Browsing by Subject "Insulin resistance"

Now showing 1 - 5 of 5
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    Determining the effect of lipid nanoemulsions on insulin signaling and the inflammatory pathways at the Blood-Brain Barrier
    (2022-01) Nair, Sanjana
    Several studies have shown that metabolic disorders such as type-2 diabetes (T2DM) play a role in propagating neurodegenerative disorders like Alzheimer’s Disease (AD)(1). As the brain is an insulin-sensitive organ and requires insulin for promoting neuronal integrity and function, impairment of insulin signaling in the CNS has huge implications for memory and cognition(2). Hyperinsulinemia observed in AD and T2DM contributes to vascular inflammation, which in turn, leads to endothelial insulin resistance by impairing insulin receptor (IR) and insulin resistance substrate (IRS)-1(1). The insulin resistance leads to a compensatory increase in circulating insulin leading to hyperinsulinemia. In addition to the impairment of insulin signaling, another hallmark of AD is lipid dysfunction(3). The lipid bilayer of the Blood-Brain Barrier (BBB) endothelial cells harbors lipid rafts that play a vital role in transcytosis and maintaining various signaling functions(3). Lipid metabolism at the BBB changes with age and diet and results in a decrease of unsaturated fatty acid content and an increase in lipid peroxidation. In this study, we hypothesize that the delivery of lipid nanoemulsion, which is rich in unsaturated fatty acids, will improve insulin signaling at the BBB, and ameliorate insulin resistance caused by cytokines like TNF-α. This, in turn, is expected to decrease VCAM-1 expression and mitigate BBB dysfunction. This hypothesis has been verified by treating BBB endothelial cells with inflammatory cytokines like TNF-α, which inhibited insulin signaling and increase the expression of vascular cell adhesion molecule-1 (VCAM-1), a marker for endothelial inflammation. Alternatively, exposure to soybean oil nanoemulsion (SNEs) like that of Humulin® triggered insulin signaling and reduced VCAM-1 expression. The results showed that the SNEs have the ability to overcome the resistance induced by TNF-α, and increased the insulin signaling to the level comparable to Humulin® control and the opposite effect was seen when the cells were treated with nanoemulsion rich in saturated fatty acids. Lipid-based nanoemulsion could be used as a strategy to mitigate insulin resistance and the consequent inflammation commonly seen in neurodegenerative disorders like AD.
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    The effect of viscous and fermentable dietary fiber consumption on adiposity, insulin resistance and fuel utilization in rats
    (2013-05) Brockman, David Andrew
    The incidence of obesity continues to be a major public health problem in the United States and comorbidities such as type 2 diabetes, cardiovascular disease and fatty liver that accompany obesity have dramatically increased over the last several decades. The health costs associated with the diagnosis and treatment of obesity-related disorders, particularly type 2 diabetes, are extraordinary and will be an enormous financial burden on the economy. Due to these dire circumstances, there is great interest in identifying foods that reduce the accumulation of adipose tissue and decrease the progression of insulin resistance. The consumption of dietary fibers that decrease the postprandial glucose curve is associated with decreased adiposity and a reduced incidence of type 2 diabetes, but it is controversial as to which property of dietary fiber is responsible for these effects. The objective of this research was to investigate the effect of increasing the small intestinal contents viscosity on the progression of obesity and type 2 diabetes. In the first study, non-fermentable hydroxypropyl methylcellulose (HPMC) was used to increase the small intestinal contents viscosity in a model of obesity with type 2 diabetes, the Zucker Diabetic Fatty rat. Rats fed HPMC showed improvements in insulin resistance and fatty liver but only a modest effect on reducing obesity. There was also a decrease in diabetic wasting as there was a greater food efficiency ratio and less urinary glucose excretion. In the second study, it was shown that adding barley flour containing a high concentration of viscous fermentable β-glucans had similar outcomes to those observed in the first study, including decreased insulin resistance and fatty liver, and a greater concentration of plasma adiponectin. In the third study, a model of diet-induced obesity was used to determine differences in fuel utilization when consuming viscous dietary fibers. Adding non-fermentable HPMC and fermentable guar gum to a high fat diet significantly decreased adiposity and fatty liver, yet there was no difference in insulin resistance. Consumption of both HPMC and guar gum increased the postprandial respiratory quotient compared to cellulose and also increased metabolic flexibility. There was no added effect of fermentability on any measure of adiposity, glucose control or fatty liver disease, indicating that SCFAs produced from fermentation had little or no effect on metabolic disease. In summary, the consumption of soluble dietary fibers that increase the viscosity of the small intestinal contents reduces the progression of obesity, insulin resistance and fatty liver, while the property of fermentation appears to have little discernable effect.
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    The effect of whole wheat and wheat milling fractions on metabolic parameters of adiposity, glucose control, and lipid metabolism using a rat model of obesity with type 2 diabetes
    (2014-01) Dos Santos, Ana
    Obesity prevalence is at an all-time high, with 1 in 3 Americans now classified as obese (1). Obesity is a debilitating condition that is associated with various co-morbidities, including type 2 diabetes (T2D), cardiovascular disease, pulmonary dysfunction, gastrointestinal disease, various cancers, and osteoarthritis. T2D is one of the most significant co-morbidities of obesity, as it often leads to other diseases such as non-alcoholic fatty liver disease (NAFLD) and hyperlipidemia. There are now 347 million people worldwide with T2D (2).The incidence of newly diagnosed cases of T2D in America is at its highest of 1.9 million per year and, according to the American Diabetes Association, and if the trend continues, 1 in 3 Americans will have diabetes by the year 2050 (3). There are many factors that increase the risk of developing T2D, some which include being overweight and physically inactive, having a genetic predisposition, and high blood pressure. In addition, there are complications that develop gradually over a period of time during T2D if blood glucose sugar levels are not properly controlled. Long-term poor glucose control puts patients at a higher risk for complications such as cardiovascular disease (CVD), neuropathy, nephropathy, and retinopathy.Obesity and diabetes are having a substantial impact on the economic state of the health care system. The total estimated cost of diagnosed diabetes in 2012 was $245 billion. This includes $176 billion in direct medical costs and $69 billion in reduced productivity, encompassing lower labor force participation from chronic disability and premature mortality (4). In addition to the economic burden, there are substantial intangible costs, such as a reduced quality of life for those people with diabetes, and often for their families and friends as well. Several epidemiological studies suggest that whole grain consumption is associated with a lower risk of obesity and T2D. Whole grain consumption has been found to have an inverse association with fat mass and insulin resistance in both humans and rats, possibly through several different mechanisms, involving mechanical, hormonal, and anti-inflammatory processes. The mechanical mechanism focuses on alterations in caloric density and absorption of nutrients, the hormonal mechanism on changes in hormone synthesis and secretion due to nutrient availability, and lastly, anti-inflammatory and anti-oxidative components in the whole grain. However, it is unclear which milling fraction of the whole grain, the bran, germ, or endosperm, may be responsible for these health benefits. Therefore, the aim of this study was to examine the effects of whole wheat and wheat milling fractions, specifically bran, germ, and endosperm, on glucose control, insulin resistance, fatty liver, and adiposity using an animal model of obesity with T2D, the Zucker Diabetic Fatty (ZDF) rat. Male ZDF rats were fed either a cornstarch-based diet (AIN-93G; obese control ), or diets containing 64% whole wheat flour, 54% refined wheat, 9.4 % wheat bran, 1.6% normal wheat germ, or high 15% wheat germ for 5 weeks. Lean ZDF littermates fed a standard AIN-93G diet served as a negative control. All animals were fed ad libitum. The refined wheat, wheat bran, and wheat germ were present in the diets in the same concentration as would be found in the whole wheat diet. The high wheat germ diet had amounts of germ 10 times that of the normal wheat germ diet. It was found that after 5 weeks, the whole wheat, refined wheat, and high and normal wheat germ groups all showed a significant improvement (p<0.05) in area under the curve during glucose and insulin tolerance tests. There were no differences in body weight or fat pad weight among the ZDF groups; however, there was a significant difference (p=0.031) in fat mass % between the whole wheat group and the obese control. The whole wheat group and all wheat fraction groups decreased the concentration of liver lipids compared to the obese control, and the bran and germ groups also had lower liver cholesterol concentration. Only the whole wheat group had a significantly lower cecum pH (p<0.0001) and greater cecal weight (p<0.0001) compared to the obese control, indicating greater fermentation of the diet. There were no significant differences in plasma adiponectin and resistin levels among the ZDF diet groups. In conclusion, the results of this study suggests that none of the wheat milling fractions stand out as responsible for the metabolic effects seen with consumption of whole wheat and that individual milling fractions of wheat are just as effective in improving insulin resistance and fatty liver as whole wheat.
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    Understanding the role of Lipocalin 2 as an important regulator of energy metabolism
    (2013-03) Zhang, Yuanyuan
    Lipocalin 2 (Lcn2) is a recently identified adipose tissue-derived cytokine which functions in innate immunity, inflammation, and insulin resistance. Nonetheless, the metabolic regulation and function of adipose Lcn2 is not completely understood. Herein, we investigated how adipose Lcn2 expression is regulated by metabolic challenges and nutrient signals, as well as how Lcn2 deficiency affects whole-body energy metabolism and lipid homeostasis. We found that Lcn2 mRNA expression was significantly upregulated during fasting and cold exposure in mice. Insulin stimulated Lcn2 expression and secretion in 3T3-L1 adipocytes in a dose-dependent manner, which was enhanced by glucose and attenuated by aspirin treatment. Multiple fatty acids also induced Lcn2 expression and secretion in adipocytes. The regulation of adipose Lcn2 by metabolic challenges and nutrient signals indicated a potential role of Lcn2 in energy metabolism. Next, we explored the metabolic consequences of Lcn2 deficiency in mice under high fat diet (HFD) conditions. We found that Lcn2 deficiency potentiated diet-induced obesity, dyslipidemia, fatty liver disease, and insulin resistance in mice. Moreover, Lcn2 knockout (KO) mice exhibited impaired adaptive thermogenesis and cold intolerance. Further studies showed that Lcn2 deficiency reduced the efficiency of cold-induced mitochondrial oxidation of lipids and blunted cold-induced activation of Uncoupling Protein 1 and expression of thermogenic and angiogenic genes, leading to lipid accumulation and thermogenic dysfunction of brown adipocytes. Interestingly, the administration of PPARgamma agonist effectively improved HFD-induced insulin resistance in Lcn2 KO mice without increasing body weight, subcutaneous fat mass, or lipid accumulation in liver. PPARgamma agonist administration also fully prevented cold-intolerant phenotype in Lcn2 KO mice. Our results indicate that Lcn2 plays a critical role in the regulation of lipid homeostasis and thermogenic activation via a possible mechanism of modulating PPARgamma activation.
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    The utility of skinfold thickness for estimating insulin resistance and serum triglycerides in adolescents
    (2010-12) Addo, Oppong Yaw
    Skinfold thickness has long been found to be highly correlated with total body fat. Yet it remains largely underutilized in comparison to other anthropometric measures. The ability of skinfold thickness to characterize adiposity-related health outcomes should contribute to its utility in studying these outcomes. Objective: To determine comparability of skinfold thickness with whole body total fat, measured by dual energy X-ray absorptiometry (DXA), and their relationships with insulin resistance and serum triglyceride levels in a large sample of US adolescents. The utility of skinfold thickness was evaluated by determining optimum subscapular percentile-cut points for identifying adolescents who are at risk of elevated insulin resistance. Methods: Pooled serial cross-sectional data from the continuous National Health and Nutrition Examination Survey (NHANES) cycles 2001-04 were analyzed. Primary data used included skinfold thicknesses, DXA-based total body fat (DXF), serum insulin and fasting glucose (for homeostasis model assessment of insulin resistance; HOMA-IR), and serum triglycerides. Data from a total of approximately 1500 US youths aged 12-18 years were used in this work. Findings from manuscript one demonstrated that skinfold thickness is comparably associated with both continuous HOMA and the upper quintile of elevated insulin resistance in adolescents as total body fat weight measured with DXA. Similarly, in manuscript two skinfold thickness was comparable to DXA in associations with variation in serum triglycerides, and in predicting adolescents who have elevated serum triglyceride levels. Additionally, subscapular skinfold was found to be better at identifying adolescent girls at risk of elevated serum triglyceride levels than DXA whole-body fat weight. In manuscript three, subscapular skinfold thickness was found to be sufficiently correlated with HOMA-IR to justify identification of age- and sex-specific percentile cut-offs for identifying elevated insulin resistance in adolescents. These new subscapular skinfold percentile cut-offs can be used as a screening tool for identifying US adolescents at risk of elevated insulin resistance, who can then be referred for subsequent follow-up and diagnostic studies. Findings from this dissertation have demonstrated that skinfolds are amply correlated with insulin resistance and serum triglyceride levels, thus supporting their wider use in anthropometric assessment of obesity and its related health outcomes in adolescents.