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1.  Physical activity and FTO genotype by physical activity interactive influences on obesity 
BMC Genetics  2016;17:47.
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.
After controlling for age and sex, participants who did not engage in regular PA exhibited higher BMI, fat mass, HC, and WC with statistical significance (P < 0.001). Although significant associations between the three FTO genotypes and adiposity measures were found, none of the FTO genotype by PA interaction assessments revealed nominally significant associations. However, several of such interactive influences exhibited considerable trend towards association.
These data suggest that adiposity measures are associated with PA and FTO variants in Latinos, but the impact of their interactive influences on these obesity measures appear to be minimal. Future studies with large sample sizes may help to determine whether individuals with specific FTO variants exhibit differential responses to PA interventions.
Electronic supplementary material
The online version of this article (doi:10.1186/s12863-016-0357-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4765034  PMID: 26908368
Genetic variations; Physical activity; Obesity-related phenotypes; Latinos
2.  Genome-Wide Linkage Scan for Genes Influencing Plasma Triglyceride Levels in the Veterans Administration Genetic Epidemiology Study 
Diabetes  2009;58(1):279-284.
OBJECTIVE—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.
RESEARCH DESIGN AND METHODS—We used phenotypic and genotypic data from 1,026 individuals distributed across 294 Mexican-American families, who were ascertained for type 2 diabetes, from the Veterans Administration Genetic Epidemiology Study (VAGES). Plasma triglyceride values were transformed, and a variance-components technique was used to conduct multipoint linkage analysis.
RESULTS—After adjusting for the significant effects of sex and BMI, heritability for plasma triglycerides was estimated as 46 ± 7% (P < 0.0001). Multipoint linkage analysis yielded the strongest evidence for linkage of plasma triglycerides near marker D12S391 on chromosome 12p (logarithm of odds [LOD] = 2.4). Our linkage signal on chromosome 12p provides independent replication of a similar finding in another Mexican-American sample from the San Antonio Family Diabetes Study (SAFDS). Combined multipoint linkage analysis of the VAGES and SAFDS data yielded significant evidence for linkage of plasma triglycerides to a genetic location between markers GATA49D12 and D12S391 on 12p (LOD = 3.8, empirical P value = 2.0 × 10−5). This region on 12p harbors the gene-encoding adiponectin receptor 2 (AdipoR2), where we previously have shown that multiple single nucleotide polymorphisms are associated with plasma triglyceride concentrations in the SAFDS. In the present study, we provided suggestive evidence in favor of association for rs929434 with triglyceride concentrations in the VAGES.
CONCLUSIONS—Collectively, these results provide strong evidence for a major locus on chromosome 12p that influences plasma triglyceride levels in Mexican Americans.
PMCID: PMC2606886  PMID: 18931038
3.  Gene and MicroRNA Expression Responses to Exercise; Relationship with Insulin Sensitivity 
PLoS ONE  2015;10(5):e0127089.
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.
Methods and Findings
Euglycemic clamps were used to measure insulin sensitivity and muscle biopsies were done at rest and 30 minutes after a single acute exercise bout in 14 healthy participants. Changes in mRNA expression were assessed using microarrays, and miRNA analysis was performed in a subset of 6 of the participants using sequencing techniques. Following exercise, 215 mRNAs were changed at the probe level (Bonferroni-corrected P<0.00000115). Pathway and Gene Ontology analysis showed enrichment in MAP kinase signaling, transcriptional regulation and DNA binding. Changes in several transcription factor mRNAs were correlated with insulin sensitivity, including MYC, r=0.71; SNF1LK, r=0.69; and ATF3, r= 0.61 (5 corrected for false discovery rate). Enrichment in the 5’-UTRs of exercise-responsive genes suggested regulation by common transcription factors, especially EGR1. miRNA species of interest that changed after exercise included miR-378, which is located in an intron of the PPARGC1B gene.
These results indicate that transcription factor gene expression responses to exercise depend highly on insulin sensitivity in healthy people. The overall pattern suggests a coordinated cycle by which exercise and insulin sensitivity regulate gene expression in muscle.
PMCID: PMC4436215  PMID: 25984722
4.  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  2015;10(4):e0119941.
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.
PMCID: PMC4382323  PMID: 25830378
5.  The Design and Conduct of a Community-Based Registry and Biorepository: A Focus on Cardiometabolic Health in Latinos 
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.
Prior to recruitment, key stakeholders from the local Latino community were engaged to develop a broad rapport within the community and seek advice regarding recruitment, enrollment, and follow-up. Self-identified community-dwelling Latinos underwent a comprehensive cardiometabolic health assessment that included anthropometrics, a fasting laboratory panel, and a 2-hour oral glucose tolerance test with measures of insulin and glucose to estimate insulin action and secretion. Separate consent was requested for future contact and banking of serum, DNA, and RNA. Research collaborations were sought out based on the cultural and metabolic profile of participants, faculty research agendas, and the potential for generating hypotheses.
A total of 667 participants (20.4% children, and 79.6% adults) were enrolled with 97% consenting to the registry and 94% to banking of samples. The prevalence of overweight/obesity was 50% in children and 81% in adults. Nearly 20% of children and more than 45% of the adults exhibited some degree of hyperglycemia. To date, more than 15 research projects have been supported through this infrastructure and have included projects on the molecular biology of insulin resistance to the sociocultural determinants of health behaviors and outcomes.
The high prevalence of obesity and cardiometabolic disease risk factors coupled with the overwhelming majority of participants consenting to be re-contacted, highlights the importance of supporting research infrastructure to generate hypotheses about obesity-related health in Latinos. Future studies that stem from the initial project will likely advance the limited understanding regarding the biocultural determinants of health disparities in the Latino community.
PMCID: PMC4225082  PMID: 24119012
insulin resistance; obesity; registry; biobank; Latino
6.  Increases in Insulin Sensitivity among Obese Youth are Associated with Gene Expression Changes in Whole Blood 
Obesity (Silver Spring, Md.)  2014;22(5):1337-1344.
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.
Design and Methods
Fifteen (7M/8F) overweight/obese (BMI percentile=96.3±1.1) Latino adolescents (15.0±0.9 years) completed a 12-week lifestyle intervention that included weekly nutrition education and 180 minutes of moderate-vigorous exercise per week. Insulin sensitivity was estimated by an oral glucose tolerance test and the Matsuda Index. Global microarray analysis profiling from whole blood was performed to examine changes in gene expression and to explore biological pathways that were significantly changed in response to the intervention.
A total of 1,459 probes corresponding to mRNA transcripts (717 up, 742 down) were differentially expressed with a fold change ≥1.2. These genes were mapped within 8 significant pathways identified, including insulin signaling, type 1 diabetes, and glycerophospholipid metabolism. Participants that increased insulin sensitivity exhibited five times the number of significant genes altered compared to non-responders (1,144 vs. 230).
These findings suggest that molecular signatures from whole blood are associated with lifestyle-induced health improvements among high-risk Latino youth.
PMCID: PMC4008712  PMID: 24470352
Gene Expression; Exercise; Diabetes; Insulin Sensitivity; Adolescent
7.  Linkage of Type 2 Diabetes on Chromosome 9p24 in Mexican Americans: Additional Evidence from the Veterans Administration Genetic Epidemiology Study (VAGES) 
Human heredity  2013;76(1):36-46.
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 analysis to localize T2DM susceptibility loci in Mexican Americans.
We used the phenotypic and genotypic data from 1,122 Mexican American individuals (307 families) who participated in the Veterans Administration Genetic Epidemiology Study (VAGES). Genome-wide linkage analysis was performed, using the variance components approach. Data from two additional Mexican American family studies, the San Antonio Family Heart Study (SAFHS) and the San Antonio Family Diabetes/Gallbladder Study (SAFDGS), were combined with the VAGES data to test for improved linkage evidence.
After adjusting for covariate effects, T2DM was found to be under significant genetic influences (h2 = 0.62, P = 2.7 × 10−6). The strongest evidence for linkage of T2DM occurred between markers D9S1871 and D9S2169 on chromosome 9p24.2-p24.1 (LOD = 1.8). Given that we previously reported suggestive evidence for linkage of T2DM at this region in SAFDGS also, we found the significant and increased linkage evidence (LOD = 4.3, empirical P = 1.0 × 10−5, genome-wide P = 1.6 × 10−3) for T2DM at the same chromosomal region when we performed genome-wide linkage analysis of the VAGES data combined with SAFHS and SAFDGS data.
Significant T2DM linkage evidence was found on chromosome 9p24 in Mexican Americans. Importantly, the chromosomal region of interest in this study overlaps with several recent genome-wide association studies (GWASs) involving T2DM related traits. Given its overlap with such findings and our own initial T2DM association findings in the 9p24 chromosomal region, high throughput sequencing of the linked chromosomal region could identify the potential causal T2DM genes.
PMCID: PMC3919448  PMID: 24060607
Type 2 diabetes; Linkage; Chromosome 9p24; Mexican Americans; VAGES
8.  Whole Blood Gene Expression Profiles in Insulin Resistant Latinos with the Metabolic Syndrome 
PLoS ONE  2013;8(12):e84002.
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<0.05 after Benjamini-Hochberg in the metabolic syndrome subjects. KEGG pathway analysis revealed significant enrichment for pathways including ribosome, oxidative phosphorylation and MAPK signaling (all Benjamini-Hochberg P<0.05). Whole blood mRNA expression changes observed in the microarray data were confirmed by quantitative RT-PCR. Transcription factor binding motif enrichment analysis revealed E2F1, ELK1, NF-kappaB, STAT1 and STAT3 significantly enriched after Bonferroni correction (all P<0.05). The results of the present study demonstrate that whole blood is a useful tissue for studying the metabolic syndrome and its underlying insulin resistance although the relationship between blood and skeletal muscle differs.
PMCID: PMC3866261  PMID: 24358323
9.  Glucose Response Curve and Type 2 Diabetes Risk in Latino Adolescents 
Diabetes Care  2012;35(9):1925-1930.
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.
A total of 156 nondiabetic Latino adolescents completed a 2-h OGTT. Monophasic and biphasic groups were compared for the following type 2 diabetes risk factors: fasting and 2-h glucose, HbA1c, glucose area under the curve (AUC), insulin sensitivity (Matsuda index), insulin secretion (insulinogenic index), and β-cell function as measured by the disposition index (insulin sensitivity × insulin secretion).
Of the participants, 107 youth were categorized as monophasic and 49 were biphasic. Compared with the monophasic group, participants with a biphasic response exhibited lower HbA1c (5.4 ± 0.3 vs. 5.6 ± 0.3%, P < 0.01) and lower glucose AUC (14,205 ± 2,382 vs. 16,230 ± 2,537 mg ⋅ dL−1 ⋅ h−1, P < 0.001) with higher insulin sensitivity (5.4 ± 3.2 vs. 4.6 ± 3.4, P ≤ 0.05), higher insulin secretion (2.1 ± 1.3 vs. 1.8 ± 1.3, P = 0.05), and better β-cell function (10.3 ± 7.8 vs. 6.0 ± 3.6, P < 0.001). Differences persisted after adjusting for age, sex, and BMI.
These data suggest that the glycemic response to an OGTT may differentiate risk for type 2 diabetes in youth. This response may be an early marker of type 2 diabetes risk among high-risk youth.
PMCID: PMC3424993  PMID: 22751962
10.  Effect of acute physiological hyperinsulinemia on gene expression in human skeletal muscle in vivo 
This study was undertaken to test the hypothesis that short-term exposure (4 h) to physiological hyperinsulinemia in normal, healthy subjects without a family history of diabetes would induce a low grade inflammatory response independently of glycemic status. Twelve normal glucose tolerant subjects received a 4-h euglycemic hyperinsulinemic clamp with biopsies of the vastus lateralis muscle. Microarray analysis identified 121 probe sets that were significantly altered in response to physiological hyperinsulinemia while maintaining euglycemia. In normal, healthy human subjects insulin increased the mRNAs of a number of inflammatory genes (CCL2, CXCL2 and THBD) and transcription factors (ATF3, BHLHB2, HES1, KLF10, JUNB, FOS, and FOSB). A number of other genes were upregulated in response to insulin, including RRAD, MT, and SGK. CITED2, a known coactivator of PPARα, was significantly downregulated. SGK and CITED2 are located at chromosome 6q23, where we previously detected strong linkage to fasting plasma insulin concentrations. We independently validated the mRNA expression changes in an additional five subjects and closely paralleled the results observed in the original 12 subjects. A saline infusion in healthy, normal glucose-tolerant subjects without family history of diabetes demonstrated that the genes altered during the euglycemic hyperinsulinemic clamp were due to hyperinsulinemia and were unrelated to the biopsy procedure per se. The results of the present study demonstrate that insulin acutely regulates the levels of mRNAs involved in inflammation and transcription and identifies several candidate genes, including HES1 and BHLHB2, for further investigation.
PMCID: PMC3581328  PMID: 18334611
gene expression; muscle; insulin action; euglycemic hyperinsulinemic clamp; inflammation
11.  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  2011;71(1):1-10.
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).
Using data from 1,089 individuals distributed across 266 families, we performed a multipoint linkage analysis to localize susceptibility loci for SBP and DBP by applying two models. In model 1, we added a sensible constant to the observed BP values in treated subjects [Tobin et al.; Stat Med 2005;24:2911–2935] to account for antihypertensive use (i.e. 15 and 10 mm Hg to SBP and DBP values, respectively). In model 2, we fixed values of 140 mm Hg for SBP and 90 mm Hg for DBP, if the treated values were less than the standard referenced treatment thresholds of 140/90 mm Hg for hypertensive status. However, if the observed treated BP values were found to be above these standard treatment thresholds, the actual observed treated BP values were retained in order not to reduce them by substitution of the treatment threshold values.
The multipoint linkage analysis revealed strong linkage signals for SBP compared with DBP. The strongest evidence for linkage of SBP (model 1, LOD = 5.0; model 2, LOD = 3.6) was found on chromosome 6q14.1 near the marker D6S1031 (89 cM) in both models. In addition, some evidence for SBP linkage occurred on chromosomes 1q, 4p, and 16p. Most importantly, our major SBP linkage finding on chromosome 6q near marker D6S1031 was independently confirmed in a Caucasian population (LOD = 3.3). In summary, our study found evidence for a major locus on chromosome 6q influencing SBP levels in Mexican-Americans.
PMCID: PMC3152483  PMID: 21293138
Hypertension; Linkage; Antihypertensive medication; Genetic location; Heritability
12.  Proteomics Reveals Novel Oxidative and Glycolytic Mechanisms in Type 1 Diabetic Patients' Skin Which Are Normalized by Kidney-Pancreas Transplantation 
PLoS ONE  2010;5(3):e9923.
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.
Methods and Findings
We evaluated protein regulation and expression in skin biopsies obtained from T1D patients with and without ESRD, to identify pathways of persistent cellular changes linked to diabetic vascular disease. We therefore examined pathways that may be normalized by restoration of normoglycemia with kidney-pancreas (KP) transplantation. Using proteomic and ultrastructural approaches, multiple alterations in the expression of proteins involved in oxidative stress (catalase, superoxide dismutase 1, Hsp27, Hsp60, ATP synthase δ chain, and flavin reductase), aerobic and anaerobic glycolysis (ACBP, pyruvate kinase muscle isozyme, and phosphoglycerate kinase 1), and intracellular signaling (stratifin-14-3-3, S100-calcyclin, cathepsin, and PPI rotamase) as well as endothelial vascular abnormalities were identified in T1D and T1D+ESRD patients. These abnormalities were reversed after KP transplant. Increased plasma levels of malondialdehyde were observed in T1D and T1D+ESRD patients, confirming increased oxidative stress which was normalized after KP transplant.
Our data suggests persistent cellular changes of anti-oxidative machinery and of aerobic/anaerobic glycolysis are present in T1D and T1D+ESRD patients, and these abnormalities may play a key role in the pathogenesis of hyperglycemia-related vascular complications. Restoration of normoglycemia and removal of uremia with KP transplant can correct these abnormalities. Some of these identified pathways may become potential therapeutic targets for a new generation of drugs.
PMCID: PMC2848014  PMID: 20360867
13.  Effect of Acute Exercise on AMPK Signaling in Skeletal Muscle of Subjects With Type 2 Diabetes 
Diabetes  2007;56(3):836-848.
Activation of AMP-activated protein kinase (AMPK) by exercise induces several cellular processes in muscle. Exercise activation of AMPK is unaffected in lean (BMI ~25 kg/m2) subjects with type 2 diabetes. However, most type 2 diabetic subjects are obese (BMI >30 kg/m2), and exercise stimulation of AMPK is blunted in obese rodents. We examined whether obese type 2 diabetic subjects have impaired exercise stimulation of AMPK, at different signaling levels, spanning from the upstream kinase, LKB1, to the putative AMPK targets, AS160 and peroxisome proliferator–activated receptor coactivator (PGC)-1α, involved in glucose transport regulation and mitochondrial biogenesis, respectively. Twelve type 2 diabetic, eight obese, and eight lean subjects exercised on a cycle ergometer for 40 min. Muscle biopsies were done before, during, and after exercise. Subjects underwent this protocol on two occasions, at low (50% VO2max) and moderate (70% VO2max) intensities, with a 4–6 week interval. Exercise had no effect on LKB1 activity. Exercise had a time- and intensity-dependent effect to increase AMPK activity and AS160 phosphorylation. Obese and type 2 diabetic subjects had attenuated exercise-stimulated AMPK activity and AS160 phosphorylation. Type 2 diabetic subjects had reduced basal PGC-1 gene expression but normal exercise-induced increases in PGC-1 expression. Our findings suggest that obese type 2 diabetic subjects may need to exercise at higher intensity to stimulate the AMPK-AS160 axis to the same level as lean subjects.
PMCID: PMC2844111  PMID: 17327455
14.  Global Relationship between the Proteome and Transcriptome of Human Skeletal Muscle 
Journal of proteome research  2008;7(8):3230-3241.
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.
PMCID: PMC2755516  PMID: 18613714
human skeletal muscle; proteomic analysis; HPLC-ESI-MS/MS; microarrays; transcriptome; tissue profiling; Gene Ontology
15.  Elevated Toll-Like Receptor 4 Expression and Signaling in Muscle From Insulin-Resistant Subjects 
Diabetes  2008;57(10):2595-2602.
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 κB (IκB)/nuclear factor κB (NFκB). 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 (IκB/NFκB) 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 IκB/NFκB 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 IκBα content, an indication of elevated IκB/NFκB signaling. The increase in TLR4 and NFκB signaling was accompanied by elevated expression of the NFκB-regulated genes interleukin (IL)-6 and superoxide dismutase (SOD)2. In primary human myotubes, acute palmitate treatment stimulated IκB/NFκB, and blockade of TLR4 prevented the ability of palmitate to stimulate the IκB/NFκB 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 NFκB.
CONCLUSIONS— Abnormal TLR4 expression and signaling, possibly caused by elevated plasma FFA levels, may contribute to the pathogenesis of insulin resistance in humans.
PMCID: PMC2551667  PMID: 18633101

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