近年來，腸促胰島素類藥物胰高血糖素樣肽－1受體（GLP-1R）激動劑（如liraglutide，exenatide）和二肽基肽酶-4（DPP-4）抑制劑（如sitagliptin，vildagliptin）在2型糖尿病治療中得到廣泛應用。然而，2型糖尿病患者中腸促胰島素效應嚴重受損。研究表明，2型糖尿病患者的腸促胰島素激素（GLP-1和GIP）分泌並不顯著降低，因此腸促胰島素效應受損主要是由於2型糖尿病患者中β細胞對腸促胰島素激素反應性降低。GIP在2型糖尿病患者中刺激胰島素分泌的功能幾乎完全消失。相比較，GLP-1刺激胰島素分泌功能在2型糖尿病患者中部分保留。2型糖尿病中腸促胰島素效應受損的具體機制目前仍不清楚。本論文主要從2型糖尿病患者的腸促胰島素效應受損的機理及對腸促胰島素類藥物療效的影響上進行相關研究。 / 我們較早的研究發現高血糖能降低胰島β細胞GLP-1R受體的表達，從而損傷胰島β細胞GLP-1R信號通路是2型糖尿中腸促胰島素受損的部分原因。由於高血脂和高血糖都是糖尿病的主要特徵，我進一步研究了高血脂對β細胞的腸促胰島素信號通路的影響。體外實驗表明，棕櫚酸能降低胰島β細胞中GLP-1R的表達，並且抑制了GLP-1刺激的cAMP產生及CREB的磷酸化；在β細胞中外源性表達GLP-1R能部分恢復棕櫚酸損傷的GLP-1刺激cAMP產生及CREB的磷酸化。此外，在db/db小鼠和HFD誘導的肥胖及糖尿病小鼠模型中，降脂藥bezafibrate和niacin 能顯著提高腸促胰島素類藥物sitagliptin 和exendin-4的降糖效果，並且伴隨著對胰島形態結構的改善以及增加胰島β細胞質量。 / 另一方面，2型糖尿病患者胰島β細胞的功能和品質持續性的減少。其中慢性的高血糖和高血脂是兩個主要因素。臨床研究發現sitagliptin的降糖效果隨著糖尿病持續的時間增加而降低，而具體機理並不清楚。我們以前研究發現高血糖損傷胰島β細胞GLP-1R的表達及其信號通路是2型糖尿病腸促胰島素效應受損的重要原因。我進一步探討了exendin-4在STZ-HFD 誘導的較輕程度糖尿病（MH）小鼠（相對較輕的高血糖以及β細胞質量減少）和重度糖尿病(SH)小鼠（嚴重高血糖以及β細胞質量減少）的治療效果。研究發現， exendin-4只在MH小鼠中顯著降低血糖，改善糖耐量，恢復正常胰島結構及增加β細胞質量。而在兩組小鼠中exendin-4 都能降低體重，增加胰腺重量，但對食都沒影響。儘管exendin-4能顯著降低MH小鼠中胰島素耐量實驗葡萄糖水平，但HORM-IR無顯著差異。此外，exendin-4處理對胰島素刺激的肝臟及肌肉組織中磷酸化AKT和GSK水準在兩組小鼠中都無明顯改變。 / 總之，我的研究強調了血糖血脂的控制在2型糖尿病患者中的重要作用。我也發現高血糖、高血脂導致2型糖尿病患者β細胞功能持續受損的同時也損傷了GLP-1R信號通路，以至腸促胰島素類藥物療效的降低。我們的研究對腸促胰島素類藥物在2型糖尿病患者中的合理使用提供了重要資訊。 / Incretin-based drugs, such as glucagon-like peptide-1 (GLP-1) receptor agonists (e.g. liraglutide and exenatide) and dipeptidyl peptidase-4 (DPP-4) inhibitors (e.g. sitagliptin and vildagliptin), which inhibit degrading intact GLP-1, have been a novel therapeutics for the treatment of type 2 diabetes. Type 2 diabetes mellitus (T2DM) is associated with reduced incretin effects. The underlying mechanism, however, is not well understood. / Our previous studies showed that hyperglycemia downregulates glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) which potentially contributes to the impaired incretin responses in cells. Whereas the effects of hyperlipidemia, another common clinical feature of T2DM, on GLP-1 response is largely unknown. In this study, I investigated the effects of free fatty acids (FFA) on incretin receptor signalings, and examined the glucose-lowering efficacy of incretin-based drugs in combination with lipid-lowering agents. I found that palmitate treatment decreased GLP-1R expression in rodent insulinoma cell lines, which was associated with impaired GLP-1 stimulated cAMP production and phosphorylation of CREB. Over-expression of GLP-1R restored the cAMP production and the phosphorylation of CREB. Treatment with bezafibrate or niacin in combination with des-fluoro-sitagliptin or exendin-4 produced more robust glycemic control associated with improved pancreatic islet morphology and islet cell function in db/db mice and HFD-fed mice. / On the other hand, chronic hyperglycemia and hyperlipidemia can cause a progressive deterioration in pancreatic beta-cell function and mass in patients with type 2 diabetes mellitus. It has been reported that the efficacy of incretin-based therapeutics is attenuated with the duration of diabetes. In our previous study, we have shown that hyperglycemia downregulates GLP-1 receptor which in turn may contribute to the impaired incretin effect in type 2 diabetes. In this study, I further investigated the efficacy of GLP-1 based drug exendin-4 in a rodent model of type 2 diabetes with different degrees of hyperglycemia and reduction of beta cell mass. I found that in moderate hyperglycemia (MH) group but not in severe hyperglycemia (SH) group, exendin-4 treatment significantly reduced fed glucose levels and plasma lipid profiles, improved glucose tolerance and glucose stimulated insulin secretion, and was associated with restored islets morphology and increased beta cell mass. Exendin-4 significantly decreased body weight gain and increased pancreatic mass both in MH and SH group. Although glucose levels were significantly reduced in MH group with exentin-4 treatment during insulin tolerance test, exendin-4 had no effects on HORM-IR, food intake, and insulin stimulated p-AKT/p-GSK in liver and muscle in both MH and SH group. / In summary, my findings highlight the importance of comprehensive lipid and glycemic control in type 2 diabetes mellitus. I found that factors including hyperglycemia and hyperlipidemia that cause progressive decline in beta cell failure impaired beta cell GLP-1R signaling as well as the efficacy of incretin-based therapies. These results add to our knowledge regarding the mechanism of incretin-based therapy in improving glycemic control in type 2 diabetic patients and provide new insights in designing treatment strategies including incretin-based therapy for type 2 diabetic patients. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Kang, Zhanfang. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 103-123). / Abstract also in Chinese. / 論文摘要 --- p.viii / Impaired Incretin Effects in Type 2 Diabetes: Mechanism and Therapeutic Implication --- p.1 / DECLARATION --- p.i / ACKNOWLEGEMENTS --- p.ii / ABBREVIATIONS --- p.iii / PUBLICATIONS AND AWARDS --- p.v / Chapter 1 --- Abstract --- p.vi / Chapter 2 --- Chapter : Introduction --- p.1 / Chapter 2.1 --- The history of incretin discovery --- p.1 / Chapter 2.2 --- The incretin hormones:GLP-1 and GIP --- p.1 / Chapter 2.3 --- Gene structure and regulation of incretin hormone gene expression --- p.2 / Chapter 2.3.1 --- Gene structure and regulation of GLP-1 gene expression --- p.2 / Chapter 2.3.2 --- Gene structure and regulation of GIP gene expression --- p.5 / Chapter 2.4 --- Secretion and metabolism of GLP-1 and GIP --- p.5 / Chapter 2.4.1 --- Regulation of GLP-1 and GIP secretion --- p.5 / Chapter 2.4.2 --- Degradation of GLP-1 and GIP by DPP-4 enzyme --- p.8 / Chapter 2.5 --- GLP-1 and GIP receptor --- p.10 / Chapter 2.6 --- biological actions of GLP-1 and GIP --- p.11 / Chapter 2.6.1 --- Actions of GLP-1 in peripheral tissues --- p.12 / Chapter 2.6.2 --- Actions of GIP in peripheral tissues --- p.17 / Chapter 2.7 --- Impaired incretin effect in type 2 diabetes patients --- p.17 / Chapter 2.7.1 --- Secretion of incretin hormones in patients with type 2 diabetes --- p.18 / Chapter 2.7.2 --- Impaired the responsiveness to GLP-1 and GIP in pancreatic beta cells --- p.19 / Chapter 2.8 --- Incretin-based drugs --- p.19 / Chapter 2.9 --- Type 2 diabetes and beta cell failure --- p.21 / Chapter 2.9.1 --- Natural history of type 2 diabetes --- p.21 / Chapter 2.9.2 --- Decline of beta cell function and mass in type 2 diabetes --- p.22 / Chapter 2.9.3 --- Factors for progressive loss of beta cell function and mass --- p.24 / Chapter 3 --- Chapter: Pharmacological reduction of free fatty acids restores the efficacy of incretin-based therapies in diabetic mouse models through beta cell GLP-1 receptor signalings --- p.30 / Chapter 3.1 --- Summary --- p.30 / Chapter 3.2 --- Introduction --- p.32 / Chapter 3.3 --- Materials and Methods --- p.35 / Chapter 3.3.1 --- Chemicals and Reagents --- p.35 / Chapter 3.3.2 --- Preparation of 8 mM sodium palmitate solution with 10.5% BSA --- p.35 / Chapter 3.3.3 --- Construct of an adenoviral vector for expressing mouse GLP-1R --- p.36 / Chapter 3.3.4 --- Cell culture and treatment --- p.37 / Chapter 3.3.5 --- RNA extraction and quantitative RT-PCR --- p.37 / Chapter 3.3.6 --- Analysis of phosphorylation of CREB --- p.38 / Chapter 3.3.7 --- Measurement of insulin secretion --- p.39 / Chapter 3.3.8 --- RT-PCR analysis of mouse GLP-1R expression --- p.39 / Chapter 3.3.9 --- Measurement of cAMP production --- p.40 / Chapter 3.3.10 --- Animals and experimental protocols --- p.40 / Chapter 3.3.11 --- Oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) --- p.41 / Chapter 3.3.12 --- Acute glucose-lowering actions of Ex-4 and D-GIP in db/db Mice --- p.41 / Chapter 3.3.13 --- Lipid levels measurement --- p.42 / Chapter 3.3.14 --- Histological analysis --- p.42 / Chapter 3.3.15 --- Statistical analysis --- p.42 / Chapter 3.4 --- Results --- p.43 / Chapter 3.4.1 --- Reduced expression of GLP-1R in palmitate-treated b cells and islets of hyperlipedemic db/db mice. --- p.43 / Chapter 3.4.2 --- Palmitate impairs GLP-1 stimulated cAMP production and p-CREB in rodent insulinoma cell lines --- p.45 / Chapter 3.4.3 --- Palmitate reduced GLP-1 and GIP stimulated insulin secretion in rat INS-1E cells --- p.46 / Chapter 3.4.4 --- Mouse GLP-1R mRNA is expressed in rat INS-1E cells after infected with Ad-GLP-1R --- p.47 / Chapter 3.4.5 --- Expression of exogenous GLP-1R restores GLP-1 stimulated cAMP production and p-CREB in palmitate-treated rodent insulinoma cell lines --- p.48 / Chapter 3.4.6 --- Lipid lowering enhances the efficacy of DPP-4 inhibitor des-fluoro-sitagliptin in db/db mice --- p.50 / Chapter 3.4.7 --- Lipid-lowering enhances the efficacy of DPP-4 inhibitor des-flouro-sitagliptin in HFD-fed mice --- p.56 / Chapter 3.4.8 --- Lipid lowering enhances the efficacy of an agonist to GLP-1R (Ex-4) but not to GIPR (D-GIP) in db/db mice --- p.59 / Chapter 3.5 --- Discussion --- p.67 / Chapter 4 --- Chapter : Further study on the impairment of incretin effect by hyperglycemia in a rodent model of type 2 diabetes --- p.71 / Chapter 4.1 --- Summary --- p.71 / Chapter 4.2 --- Introduction --- p.73 / Chapter 4.3 --- Materials and Methods --- p.76 / Chapter 4.3.1 --- Animals and treatment --- p.76 / Chapter 4.3.2 --- Oral glucose tolerance test and insulin tolerance test --- p.76 / Chapter 4.3.3 --- Plasma parameters --- p.77 / Chapter 4.3.4 --- Histological staining and quantification of beta cell mass --- p.77 / Chapter 4.3.5 --- Insulin signaling analysis --- p.78 / Chapter 4.3.6 --- Western blot analysis --- p.78 / Chapter 4.3.7 --- Statistical analysis --- p.79 / Chapter 4.4 --- Results --- p.80 / Chapter 4.4.1 --- Exendin-4 reduced fed glucose levels in MH mice but not in SH mice --- p.80 / Chapter 4.4.2 --- Exendin-4 reduced body weight gain and did not affect food intake in both MH mice and SH mice --- p.81 / Chapter 4.4.3 --- Exendin-4 improved glucose tolerance and glucose stimulated insulin secretion in MH mice but not in SH mice --- p.83 / Chapter 4.4.4 --- Effects of exendin-4 on insulin sensitivity in MH and SH mice --- p.84 / Chapter 4.4.5 --- Effects of exendin-4 on lipid profiles in MH and SH mice --- p.86 / Chapter 4.4.6 --- Effects of exendin-4 on tissues weight in MH and SH mice --- p.87 / Chapter 4.4.7 --- Pancreatic islet morphology and analysis of beta cell mass --- p.88 / Chapter 4.4.8 --- Exendin-4 had no significant effects on insulin signaling pathway in liver and muscle --- p.91 / Chapter 4.5 --- Discussion --- p.94 / Chapter 5 --- Chapter : Summary --- p.100 / Chapter 6 --- References --- p.103

Este estudo, com delineamento tipo caso-controle, teve como proposta testar as hipóteses de que a amamentação ao seio é um fator de proteção para o DMID e o leite de vaca, introduzido precocemente na alimentação infantil, é um fator de risco para a doença. Os casos foram identificados na Associação de Diabetes Juvenil de São Paulo e no ambulatório de Endocrinologia da Escola Paulista de Medicina. Trezentos e quarenta e seis casos, com idade inferior a 18 anos no momento da entrevista, foram comparados com 346 controles pareados aos casos segundo sexo, idade e local de residência. Foram consideradas como variáveis de principal interesse a duração do aleitamento exclusivamente ao seio, a idade da introdução de alimentos lácteos na dieta e ter recebido leite em pó na maternidade. Foram consideradas como variáveis de controle as idades da mãe e do pai no momento do nascimento da criança, o histórico da mãe de rubéola congênita, a duração da gestação, o peso e o comprimento ao nascer, a situação de vacinação, os antecedentes relativos a doenças viróticas da criança, o histórico da criança de episódios graves de diarréia, a data da insulinoterapia, os antecedentes familiares de DMID e DMNID, a renda familiar per capita e a ordem de nascimento da criança. Utilizaram-se o teste t de Student pareado para a comparação das médias das variáveis cujos valores têm distribuição normal e o teste pareado dos sinais dos postos de Wilcoxon para as demais, a técnica de tábua de vida atuarial para se conhecer, aos 7 e aos 60 dias, a proporção de crianças ainda em aleitamento exclusivamente ao seio e sem introdução de alimentos lác- teos. O modelo de regressão logística condicional foi utilizado tanto para as análises da gradação dos odds ratios como para ajustar os efeitos sobre o DMID das três variáveis de interesse a possíveis variáveis de confusão. Os resultados encontrados neste estudo indicam que são fatores de risco para o DMID a ausência de aleitamento exclusivamente, especialmente durante a primeira semana de vida (OR = 2,13, IC: 1,28 - 3,55) e a idade da introdução de alimentos lácteos, especialmente quando esses alimentos são introduzidos durante os primeiros sete dias de vida (OR = 2,29; IC: 1,37 - 3,83). / This case-control study aimed to test the assumption that breast feeding protects against insulin-dependent diabetes mellitus, and that the early introduction of cow milk into the infant diet is a risk factor for the disease. The cases were identified in the Juvenile Diabetes Association of São Paulo, and in the Out-patients Endocrinology Department of the Escola Paulista de Medicina. Three hundred and forty-six cases among patients younger than eighteen years old at the time of the interview were compared with 346 paired control cases for sex, age and place of residence. The main variables were the duration of exclusive breast feeding , the age at which milk products were introduced into the diet, and whether powdered milk was given in the maternity unit. The ages of the parents when the child was born, history of congenital rubella in the mother, duration of gestation, weight and height at birth, vaccination status, the child\'s viral disease history, the child\'s history of severa attacks of diarrhea, the date of insulin therapy, previous familial history of insulin-dependent diabetes mellitus and non-insulin-dependent diabetes mellitus, the per-capita income of the family, and the order of birth of the child. Student\'s paired test was used to compare the mean values of variables with normal distribution, and Wilcoxon\'s signed ranks test was used for all other variables. The actuarial life table technique was used at 7 and 60 days in order to determine the proportion of children still being exclusively breast fed without the introduction of milk products. The conditional logistical regression method was used in dose-response analyses of the odds ratio and to adjust for the effect of the three variables of interest and possible confounding variables on insulin-dependent diabetes mellitus. The findings of this study indicate that the lack of exclusive breast feeding is a risk factor to insulin-dependent diabetes mellitus, particularly during the first week of life (OR=2.13; IC: 1.28-3.55) and that the age at introduction of milk products is a risk factor for the disease, particularly when these products are introduced during the first seven days of life (OR=2.29; IC: 1.37 -33.83).

Latinos are the fastest growing minority group in the Unites States (Fry, 2008). One in eight adult Latinos living in the United States has diabetes (CDC, 2011), and by the year 2020 diabetes is expected to increase by 107% in the Latino population (Caballero & Tenzer, 2007). Within the general diabetic population approximately 26% of the diabetic population requires the use of insulin in the management of their diabetes (DHHS: NDIC, 2011), making insulin-dependent diabetes a prevalent experience. The literature on how diabetes is experienced is divided. Clinical assessment literature strives to measure how people are coping with the illness and how one's experience with the disease impacts self-care. Literature on the diabetes experience is limited; however, the overall image that emerges is the negative expectation associated with having diabetes such as loss and suffering. Little is known about insulin-dependent diabetes as a lived experience, particularly among Latinos. The purpose of this research is to understand the experience of having insulin-dependent diabetes among adult Latinos, because focusing on this experience clarifies how daily nuances of living with the illness gives meaning to insulin-dependent diabetes. Increased understanding of how people interpret their illness can improve diabetes management, specifically within patient and social work interactions, and promote competent social work practice. The guiding research question for this research is, "what is the lived experience of insulin-dependent diabetes among Adult Latinos in a Primary Care Clinic in San Antonio?" This study uses van Manen's (1990) hermeneutic phenomenological approach to guide the research in capturing the nature of the phenomenon in order to gain a deeper understanding of the meaning Latinos attribute to daily experiences of having insulin-dependent diabetes. Utilizing a phenomenologically designed interview guide, this study includes interviews with 10 participants from a predominantly Latino, safety-net clinic in Texas with a 60% diabetes diagnosis rate. Five essential themes arose in exploring the lived experience of insulin-dependent diabetes among adult Latinos in a primary clinic in San Antonio. The themes include 1. diabetes goes against the natural state of the human body; 2. diabetes rules everything 3. insulin is the fast track to deterioration; 4. the relationships don't end, but they're not the same; and 5. managing diabetes with a broken system. The theme "diabetes goes against the natural state of the human body" is considered a core theme because it represents the other themes. Of those themes identified three support the current literature found on living with diabetes. The three themes insulin is the fast track to deterioration, managing diabetes with a broken system, and the subtheme love hate relationship with food are emerging themes identified by the study

The aim of this study was to document and explore the perceived role of nurses and their attitudes and beliefs when providing health promotion strategies and health education for hospitalised people who have diabetes mellitus (diabetes). As part of the exploratory, descriptive study key steps undertaken included : 1/. Determining the strategies the nurses currently use to provide health promotion and health education to patients; 2/. Documenting of the role nurses play in referring people to diabetes educators; 3/. and 3/. Determining the extent to which nurses feel able to fulfil the roles of health promotion and health education. The study reported in this thesis was conducted in Western Sydney within a socially, culturally and economically diverse population. Study participants were nurses working in medical or surgical wards. The study reveals that nurses require support from all levels of the healthcare system. Additionally, all levels of the healthcare system need to work together to investigate, implement and evaluate new models of care that are responsive to the dynamic state of the contemporary health care systems. / Master of Nursing (Hons)

Globally the diabetes epidemic is a major health challenge. Associated with the diagnosis of diabetes is the morbidity and premature mortality stemming from the complications of the disease. It was identified that approximately 50% of clients who attended a diabetes centre in an outer western metropolitan region of Sydney were not completing diabetes education. A strategy employed to overcome this was the introduction of a 2 ½ hour group diabetes education program called the Ongoing Education System (OES), for persons with Type 2 diabetes, that enabled completion of education at this one session. However, debate occurred among health professionals at the Wentworth Diabetes Service (WDS) as to the effectiveness of the OES as compared to the traditional individual education sessions. (one-on-one education). The purpose of this study was to compare the outcomes of two modes of diabetes education for completing education for clients with Type 2 diabetes , namely individual education (Treatment A) and the OES group education (Treatment B). The findings overall revealed no difference in the outcomes of participants who received individual education and those who received the OES at completion of education as well as at 6 and 12 month post education. A secondary finding of this study was the significant influence gender and age exerted on the outcomes of the education programs. One significant implication from the findings for both the person diagnosed with Type 2 diabetes and the health care organisation is that the OES provides a cost effective alternative to individual education that encourages clients to complete diabetes education thereby enabling the person to achieve an optimal quality of life. In addition this study provides research evidence for the benefit of current practice in diabetes education. / Doctor of Philosophy (PhD)

Peptide YY (PYY) is a gut-derived hormone that is renowned for its effects on satiety. Reduced satiety in obese people has been attributed to low fasting and postprandial PYY levels. However, it has not been determined whether low PYY levels are the cause or the outcome of obesity. Moreover, the long-term role of PYY in regulating energy balance is unclear. Results presented in this thesis, using PYY-deficient mice (PYY-/-) and PYY transgenic mice (PYYtg) highlight that PYY indeed has an important role in regulating energy balance and glucose homeostasis in vivo. PYY knockout mice became obese with ageing or high-fat feeding linked to a hyperinsulinemic phenotype associated with hypersecretion of insulin from isolated pancreatic islets. These findings suggested that PYY deficiency may be a predisposing factor for the development of obesity and type 2 diabetes. On the other hand, PYYtg mice exhibited decreased adiposity and increased metabolism under high-fat feeding. Furthermore, PYYtg/ob mice had improved glucose tolerance and decreased adiposity. These latter studies suggested that high circulating PYY levels may protect against the development of obesity and type 2 diabetes. Interestingly, both animal models support PYY as an important regulator of the somatotropic axis. These preliminary findings prompted investigations in understanding whether low PYY levels may be a predisposing factor for the development of obesity and type 2 diabetes in human subjects. In a population of healthy human subjects that had a predisposition to the development of type 2 diabetes and obesity, fasting PYY levels were lower than in normal subjects. Moreover, low fasting PYY levels strongly correlated with decreased insulin sensitivity and high levels of fasting insulin. Collectively, these findings suggest that low circulating levels of PYY could contribute to increased adiposity, insulin resistance and type 2 diabetes. Therefore determination of PYY levels may be a method of detecting whether people are predisposed to becoming obese and insulin resistant. This work also suggests that treatments that enhance circulating PYY levels may be protective in the development of obesity and type 2 diabetes.

Regular physical activity improves insulin action and is an effective therapy for the treatment and prevention of type 2 diabetes. However, little is known of the mechanisms by which exercise improves insulin action in muscle. These studies investigate the actions of a single bout of exercise and short-term endurance training on insulin signalling. Twenty-four hours following the completion of a single bout of endurance exercise insulin action improved, although greater enhancement of insulin action was demonstrated following the completion of endurance training, implying that cumulative bouts of exercise substantially increase insulin action above that seen from the residual effects of an acute bout of prior exercise. No alteration in the abundance and phosphorylation of proximal members of the insulin-signalling cascade in skeletal muscle, including the insulin receptor and IRS-1 were found. A major finding however, was the significant increase in the serine phosphorylation of a known downstream signalling protein, Akt (1.5 fold, p ≤0.05) following an acute bout of exercise and exercise training. This was matched by the observed increase in protein abundance of SHPTP2 (1.6 fold, p ≤0.05) a protein tyrosine phosphatase, in the cytosolic fraction of skeletal muscle following endurance exercise. These data suggest a small positive role for SHPTP2 on insulin stimulated glucose transport consistent with transgenic mice models. Further studies were aimed at examining the gene expression following a single bout of either resistance or endurance exercise. There were significant transient increases in IRS-2 mRNA concentration in the few hours following a single bout of both endurance and resistance exercise. IRS-2 protein abundance was also observed to significantly increase 24-hours following a single bout of endurance exercise indicating transcriptional regulation of IRS-2 following muscular contraction. One final component of this PhD project was to examine a second novel insulin-signalling pathway via c-Cbl tyrosine phosphorylation that has recently been shown to be essential for insulin stimulated glucose uptake in adipocytes. No evidence was found for the tyrosine phosphorylation of c-Cbl in the skeletal muscle of Zucker rats despite demonstrating significant phosphorylation of the insulin receptor and Akt by insulin treatment and successfully immunoprecipitating c-Cbl protein. Surprisingly, there was a small but significant increase in c-Cbl protein expression following insulin-stimulation, however c-Cbl tyrosine phosphorylation does not appear to be associated with insulin or exercise-mediated glucose transport in skeletal muscle.

Type 2 diabetes (T2DM) currently affects more than three million African American adults with double the number expected by 2025. The most effective and safest treatment for T2DM is lifestyle change therapy, including healthful eating, monitoring of blood glucose, and physical activity. However, current lifestyle change interventions are limited in their scope to alter the behaviors of individuals to more healthful ones. These limitations may be attributed, in part, to a lack of attention given to enhancing an individual’s psychosocial process variables, such as resilience, coping skills, selfleadership, and empowerment. Incorporating resilience education into lifestyle change therapies is a novel approach that addresses the behavior modification limitations of current interventions by aiming to enhance psychosocial process variables. Therefore, the purpose of this project was to conduct a six-month pilot study to determine the feasibility of our resilience and diabetes self-management intervention, The Diabetes Coaching Program: Transforming Lives Through Resilience Education, in a convenience sample of African American adults (n=16) with T2DM. The intervention included four weekly resilience and diabetes education classes and eight bi-weekly support group sessions. Survey data and blood samples were collected at baseline and at six months. Twelve participants completed the study (75% retention). Results indicated that higher perceived stress scores were associated with less resilience, fewer adaptive coping skills, lower selfleadership, lower diabetes empowerment and greater depressive symptoms. However, diabetes empowerment was the only psychosocial process variable to be significantly enhanced by the intervention at six months. Weight, BMI, HbA1c, total cholesterol, LDL cholesterol, blood pressure, and IGF-1 levels were significantly decreased at six months, whereas, lymphocyte proliferation and physical activity were significantly increased. These data indicate that our intervention has the potential to improve diabetes selfmanagement among African Americans with T2DM and increase positive health outcomes, though further studies are needed to confirm these findings. Additionally, several lessons were learned from conducting the pilot study that may be useful for improving the intervention for future studies, including: recruitment and retention strategies; cultural competency issues; the use of complementary and alternative medicine practices by African Americans with T2DM; and approaches for increasing participant self-assessment and goal-setting. / text

published_or_final_version / Public Health / Master / Master of Public Health

published_or_final_version / Nursing Studies / Master / Master of Nursing