BACKGROUND: Long-term exposure to fine particulate matter (PM2.5) has been identified as a potential risk factor for developing type 2 diabetes mellitus (T2DM). Given the rising prevalence of T2DM and unhealthy concentrations of PM2.5 in China, our attention is brought to examining the association in this region of the world. Furthermore, rural China, although largely ignored, also finds itself suffering from increased risks of T2DM and high levels of PM2.5. OBJECTIVE: The goal of this study is to characterize the relationship between long-term exposure to PM2.5 and the risk of T2DM in rural China. We do so by confirming that greater long-term exposure to PM2.5 is associated with a higher risk of T2DM incidence, assessing the potential multiplicative and additive interactions with important covariates, and identifying constituents of PM2.5 that may be responsible for the effect PM2.5 on the increased incidence of T2DM. CONCLUSIONS: Greater long-term exposure to PM2.5 is associated with increased risk of developing T2DM in rural Deqing County, Zhejiang, China. Smoking status modifies the relationship between PM2.5 and T2DM incidence on a multiplicative scale. There is no synergism between smoking and PM2.5 in association with T2DM incidence. There is no conclusive evidence on which constituents of PM2.5 play greater roles in the adverse effects of PM2.5 on T2DM incidence.

Individuals with diabetes mellitus often develop complications that traditionally have been separated into microvascular pathologies, such as retinopathy, nephropathy and neuropathy, or macrovascular pathologies, including cardiovascular disease. Increasing evidence suggests that these micro- and macro-vascular complications may be linked. Our objective is to determine if direct effects of hyperglycemia on a microvascular bed that supplies cells in large arteries, the vasa vasorum, promotes diabetes-associated accelerated atherosclerosis. Normoglycemic apolipoprotein-E deficient (ApoE-/-) mice showed continuous atherosclerosis progression throughout the study that was directly correlated to increased vasa vasorum density with time. Hyperglycemic ApoE-/- Ins2+/Akita mice and streptozotocin-injected (STZ) ApoE-/- mice also demonstrated progressive plaque growth over time, but had accelerated atherosclerosis at 15 weeks of age compared to normoglycemic controls. The increased atherosclerosis in hyperglycemic mice correlated with impaired angiogenesis at 10 and 15 weeks of age. These mice showed increased expression for a marker of hypoxia in the atherosclerotic lesions yet decreased expression of vascular endothelial growth factor (VEGF), suggesting disruption of hypoxia-mediated angiogenesis. Cell culture experiments suggested that alternative splicing of an antiangiogenic form of VEGF in macrophages as well as post-translational modifications of macrophages and smooth muscle cells may contribute to reduced VEGF expression and decreased vasa vasorum neovascularization. After 25 weeks of age, vasa vasorum expansion plateaued in normoglycemic mice but continued to increase in hyperglycemic ApoE-/- STZ-injected mice. The increase in vasa vasorum neovascularization correlates to increases in plasma cholesterol. We have shown that hyperglycemia alters the microvascular structure of the vasa vasorum in two distinct mouse models of diabetes. Initially, elevations in glucose correlate to a significant reduction in lesion vascularization that results in increased lesional hypoxia that may promote the development and progression of atherosclerosis. At later time points there appears to be a burst of neovascularization that correlate with increases in cholesterol. / Thesis / Master of Science (MSc) / People with diabetes have elevated glucose levels that affect the vessels that distribute blood in our body. This puts them at higher risk of developing cardiovascular disease and having heart attacks and strokes. One set of vessels, known as the vasa vasorum, delivers blood to the walls of larger vessels. The primary goals of this study are 1) to determine if diabetes affects the vasa vasorum and, 2) to determine if changes to the vasa vasorum increase a person’s risk of developing cardiovascular disease. The results of this study show that diabetes in mice decreases the number of vasa vasorum vessels. The decrease in vasa vasorum blood vessels appears to influence the larger blood vessels they supply which promotes an environment that is more prone to cardiovascular disease. This information could be used in the future to develop drugs that target the vasa vasorum and possibly decrease cardiovascular events.

Diabetes Mellitus is chronic lifelong condition that continues to be a global health concern. Despite the development of insulin therapy in 1921, many diabetics are likely to endure a number of co-morbidities that impact their quality of life. Today, the search for additional diabetic therapies incorporates the investigation of various organ systems for their potential in attenuating disease development. Skeletal muscle is a striated tissue that is integral to metabolism, movement, and overall wellbeing, yet its significance to Diabetes Mellitus remains understudied, as compared to other metabolic tissues. Previous work has identified that diabetes promotes adverse changes to skeletal muscle physiology, function, and morphology, contributing to a complication referred to as diabetic myopathy. The capacity to adapt to changing internal and external cues, as achieved through skeletal muscle plasticity, permits the maintenance of skeletal muscle health; a term encompassing its metabolism, function, and/or structure. This malleability is primarily regulated by the function of muscle progenitor stem cells, referred to as satellite cells. While past research has shown that satellite cells are hindered in various diabetic states, the precise mechanisms through which these observations occur remain to be elucidated. The data presented herein identify impaired satellite cell activation in two sub-types of diabetes (Pre-Diabetes and Type 1 Diabetes), and shows that such results are mediated by alterations to intrinsic signalling cascades. Additional insight into a potential unifying mechanism mediating this response led to the identification of Lipocalin-2 and its influence on satellite cell function and muscle plasticity. The results uncovered in these studies have enhanced our understanding of the response of satellite cells in diabetes, and have identified a prospective therapeutic target for the attenuation of diabetic myopathy. / Dissertation / Doctor of Philosophy (PhD)

This document only includes an excerpt of the corresponding thesis or dissertation. To request a digital scan of the full text, please contact the Ruth Lilly Medical Library's Interlibrary Loan Department (rlmlill@iu.edu).

This document only includes an excerpt of the corresponding thesis or dissertation. To request a digital scan of the full text, please contact the Ruth Lilly Medical Library's Interlibrary Loan Department (rlmlill@iu.edu).

CD4+Foxp3+ Tregs can be induced in vitro by TGF-b stimulation. Here, CNS1 deficient CD4+ T cells were found to show compromised Foxp3 upregulation in vitro compared to CNS1 WT CD4+ T cells. Moreover, we could demonstrate that antigen-specific CD4+Foxp3+ Tregs can be induced in vivo by tolerogenic antigen stimulation. Parenteral application of agonist BDC2.5 mimetope induced Foxp3 expression in CD4+ BDC2.5 tg cells. We could show that induction of Foxp3 expression by tolerogenic peptide stimulation is impaired in CNS1 deficient CD4+ BDC2.5 tg cells compared to CNS1 WT CD4+ BDC2.5 tg controls. These results indeed indicate that in vivo induced Tregs share mechanistic characteristics with naturally occurring pTregs. Additional in vivo experiments with blocking monoclonal anti-TGF-b demonstrated that high dosage TGF-b blockade abrogated peptide-induced Foxp3 expression in CNS1 WT BDC2.5 tg CD4+ cells, akin to what is seen for impaired Foxp3 upregulation in peptide-stimulated CNS1 KO BDC2.5 tg CD4+ cells without anti-TGF-b-treatment. Adoptive transfer of CD4+CD25- T cells in T cell deficient recipients dramatically increased CD4+Foxp3+ Treg frequencies in both CNS1 WT CD4+ and CNS1 KO CD4+ donor cells. Despite an initially lower increase in Foxp3 expression in CNS1 KO donor cells compared to CNS1 WT donor cells early after transfer, in this setting impaired Treg induction in CNS1 deficient cells was not preserved over time. Consequently, diabetes onset and progression were indistinguishable between mice that received CNS1 WT or CNS1 KO donor cells. Additional Foxp3 induction by peptide stimulation of immunodeficient recipients after transfer of CNS1 WT BDC2.5. tg or CNS1 KO BDC2.5 tg donor cells was not detectable. / CD4+Foxp3+ Tregs können in vitro mittels TGF-b-Stimulation induziert werden. Im Rahmen dieses Projekts konnte bestätigt werden, dass CNS1-defiziente CD4+ T-Zellen im Vergleich zu CD4+ CNS1 WT-Zellen in vitro eine eingeschränkte Foxp3-Hochregulation zeigen. Des Weiteren konnten wir Antigen-spezifische CD4+Foxp3+ Tregs mittels tolerogener Antigenstimulation in vivo induzieren. Parenteral appliziertes BDC2.5-Mimetop induzierte die Foxp3 Expression in CD4+ BDC2.5 transgenen T-Zellen. Hierbei zeigten CNS1 KO BDC2.5 transgene CD4+ T-Zellen im Vergleich zu CNS1 WT BDC2.5 transgenen CD4+ T-Zell-Kontrollen eine eingeschränkte Hochregulation der Foxp3 Expression nach Mimetop-Stimulation. Peptid-induzierte CD4+Foxp3+ Tregs verhalten sich somit ähnlich wie natürlich vorkommende pTregs. Unter Verwendung höherer Dosen von anti-TGF-b zeigte sich bei Mimetop-Stimulation im in vivo Experiment eine eingeschränkte Foxp3-Hochregulation der CNS1 WT CD4+ BDC2.5 transgenen T-Zellen, ähnlich wie es bei CNS1 KO CD4+ BDC2.5 transgenen T-Zellen ohne anti-TGF-b-Behandlung zu beobachten war. ...

This document only includes an excerpt of the corresponding thesis or dissertation. To request a digital scan of the full text, please contact the Ruth Lilly Medical Library's Interlibrary Loan Department (rlmlill@iu.edu).

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There is strong evidence that skeletal muscle health is compromised in persons with type 1 diabetes mellitus (T1D). These impairments include reduced strength, mitochondrial dysfunction, and decreased satellite cell (SC) content. Maintaining healthy muscle requires successful muscle repair. Preclinical models of T1D consistently show impaired muscle regeneration. To date, the impact of T1D on human skeletal muscle repair has not been established; however, attenuated repair would account for the reduced functional capacity and premature institutionalization that often characterizes those with diabetes. The purpose of this study was to determine the impact of T1D on the recovery of skeletal muscle function, morphology, and ultrastructure after 300 unilateral eccentric contractions (90°/s) of the knee extensors. Eighteen men and women (18-30 years old) with (n=9) and without (n=9) T1D performed the exercise protocol. Pre-damage, and at 48- and 96-hours post-damage, subjects gave a blood sample and vastus lateralis biopsy, and performed a maximal isometric knee extension. Given the sex-specific differences in muscle damage, control and T1D men and women were analyzed together and separately. Force production and recovery were comparable between control and T1D men and women. Exercise-related increases in creatine kinase activity and ultrastructural damage were also comparable between groups. There was a trend towards T1D men having more type 2 fast-twitch muscle fibers than T1D women (p=0.055). While baseline SC content was not different between groups, proliferating SC content was trending lower at 48-, and higher at 96-hours post-damage in T1D women compared to controls (p=0.07). In those with T1D, there was no correlation between muscle damage and HbA1c, but HbA1c was strongly correlated with vigorous physical activity (r=0.881, p=0.002). Contrary to preclinical studies, our data is the first to show that skeletal muscle repair is largely unaltered in otherwise healthy young adults with T1D. We attribute these differences to glycemic control and speculate that muscle repair is unaffected if individuals are optimally managing their diabetes. Considering the exercise-related dysglycemia seen in T1D, our results emphasize a need to define the dose of physical activity required for those with diabetes to properly regulate their blood glucose levels. We expect that this would in turn, improve skeletal muscle health and ultimately, extend the healthy lifespan of those living with T1D. / Thesis / Master of Science in Medical Sciences (MSMS) / Type 1 diabetes mellitus (T1D) is a chronic disease where the body does not make enough insulin to control blood glucose levels. Overtime, unstable blood glucose levels can damage major organ systems, including skeletal muscle. Skeletal muscle plays a pivotal role in regulating our physical and metabolic capacities. In those with T1D, exercise-mediated improvements in muscle health have been shown to delay health complications. However, we do not know how diabetic skeletal muscle repairs from exercise in humans. In this thesis, we investigated the ability of skeletal muscle to recover from damaging exercise in young adults with T1D. For the first time, we showed that skeletal muscle repair was similar between otherwise healthy young adults with T1D and those without diabetes. Our findings suggest that persons with T1D can engage in high levels of physical activity without compromising their muscle health. Further studies are needed to understand how exercise type, intensity, and duration impact glycemic control in men and women with T1D.

Type 2 Diabetes Mellitus (T2DM), a metabolic disorder denoted by elevated blood glucose levels and insufficient insulin action, is growing in prevalence worldwide . Barriers to improving disease outcome resolve primarily around identifying and intervening during the preliminary stages of insulin resistance, a state clinically referred to as pre-diabetes. Emerging evidence suggests that mitochondrial dysfunction may underlie , and potentially precede, progressive insulin resistance, suggesting that biomarkers indicative of mitochondrial dysfunction could predict disease risk and status. In this study, we examined epigenetic modifications, in the form of DNA methylation, in the promoter region of peroxisome proliferator activated receptor gamma coactivator 1 alpha (PGC-1α), a known regulator of mitochondrial biogenesis. Following the initiation of a high fat diet, we observed significant genotypic (DNA methylation) and phenotypic (mitochondrial copy number) alterations in C57/BL6 rodent models. These changes preceded overt disease onset, as classified by clinically utilized indices, which included the homeostatic model assessment for insulin resistance (HOMA-IR), the homeostatic model assessment for β-cell dysfunction (HOMA- β), and the quantitative insulin-sensitivity check index (QUICKI). Our data indicate that methylation analysis may serve as an effective clinical parameter to use in conjunction with physiological criterion for the diagnosis of pre-diabetes and the assessment of T2DM disease risk, and adds to the growing body of work seeking to elucidate the role. / Doctor of Philosophy / High blood glucose, referred to as type 2 diabetes (T2DM), increases the risk for heart and kidney disease, blindness, stroke, and death. Efforts to prevent T2DM have centered primarily around behavioral interventions, which include increased physical activity and decreased caloric intake. Importantly, the interventions are most effective when implemented early on in disease progression. In this study, we sought to examine the effects of a high fat diet on the epigenetic profile of PGC-1α, a gene responsible for maintaining mitochondrial biogenesis. The mitochondria, the powerhouse of the cell, is responsible for maintaining the energy systems in the body. Therefore, we examined how increasing in caloric intake resulted in changes in the epigenetic profile of the PGC-1α promoter, and how these changes impacted mitochondrial number. Further, we sought to examine how hypermethylation of PGC-1α led to changes in gene and protein expression in the mitochondria. Results from our study indicate that DNA methylation changes preceded disease onset, as characterized by the homeostatic model assessment for insulin resistance (HOMA-IR), the homeostatic model assessment for β-cell dysfunction (HOMA- β), and the quantitative insulin-sensitivity check index (QUICKI). Our data indicate that methylation analysis may serve as diagnostic and risk assessment tool for pre-diabetes and T2DM in conjunction with physiological measures.