Type 2 diabetes mellitus self-management is a challenging process that brings forward a variety of emotional responses. The purpose of this work was to explore relationships between diabetes distress, self-efficacy and resilience and outcomes of glycosylated hemoglobin, quality of life and health status. A cross sectional descriptive design was used for this pilot study of 78 individuals enrolled from an Endocrine clinic in the Midwest United States and a Primary Care clinic in the southeast United States. Data were analyzed using descriptive statistics to characterize the sample and model variables. Spearman’s correlation was completed to identify relationships among variables. A stepwise building approach was used to identify significant interactions and determine predictors of the study outcomes. The results of this study confirm the presence of facilitators and barriers in type 2 diabetes mellitus self-management and their relationships with distal outcomes. The findings demonstrate that diabetes distress is a predictor of health status and quality of life. The findings of this study provide a link to other facilitator and barrier variables such as provider collaboration, diabetes self-management education, treatment regimen, ethnicity and years since diagnosis which can be incorporated into the comprehensive theoretical model. This study contributes to the understanding of the emotional aspect of diabetes as it relates to self-management of T2DM. Continuing this work will allow researchers to examine and better understand important factors of self-management. This ongoing work will hopefully lead to improved support in self-management efforts and better outcomes.

In Aedes aegypti, development and reproduction are regulated by juvenile hormone III (JH). This master regulatory hormone is synthesized by the corpora allata (CA), a pair of endocrine glands with neural connections to the brain. JH titers are largely determined by the rate of biosynthetic activity of the CA and are regulated by inhibitory and stimulatory factors. Like JH, the ecdysteroid 20-hydroxyecdysone (20E) is a key hormonal regulator and has been proposed as an allatoregulator in other insects. However, its part in the regulation of JH biosynthesis of mosquitoes was unknown. The specific aims of this dissertation were to (1) evaluate if 20E plays a role in the activation of the late pupal CA and (2) evaluate if 20E plays a role in the reactivation of JH synthesis in blood-fed females. To this end, we evaluated if 20E could prematurely activate JH biosynthesis in the CA of an early pupa (24h prior to eclosion or -24h). Remarkably, in vitro stimulation with 20E at -24h initiated JH synthesis at a time when transcript levels for most JH biosynthetic enzymes are low. Moreover, the application of 20E correlated with an increase in the enzymatic activity of juvenile hormone acid methyltransferase (JHAMT), a critical enzyme of the biosynthetic pathway. Additionally, separation of the CA from the brain increased JH synthesis. Together, these results indicate that 20E acts as a developmental mediator of CA maturation which overrides an inhibitory effect of the brain. In our previous aim we demonstrated that 20E mediates activation of the pupal CA which ensures the development of ovarian follicles of the newly emerged female. For mosquitoes, a blood-meal is required to complete vitellogenesis and results in suppression of CA activity. However, the CA must be reactivated to initiate the second gonotrophic cycle. Our findings show that in vitro stimulation with 20E at 24h post blood feeding reactivates the gland. Again, stimulation with the ecdysteroid resulted in increased activity of another key enzyme, farnesal dehydrogenase (FALDH). These results suggest a stimulatory role of 20E on the biosynthetic activity of the CA in the blood fed female.

Abstract not available

<p><strong><p>Abstract</p><em><p>Background and aim:</p>Diabetes mellitus (DM) is a chronic and progressive illness that affects all type of populations and ages. According to World health organization (WHO) by 2030 it will be 366 million people effected world wild. Many new drugs are Glucagon-like peptide-1 (GLP-1) based therapy for treatment of type 2diabetes. GLP-1 is released from the intestinal L-cells, and is a potent stimulator of glucose-dependent insulin secretion. The aim of this study was to investigate the effect of GLP-1 and its stable analogs on cell proliferation of GLP-1 secreting GLUTag cells. <em><p>Material and methods:</p>GluTag cells were incubated for 48h in DMEM medium containing (0.5% fetal bovine serum and 100 IU/ml penicillin and 100 μg/ml streptomycin and 3mM glucose concentration) in the present or absence of the agents. DNA synthesis was measured using 3H- thymidine incorporation and Ki67 antigen staining. Western blot were performed to investigate the present of GLP-1 receptor in GLUTag cells. <em><p>Results/conclusions:</p><p>These results suggest that GLP-1 regulates proliferation of the GLP-1-secreting cell through a feedback mechanism via its receptor. Since serum GLP-1 levels are decreased in type 2 diabetic patients, the effect of GLP-1 on the GLP-1-secreting cell proliferation suggested here provides a novel beneficial long-term effect of the incretin-based drugs in clinical practice i.e. through increase of the GLP-1-secreting cell mass, augmenting the incretin effect. In addition, the feedback mechanism action of GLP-1 reveals a new insight in regulation manner of the L-cell proliferation.</p>GLP-1(7-36) increased cell proliferation in GLUTag cells, an effect which was blocked by the GLP-1 receptor antagonist exendin(9-39). The GLP-1 receptor was expressed in GluTag cells. <em><p>Keywords:</p>Incretin hormone<em>, GLP-1, GLP-1 receptor, Exendin-4, Diabetes </em></em></em></em></em></strong></p>

4-nonylphenol (NP), a surfactant degradation product, is an unregulated, ubiquitous aquatic contaminant and endocrine disruptor, for which aquatic life criteria are currently under development by U.S. EPA. The effects of NP on estuarine amphipods and chinook salmon fry were investigated, and this dissertation reports research into the impacts of NP bioaccumulation on the amphipods and resultant endocrine disruption of their juvenile salmon predators. Sensitivity to, and bioaccumulation of, NP by benthic amphipods were quantified. Factors affecting the bioavailability of NP to three species of amphipod (Eohaustorius estuarius, Grandidierella japonica, and Corophium salmonis) were determined in contaminated sediments. Standard bioassay techniques were modified to determine toxicity and bioaccumulation, with varying amounts and differing nutritional qualities of sedimentary organic carbon. �����C-Ring-labeled NP was used as a tracer in the experiments to quantify amphipod exposures. NP was acutely toxic to Eohaustorius estuarius from aqueous exposures, mean (+/-SD) LC50=227 ��g/L +/- 56, 1 h mean reburial EC50=138 +/- 36. The predicted LC50 for NP (202 ��g/L) from an amphipod-derived structure-activity relationship was not significantly different (p>0.05) from our empirically derived LC50 (227 ��g/L). All three amphipod species accumulated significant NP body burdens. Accumulation was inversely proportional to the total amount of organic carbon, but it did not differ between types of organic matter. Calculated accumulation factors indicated that amphipods could be an important and previously unrecognized source of NP to higher trophic levels. Plasma vitellogenin (Vtg) was quantified in juvenile chinook salmon following dietary exposure to NP contaminated amphipods and aqueous exposure to multiple NP concentrations. Fry that had fed upon contaminated amphipods did not have significantly greater Vtg levels than controls; however, Vtg was detected in 30 percent of fry. NP aqueous concentrations at 60 and 240 ��g/L significantly induced Vtg in fry following 5 d exposures. The 240 ��g/L aquatic NP treatment fry had comparable levels of Vtg to the positive control treatment in which fry were injected 17B-estradiol. These results indicate that amphipods are potential vectors of sediment NP to higher trophic levels within the water column, including juvenile chinook salmon. / Graduation date: 2003

WW-domain binding protein-2 (WBP-2) was cloned as an E6-associated protein (E6-AP) interacting protein and its role in steroid hormone receptor (SHR) function was investigated. We show that WBP-2 differs from other SHR coactivators, as it specifically enhanced the transactivation functions of progesterone receptor (PR) and estrogen receptor (ER alpha), whereas it had no significant effect on the androgen receptor, glucocorticoid receptor or the activation functions of p53 or VP-16. We also demonstrated that, like other well characterized coactivators, WBP-2 contains an intrinsic activation domain. Depletion of endogenous WBP-2 with small interfering RNAs indicated that normal physiological protein level of WBP-2 was required for the proper functioning of ER alpha and PR. Moreover, chromatin immunoprecipitation (ChIP) assays demonstrate the hormone-dependent recruitment of WBP-2 onto an estrogen-responsive promoter. As we initially identified WBP-2 as an E6-AP interacting protein, we investigated whether WBP-2 and E6-AP function in concert. Our data shows that WBP-2 and E6-AP each enhance PR function and when co-expressed they additively enhance the transactivation functions of PR. However, WBP-2 was also able to enhance the transactivation functions of ER alpha and PR in mouse embryonic fibroblast cells generated from E6-AP knockout mice lines, suggesting that the coactivation functions of WBP-2 was not dependent on E6-AP. The further elucidate the molecular mechanism of action of WBP-2; we dissected the functional importance of the polyproline (PY) motifs contained within the WBP-2 protein. Mutational analysis suggests that one of three PY motifs, PY3 of WBP-2 was essential for its coactivation and intrinsic activation functions. In this study, we also demonstrate that the WBP-2 binding protein, Yes-kinase associated protein 1 (YAP1) acts as a secondary coactivator of ER alpha and PR. However, the coactivation function of YAP1 is revealed only in the presence of wild-type WBP-2 and not with the PY motif 3 mutant WBP-2. This is consistent with our observations that, unlike the wild-type WBP-2, the PY motif 3 mutant WBP-2 does not interact with YAP1. Our quantitative reChIP assays demonstrates an estrogen-dependent recruitment and association of ER alpha with both WBP-2 and YAP1. The hormone-dependent recruitment of YAP1 to ER alpha responsive promoter is dependent on the physiological expression levels of WBP-2. This is consistent with, our observation that the coactivation functions of YAP1 is dependent on WBP-2, and is also in agreement with other known secondary coactivators that get recruited to SHR responsive promoter via their interaction with primary coactivators. Surprisingly, the association of WBP-2 with ER alpha and its recruitment to the ER alpha target promoter was abrogated by YAP1 knock-down, suggesting that WBP-2 and YAP1 may stabilize each other at the promoter, and consequently, are functionally interdependent. Taken together our data establish the role of WBP-2 and YAP1 as selective coactivators for ER alpha and PR transactivation pathways.

Abstract Background and aim: Diabetes mellitus (DM) is a chronic and progressive illness that affects all type of populations and ages. According to World health organization (WHO) by 2030 it will be 366 million people effected world wild. Many new drugs are Glucagon-like peptide-1 (GLP-1) based therapy for treatment of type 2diabetes. GLP-1 is released from the intestinal L-cells, and is a potent stimulator of glucose-dependent insulin secretion. The aim of this study was to investigate the effect of GLP-1 and its stable analogs on cell proliferation of GLP-1 secreting GLUTag cells. Material and methods: GluTag cells were incubated for 48h in DMEM medium containing (0.5% fetal bovine serum and 100 IU/ml penicillin and 100 μg/ml streptomycin and 3mM glucose concentration) in the present or absence of the agents. DNA synthesis was measured using 3H- thymidine incorporation and Ki67 antigen staining. Western blot were performed to investigate the present of GLP-1 receptor in GLUTag cells. Results/conclusions: These results suggest that GLP-1 regulates proliferation of the GLP-1-secreting cell through a feedback mechanism via its receptor. Since serum GLP-1 levels are decreased in type 2 diabetic patients, the effect of GLP-1 on the GLP-1-secreting cell proliferation suggested here provides a novel beneficial long-term effect of the incretin-based drugs in clinical practice i.e. through increase of the GLP-1-secreting cell mass, augmenting the incretin effect. In addition, the feedback mechanism action of GLP-1 reveals a new insight in regulation manner of the L-cell proliferation. GLP-1(7-36) increased cell proliferation in GLUTag cells, an effect which was blocked by the GLP-1 receptor antagonist exendin(9-39). The GLP-1 receptor was expressed in GluTag cells. Keywords: Incretin hormone, GLP-1, GLP-1 receptor, Exendin-4, Diabetes

Oestrogens are produced by aromatisation of androgens by the aromatase enzyme. In the vertebrate brain this synthesis has vital functions in nerve protection, cell proliferation and nerve development during injury respectively brain development. Brain oestrogens are also crucial in activating certain reproductive and aggressive behaviours in mammals and birds. Teleosts have remarkably high activity of brain aromatase (bAA) compared to mammals and birds; 100-1000 times higher in brain regions like the hypothalamus, pre-optic area and optic tectum. The role of brain oestrogens in teleost behaviour is, however, less clear than in e.g. songbirds and rodents. This thesis studies the potential role of brain aromatase and brain oestrogens in the reproductive behaviour of the guppy male (Poecilia reticulata), how guppy brain aromatase responds to steroids and is distributed in the adult brain. The thesis shows that male behaviour can be affected by brain aromatase. Reduction of bAA by aromatase inhibitor treatment reduced the sexual behaviours sigmoid display and gonopodium swinging (I) and oestrogen receptor blocking with an oestrogen antagonist reduced the number of successful mating attempts (II). The anatomical study (IV) showed that brain aromatase is distributed in areas of the adult guppy brain that are connected to reproductive control and behaviour in vertebrates. Guppy bAA is stimulated by both androgens and oestrogens (III) but is more sensitive to oestrogens, especially in males, and could thus be used as an indicator of endocrine disruption at low concentrations found in the environment. The thesis can also conclude that females possess more brain aromatase than males, and that although it is expressed in the same pattern throughout the brain in both genders the enzymatic activity is differently distributed between the sexes. / Aromatase and androgens in fish reproductive behaviour

The bank vole (Microtus arvalis) develops glucose intolerance both when kept in captivity and in the wild state. Glucose intolerant bank voles kept in captivity exhibited polydipsia, polyuria, hyperglycemia, hyperinsulinemia, islet autoantibodies and a markedly changed islet structure resembling so–called hydropic degeneration. Islets showing hydropic degeneration have reduced β–cell mass. However, the relative islet size to total pancreas area was not changed. Pancreatic islet isolated from glucose intolerant bank voles had an altered islet function showing signs of being exposed to an increased functional demand on their β–cells. Also, islets from male bank voles seem more affected than the islets from females. Islets isolated from glucose tolerant male bank voles cultured for 5 days at 28 mM glucose did not reveal any change in insulin gene expression or insulin biosynthesis rate. However, islets from female bank voles displayed a glucose concentration dependent response. This suggests that there is gender difference in that, islets of female more easily than islets of males adapt to elevated glucose concentration. Furthermore, islets isolated from glucose tolerant males had reduced insulin gene expression after exposure to proinflammatory cytokines for 48 hrs. This effect seemed to be NO-independent since only a minor elevation of nitrite accumulation in the medium was seen, and the use of iNOS inhibitor could not counteract the cytokine effect. The observed response seen in bank vole islets upon exposure to various glucose concentrations or proinflammatory cytokines is similar to those seen in studies of human islets. The bank vole may therefore represent a novel animal model for the study of diabetes. An unresolved issue is the role of the Ljungan virus which is found in the bank vole colony. Bank voles developing glucose intolerance display features of both human type 1 and type 2 diabetes, where environmental factors seems to play an important role as determinant. Our findings suggest that bank voles bred in the laboratory may develop more of a type 2 diabetes. However, bank voles caught in nature instead may rather develop a type 1 form of the disease.

Androgens (such as testosterone) have been shown to increase lean body mass and reduce fat body mass in men through activation of androgen receptors (AR). While this suggests a potential clinical use for androgens, attempts at utilization of this class of hormones as a therapeutic are limited by side effects due to indiscriminate AR activation in various tissues. Thus, a greater understanding of the tissues and cells involved in promoting these changes would be beneficial. Here we show that selective overexpression of AR in muscle cells of transgenic (HSA-AR) rodents both increases lean muscle mass and significantly reduces fat mass in males. Similar effects can be induced in HSA-AR females treated with testosterone. Metabolic analyses of HSA-AR males show that these animals demonstrate increased O2 consumption and hypermetabolism. Thus, targeted activation of AR in muscle regulates body composition and metabolism, suggesting a novel target for drug development.