Thesis (doctoral)--Universität der Bundeswehr München, 1995. / Includes bibliographical references.

Thesis (doctoral)--Universität der Bundeswehr München, 1995. / Includes bibliographical references.

Exposure to certain stressors during a sensitive period around puberty can lead to enduring effects on an animal’s response to estradiol. In estradiol-influenced behaviors, such as sexual receptivity, hippocampal-dependent learning and memory, depression-like behavior, and anxiety-like behaviors, exposure to a peripubertal stressor such as shipping stress or an injection of lipopolysaccharide (LPS) can eliminate or even reverse the normal response to estradiol. In addition to regulating these behaviors, estradiol play a role in the regulation of body weight. While some of the previous studies touched on short-term effects on body weight, no systemic long-term study of the effects of a peripubertal stressor on body weight, particularly without interruption by ovariectomy, have been undertaken. This paper introduces a hypothesis that proposes that increased adiposity following exposure to a peripubertal stressor leads to the changes to estrogen-dependent behaviors through altered levels of estrogens and changes to estrogen receptors. The first chapter examines body weight data collected during studies with other aims, and then proposes an experiment to test whether either of two peripubertal stressors results in increased weight gain and body weight. The following chapter proposes further experiments designed to determine the proximate mechanisms leading to weight gain following peripubertal stressors and the role of diet on weight gain. The final chapter proposes experiments to test the effects of adiposity on peripheral levels of testosterone, aromatase, estradiol, and estrone; central levels of estradiol and estrone; and estrogen receptors in the brain.

<p>The risk of fracture is higher in adults with type 2 diabetes compared to controls without type 2 diabetes, despite normal or higher than normal bone mineral density (BMD). In addition to BMD, bone strength depends on other factors such as structural and material <em>bone qualities</em>, which are not accounted for in BMD measurements. The objective was to determine whether structural and material <em>bone qualities</em> are different in adults with type 2 diabetes compared to controls without type 2 diabetes. First, a cross-sectional study was undertaken using MRI to investigate distal radius trabecular bone microarchitecture, a structural <em>bone quality.</em> In women with type 2 diabetes, trabecular bone holes were larger compared to controls, which is important because greater trabecular bone hole size is related to reduced bone strength. Next, a two year prospective study was conducted with the participants involved in the cross-sectional study to determine whether changes in trabecular bone microarchitecture are different in women with type 2 diabetes compared to controls. There was a greater increase in the number of trabecular bone holes in women with type 2 diabetes compared to controls, which provides early evidence of trabecularization of cortical bone in women with type 2 diabetes. In the third study, quantitative backscattered electron imaging (qBEI) was used to derive bone mineralization density distribution (BMDD) outcomes for bone samples from adults with and without type 2 diabetes to compare material <em>bone quality. </em>There was evidence of elevated bone calcium concentration and reduced mineralization heterogeneity in bone samples from adults with type 2 diabetes compared to controls, which may contribute to bone brittleness. In summary, differences in structural and material <em>bone qualities </em>identified in this body of work provide explanations for elevated fracture risk in adults with type 2 diabetes.</p> / Doctor of Science (PhD)

Prostate and breast cancer are the leading causes of cancer-related death in men and women, respectively, and metastasis is the primary factor underlying the high mortality rates.1 Snail transcription factor is an important molecule that drives prostate and breast cancer metastasis through the process of epithelial mesenchymal transition (EMT). Proteolytic enzymes that promote invasion and metastasis such as the lysosomal cysteine protease cathepsin L (Cat L) have been shown to degrade E-cadherin, promoting the epithelial mesenchymal transition (EMT).2 It has also been shown that silencing Cat L can inhibit transforming growth factor-beta (TGF-β)-mediated EMT by suppressing Snail transcription factor.3 Several recent studies have highlighted an additional unexpected localization and site of action for Cat L within the nucleus in breast, colon and prostate cancer.4 Natural products have been shown to be efficacious in prevention and possible treatment of cancer.5 Specifically, we have been studying Muscadine Grape Skin Extract (MSKE) as a possible candidate to inhibit Snail signaling. MSKE has previously been shown to promote prostate cancer apoptosis.6 We hypothesized that Snail promotes nuclear localization of Cat L, which promotes EMT associated with increased migration and invasion, and that antagonizing Snail-Cat L signaling would lead to mesenchymal epithelial transition (MET). We showed for the first time that MSKE promotes apoptosis through induction of endoplasmic reticulum stress response and autophagy. Additionally, MSKE could inhibit Snail-mediated EMT via scavenging reactive oxygen species. Moreover, Snail could promote nuclear localization of Cat L, which then promoted cleavage of CDP/Cux, increased Snail transcription and decreased E-cadherin transcription by direct promoter binding of cleaved CDP/Cux, leading to EMT associated with increased migration and invasion. Interestingly, Z-FY-CHO, a small molecule specific inhibitor of Cat L, as well as MSKE could antagonize this signaling by promoting nuclear to cytoplasmic re-localization of Cat L. Therefore, we have dissected novel mechanisms of action of Snail and how it can be antagonized by MSKE natural product.

Introduction: Rates of childhood-onset type 1 diabetes (T1D) are steadily increasing among American youth, yet Black Americans are more likely to suffer from serious T1D-related complications caused by poor glycemic control. The aim of this thesis is to determine the external factors that are causing discrepancies in the development, diagnosis, treatment, and long-term management of T1D in Black youth. Methods: Epidemiological studies were compiled from the American Diabetes Association, Center for Disease Control (CDC), International Diabetes Foundation (IDF), Kaiser Family Foundation (KFF), and the Claremont Colleges Library network to identify the sociocultural aspects that negatively affect long-term glycemic control in Black youth. Results: Studies indicate that Black youth with T1D are more likely to face disadvantages in treatment regimen which are attributed to insurance coverage, socioeconomic status, education level, and implicit bias. Most studies demonstrate that these factors result in poor glycemic control, which subsequently leads to severe dysglycemia-related complications later in life. Conclusion and Discussion: Many Black youth who suffer from T1D receive insufficient healthcare, which is often exacerbated by a lack of social and economic resources. As a result, they may not have the means to maintain consistent, healthy glycemic levels. System-level changes are necessary to change the morbidity and mortality of T1D in Black youth. Future research should include the analysis of other racial minority groups in order to uncover additional institutional disparities.

Up to 60% of individuals with type 2 diabetes (T2DM) do not participate in regular physical activity (PA) despite the known benefits. To encourage these individuals to increase PA behavior, this study tested the feasibility and implementation of a nurse-directed counseling intervention using continuous glucose monitoring system (CGMS). The study used a framework derived from self-efficacy theory to 1) compare changes in self-efficacy, BP and activity counts between participants receiving CGMS counseling and standard T2DM counseling, 2) examine relationships between PA self-efficacy and BP and activity counts, 3) evaluate recruitment, retention, and screening strategies, and 4) assess instrument reliability and utility. Adults (N=52) with T2DM (non-insulin requiring, inactive) were randomized to intervention (n=27) or control groups (n=25). Both groups received 90 minutes of diabetes education with a follow-up phone call at 4 weeks. The intervention group also received feedback on their own CGMS graphs and a role model's graph depicting PA related reductions in glucose levels. PA benefits/barriers were discussed and goals were set. Outcomes were recorded at 1 and 8 weeks. Participants were older (57±14 years), predominantly (90%) white, about half (52%) female, and had diabetes for 8±7 years. Relative to the control group, participants receiving the intervention had higher self-efficacy scores at 8 weeks, indicating more confidence in sticking to a PA program. Their light/sedentary activity minutes decreased significantly and moderate activity minutes increased significantly; systolic BP, A1c and BMI decreased significantly. Only self-efficacy for "Sticking to it" was positively associated with moderate activity. The most successful recruitment media was multiple newspaper press releases. Most referrals came from endocrinology physicians. Of 231 study volunteers, 106 did not meet the criterion of A1c≥7.5%. These data suggest that CGMS feedback is feasible for counseling individuals with T2DM to improve PA and may improve risk factors for diabetes-related complications. Newspaper press releases are effective for recruiting participants with T2DM. Less restrictive inclusion criteria in a larger study may allow more participation by sedentary individuals with T2DM but may reduce effect size. CGMS was well tolerated and its data aided diabetes-related teaching.

Strategies aimed at expanding functional beta cell mass remain a prime goal of diabetes research. Both the insulin signaling pathway, as well as the G1/S transition of the cell cycle are critically important for the maintenance of beta cell mass. We previously demonstrated in a mouse model of diabetes, insulin receptor substrate 2 (Irs2) deficient mice, that beta cell failure was attributed to reduced islet expression of Cyclin D2, and that overexpressing Cyclin D2 rescued proliferation in Irs2 deficient beta cells in vitro. Since Cyclin D2 partners with CDK4 to drive cell cycle progression, we hypothesized that an activated form of CDK4, Cdk4-R24C (resistant to inhibition by the INK4A cell cycle inhibitor p16), would rescue the in vivo proliferation defect in Irs2 deficient mice. Interestingly, Irs2 knockout mice with the active Cdk4 R24C allele, displayed rescued blood glucose, and normalized glucose tolerance, without affecting peripheral insulin resistance. I found that both and beta cell mass and proliferation were rescued in vivo, contributing to the rescue of glucose tolerance. Interestingly, the dedifferentiated phenotype of Irs2 knockout islets (ALDH1A3+ cells, nuclear FOXO1 and suppressed PDX1) was completely restored with the active Cdk4 allele, suggesting that CDK4 may play a role in promoting beta cell differentiation. Utilizing various in vitro models where FOXO1 represses Pdx1, overexpression of CDK4/CyclinD2 was consistently able to rescue the FOXO1-mediated repression of Pdx1, without significant impacts on FOXO1 subcellular localization. These results suggested that FOXO1 regulation in the beta cell is more complex than previously described, and also suggested that CDK4/Cyclin D2 may be instead modulating the acetylation status of FOXO1, impacting its transcriptional activity. To this end, inhibiting histone acetylate transferases (HATs) partially rescued FOXO1-mediated Pdx1 suppression, while inhibiting histone deacetylase enzymes (HDACs) showed the reverse effect of trending towards blocking the Cyclin D2/CDK4-mediated rescue of Pdx1. Finally, I found that CDK4/Cyclin D2 increases phosphorylation of sirtuin 1 (SIRT1), an HDAC that modulates the acetylation status, and transcriptional activity of FOXO1, and that CDK4/Cyclin D2 promotes FOXO1 degradation. In sum, we conclude that activated CDK4 rescues beta cell failure due to IRS2 deficiency through multiple mechanisms related to not only cell cycle regulation but also to beta cell differentiation status, primarily through modulation of FOXO1 transcriptional activity.

The ever-increasing prevalence of diabetes mellitus and its associated healthcare costs in the United States has led to our healthcare system's need for cost-effective health resources and chronic disease management. The interventions of Community Health Workers (CHWs) can cost-effectively improve population health and prevent the unnecessary utilization of some medical services especially in rural, low-income, minority populations, where there is often limited access to healthcare. The purpose of this study is to investigate the relationship between the number of total CHWs in rural counties and the mean diabetes-related preventable hospitalization rates in Latino patients diagnosed with diabetes in those rural counties. The main goal of this research study is to contribute to the existing literature about the importance of CHWs especially in rural counties and the effect their presence has on diabetes-related preventable hospitalizations. Quantitative rural county data sets were analyzed to determine the correlation between the number of CHWs per rural county and the rate of diabetes-related preventable hospitalizations per rural county. Due to the COVID-19 pandemic outbreak, this research project was modified to be completed in a timely manner. A statistically insignificant moderately negative linear relationship was found between the two variables. Therefore, there was not enough statistical evidence in the sample to say that this correlation exists in the rural America population. Future research is needed to investigate this relationship more thoroughly.

Noninvasive assessment of diabetic cardiovascular autonomic neuropathy (AN): Cardiac and vascular dysfunctions resulting from AN are complications of diabetes, often undiagnosed. Our objectives were to: 1) determine sympathetic and parasympathetic components of compromised blood pressure regulation in patients with polyneuropathy, and 2) rank noninvasive indexes for their sensitivity in diagnosing AN. Continuous 12-lead electrocardiography (ECG), blood pressure (BP), respiration, regional blood flow and bio-impedance were recorded from 12 able-bodied subjects (AB), 7 diabetics without (D0), 7 with possible (D1) and 8 with definite polyneuropathy (D2), during 10 minutes supine control, 30 minutes 70-degree head-up tilt and 5 minutes supine recovery. During the first 3 minutes of tilt, systolic BP decreased in D2 while increased in AB. Parasympathetic control of heart rate, baroreflex sensitivity, and baroreflex effectiveness and sympathetic control of heart rate and vasomotion were reduced in D2, compared with AB. Baroreflex effectiveness index was identified as the most sensitive index to discriminate diabetic AN. Four-dimensional multiscale modeling of ECG indexes of diabetic autonomic neuropathy: QT interval prolongation which predicts long-term mortality in diabetics with AN, is well known. The mechanism of QT interval prolongation is still unknown, but correlation of regional sympathetic denervation of the heart (revealed by cardiac imaging) with QT interval in 12-lead ECG has been proposed. The goal of this study is to 1) reproduce QT interval prolongation seen in diabetics, and 2) develop a computer model to link QT interval prolongation to regional cardiac sympathetic denervation at the cellular level. From the 12-lead ECG acquired in the study above, heart rate-corrected QT interval (QTc) was computed and a reduced ionic whole heart mathematical model was constructed. Twelve-lead ECG was produced as a forward solution from an equivalent cardiac source. Different patterns of regional denervation in cardiac images of diabetic patients guided the simulation of pathological changes. Minimum QTc interval of lateral leads tended to be longer in D2 than in AB. Prolonging action potential duration in the basal septal region in the model produced ECG and QT interval similar to that of D2 subjects, suggesting sympathetic denervation in this region in patients with definite neuropathy.