Type 2 diabetes and metabolic syndrome are the metabolic disorders which constitute a major public health problem in both developed and developing countries. Various studies have suggested the genetic susceptibility to the disorders. The main aim of the thesis was to investigate the putative association of single nucleotide polymorphisms with Type 2 diabetes (T2D), metabolic syndrome (MetS) and the major components of metabolic syndrome. This study used meta‐analysis, polymerase chain reaction (PCR) based restriction fragment length polymorphism (RFLP) and Sanger sequencing methods to analyse the results. The single nucleotide polymorphism rs57829442 of peroxisome proliferator‐activated receptor‐γ coactivator‐1 (PPARGC1A) gene and its relation to risk of type 2 diabetes has been studied in the United Kingdom population. A meta‐analysis of genetic variant rs8192678 (Gly482Ser) of peroxisome proliferator‐activated receptor‐γ coactivator‐1 (PPARGC1A) gene and its association with the components of metabolic syndrome has been studied. An association of the genetic variants rs8192678 (Gly482Ser) of the PPARGC1A gene, rs7903146 of Transcription Factor 7 Like 2 (TCF7L2) gene, rs9939609 of Fat mass and obesity‐associated (FTO) gene and rs1801282 (Pro12Ala) of peroxisome proliferator‐activated receptor gamma (PPARG) gene with the metabolic syndrome and its components has been studied in the Nepalese population. The results showed that variant rs57829442 of PPARGC1A is not associated with T2D in the United Kingdom population. Further investigation with increased sample size is warranted. In the meta‐analysis, the variant rs8192678 (Gly482Ser) of PPARGC1A gene was found to be significantly associated with body mass index (BMI) in Asian populations under dominant genetic model, total cholesterol (TC) in non‐Asian population under recessive genetic model and with fasting plasma glucose (FPG) under a recessive model in overall and non‐Asian populations. No significant association of the variants rs8192678 (Gly482Ser), rs7903146, rs9939609 and rs1801282 (Pro12 Ala) was found associated with MetS under dominant, recessive, co‐dominant and additive models in the Nepalese population. However, the genotypes (AG and AA) of rs8192678 (Gly482Ser) had a statistically significant protective effect on systolic blood pressure. The genotypes with the risk allele of rs9930609 of FTO gene was significantly associated with weight, waist circumference and diastolic blood pressure under dominant genetic model and with BMI under both dominant and recessive genetic models in the Nepalese population. To the best of our knowledge, this is the first study to report the findings in the Nepalese population.

This thesis reviews and augments existing evidence surrounding the psychosocial aspects of living with Type 2 diabetes. There is a specific emphasis on the factors which underpin diabetes distress in individuals with Type 2 diabetes, which pertains also to the influence of partners or spouses on psychological adjustment to diabetes. This research develops and presents a conceptual framework of the key determinants of diabetes distress, providing focus and content for an intervention to address distress among couples living with Type 2 diabetes. Chapter 1 introduces the concept of diabetes distress; including prevalence, clinical relevance, and the cognitive, interpersonal and behaviour factors which are believed to drive this condition-specific distress. There is also an emphasis on existing strategies to improve both psychological and medical outcomes in Type 2 diabetes, which identified a need to evolve psychosocial support for individuals who are struggling to manage diabetes. Importantly, this chapter provided a rationale and direction for the studies reported in prospective chapters. Chapter 2 broadens the focus of psychosocial support in diabetes, to consider also the importance of considering partners or spouses in interventions to improve health outcomes in the context of different chronic physical conditions. This systematic review conveys the benefits of partner inclusion in interventions and highlights a number of shortcomings pertaining to couples intervention work. In particular, the review identifies a scarcity of couples intervention work in the context of Type 2 diabetes. The cross-sectional questionnaire study in Chapter 3 captures the predictive influence of illness perception clusters, coping styles, and relationship quality on diabetes distress in individuals with Type 2 diabetes. Of note, this work identifies negative belief and coping patterns which coincide and exacerbate distress, and presents a novel method of distinguishing those most at risk of elevated diabetes distress. Chapter 4 investigates the influence of partners’ diabetes beliefs on diabetes distress over time. This study demonstrates the moderating influence of partners’ illness perceptions on the association between persons with Type 2 diabetes illness perceptions and diabetes distress, and reveals that such effects persist overtime. Furthermore, Chapter 5 explores narratives of diabetes distress among couples living with Type 2 diabetes and among healthcare professionals, by means of individual semi-structured interviews and focus groups. Expanding on the findings of Chapters 3 and 4, this qualitative work compares experiences of distress from the perspectives of individuals with diabetes and those who support them in a personal and professional capacity, in an attempt to understand how communication and interpersonal conflicts might emerge in day to day life. Importantly, Chapter 5 discerns a perceived need for an intervention to reduce diabetes distress in individuals with Type 2 diabetes and their loved ones, and provides direction for the design and implementation of an intervention of this nature. Chapter 6 draws upon existing and primary evidence pertaining to the cognitive, interpersonal, and behavioural factors which underpin diabetes distress, and provides recommendations for the design and implementation of an intervention to address diabetes distress in couples living with Type 2 diabetes. The feasibility study described in Chapter 7 assesses the acceptability, potential effectiveness, and practical implementation of a brief psychoeducational intervention to address diabetes distress in people with Type 2 diabetes and their partners or family members. The findings of Chapter 7 highlight important strengths and shortcomings of providing an intervention of this nature, which are expanded on in the main discussion in Chapter 8. Chapter 8 provides a broad overview of the rationale for this PhD research and reflects on the primary work undertaken to date. Crucially, this discussion chapter provides recommendations on how key strengths of the feasibility study described in Chapter 7 can be enhanced and how observed shortcomings can be addressed in future studies. Finally, there is consideration of how aspects of the intervention described in Chapters 6 and 7 may feasibly be incorporated into existing programmes of diabetes support.

American Indian and Alaska Native adults are 2.6 times more likely to have adult onset diabetes resulting from higher weight at birth. Pregnant women, providers, and Indian Health Service administrators may benefit from timely information during pregnancy to intervene and prevent Type 2 diabetes. The purpose of this study was to examine the role of birth weight in the development of Type 2 diabetes among Southeast Alaska (SEA) Natives. Guided by the socioecological model, this study examined the extent to which birth weight and gestational age predict the incidence of Type 2 diabetes. The study used a quantitative research design with retrospective analysis of 540 Native children born in SEA whose data were abstracted from birth journals and electronic medical records at ages 43-53. A t test indicated a significant positive correlation between gestational birth weight and incidence of Type 2 diabetes (t(285) = 13.91, p < .001). Birth weight for gestational age was associated with frequency of Type 2 diabetes, where small for gestational age (SGA) had the lowest risk (1.42%), average for gestational age (AGA) at medium risk (8.76%), and large for gestational age (LGA) had the highest risk at 32.25% (x^2(12) = 63.29, p < .0005). Findings indicate that adult Type 2 diabetes among the SEA Native population is due to excess intrauterine fetal weight gain. The positive social change implications include preventing Type 2 diabetes in SEA Natives by controlling weight gain during pregnancy; the findings also suggest using diagnostic risk profiles for those who are LGA at birth for the management of diabetes and prevention of obesity and chronic disease.

A research report from the Centers for Disease Control and Prevention (CDC) indicated that more than 50% of people with diabetes mellitus (DM) in the United States (U.S.) also have arthritis. The diabetes population is disproportionately affected by arthritis, but there has been limited and inconsistent research to confirm the association between type 2 diabetes mellitus (T2DM) and rheumatoid arthritis (RA). The current study aimed to identify an association between T2DM and RA for noninstitutionalized U.S. adults between 1999 and 2012 using a nationally representative sample from the National Health and Nutrition Examination Survey (NHANES) database (n =31,488 ). A quantitative, cross-sectional investigation was conducted to determine if patients with T2DM had an increased prevalence of RA. The current study also sought to identify characteristics that could affect the association between both groups and the prevalence of cardiovascular disease (CVD) in this population. Prevalence and adjusted odds ratios (OR) using logistic regression were calculated. The results show evidence of a strong association between T2DM and concomitant RA. Prevalence of RA was significantly higher in participants with T2DM compare to those without T2DM. Important factors in this association were gender, ethnicity, education, disability, and work functioning. The prevalence of CVD and adjusted OR of association were doubled in participants with T2DM and RA when compared to participants who had just one of the conditions; the OR of association was quadrupled when compared to those without this comorbidity. This study may provide patients and health care providers with a better understanding of the need for management of both conditions in a interdisciplinary manner

Emerging evidence suggests that an important mechanism for the negative feedback control of insulin signalling involves the inhibition of tyrosine phosphorylation of IRS-1 by its prior serine/threonine (ser/thr) phosphorylation. IRS-1 ser/thr phosphorylation has been linked to the dissociation of IRS-1 from the insulin receptor and PI3K, and its degradation via a proteasome-dependent pathway. Studies in animal models have shown that increases in plasma free fatty acids (FFAs) are associated with reduced IRS-1-signalling, and so it has been postulated that elevated FFA cause insulin resistance by activating pathways that negatively regulate insulin action, including hyper-phosphorylation of ser/thr residues in IRS-1. We have shown that in the case of linoleate-induced insulin resistance in L6 rat skeletal muscle cells, the inhibition of IRS-1-dependent signalling arises via effects on both the phosphorylation status and degradation of IRS-1, which are mediated, in part, by IKKb. In addition, the reduction of IRS-1 mRNA levels allude to transcriptional effects of linoleate treatment that also contribute to the observed reduction in the total levels of this protein. PtdOH, particularly dilinoleoyl PtdOH, was found to be significantly increased in linoleate treated L6 cells, and sufficient to induce at least some of the effects on insulin-signalling that are observed upon linoleate treatment. It is unlikely, however, that IKKb and PtdOH are components of the same inhibitory pathway, since inhibiting IKKb activity did not alleviate the effects of PtdOH on IRS-1 tyrosine (tyr) phosphorylation. Moreover, although an integral component of the mechanism by which linoleate induces insulin-resistance in L6 cells, it appears that restoring IRS-1 function in linoleate treated cells is not sufficient to reverse insulin resistance. Hence, we hypothesise that linoleate induces multiple inhibitory pathways in L6 cells, with at last two of these involving IKKb- and PtdOH-dependent inhibition of IRS-1 signalling, which act in parallel to reduce glucose disposal and cause insulin resistance in this model.

Patients with type 2 diabetes have reduced gene expression of Heat Shock Protein (HSP) 72 which correlates with reduced insulin sensitivity. Heat therapy, which activates HSP72, improves clinical parameters in these patients. Activation of several inflammatory signalling proteins such as c-jun amino terminal kinase (JNK) can induce insulin resistance but HSP72 can block the induction of these molecules in vitro. Whether up-regulation of HSP72 can protect against insulin resistance is not known. In experiments reported in this thesis we show that HSP72 protects against insulin resistance and blocks the activation of JNK in vivo. We first show that mice that underwent weekly heat shock therapy to increase intramuscular HSP72 protein expression were protected from high fat diet (HFD)-induced hyperinsulinemia, hyperglycemia and glucose intolerance, factors associated with reduced JNK phosphorylation. To determine whether the elevation in intramuscular HSP72 expressio n and protection from insulin resistance are causally linked, we studied muscle specific HSP72 overexpression mice (HSP72+/+). Compared with wild-type mice, HSP72+/+ mice were protected from hyperglycemia, hyperinsulinemia, glucose intolerance and insulin resistance when placed on a HFD, factors associated with a complete inhibition of HFD-induced JNK phosphorylation in skeletal muscle. Finally, we show that HSP72+/+ mice display greater mitochondrial enzyme activity in the liver, adipose tissue and skeletal muscle, corresponding to reduced plasma free fatty acid levels, white adipose tissue mass and alterations in circulating adipokines. These data identify HSP72 as being pivotal in protecting against obesity-induced insulin resistance possibly by blocking JNK and/or by up-regulation of mitochondrial oxidative capacity.

<p>Globalization scholars have disagreed about the effects of globalization on the production and reproduction of difference: Do fundamental differences endure, do cultures converge, or is there hybridization? This dissertation analyzes the durability of distinct medical cultures in two technologically advanced healthcare systems that rely on an evidence-based, biomedical approach. Durability refers to the tendency to maintain or develop diverse, even idiosyncratic, practices and beliefs--even as the forces of globalization are perceived to be pressing health practices everywhere toward a single global standard. To do so, this dissertation offers a comparative, empirically based argument using the case of type 2 diabetes in the U.S. and Japan. As an inductive, theory-constructing project, the argument has at its foundation 11 months of ethnographic field work in Japanese hospitals and clinic exam rooms, 115 semi-structured interviews with patients and biomedical health practitioners in Japan, and 25 interviews with American health care providers and patients. I argue that physicians in both research sites, Okayama, Japan and North Carolina, USA, practice empirical biomedicine, but that empirical biomedicine is not all there is to biomedical practice. Practicing physicians in both contexts act not only on increasingly globalized professional standards, but also on local knowledge, on their own explanatory models for type 2 diabetes, and in reaction to local patient populations' explanatory models. Further, local knowledge and patient interactions shape the ways in which practicing physicians interpret global standards and best practices. Occasionally, they may even be reshaped beyond recognition without interfering with physicians' self-evaluation as participants in a universal, standardized scientific project. The interaction of globalizing standards of practice, local knowledge, and local explanatory models of illness can result in dramatically divergent medical practice across different social contexts--in this case, the U.S. and Japan.</p> / Dissertation

Type II diabetes and hyperinsulinemia are associated with increased risks of developing colorectal cancer (CRC). Detailed mechanisms underlying this correlation, however, are yet to be explored. The present study demonstrates that insulin increases the expression of proto-oncogenes c-Myc and cyclin D1 via both translational and transcriptional mechanisms. We show here that insulin stimulates c-Myc gene translation via an Akt/PKB-dependent mechanism involving the mTOR signaling pathway. More importantly, we show for the first time that transcriptional stimulation of c-Myc and cyclin D1 expression by insulin involves a novel Akt/PKB-independent signal crosstalk between insulin and canonical Wnt signaling pathways. We then identified p21-activated protein kianse 1 (PAK-1) as a novel mediator for insulin and Wnt/beta-catenin (b-cat) molecular crosstalk, involving MEK/ERK signaling. Furthermore, we found that insulin treatment leads to increased b-cat phosphorylation at Ser675, and this is associated with increased b-cat nuclear content and increased b-cat interaction with Tcf/Lef-binding elements (TBEs) of the human c-Myc gene promoter. Lastly, we demonstrated that insulin signaling directly alters the expression levels of components of the Wnt signaling pathway, including fizzled homology 4 (Fdz-4) and TCF7L2 (=TCF-4). This study not only demonstrated the existence of signaling crosstalk between insulin and canonical Wnt signaling pathways at multiple levels, it reveals molecular mechanisms for observed correlation between CRC and hyperinsulinemia. The growing evidence implicating PAK-1 in various human tumorigenesis has emerged PAK-1 as a potential therapeutic target. Our discovery of PAK-1 functioning as a novel central mediator for insulin and Wnt signaling crosstalk in intestinal cells suggests that PAK-1 may potentially be a good target candidate for treating patients with CRC, especially those who have Type II diabetes or experience hyperinsulinemia.

Methylglyoxal (MG) is a reactive á-oxoaldehyde and a glucose metabolite. Previous studies in our laboratory have shown that MG induces the production of reactive oxygen species (ROS), such as superoxide (O2.-), nitric oxide (NO) and peroxynitrite (ONOO-), in vascular smooth muscle cells (VSMCs, A-10 cells). However, the effect of endogenous MG and mechanisms of MG-induced oxidative stress have not been thoroughly explored. The present study investigated fructose (a precursor of MG)- induced ONOO- formation in A-10 cells and whether this process was mediated via endogenous MG formation; roles of MG in regulating mitochondrial ROS (mtROS) production and mitochondrial functions in A-10 cells; and effect of MG on neutrophils in patients with type 2 diabetes mellitus (T2DM). Fructose induced intracellular production of MG in a concentration- and time- dependent manner. A significant increase in the production of NO, O2.−, and ONOO− was observed in the cells exposed to fructose or MG. Fructose- or MG-induced ONOO− generation was significantly inhibited by MG scavengers and by O2.− or NO inhibitors. The data showed that fructose treatment increased the formation of ONOO− via increased NO and O2.− production in A-10 cells, and this effect was directly mediated by an elevated intracellular concentration of MG. By inhibiting complex III and manganese superoxide dismutase activities, MG induced mitochondrial overproduction of O2.-, and mitochondrial ONOO- further. MG also reduced mitochondrial ATP synthesis, indicating the dysfunction of mitochondria. In addition, MG increased plasma NO levels in patients with T2DM, which reflected the oxidative status in those patients. MG-induced oxidative stress in patients with T2DM significantly enhanced levels of cytokines released from neutrophils. Moreover, the neutrophils from T2DM patients showed a greater proclivity for apoptosis, which was further increased by in vitro MG treatment. Our data demonstrate that MG-induced oxidative damage, particularly ONOO- production, contributes to the pathogenesis of T2DM and its vascular complications.

Canadian statistics indicate that the incidence of obesity is rising, and that the prevalence of type 2 diabetes mellitus (T2DM) within this group is significantly higher than those of a healthy weight. Preliminary evidence has shown that the oil-rich grain, Salvia hispanica L. (Salba), improves glycemic control, suppresses appetite, and affects additional cardiovascular disease (CVD) risk factors. This study followed a randomized, double-blind, placebo-controlled, parallel design in a sub-set population of twenty individuals who were overweight or obese and had T2DM. Participants received supplements of Salba, or an energy- and fibre-matched control, and followed a hypocaloric diet for 24 weeks. Findings of this study reveal that Salba does not significantly affect weight loss, glycemic control or other CVD risk factors. These findings are preliminary and highlight the complexities of weight loss research. Further investigation into the potential health benefits of Salba is currently being carried out.