index (BMI), physical activity, and the rs6265 nonconservative polymorphism among 349 Latinos aged ≥18 years enrolled in the Arizona Insulin Resistance Registry..Data on physical activity were acquired using a self-reported questionnaire. BDNF serum levels were measured utilizing a modified ELISA method, and the rs6265 polymorphism was genotyped by the Assay-by-Design service. Two sample t-tests or chi-squared tests were employed to compare demographics and outcomes between physically active and nonactive groups as well as between rs6265 CC and CT+TT groups..BDNF levels and rs6265 polymorphism did not differ significantly between the physically active (N = 195) and nonactive group (N = 154). Participants with the rs6265 polymorphism did not show any significant difference in BDNF levels or BMI when compared with those with the normal functional variant. Higher BDNF levels were significantly associated with higher age (r = 0.11, P = 0.04) and higher 2-hr glucose level (r = 0.11, P = 0.04)..In this cross-sectional study, the rs6265 polymorphism was not associated with a higher risk of obesity, or lower circulating levels of BDNF. Thus, the rs6265 polymorphism may have a different impact in Latinos as compared with other previously studied populations.
• Mandarino, L. J., Nair, A., Baier, L. J., Wagner, G. R., Finlayson, J., Ma, W., Mengos, A., Langlais, P. R., Coletta, D. K., Willis, W. T., & Luo, M. (2019). Deletion of the Mitochondrial Protein VWA8 Induces Oxidative Stress and an HNF4α Compensatory Response in Hepatocytes.. Biochemistry.
• Rau, C., Li, T., Hernandez, J. D., Masuda, M. Y., Zhang, X., Wang, P., Coletta, D. K., & Defilippis, E. (2019). 2102-P: Upregulation of Adipose Tissue APOE Expression by ω3PUFA Supplementation Associates with Decreased Plasma FFA Levels and Improves Insulin Sensitivity in Obese Subjects. Diabetes, 68(Supplement_1). doi:10.2337/db19-2102-p
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  Inflammation of adipose tissue (AT) is key for the development of insulin resistance (IR) in obesity. We previously showed that 3 months supplementation of fish oil (FO, 4g/day), a well-known anti-inflammatory agent, induced 25% improvement in glucose disposal during euglycemic-hyperinsulinemic clamp in 13 obese, insulin resistant subjects (ADA abstract Hernandez J., et al 2017). To explore the mechanism(s) linked to this improvement, we first performed a microarray analysis of subcutaneous (SC) AT samples pre and post FO supplementation. Functional analysis indicated anti-inflammatory pathways as the principal pathways to be enriched after FO supplementation. We identified APOE (1.87 Fold Change (FC) Post vs. Pre-FO, P=0.004) among the most significantly enhanced genes, as APOE was common to the top 5 enriched anti-inflammatory pathways. RT-PCR analysis confirmed the changes in expression levels of several genes in these pathways including APOE, APOC1, MS4A6E, MMP9, MMP7, DEFB132, C1QTNF7, and POPDC3, thereby validating the microarray findings. Plasma and SC AT RT-PCR analysis showed significantly decreased inflammatory markers (IL1B: -0.28 FC, P=0.04, MCP1: -0.44 FC, P=0.04, CD68: -0.36 FC P=0.01) post vs. pre-FO. Additionally, mRNA adiponectin levels increased (FC +0.45 Post vs. Pre, P=0.02), while leptin decreased (FC -.030 Post vs. Pre, P=0.02). Furthermore, ω3PUFA supplementation significantly reduced plasma FFA levels (Post-FO: 0.578+0.061mM vs. Pre-FO: 0.719 +0.055mM P Disclosure C. Rau: None. T. Li: None. J.D. Hernandez: None. M.Y. Masuda: None. X. Zhang: None. P. Wang: None. D.K. Coletta: None. E. DeFilippis: None. Funding Arizona Department of Health Services (14-00003606); Kathryn H. and Roger Penske Career Development Award
• Fonseca-Portilla, R., Krell-Roesch, J., Shaibi, G. Q., Caselli, R. J., Mandarino, L. J., Zhang, N., Hentz, J. G., Coletta, D. K., de Filippis, E. A., Dawit, S., & Geda, Y. E. (2018). Brain-Derived Neurotrophic Factor and Its Associations with Metabolism and Physical Activity in a Latino Sample. Metabolic syndrome and related disorders.
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  Brain-derived neurotrophic factor (BDNF) is associated with body weight and other health conditions but remains understudied in the Latino population. The aim of this study was to examine the associations of BDNF serum levels with body mass index (BMI), physical activity, and the rs6265 nonconservative polymorphism among 349 Latinos aged ≥18 years enrolled in the Arizona Insulin Resistance Registry.
• Coletta, D. K., Day, S. E., Coletta, R. L., Kim, J. Y., Garcia, L. A., Campbell, L. E., Benjamin, T. R., Roust, L. R., De Filippis, E. A., & Mandarino, L. J. (2017). Potential epigenetic biomarkers of obesity-related insulin resistance in human whole-blood. Epigenetics, 12(4), 254-263. doi:10.1080/15592294.2017.1281501
• Day, S. E., Coletta, R. L., Kim, J. Y., Garcia, L. A., Campbell, L. E., Benjamin, T. R., Roust, L. R., De Filippis, E. A., Mandarino, L. J., & Coletta, D. K. (2017). Potential Epigenetic Biomarkers of Obesity Related Insulin Resistance in Human Whole-blood. Epigenetics, 0.
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  Obesity can increase the risk of complex metabolic diseases, including insulin resistance. Moreover, obesity can be caused by environmental and genetic factors. However, the epigenetic mechanisms of obesity are not well defined. Therefore, the identification of novel epigenetic biomarkers of obesity allows for a more complete understanding of the disease and its underlying insulin resistance. The aim of our study was to identify DNA methylation changes in whole-blood that were strongly associated with obesity and insulin resistance. Whole-blood was obtained from lean (n = 10; BMI = 23.6 ± 0.7 kg/m(2)) and obese (n = 10; BMI = 34.4 ± 1.3 kg/m(2)) participants in combination with euglycemic hyperinsulinemic clamps to assess insulin sensitivity. We performed reduced representation bisulfite sequencing on genomic DNA isolated from the blood. We identified 49 differentially methylated cytosines (DMCs; q
• Day, S. E., Garcia, L. A., Coletta, R. L., Campbell, L. E., Benjamin, T. R., De Filippis, E. A., Madura, J. A., Mandarino, L. J., Roust, L. R., & Coletta, D. K. (2017). Alterations of sorbin and SH3 domain containing 3 (SORBS3) in human skeletal muscle following Roux-en-Y gastric bypass surgery. Clinical Epigenetics.
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  Obesity can increase the risk of complex metabolic diseases, including insulin resistance. Moreover, obesity can be caused by environmental and genetic factors. However, the epigenetic mechanisms of obesity are not well defined. Therefore, the identification of novel epigenetic biomarkers of obesity allows for a more complete understanding of the disease and its underlying insulin resistance. The aim of our study was to identify DNA methylation changes in whole-blood that were strongly associated with obesity and insulin resistance. Whole-blood was obtained from lean (n = 10; BMI = 23.6 ± 0.7 kg/m(2)) and obese (n = 10; BMI = 34.4 ± 1.3 kg/m(2)) participants in combination with euglycemic hyperinsulinemic clamps to assess insulin sensitivity. We performed reduced representation bisulfite sequencing on genomic DNA isolated from the blood. We identified 49 differentially methylated cytosines (DMCs; q
• Campbell, L. E., Langlais, P. R., Day, S. E., Coletta, R. L., Benjamin, T. R., De Filippis, E. A., Madura, J. A., Mandarino, L. J., Roust, L. R., & Coletta, D. K. (2016). Identification of Novel Changes in Human Skeletal Muscle Proteome After Roux-en-Y Gastric Bypass Surgery. Diabetes, 65(9), 2724-31.
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  The mechanisms of metabolic improvements after Roux-en-Y gastric bypass (RYGB) surgery are not entirely clear. Therefore, the aim of our study was to investigate the role of obesity and RYGB on the human skeletal muscle proteome. Basal muscle biopsies were obtained from seven obese (BMI >40 kg/m(2)) female subjects (45.1 ± 3.6 years) pre- and 3 months post-RYGB, and euglycemic-hyperinsulinemic clamps were used to assess insulin sensitivity. Four age-matched (48.5 ± 4.7 years) lean (BMI
• Coletta, D. K., Campbell, L. E., Weil, J., Kaplan, B., Clarkson, M., Finlayson, J., Mandarino, L. J., & Chakkera, H. A. (2016). Changes in Pre- and Post-Exercise Gene Expression among Patients with Chronic Kidney Disease and Kidney Transplant Recipients. PloS one, 11(8), e0160327.
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  Decreased insulin sensitivity blunts the normal increase in gene expression from skeletal muscle after exercise. In addition, chronic inflammation decreases insulin sensitivity. Chronic kidney disease (CKD) is an inflammatory state. How CKD and, subsequently, kidney transplantation affects skeletal muscle gene expression after exercise are unknown.
• Day, S. E., Coletta, R. L., Kim, J. Y., Campbell, L. E., Benjamin, T. R., Roust, L. R., De Filippis, E. A., Dinu, V., Shaibi, G. Q., Mandarino, L. J., & Coletta, D. K. (2016). Next-generation sequencing methylation profiling of subjects with obesity identifies novel gene changes. Clinical epigenetics, 8, 77.
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  Obesity is a metabolic disease caused by environmental and genetic factors. However, the epigenetic mechanisms of obesity are incompletely understood. The aim of our study was to investigate the role of skeletal muscle DNA methylation in combination with transcriptomic changes in obesity.
• Kim, J. Y., DeMenna, J. T., Puppala, S., Chittoor, G., Schneider, J., Duggirala, R., Mandarino, L. J., Shaibi, G. Q., & Coletta, D. K. (2016). Physical activity and FTO genotype by physical activity interactive influences on obesity. BMC genetics, 17, 47.
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  Although the effect of the fat mass and obesity-associated (FTO) gene on adiposity is well established, there is a lack of evidence whether physical activity (PA) modifies the effect of FTO variants on obesity in Latino populations. Therefore, the purpose of this study was to examine PA influences and interactive effects between FTO variants and PA on measures of adiposity in Latinos.
• Tran, L., Hanavan, P. D., Campbell, L. E., De Filippis, E., Lake, D. F., Coletta, D. K., Roust, L. R., Mandarino, L. J., Carroll, C. C., & Katsanos, C. S. (2016). Prolonged Exposure of Primary Human Muscle Cells to Plasma Fatty Acids Associated with Obese Phenotype Induces Persistent Suppression of Muscle Mitochondrial ATP Synthase β Subunit. PloS one, 11(8), e0160057.
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  Our previous studies show reduced abundance of the β-subunit of mitochondrial H+-ATP synthase (β-F1-ATPase) in skeletal muscle of obese individuals. The β-F1-ATPase forms the catalytic core of the ATP synthase, and it is critical for ATP production in muscle. The mechanism(s) impairing β-F1-ATPase metabolism in obesity, however, are not completely understood. First, we studied total muscle protein synthesis and the translation efficiency of β-F1-ATPase in obese (BMI, 36±1 kg/m2) and lean (BMI, 22±1 kg/m2) subjects. Both total protein synthesis (0.044±0.006 vs 0.066±0.006%·h-1) and translation efficiency of β-F1-ATPase (0.0031±0.0007 vs 0.0073±0.0004) were lower in muscle from the obese subjects when compared to the lean controls (P
• Coletta, D. K., Fernandez, M., Cersosimo, E., Gastaldelli, A., Musi, N., & Defronzo, R. A. (2015). The effect of muraglitazar on adiponectin signalling, mitochondrial function and fat oxidation genes in human skeletal muscle in vivo.. Diabetic medicine : a journal of the British Diabetic Association, 32(5), 657-64. doi:10.1111/dme.12664
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  The molecular mechanisms by which muraglitazar (peroxisome proliferator-activated receptor γ/α agonist) improves insulin sensitivity in Type 2 diabetes mellitus are not fully understood. We hypothesized that muraglitazar would increase expression of 5'-monophosphate-activated protein kinase and genes involved in adiponectin signalling, free fatty acid oxidation and mitochondrial function in skeletal muscle..Sixteen participants with Type 2 diabetes received muraglitazar, 5 mg/day (n = 12) or placebo (n = 4). Before and after 16 weeks, participants had vastus lateralis muscle biopsy followed by 180 min euglycaemic hyperinsulinaemic clamp..Muraglitazar increased plasma adiponectin (9.0 ± 1.1 to 17.8 ± 1.5 μg/ml, P 
• Coletta, D. K., Tran, L., Mandarino, L. J., Katsanos, C. S., Coletta, D. K., & Campbell, L. (2015). Skeletal Muscle β-F1-ATPase Translation is Inhibited by Hyperlipidemia-Induced miR-127-5p Expression in Human Obesity. The FASEB Journal, 29(S1). doi:10.1096/fasebj.29.1_supplement.974.6
• Gonzalez-Garcia, Z. M., Kullo, I. J., Coletta, D. K., Mandarino, L. J., & Shaibi, G. Q. (2015). Osteocalcin and Type 2 Diabetes Risk in Latinos: A life course approach.. AMERICAN JOURNAL OF HUMAN BIOLOGY, 27(6), 859-861.
• González-García, Z. M., Kullo, I. J., Coletta, D. K., Mandarino, L. J., & Shaibi, G. Q. (2015). Osteocalcin and type 2 diabetes risk in Latinos: a life course approach. American journal of human biology : the official journal of the Human Biology Council, 27(6), 859-61.
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  To examine associations between circulating levels of the bone-derived protein osteocalcin (OC) and type 2 diabetes (T2D) risk in Latino children and adults.
• Kim, J. Y., Campbell, L. E., Shaibi, G. Q., & Coletta, D. K. (2015). Gene expression profiling and association of circulating lactoferrin level with obesity-related phenotypes in Latino youth.. Pediatric obesity, 10(5), 338-44. doi:10.1111/ijpo.269
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  Low-grade inflammation is an underlying feature of obesity and identifying inflammatory markers is crucial to understanding this disease. Therefore, the purpose of this study was twofold: (i) to perform a global microarray analysis and (ii) to investigate the role of lactoferrin (LTF), one of the most altered genes, in relation to obesity in Latino youth..Non-diabetic Latino youth (71 males/92 females; 15.6 ± 3.2 years) were studied. A subset of 39 participants was randomly selected for global microarray analysis profiling from the whole blood sample. Serum LTF was compared between lean (n = 78) and overweight/obese (n = 85) participants..Microarray analysis revealed that a total of 1870 probes were altered in expression ≥1.2-fold and P 
• McLean, C. S., Mielke, C., Cordova, J. M., Langlais, P. R., Bowen, B., Miranda, D., Coletta, D. K., & Mandarino, L. J. (2015). Gene and MicroRNA Expression Responses to Exercise; Relationship with Insulin Sensitivity. PloS one, 10(5), e0127089.
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  Healthy individuals on the lower end of the insulin sensitivity spectrum also have a reduced gene expression response to exercise for specific genes. The goal of this study was to determine the relationship between insulin sensitivity and exercise-induced gene expression in an unbiased, global manner.
• Winnier, D. A., Fourcaudot, M., Norton, L., Abdul-Ghani, M. A., Hu, S. L., Farook, V. S., Coletta, D. K., Kumar, S., Puppala, S., Chittoor, G., Dyer, T. D., Arya, R., Carless, M., Lehman, D. M., Curran, J. E., Cromack, D. T., Tripathy, D., Blangero, J., Duggirala, R., , Göring, H. H., et al. (2015). Transcriptomic identification of ADH1B as a novel candidate gene for obesity and insulin resistance in human adipose tissue in Mexican Americans from the Veterans Administration Genetic Epidemiology Study (VAGES). PloS one, 10(4), e0119941.
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  Type 2 diabetes (T2D) is a complex metabolic disease that is more prevalent in ethnic groups such as Mexican Americans, and is strongly associated with the risk factors obesity and insulin resistance. The goal of this study was to perform whole genome gene expression profiling in adipose tissue to detect common patterns of gene regulation associated with obesity and insulin resistance. We used phenotypic and genotypic data from 308 Mexican American participants from the Veterans Administration Genetic Epidemiology Study (VAGES). Basal fasting RNA was extracted from adipose tissue biopsies from a subset of 75 unrelated individuals, and gene expression data generated on the Illumina BeadArray platform. The number of gene probes with significant expression above baseline was approximately 31,000. We performed multiple regression analysis of all probes with 15 metabolic traits. Adipose tissue had 3,012 genes significantly associated with the traits of interest (false discovery rate, FDR ≤ 0.05). The significance of gene expression changes was used to select 52 genes with significant (FDR ≤ 10(-4)) gene expression changes across multiple traits. Gene sets/Pathways analysis identified one gene, alcohol dehydrogenase 1B (ADH1B) that was significantly enriched (P < 10(-60)) as a prime candidate for involvement in multiple relevant metabolic pathways. Illumina BeadChip derived ADH1B expression data was consistent with quantitative real time PCR data. We observed significant inverse correlations with waist circumference (2.8 x 10(-9)), BMI (5.4 x 10(-6)), and fasting plasma insulin (P < 0.001). These findings are consistent with a central role for ADH1B in obesity and insulin resistance and provide evidence for a novel genetic regulatory mechanism for human metabolic diseases related to these traits.
• Coletta, D. K. (2014). Association of Common Genetic Variants with Diabetes and Metabolic Syndrome Related Traits in the Arizona Insulin Resistance Registry: A Focus on Mexican American Families in the Southwest. Hum Hered.
• Coletta, D. K. (2014). Gene expression profiling and association of circulating lactoferrin level with obesity-related phenotypes in Latino youth. Pediatric Obesity.
• Coletta, D. K. (2014). The effect of muraglitazar on adiponectin signalling, mitochondrial function and fat oxidation genes in human skeletal muscle in vivo. Diabet. Med..
• DeMenna, J., Puppala, S., Chittoor, G., Schneider, J., Kim, J. Y., Shaibi, G. Q., Mandarino, L. J., Duggirala, R., & Coletta, D. K. (2014). Association of common genetic variants with diabetes and metabolic syndrome related traits in the Arizona Insulin Resistance registry: a focus on Mexican American families in the Southwest. Human heredity, 78(1), 47-58.
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  The increased occurrence of type 2 diabetes and its clinical correlates is a global public health issue, and there are continued efforts to find its genetic determinant across ethnically diverse populations. The aims of this study were to determine the heritability of diabetes and metabolic syndrome phenotypes in the Arizona Insulin Resistance (AIR) registry and to perform an association analysis of common single nucleotide polymorphisms (SNPs) identified by GWAS with these traits. All study participants were Mexican Americans from the AIR registry.
• Miranda, D. N., Coletta, D. K., Mandarino, L. J., & Shaibi, G. Q. (2014). Increases in insulin sensitivity among obese youth are associated with gene expression changes in whole blood. Obesity (Silver Spring, Md.), 22(5), 1337-44.
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  Lifestyle intervention can improve insulin sensitivity in obese youth, yet few studies have examined the molecular signatures associated with these improvements. Therefore, the purpose of this study was to explore gene expression changes in whole blood that are associated with intervention-induced improvements in insulin sensitivity.
• Coletta, D. K. (2013). Linkage of Type 2 Diabetes on Chromosome 9p24 in Mexican Americans: Additional Evidence from the Veterans Administration Genetic Epidemiology Study (VAGES). Hum Hered.
• Coletta, D. K. (2013). Whole Blood Gene Expression Profiles in Insulin Resistant Latinos with the Metabolic Syndrome. PLoS ONE.
• Farook, V. S., Coletta, D. K., Puppala, S., Schneider, J., Chittoor, G., Hu, S. L., Winnier, D. A., Norton, L., Dyer, T. D., Arya, R., Cole, S. A., Carless, M., Göring, H. H., Almasy, L., Mahaney, M. C., Comuzzie, A. G., Curran, J. E., Blangero, J., Duggirala, R., , Lehman, D. M., et al. (2013). Linkage of type 2 diabetes on chromosome 9p24 in Mexican Americans: additional evidence from the Veterans Administration Genetic Epidemiology Study (VAGES). Human heredity, 76(1), 36-46.
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  Type 2 diabetes (T2DM) is a complex metabolic disease and is more prevalent in certain ethnic groups such as the Mexican Americans. The goal of our study was to perform a genome-wide linkage (GWL) analysis to localize T2DM susceptibility loci in Mexican Americans.
• Mandarino, L. J., Vital, V., Coletta, D. K., & Shaibi, G. Q. (2013). The Design and Conduct of a Community-Based Registry and Biorepository: A Focus on Cardiometabolic Health in Latinos: Arizona Insulin Resistance Registry and Repository. Clinical and Translational Science, 6(6), 429-434. doi:10.1111/cts.12114
• Shaibi, G. Q., Coletta, D. K., Vital, V., & Mandarino, L. J. (2013). The design and conduct of a community-based registry and biorepository: a focus on cardiometabolic health in Latinos. Clinical and translational science, 6(6), 429-34.
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  Latinos are disproportionately impacted by obesity and type 2 diabetes but remain underrepresented in biomedical research. Therefore, the purpose of this project was to develop a research registry and biorepository to examine cardiometabolic disease risk in the Latino community of Phoenix, Arizona. The overarching goal was to establish the research infrastructure that would encourage transdisciplinary research regarding the biocultural mechanisms of obesity-related health disparities and facilitate access to this research for the Latino community.
• Tangen, S. E., Tsinajinnie, D., Nuñez, M., Shaibi, G. Q., Mandarino, L. J., & Coletta, D. K. (2013). Whole blood gene expression profiles in insulin resistant Latinos with the metabolic syndrome. PloS one, 8(12), e84002.
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  Although insulin resistance in skeletal muscle is well-characterized, the role of circulating whole blood in the metabolic syndrome phenotype is not well understood. We set out to test the hypothesis that genes involved in inflammation, insulin signaling and mitochondrial function would be altered in expression in the whole blood of individuals with metabolic syndrome. We further wanted to examine whether similar relationships that we have found previously in skeletal muscle exist in peripheral whole blood cells. All subjects (n=184) were Latino descent from the Arizona Insulin Resistance registry. Subjects were classified based on the metabolic syndrome phenotype according to the National Cholesterol Education Program's Adult Treatment Panel III. Of the 184 Latino subjects in the study, 74 were classified with the metabolic syndrome and 110 were without. Whole blood gene expression profiling was performed using the Agilent 4x44K Whole Human Genome Microarray. Whole blood microarray analysis identified 1,432 probes that were altered in expression ≥ 1.2 fold and P
• Coletta, D. K. (2012). Glucose Response Curve and Type 2 Diabetes Risk in Latino Adolescents. Diabetes Care.
• Kim, J. Y., Coletta, D. K., Mandarino, L. J., & Shaibi, G. Q. (2012). Glucose response curve and type 2 diabetes risk in Latino adolescents. Diabetes care, 35(9), 1925-30.
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  In adults, the shape of the glucose response during an oral glucose tolerance test (OGTT) prospectively and independently predicts type 2 diabetes. However, no reports have described the utility of this indicator in younger populations. The purpose of this study was to compare type 2 diabetes risk factors in Latino adolescents characterized by either a monophasic or biphasic glucose response during an OGTT.
• Coletta, D. K., & Mandarino, L. J. (2011). Mitochondrial dysfunction and insulin resistance from the outside in: extracellular matrix, the cytoskeleton, and mitochondria. American journal of physiology. Endocrinology and metabolism, 301(5), E749-55.
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  Insulin resistance in skeletal muscle is a prominent feature of obesity and type 2 diabetes. The association between mitochondrial changes and insulin resistance is well known. More recently, there is growing evidence of a relationship between inflammation, extracellular remodeling, and insulin resistance. The intent of this review is to propose a potentially novel mechanism for the development of insulin resistance, focusing on the underappreciated connections among inflammation, extracellular remodeling, cytoskeletal interactions, mitochondrial function, and insulin resistance in human skeletal muscle. Several sources of inflammation, including expansion of adipose tissue resulting in increased lipolysis and alterations in pro- and anti-inflammatory cytokines, contribute to the insulin resistance observed in obesity and type 2 diabetes. In the experimental model of lipid oversupply, an inflammatory response in skeletal muscle leads to altered expression extracellular matrix-related genes as well as nuclear encoded mitochondrial genes. A similar pattern also is observed in "naturally" occurring insulin resistance in muscle of obese nondiabetic individuals and patients with type 2 diabetes mellitus. More recently, alterations in proteins (including α-actinin-2, desmin, proteasomes, and chaperones) involved in muscle structure and function have been observed in insulin-resistant muscle. Some of these cytoskeletal proteins are mechanosignal transducers that allow muscle fibers to sense contractile activity and respond appropriately. The ensuing alterations in expression of genes coding for mitochondrial proteins and cytoskeletal proteins may contribute to the mitochondrial changes observed in insulin-resistant muscle. These changes in turn may lead to a reduction in fat oxidation and an increase in intramyocellular lipid, which contributes to the defects in insulin signaling in insulin resistance.
• Puppala, S., Coletta, D. K., Schneider, J., Hu, S. L., Farook, V. S., Dyer, T. D., Arya, R., Blangero, J., Duggirala, R., DeFronzo, R. A., & Jenkinson, C. P. (2011). Genome-wide linkage screen for systolic blood pressure in the Veterans Administration Genetic Epidemiology Study (VAGES) of Mexican-Americans and confirmation of a major susceptibility locus on chromosome 6q14.1. Human heredity, 71(1), 1-10.
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  Hypertension or high blood pressure is a strong correlate of diseases such as obesity and type 2 diabetes. We conducted a genome-wide linkage screen to identify susceptibility genes influencing systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Mexican-Americans from the Veterans Administration Genetic Epidemiology Study (VAGES).
• Bajaj, M., Baig, R., Suraamornkul, S., Hardies, L. J., Coletta, D. K., Cline, G. W., Monroy, A., Koul, S., Sriwijitkamol, A., Musi, N., Shulman, G. I., & DeFronzo, R. A. (2010). Effects of pioglitazone on intramyocellular fat metabolism in patients with type 2 diabetes mellitus. The Journal of clinical endocrinology and metabolism, 95(4), 1916-23.
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  Lipotoxicity (increased tissue fat content) has been implicated in the development of muscle insulin resistance and type 2 diabetes mellitus (T2DM).
• Chavez, A. O., Kamath, S., Jani, R., Sharma, L. K., Monroy, A., Abdul-Ghani, M. A., Centonze, V. E., Sathyanarayana, P., Coletta, D. K., Jenkinson, C. P., Bai, Y., Folli, F., Defronzo, R. A., & Tripathy, D. (2010). Effect of short-term free Fatty acids elevation on mitochondrial function in skeletal muscle of healthy individuals. The Journal of clinical endocrinology and metabolism, 95(1), 422-9.
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  Mitochondrial dysfunction has been proposed as an underlying mechanism in the pathogenesis of insulin resistance and type 2 diabetes mellitus.
• Coletta, D. K. (2010). Effect of Short-Term Free Fatty Acids Elevation on Mitochondrial Function in Skeletal Muscle of Healthy Individuals. The Journal of Clinical Endocrinology & Metabolism.
• Coletta, D. K. (2010). Proteomics Reveals Novel Oxidative and Glycolytic Mechanisms in Type 1 Diabetic Patients' Skin Which Are Normalized by Kidney-Pancreas Transplantation. PLoS ONE.
• Folli, F., Guzzi, V., Perego, L., Coletta, D. K., Finzi, G., Placidi, C., La Rosa, S., Capella, C., Socci, C., Lauro, D., Tripathy, D., Jenkinson, C., Paroni, R., Orsenigo, E., Cighetti, G., Gregorini, L., Staudacher, C., Secchi, A., Bachi, A., , Brownlee, M., et al. (2010). Proteomics reveals novel oxidative and glycolytic mechanisms in type 1 diabetic patients' skin which are normalized by kidney-pancreas transplantation. PloS one, 5(3), e9923.
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  In type 1 diabetes (T1D) vascular complications such as accelerated atherosclerosis and diffused macro-/microangiopathy are linked to chronic hyperglycemia with a mechanism that is not yet well understood. End-stage renal disease (ESRD) worsens most diabetic complications, particularly, the risk of morbidity and mortality from cardiovascular disease is increased several fold.
• Chavez, A. O., Coletta, D. K., Kamath, S., Cromack, D. T., Monroy, A., Folli, F., DeFronzo, R. A., & Tripathy, D. (2009). Retinol-binding protein 4 is associated with impaired glucose tolerance but not with whole body or hepatic insulin resistance in Mexican Americans. American journal of physiology. Endocrinology and metabolism, 296(4), E758-64.
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  Retinol-binding protein-4 (RBP4), a novel protein secreted mainly by adipose tissue, has been associated with insulin resistance in obese subjects and in individuals with type 2 diabetes mellitus (T2DM). We examined the relationship between plasma RBP4 levels, expression of RBP4 in skeletal muscle and adipose tissue, and insulin sensitivity in Mexican Americans with varying degrees of obesity and glucose tolerance. Seventy-two subjects [16 lean normal-glucose-tolerant (NGT), 17 obese NGT, and 39 subjects with impaired fasting glucose/impaired glucose tolerance/T2DM] received an oral glucose tolerance test (OGTT) and euglycemic-hyperinsulinemic clamp. Insulin secretion was measured as insulinogenic index during OGTT. In a subset of subjects, hepatic glucose production was measured by 3-[3H]glucose infusion, biopsies of the vastus lateralis muscle and subcutaneous adipose tissue were obtained under basal conditions, and quantitative RT-PCR was performed to measure the RBP4 mRNA gene expression. Plasma RBP4 was significantly elevated in impaired glucose tolerance/T2DM compared with NGT lean or obese subjects. Plasma RBP4 levels correlated with 2-h glucose, triglycerides, and hemoglobin A1c. There was no association between RBP4 levels and whole body insulin sensitivity measured with either the euglycemic insulin clamp or OGTT, basal hepatic glucose production rates, and the hepatic insulin resistance index. There was no correlation between plasma RBP4 levels and indexes of insulin secretion. RBP4 mRNA expression in skeletal muscle was similar in lean NGT subjects, obese NGT subjects, and T2DM subjects. There was no difference in RBP4 mRNA expression in adipose tissue between lean and obese NGT subjects or between NGT and T2DM individuals. Plasma RBP4 levels are elevated in T2DM and associated with impaired glucose tolerance, but not associated with obesity or insulin resistance or impaired insulin secretion in Mexican Americans.
• Coletta, D. K. (2009). Impaired regulation of the TNF-α converting enzyme/tissue inhibitor of metalloproteinase 3 proteolytic system in skeletal muscle of obese type 2 diabetic patients: a new mechanism of insulin resistance in humans. Diabetologia.
• Coletta, D. K. (2009). Pioglitazone stimulates AMP-activated protein kinase signalling and increases the expression of genes involved in adiponectin signalling, mitochondrial function and fat oxidation in human skeletal muscle in vivo: a randomised trial. Diabetologia.
• Coletta, D. K., Schneider, J., Hu, S. L., Dyer, T. D., Puppala, S., Farook, V. S., Arya, R., Lehman, D. M., Blangero, J., DeFronzo, R. A., Duggirala, R., & Jenkinson, C. P. (2009). Genome-wide linkage scan for genes influencing plasma triglyceride levels in the Veterans Administration Genetic Epidemiology Study. Diabetes, 58(1), 279-84.
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  Elevated plasma triglyceride concentration is a component of the insulin resistance syndrome and is commonly associated with type 2 diabetes, obesity, and coronary heart disease. The goal of our study was to perform a genome-wide linkage scan to identify genetic regions that influence variation in plasma triglyceride levels in families that are enriched with individuals with type 2 diabetes.
• Abdul-Ghani, M. A., Matsuda, M., Jani, R., Jenkinson, C. P., Coletta, D. K., Kaku, K., & DeFronzo, R. A. (2008). The relationship between fasting hyperglycemia and insulin secretion in subjects with normal or impaired glucose tolerance. American journal of physiology. Endocrinology and metabolism, 295(2), E401-6.
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  To assess the relationship between the fasting plasma glucose (FPG) concentration and insulin secretion in normal glucose tolerance (NGT) and impaired glucose tolerance (IGT) subjects, 531 nondiabetic subjects with NGT (n = 293) and IGT (n = 238; 310 Japanese and 232 Mexican Americans) received an oral glucose tolerance test (OGTT) with measurement of plasma glucose, insulin, and C-peptide every 30 min. The insulin secretion rate was determined by plasma C-peptide deconvolution. Insulin sensitivity (Matsuda index) was measured from plasma insulin and glucose concentrations. The insulin secretion/insulin resistance (IS/IR) or disposition index was calculated as DeltaISR/DeltaG / IR. As FPG increased in NGT subjects, the IS/IR index declined exponentially over the range of FPG from 70 to 125 mg/dl. The relationship between the IS/IR index and FPG was best fit with the equation: 28.8 exp(-0.036 FPG). For every 28 mg/dl increase in FPG, the IS/IR index declined by 63%. A similar relationship between IS/IR index and FPG was observed in IGT. However, the decay constant was lower than in NGT. The IS/IR index for early-phase insulin secretion (0-30 min) was correlated with the increase in FPG in both NGT and IGT (r = -0.43, P < 0.0001 and r = -0.20, P = 0.001, respectively). However, the correlation between late-phase insulin secretion (60-120 min) and FPG was not significant. In conclusion, small increments in FPG, within the "normal" range, are associated with a marked decline in glucose-stimulated insulin secretion and the decrease in insulin secretion with increasing FPG is greater in subjects with NGT than IGT and primarily is due to a decline in early-phase insulin secretion.
• Coletta, D. K. (2008). Effect of acute physiological hyperinsulinemia on gene expression in human skeletal muscle in vivo. AJP: Endocrinology and Metabolism.
• Coletta, D. K. (2008). The relationship between fasting hyperglycemia and insulin secretion in subjects with normal or impaired glucose tolerance. AJP: Endocrinology and Metabolism.
• Coletta, D. K., Fernandez, M., Tantiwong, P., Jenkinson, C. P., Musi, N., Cersosimo, E., & Defronzo, R. A. (2008). Muraglitazar Increases the Expression of Genes Involved in Mitochondrial Function and Fat Oxidation in Human Skeletal Muscle in vivo. DIABETES, 57, A371-A371.
• Coletta, D. K., Yi, Z., Bowen, B. P., Hwang, H., Jenkinson, C. P., Lefort, N., Bajaj, M., Kashyap, S., Berria, R., De Filippis, E. A., & Mandarino, L. J. (2008). Global Relationship between the Proteome and Transcriptome of Human Skeletal Muscle. Journal of Proteome Research, 7(8), 3230-3241. doi:10.1021/pr800064s
• Jenkinson, C. P., Coletta, D. K., Flechtner-Mors, M., Hu, S. L., Fourcaudot, M. J., Rodriguez, L. M., Schneider, J., Arya, R., Stern, M. P., Blangero, J., Duggirala, R., & DeFronzo, R. A. (2008). Association of genetic variation in ENPP1 with obesity-related phenotypes. Obesity (Silver Spring, Md.), 16(7), 1708-13.
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  Ectonucleotide pyrophosphatase phosphodiesterase (ENPP1) is a positional candidate gene at chromosome 6q23 where we previously detected strong linkage with fasting-specific plasma insulin and obesity in Mexican Americans from the San Antonio Family Diabetes Study (SAFDS). We genotyped 106 single-nucleotide polymorphisms (SNPs) within ENPP1 in all 439 subjects from the linkage study, and measured association with obesity and metabolic syndrome (MS)-related traits. Of 72 polymorphic SNPs, 24 were associated, using an additive model, with at least one of eight key metabolic traits. Three traits were associated with at least four SNPs. They were high-density lipoprotein cholesterol (HDL-C), leptin, and fasting plasma glucose (FPG). HDL-C was associated with seven SNPs, of which the two most significant P values were 0.0068 and 0.0096. All SNPs and SNP combinations were analyzed for functional contribution to the traits using the Bayesian quantitative-trait nucleotide (BQTN) approach. With this SNP-prioritization analysis, HDL-C was the most strongly associated trait in a four-SNP model (P=0.00008). After accounting for multiple testing, we conclude that ENPP1 is not a major contributor to our previous linkage peak with MS-related traits in Mexican Americans. However, these results indicate that ENPP1 is a genetic determinant of these traits in this population, and are consistent with multiple positive association findings in independent studies in diverse human populations.
• Reyna, S. M., Ghosh, S., Tantiwong, P., Meka, C. S., Eagan, P., Jenkinson, C. P., Cersosimo, E., Defronzo, R. A., Coletta, D. K., Sriwijitkamol, A., & Musi, N. (2008). Elevated toll-like receptor 4 expression and signaling in muscle from insulin-resistant subjects. Diabetes, 57(10), 2595-602.
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  OBJECTIVE- Tall-like receptor (TLR)4 has been implicated in the pathogenesis of free fatty acid (FFA)-induced insulin resistance by activating inflammatory pathways, including inhibitor of kappaB (IkappaB)/nuclear factor kappaB (NFkappaB). However, it is not known whether insulin-resistant subjects have abnormal TLR4 signaling. We examined whether insulin-resistant subjects have abnormal TLR4 expression and TLR4-driven (IkappaB/NFkappaB) signaling in skeletal muscle. RESEARCH DESIGN AND METHODS- TLR4 gene expression and protein content were measured in muscle biopsies in 7 lean, 8 obese, and 14 type 2 diabetic subjects. A primary human myotube culture system was used to examine whether FFAs stimulate IkappaB/NFkappaB via TLR4 and whether FFAs increase TLR4 expression/content in muscle. RESULTS- Obese and type 2 diabetic subjects had significantly elevated TLR4 gene expression and protein content in muscle. TLR4 muscle protein content correlated with the severity of insulin resistance. Obese and type 2 diabetic subjects also had lower IkappaBalpha content, an indication of elevated IkappaB/NFkappaB signaling. The increase in TLR4 and NFkappaB signaling was accompanied by elevated expression of the NFkappaB-regulated genes interleukin (IL)-6 and superoxide dismutase (SOD)2. In primary human myotubes, acute palmitate treatment stimulated IkappaB/NFkappaB, and blockade of TLR4 prevented the ability of palmitate to stimulate the IkappaB/NFkappaB pathway. Increased TLR4 content and gene expression observed in muscle from insulin-resistant subjects were reproduced by treating myotubes from lean, normal-glucose-tolerant subjects with palmitate. Palmitate also increased IL-6 and SOD2 gene expression, and this effect was prevented by inhibiting NFkappaB. CONCLUSIONS- Abnormal TLR4 expression and signaling, possibly caused by elevated plasma FFA levels, may contribute to the pathogenesis of insulin resistance in humans.
• Yi, Z., Bowen, B. P., Hwang, H., Jenkinson, C. P., Coletta, D. K., Lefort, N., Bajaj, M., Kashyap, S., Berria, R., De Filippis, E. A., & Mandarino, L. J. (2008). Global relationship between the proteome and transcriptome of human skeletal muscle. Journal of proteome research, 7(8), 3230-41.
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  Skeletal muscle is one of the largest tissues in the human body. Changes in mRNA and protein abundance in this tissue are central to a large number of metabolic and other disorders, including, commonly, insulin resistance. Proteomic and microarray analyses are important approaches for gaining insight into the molecular and biochemical basis for normal and pathophysiological conditions. With the use of vastus lateralis muscle obtained from two groups of healthy, nonobese subjects, we performed a detailed comparison of the muscle proteome, obtained by HPLC-ESI-MS/MS, with the muscle transcriptome, obtained using oligonucleotide microarrays. HPLC-ESI-MS/MS analysis identified 507 unique proteins as present in four out of six subjects, while 5193 distinct transcripts were called present by oligonucleotide microarrays from four out of six subjects. The majority of the proteins identified by mass spectrometry also had their corresponding transcripts detected by microarray analysis, although 73 proteins were only identified in the proteomic analysis. Reflecting the high abundance of mitochondria in skeletal muscle, 30% of proteins detected were attributed to the mitochondrion, as compared to only 9% of transcripts. On the basis of Gene Ontology annotations, proteins assigned to mitochondrial inner membrane, mitochondrial envelope, structural molecule activity, electron transport, as well as generation of precursor metabolites and energy, had more corresponding transcripts detected than would be expected by chance. On the contrary, proteins assigned to Golgi apparatus, extracellular region, lyase activity, kinase activity, and protein modification process had fewer corresponding transcripts detected than would be expected by chance. In conclusion, these results provide the first global comparison of the human skeletal muscle proteome and transcriptome to date. These data show that a combination of proteomic and transcriptic analyses will provide data that can be used to test hypotheses regarding the pathogenesis of muscle disorders as well as to generate observational data that can be used to form novel hypotheses.
• Coletta, D. K. (2007). Effect of Acute Exercise on AMPK Signaling in Skeletal Muscle of Subjects With Type 2 Diabetes: A Time-Course and Dose-Response Study. Diabetes.
• Coletta, D. K. (2007). P2 Promoter Variants of the Hepatocyte Nuclear Factor 4  Gene Are Associated With Type 2 Diabetes in Mexican Americans. Diabetes.
• Coletta, D. K. (2007). The relative contributions of insulin resistance and beta cell failure to the transition from normal to impaired glucose tolerance varies in different ethnic groups. Diabetes & Metabolic Syndrome: Clinical Research & Reviews.
• Coletta, D. K., Schneider, J., Stern, M. P., Blangero, J., DeFronzo, R. A., Duggirala, R., & Jenkinson, C. P. (2007). Association of neuropeptide Y receptor Y5 polymorphisms with dyslipidemia in Mexican Americans. OBESITY, 15(4), 809-815.
• Berria, R., Wang, L., Richardson, D., Finlayson, J., Belfort, R., Pratipanawatr, T., De Filippis, E., Kashyap, S., & Mandarino, L. (2006). Increased collagen content in insulin-resistant skeletal muscle. American Journal of Physiology - Endocrinology and Metabolism, 290(3). doi:10.1152/ajpendo.00202.2005
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  Oversupply and underutilization of lipid fuels are widely recognized to be strongly associated with insulin resistance in skeletal muscle. Recent attention has focused on the mechanisms underlying this effect, and defects in mitochondrial function have emerged as a potential player in this scheme. Because evidence indicates that lipid oversupply can produce abnormalities in extracellular matrix composition and matrix changes can affect the function of mitochondria, the present study was undertaken to determine whether muscle from insulin-resistant, nondiabetic obese subjects and patients with type 2 diabetes mellitus had increased collagen content. Compared with lean control subjects, obese and type 2 diabetic subjects had reduced muscle glucose uptake (P < 0.01) and decreased insulin stimulation of tyrosine phosphorylation of insulin receptor substrate-1 and its ability to associate with phosphatidylinositol 3-kinase (P < 0.01 and P < 0.05). Because it was assayed by total hydroxyproline content, collagen abundance was increased in muscle from not only type 2 diabetic patients but also nondiabetic obese subjects (0.26 ± 0.05, 0.57 ± 0.18, and 0.67 ± 0.20 μg/mg muscle wet wt, lean controls, obese nondiabetics, and type 2 diabetics, respectively), indicating that hyperglycemia itself could not be responsible for this effect. Immunofluorescence staining of muscle biopsies indicated that there was increased abundance of types I and III collagen. We conclude that changes in the composition of the extracellular matrix are a general characteristic of insulin-resistant muscle. Copyright © 2006 the American Physiological Society.
• Coletta, D. K. (2006). Association between variants in the genes for adiponectin and its receptors with insulin resistance syndrome (IRS)-related phenotypes in Mexican Americans. Diabetologia.
• Coletta, D. K. (2006). Insulin Secretion and Action in Subjects With Impaired Fasting Glucose and Impaired Glucose Tolerance: Results From the Veterans Administration Genetic Epidemiology Study. Diabetes.
• Coletta, D. K. (2006). The Primary Amine Metabolite of Sibutramine Stimulates Lipolysis in Adipocytes Isolated from Lean and Obese Mice and in Isolated Human Adipocytes. Horm Metab Res.
• Coletta, D. K. (2006). The sibutramine metabolite M2 improves muscle glucose uptake and reduces hepatic glucose output: preliminary data.. Diab Vasc Dis Res.
• Coletta, D. K. (2005). Increased collagen content in insulin-resistant skeletal muscle. AJP: Endocrinology and Metabolism.
• Coletta, D. K. (2005). Lipid Infusion Decreases the Expression of Nuclear Encoded Mitochondrial Genes and Increases the Expression of Extracellular Matrix Genes in Human Skeletal Muscle. Journal of Biological Chemistry.
• Coletta, D. K. (2005). The quantitative trait linkage disequilibrium test: a more powerful alternative to the quantitative transmission disequilibrium test for use in the absence of population stratification. BMC Genet.
• Coletta, D. K. (2004). Adiponectin receptors gene expression and insulin sensitivity in non-diabetic Mexican Americans with or without a family history of Type 2 diabetes. Diabetologia.

Proceedings Publications

• Garcia, J., Coletta, D., Sun, X., Lynn, H., Casanova, N., Karnes, J., Camp, S., & Ellid, N. (2020). Nicotinamide Phosphoribosyl Transferase (NAMPT) Genotype-Phenotype Haplotype and Elevated Extracellular NAMPT Levels Predict Mortality Outcomes in Acute Respiratory Distress Syndrome (ARDS). In American Thoracic Society International.
• Rafikov, R., Mandarino, L., Coletta, D., & Rafikova, O. (2020). Pulmonary Arterial Hypertension Induces a Distinct Signature of Circulating Metabolites. In Conference.
• Garcia, J., Sun, X., Coletta, D., Casanova, N., Lynn, H., Bime, C., & Gonzales Ganay, M. (2019). The mTOR Pathway Genes Are Differentially Methylated in African- and Hispanic- Americans Who Fail to Survive Acute Respiratory Distress Syndrome (ARDS). In American Thoracic Society.

Presentations

• Coletta, D. K. (2024, April). Obesity and Type 2 Diabetes Mellitus: Insights from Skeletal Muscle Extracellular Matrix Remodeling. COM-T Research Day. Tucson, AZ.
• Coletta, D. K. (2024, August). Obesity and Type 2 Diabetes Mellitus: Insights from Skeletal Muscle Extracellular Matrix Remodeling. Arizona Diabetes Initiative Club. Tucson, AZ.
• Coletta, D. K. (2024, July). How to Successfully Publish High-Quality Scientific Papers. Research Graduate Student Career Development Boot Camp. Tucson, AZ.
• Coletta, D. K. (2024, March). 'Storytime for Parents in Academia'. American Physiological Society. Long Beach, CA.
• Coletta, D. K. (2024, September). Obesity and Type 2 Diabetes Mellitus: Insights from Skeletal Muscle Extracellular Matrix Remodeling. Medical Student Research Association Datablitz. Tucson, AZ.
• Zapata Bustos, R., & Coletta, D. K. (2024, June). Methylation of MicroRNAs in Human Skeletal Muscle Following Acute Exercise. American Diabetes Association.
• Wu, L., Garcia, L. A., McCabe, K., Lipinski, A., Langlais, P. R., & Coletta, D. K. (2022, Oct). Proteomic Profiling of Sildenafil Effects in C2C12 Muscle Cells. The Arizona Physiological Society Annual Meeting 2022. Phoenix, Arizona: American Physiological Society.
• Coletta, D. K. (2021, November). DNA Methylation Response to Exercise Training Is Lower in Insulin Resistant Skeletal Muscle. ObesityWeek®. Virtual: The Obesity Society.
• Coletta, D. K. (2020, June). Exercise Training Alters Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1 Alpha (PGC-1 alpha) DNA Methylation in Human Skeletal Muscle. American Diabetes Association 80th Scientific Sessions. Chicago, IL: Diabetes Journal.
  More info

  Oral presentation at the American Diabetes Association conference scheduled in Chicago, IL. Rescheduled to virtual [due to COVID].
• Hamzaoui, Y., & Coletta, D. K. (2020, November). Exercise Training Alters Global DNA Methylation In in Human Skeletal Muscle. Arizona Physiological Society Scientific Sessions. Tucson, AZ: American Physiological Society.
  More info

  Oral presentation at the Arizona Physiological Society conference scheduled in Tucson, AZ. Rescheduled to virtual [due to COVID].
• Mandarino, L. J., Grandjean, D. N., De Filippis, E. A., Coletta, D. K., Langlais, P. R., & Zapata Bustos, R. (2020, June). Lower Response of Connective Tissue Growth Factor (CTGF) to Exercise Characterizes Insulin Resistant Muscle. American Diabetes Association 80th scientific sessions. Chicago, IL: American Diabetes Association.
  More info

  Rocio Zapata-Bustos, Paul Langlais, Dawn Coletta, Elena A. De Filippis, Danielle Grandjean, Lawrence J. MandarinoLower Response of Connective Tissue Growth Factor (CTGF) to Exercise Characterizes Insulin Resistant Muscle
• Coletta, D. K. (2019, November). Insulin Resistant Muscle has Altered DNA methylation in Mechanosignaling Genes. Obesity Annual Meeting. Las Vegas, Nevada: Obesity.
  More info

  Oral presentation at the Obesity Week conference in Las Vegas, Nevada

Poster Presentations

• Coletta, D. K. (2024, March).

  Acute Exercise Alters Skeletal Muscle DNA Methylation in Sedentary Participants

  . American Physiological Society. Long Beach, CA.
• Langlais, P. R., Coletta, D. K., Lipinski, A. A., & Odeneye, R. E. (2024, January). Proteomic Profiling of Differentiated Myotubes Identifies Protein Candidates Potentially Involved in Insulin-Stimulated Glucose Uptake. University of Arizona Physiology Undergraduate Biology Research Symposium.
• Langlais, P. R., Lee, N. Y., Coletta, D. K., Giphart, A., Barbour, S., McGraw, M. B., Montoya, J. A., & Lu, E. J. (2024, October). A Microtubule-Acetylation Specific Inhibitor Induces Insulin Resistance. 17th Arizona Physiological Society Annual Meeting.
• Langlais, P. R., Lee, N. Y., Coletta, D. K., Peper, T. J., Barbour, S., Giphart, A., Montoya, J. A., Lu, E. J., & McGraw, M. B. (2024, November). Inhibition of Microtubule Stabilization Causes Insulin Resistance . American College of Physicians Arizona Chapter Annual Scientific Meeting.
• Reed, B. L., & Coletta, D. K. (2024, March). IMST to Improve Cardiometabolic Health in T2DM Patients:The Diabetes Inspiratory Training (DIT) Clinical Trial. American Physiological Society. Long Beach, CA.
• Grijalva, A., Benson, D., Fink, J., Zhang, X., Coletta, D. K., Langlais, P. R., Pandey, A., Mangiola, A., Koevary, J., Lancaster, J., & Goldman, S. (2023, November). Immune Modulation to Treat Ischemic Heart Failure. American Heart Association Annual Meeting.
• Odeneye, R. E., Lipinski, A. A., Coletta, D. K., & Langlais, P. R. (2023, August). Proteomic Profiling of Differentiated Myotubes Identifies Protein Candidates Potentially Involved in Insulin-Stimulated Glucose Uptake. Undergraduate Biology Research Program.
• Standage-Beier, C., Garcia, L. A., Parra, O. D., De Filippis, E., Shaibi, G. Q., Mandarino, L. J., & Coletta, D. K. (2022, Nov). Association of Vitamin D Receptor Polymorphisms-Taq1/Apa1/Fok1 with Cardiometabolic Phenotypes; Varied by Age in Hispanics. The Obesity Society. San Diego, CA: Obesity.
• Standage-Beier, C., Garcia, L. A., Parra, O. D., De Filippis, E., Shaibi, G. Q., Mandarino, L. J., & Coletta, D. K. (2022, Oct). Association of Vitamin D Receptor Polymorphisms-Taq1/Apa1/Fok1 with Cardiometabolic Phenotypes; Varied by Age in Hispanics. The Arizona Physiological Society Annual Meeting 2022. Phoenix, Arizona: American Physiological Society.
• Wu, L., Garcia, L. A., McCabe, K., Lipinski, A., Langlais, P. R., & Coletta, D. K. (2022, Nov). Proteomic Profiling of Sildenafil Effects in C2C12 Muscle Cells. The Obesity Society. San Diego, CA: Obesity.
• Mandarino, L. J., Grandjean, D. N., De Filippis, E. A., Coletta, D. K., Langlais, P. R., & Zapata Bustos, R. (2020, June/Summer). Lower Response of Connective Tissue Growth Factor (CTGF) to Exercise Characterizes Insulin Resistant Muscle. American Diabetes Association 80th scientific sessions. Chicago, IL: American Diabetes Association.
  More info

  Rocio Zapata-Bustos, Paul Langlais, Dawn Coletta, Elena A. De Filippis, Danielle Grandjean, Lawrence J. MandarinoLower Response of Connective Tissue Growth Factor (CTGF) to Exercise Characterizes Insulin Resistant Muscle
• Coletta, D. K. (2018, June). Exercise Training Alters Sorbin and SH3 Domain Containing 3 DNA Methylation in Human Skeletal Muscle. American Diabetes Association Annual Meeting. Orlando, Florida: American Diabetes Association.

Others

• Coletta, D. K. (2014). Genetic and Epigenetics of Type 2 Diabetes. Pathobiology of Human Disease.