Dawn K Coletta

Interests

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.

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

Courses

Scholarly Contributions

Journals/Publications

• 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.
• 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.
• 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
• 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.
• 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
• 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.
• 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.
• 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.
• 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.
• 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.

Presentations

• Coletta, D. K. (2019, November). Insulin Resistant Muscle has Altered DNA methylation in Mechanosignaling Genes. Obesity Annual Meeting. Las Vegas, Nevada: Obesity.
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  Oral presentation at the Obesity Week conference in Las Vegas, Nevada

Poster Presentations

• 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.