Browsing by Subject "Insulin resistance"
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Item A study of the expression of IRS-1, a putative component of the insulin signaling pathway(Texas Tech University, 1993-05) Rice, K. MichaelThe study of insulin signaling is important because of its relevancy to the disease non-insuUn dependent diabetes mellitus (NIDDM). NIDDM is die most common endocrine and serious metabolic disorder in industrialized nations. The sequelae of the disease are serious multi-system disorders with high morbidity and mortality. The enormity of the disease has been the impetus fueling research of NIDDM for many years. Current understanding of the etiology of NIDDM implicates insulin resistance as the primary symptom responsible for causing the disease. Insulin resistance refers to the inability of insulin to signal intracellular responses. In general, research data best support a hypothesis that insulin resistance is due to an unknown post-receptor defect in the insulin-signaling mechanism. My dissertation deals with the investigations how the protein IRS-1 (insulin receptor substrate), a putative second messenger in the phosphoprotein pathway a component of the insulin signaling pathway, is regulated and the relationship of IRS-1 regulation to insulin responsiveness. Cellular concentrations of IRS-1 in 3T3-L1 adipocytes were found to be upregulated in an insulin- and dexamethasone-dependent manner during the differentiation of these cells from fibroblasts. This result suggested that IRS-1 might also be regulated by these substances in the mature adipocytes. Subsequent research has revealed that IRS- 1 was down-regulated by these substances in the adipocytes. Elucidation of the insulin mechanism down-regulating IRS-1 can be explained by destabilization of the protein without contribution from IRS-1 mRNA regulation. The mechanism by which the degradation of IRS-1 is signaled has been determined to be dependent upon a phosphorylation event and intracellular calcium. Although the exact physiological function of IRS-1 is unknown, it has been ascertained that the development of insulin resistance, as measured by 2-deoxyglucose uptake, has similar kinetics as the down-regulation of IRS-1 induced by insulin. Removal of insulin and the subsequent recovery of insulin responsiveness and IRS-1 concentrations have similar kinetics. The ED50 values for the down-regulation of both IRS-1 and 2-deoxyglucose uptake are approximately the same and occur at physiological levels. Results from these experiments provide support that insulin regulates IRS-1 by a mechanism involving the degradation of the protein and provides a working hypothesis on which to investigate the role of IRS-1 in the etiology of insulin resistance.Item Effect of Fibrin Degradation Products on Inflammation and Adipocyte Glucose Disposal(2013-05) Kang, Minsung; Paton, Chad M.; Moustaid-Moussa, Naima; Cooper, Jamie A.Obesity, the most predominant disease in the world, is strongly associated with chronic inflammation which is directly correlated with insulin resistance (IR). Obesity also results in hyperfibrinogenemia. Fibrinogen, a glycoprotein involved in coagulation, is converted to fibrin via thrombin to form a blood clot and fibrin is degraded into two D (FDP-D) and one E (FDP-E) fragment by plasmin. Previous studies show that fibrinogen and fibrin induce inflammation but effect of FDP is unknown. FDP-D is used as a biomarker of hypercoagulability and has less bioactivity so we decided to focus on examining the effect of FDP-E on inflammation and adipocyte glucose disposal. First, cytokine mRNA expression in primary macrophages treated with FDP-E was measured and the results showed that FDP-E induces inflammation (55.9±7.1 fold change in MCP-1). RAW264.7 macrophages and 3T3-L1 adipocytes were treated with FDP-E from 0- to 100nM or for different times from 1 to 12 hours. FDP-E had the greatest effect at 100nM for 6 hours in both macrophages (29.5±9.8 fold change in MCP-1) and adipocytes (11.3±3.1 fold change in MCP-1). Next, adipocytes were treated with increasing concentrations of conditioned medium from FDP-E treated macrophages or FDP-E itself to assess the indirect or direct effects on glucose uptake. After 24 hours, the capacity for glucose uptake using radiolabeled 3H-2-deoxy-D-glucose was determined. There was no significant difference in conditioned medium treated cells but FDP-E itself suppressed insulin stimulated glucose uptake significantly (71% reduction; p=0.00001). We found that FDP-E induces inflammation in macrophages and adipocytes and decreases glucose uptake in adipocytes. From these results, we can conclude that FDP-E could be a key molecule in obesity, inflammation, and insulin resistance.Item Impacts of Maternal Obesity on Metabolic Profiles in Postpartum Ewes(2011-10-21) McKnight, Jason RayThis study determined the effects of gestational obesity on the long-term metabolic status of the mother and if obesity management during or after pregnancy could attenuate these effects. At 120 days prior to estrus, 8 ewes received 100 percent of NRC nutrient requirements (control group) and 24 ewes had free access to feed (obesity induction). Beginning on day 42 of gestation, 8 obese ewes were restricted to 65 percent of NRC nutrient requirements. Following parturition, controls and all but one group of obese ewes were fed 100 percent of NRC nutrient requirements. At postpartum days (PPD) 1 and 150, glucose tolerance tests were administered to ewes. At both PPD1 and PPD150, obesity resulted in insulin resistance, impairment of whole-body glucose utilization, increased levels of circulating leptin, and altered profiles of amino acids in plasma; however, these effects were diminished in ewes receiving obesity management during or after gestation. Additionally at PPD150, obesity increased the circulating levels of ammonia and urea in ewes, which was prevented by realimentation to 100 percent NRC requirements. These results indicate that weight reduction in obese dams during pregnancy or after parturition can beneficially ameliorate the adverse effects of gestational obesity on the mother.Item Interaction of insulin like growth factor-1 and resistance training on skeletal muscle mass and function(2002) Lee, Suk-Ho, 1968-; Farrar, Roger P.In the present study, the effects of IGF-1 overexpression, resistance training and their interaction on muscle mass and function were examined in both mouse and rat models. In addition, the effect of IGF-1 overexpression on the reversal of training-induced adaptations in skeletal muscle mass and function during varying lengths of detraining was measured. The resistance training consisted of a ladder climbing protocol. Overexpression of IGF-1 was localized to one hindlimb via injections containing adeno-associated virus and the contralateral hindlimb served as an internal control. IGF-1 overexpression alone resulted in an increase in mass and peak tetanic tension (Po) of the flexor hallucis longus (FHL) muscle in both rat and mouse model. Eight weeks of resistance training alone resulted in an increase in mass and peak tetanic tension (Po) of the flexor hallucis longus (FHL) muscle only in rat model. The combination of resistance training and IGF-1 overexpression resulted in further increase in muscle mass and Po in rat model, giving evidence of an additive effect. Overexpression of IGF-1 significantly attenuated the loss of muscle mass in FHL during 12 weeks of detraining. These data suggest a beneficial effect of combination of resistance training and IGF-1 overexpression on skeletal muscle mass and function.Item Mechanisms mediating beneficial effects of Eicosapentaenoic Acid (EPA) in insulin resistance and obesity: Studies in muscle(2013-08) Aljawadi, Arwa; Moustaid-Moussa, Naima; Murimi, Mary; Wang , ShuObesity is a major epidemic problem in the US and worldwide. It is associated with several other chronic diseases such as type-2 diabetes mellitus, insulin resistance, cardiovascular disease and some types of cancers [1-4]. Major contributors to the obesity epidemics include sedentary lifestyle and lack of physical activity, increased consumption of energy dense foods as well as genetic and other environmental factors [1, 2]. Omega-3 polyunsaturated fatty acids (PUFA) are known to confer multiple health benefits such as, improvements in blood pressure and cardiovascular health and alleviation of symptoms associated with anti-inflammatory diseases such as rheumatoid arthritis [5, 6]. Previous research from Dr. Moustaid-Moussa’s lab showed that feeding mice high-fat (HF) diets enriched with the omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) decreased inflammation, adiposity and insulin resistance compared to mice fed only the high fat diet. Skeletal muscle is well known for its key role metabolic homeostasis. Accordingly, we sought to investigate mechanisms by which EPA ameliorates glucose tolerance, lipid metabolism and inflammation. Specifically, we investigated effects of EPA on skeletal muscle taken from mice fed high fat diets with or without EPA. In addition, we used C2C12 cells, a skeletal muscle model that is used to study myocytes differentiation and metabolism in vitro, to further dissect the mechanisms mediating EPA on skeletal muscle. Metabolomic, gene and protein expression approaches were used to determine the role of EPA in skeletal muscle. In vivo, our analyses showed that fatty acid and amino acid profiles were altered by the EPA diet. Both saturated fatty acids and docosahexaenoate (DHA, a polyunsaturated fatty acid downstream of EPA) were elevated in muscle from the EPA group. Furthermore, essential amino acids for muscle protein synthesis and growth, namely branched chain amino acids (BCAAs) were increased by the EPA diet. However, no significant changes were observed in fatty acid oxidation between HF and HF-EPA fed animals. In vitro, preliminary data showed that treating C2C12 cells with EPA tended to increase the expression of genes involved in both fatty acid synthesis and oxidation. In conclusion, EPA didn’t significantly affect fatty acid oxidation but increased de novo lipogenesis and BCAA synthesis in vivo. By contrast, EPA treatment increased both fatty acid synthesis and oxidation in vitro. However, additional experiments are needed to confirm these findings and gain further insight into mechanisms by which EPA prevents high fat diet-induced obesity, inflammation and insulin resistance in both animal models and human subjects.Item Metabolic syndrome and insulin resistance in overweight/obese women in early postpartum(2009-12) Lu, Hongxing; Freeland-Graves, Jeanne H.; Jolly, Christopher A.; Ciolino, Henry P.; Lewis, Karron G.; Xu, BugaoMetabolic syndrome includes several metabolic and hormonal disorders, such as abdominal obesity, insulin resistance, and lower blood ghrelin. Women with breastfeeding history exhibit a reduced risk for metabolic syndrome in later life. The purpose of aim 1 was to determine the incidence of metabolic syndrome in low income, overweight/obese women in early postpartum and to assess its relationship to lactation status. It has been found that the incidence of metabolic syndrome is much higher in formula feeding women than that of the breastfeeding ones (44.3% vs. 22.4%, p < 0.01). The breastfeeding mothers had reduced triglycerides (109.07 mg/dl vs. 143.10 mg/dl, p < 001) and elevated serum high-density lipoprotein (HDL)-cholesterol (58.59 mg/dl vs. 51.76 mg/dl, p < 0.01). The goal of aim 2 was to explore associations between ghrelin, metabolic syndrome and infant feeding methods in low income, overweight/obese women in early postpartum. In our study, the breastfeeding mothers in early postpartum had higher plasma ghrelin, as compared to those who formula fed (584.73 pg/ml vs. 450.77 pg/ml, p < 0.01). Additionally, it is found that plasma ghrelin was negatively associated with incidence and numbers of risk factors for metabolic syndrome, before and after controlling for body mass index (BMI). After adjusting for ghrelin in logistic regression analyses, significant relationships between lactation status and metabolic syndrome disappeared. Thus, the protective function of breastfeeding against metabolic syndrome in overweight/obese women in early postpartum may related to the plasma ghrelin values. The purpose of aim 3 was to detect the influence of weight loss on insulin resistance and plasma adiponectin, zinc (Zn), manganese (Mn) and copper (Cu) in low income, overweight/obese women in early postpartum. After an eight-week weight loss intervention, plasma levels of adiponectin, Zn and Mn were significantly enhanced, and plasma concentrations of insulin (7.53±0.56 vs. 6.23±0.49, p <0.01) and insulin resistance (1.84±0.15 vs. 1.44±0.12, p <0.01) were reduced. The increase of adiponectin, Zn and Mn was positively associated with weight reduction. However, the plasma Cu was not significantly affected. The relationships between weight loss and reduced insulin resistance disappeared after adjusting the increases of adiponectin, Zn and Mn during weight loss. Thus, weight loss had beneficial effects on insulin resistance, plasma values of adiponectin Zn and Mn. It is plausible that the influence of weight loss on insulin resistance may be associated with improvements of plasma of adiponectin, Zn and Mn. Collectively, the results of this study demonstrate the important benefits of breastfeeding on prevention of metabolic syndrome in overweight/obese women in early postpartum. This study also emphasizes the influence of ghrelin on risk factors of metabolic syndrome and lactation status.Item Regulation of the expression of adiponectin, resistin, and GLUT4 in omental adipose tissue of baboon(2003) Tejero-Barrera, Maria Elizabeth; Freeland-Graves, Jeanne H.The purpose of this research was to identify the chromosomal regions influencing the mRNA expression of the hormones resistin and adiponectin, and the glucose transporter 4 (GLUT4) in omental adipose tissue of baboons. These baboon genes were cloned using a two-step reverse transcription- polymerase chain reaction (RT-PCR) technique. Real- time, quantitative RT-PCR assays were developed and standardized for measurement of mRNA levels of each gene. Total RNA was isolated from 460 samples of adipose tissue from adult pedigreed baboons, and used for the quantification of adiponectin, resistin and GLUT4 mRNA. Quantitative genetic analyses were conducted using the mRNA abundance of each gene as a quantitative phenotype applying the variance decomposition approach. Heritabilities were calculated for resistin (h2 = 0.23, p = 0.005), adiponectin (h2 = 0.23, p = 0.001) and GLUT4 (h2 = 0.24, p = 0.001). Genome scan analyses were conducted to locate the chromosomal regions influencing the expression of the studied genes. The identified regions and corresponding LOD scores are: 19p13 (LOD score = 3.8) for resistin, 6q13 (LOD score =1.6) for adiponectin mRNA and same location (LOD score =1.0) for adiponectin protein, and 10q24-26 (LOD score = 1.4) for GLUT4 mRNA. A parallel study in 120 baboons indicated a relationship between body weight and indicators for insulin sensitivity, and an association between adiponectin levels and insulin resistance (HOMA-IR index) in baboons. No correlation between the analyzed phenotypes and resistin expression in monocytes was found. The relationships between mRNA expression in adipose tissue of resistin, adiponectin and GLUT4 and circulating levels of selected cytokines (TNFa, IL-6 and IL-1b) and phenotypes associated to insulin resistance were investigated in a sub-sample of unrelated baboons (n=40). Resistin expression in adipose tissue was related to insulin sensitivity, adiponectin mRNA was inversely associated with cytokines in plasma, and GLUT4 abundance and the HOMA-IR index were correlated. Collectively, these results revealed novel findings on the genetic component of the endocrine function of adipose tissue, and confirmed the value of the baboon as a model for the genetic study of obesity-related conditions.Item Visfatin, retinol binding protein-4, and vaspin concentrations in plasma and different tissues and their relationship to insulin resistance in morbidly obese subjects(2013-05) Goktas, Zeynep; Wang, Shu; Boylan, Lee M.; Reed, Debra; Shen, Chwan-Li; SanFrancisco, SusanThe purpose of this study was to measure visfatin, vaspin, and retinol binding protein-4 (RBP-4) gene expression levels and protein concentrations in subcutaneous, omental, and mesenteric adipose tissue, liver, muscle tissue, and plasma in severely obese patients and to investigate the relationship between these proteins and insulin resistance markers. Thirty eight morbidly obese (BMI ≥40) subjects had the subcutaneous, omental, and mesenteric adipose, liver, and muscle tissues and blood samples taken at the time of Roux-en-Y surgeries. Visfatin, vaspin and RBP-4 gene expressions were measured by Real Time PCR, and their protein concentrations were measured with ELISA kits (Adipogen, Korea). Subjects were divided into three groups as normal (n=13), pre-diabetic (n=12) and diabetic (n=13) according to blood HbA1c levels. Results were analyzed using ANOVA and Pearson correlation with p <0.05 being significant. Visfatin gene expression levels were significantly lower in subcutaneous adipose tissue in all three diabetic classification groups. Omental visfatin expression levels were positively correlated with blood HbA1c levels (r = 0.351) and Homeostasis Model of Assessment - Insulin Resistance (HOMA-IR) (r = 0.401). Livers (23.1 ± 8.53 ng/mg protein) and muscle tissues (9.9 ± 8.74 ng/mg protein) had the highest and lowest visfatin protein concentrations, respectively. Omental visfatin protein concentrations were positively correlated with HOMA-IR (r=0.456) and blood HbA1c (r=0.481). Livers had the highest RBP-4 expression levels. Omental RBP-4 expression levels were positively correlated with HOMA-IR (r=0.355 ) and blood glucose levels (r=0.454). Livers (11621 ± 1033.5 ng/mg protein) had the highest RBP-4 protein concentrations, and mesenteric (339.4 ± 47.78 ng/mg protein) had the lowest concentrations. RBP-4 protein concentrations in omental were positively correlated with blood glucose levels (r = 0.363). Omental vaspin expression levels were positively correlated with blood HbA1c levels. Livers (2.19 ± 0.34 ng/mg protein) and mesenteric adipose tissues (0.36 ± 0.16 ng/mg protein) had the highest and lowest vaspin protein concentrations, respectively. Mesenteric vaspin protein concentrations were positively correlated with HOMA-IR, blood glucose, and HbA1c levels. In conclusion, visfatin, vaspin, and RBP-4 might play important roles in insulin resistance. Higher concentrations of visfatin and RBP-4 in omental adipose tissues and vaspin in mesenteric adipose tissues were associated with higher levels of insulin resistance. The correlations of visfatin, vaspin, and RBP-4 with insulin resistance are tissue-dependent. Further studies are needed to investigate the underlying mechanisms of these inflammatory factors in insulin resistance.