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

The relationship between physicians' perceptions of Mexican American patients at risk for Type 2 diabetes and the subsequent care they provide was studied. Primary care providers responded to questionnaires about their health promotion practices. A 2x2 analysis of variance was used to identify differences in reported treatment of patients that accounted for both ethnicity and risk. Results indicated Hispanic patients received less time with their providers than Caucasian patients regardless of risk for Type 2 diabetes. Both groups received about the same reported care in terms of information gathered for diagnosis, diagnosis made, and treatment regimen prescribed. Data also suggested that providers' scores for treatment regimen and information gathered were disappointingly low, which may not only account for the lack of statistically significant findings, but may reflect a larger issue within the medical care field.

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.

Purpose: To examine the effectiveness of a community-based intensive multifactorial clinical intervention for patients with Type 2 diabetes, to evaluate the feasibility of achieving clinical targets for glycemic control in a community setting, and to identify factors that are predictive of glycemic control in this cohort (age, gender, disease duration, continuity of care, pharmacologic treatment, diabetes self-care and smoking status). Methods: Participants with Type 2 diabetes referred to the Diabetes Clinic following dissemination of the 2003 Clinical Practice Guidelines of Canadian Diabetes Association and who attended a minimum of two physician visits within a twelve month period were deemed eligible for participation. 70 patients were included in this retrospective study. Baseline and twelve month values for the following biomedical outcomes were collected via chart audit: BMI, hemoglobin A1c, blood pressure (systolic, diastolic) and lipid profile (HDL, LDL, triglycerides, total cholesterol, TC:HDL ratio). Data for identification of predictive factors for glycemic control were also retrieved by chart audit. Results: The results of the paired t-test yielded a significant improvement in hemoglobin A1c (p<0.05), systolic blood pressure (p<0.01), HDL-cholesterol (p<0.05), LDL-cholesterol (p<0.01), total cholesterol (p<0.05) and total cholesterol:HDL ratio (p<0.05) over twelve months. No significant difference in BMI, diastolic blood pressure or triglycerides was reported over twelve months. Over half the sample (52.9%) achieved clinical targets for glycemic control (hemoglobin A1c <7.0%) at twelve months. Logistic regression analysis identified disease duration (O.R. = 0.90, 95% CI Exp(B) = 0.079 - 0.773, p = 0.01) and continuity of care (O.R. = 0.25, 95% CI Exp(B) = 0.831 - 0.969, p = 0.02) as significant predictors of glycemic control at twelve months. Conclusions: These findings demonstrate the effectiveness of this community-based intensive multifactorial clinical intervention for patients with Type 2 diabetes and show that the implementation of CPGs related to glycemic control is feasible in a community-based setting. Additionally, patients in this cohort with increased disease duration and increased continuity of care were less likely to achieve clinical targets for glycemic control following a twelve month intensive multifactorial clinical intervention for Type 2 diabetes. In summary, health professionals should strive to implement similar intensive multifactorial interventions in community practice in order to decrease the likelihood of diabetes-related complications and improve the patients quality of life.

<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

Glucose transporter GLUT4 allows glucose uptake into muscle and adipose cells. Insulin promotes recruitment and plasma membrane insertion of GLUT4 vesicles that can recycle constitutively. Obesity and type 2 diabetes mellitus are associated with defects in insulin-induced GLUT4 recruitment. Knowledge of alternative modes and steps of GLUT4 traffic in L6-GLUT4myc muscle cells may reveal possible targets for therapeutic intervention in insulin-resistant patients. Hypertonicity and Platelet Derived Growth Factor also increase surface GLUT4 levels but it was unknown if they tap on the same intracellular GLUT4 depots as insulin. We explored whether GLUT4 vesicles recycle using different compartments and mechanisms for the surface gain elicited by each stimulus. We hypothesized that all vesicle fusion steps require NSF but depend on individual v-SNAREs. Specifically, we tested effects of ATPase-deficient NSF or VAMP7 siRNA transfections, and endosomal ablation on GLUT4 traffic. We show that VAMP7 was required for basal and hypertonic recycling, while VAMP2 is exclusively used in response to insulin. As insulin action bifurcates downstream of phosphatidylinositol 3-kinase, we also hypothesized that the Rac-to-actin and Akt-to-AS160 branches regulate distinct GLUT4 traffic steps. For this we determined GLUT4myc localization in rounded myoblasts relative to a surface marker. Interfering with Rac, actin dynamics or actin-binding α-actinin4 maintained GLUT4 in a perinuclear region even under insulin-stimulation. Interfering with AS160 allowed significant GLUT4 accumulation beneath the membrane, but not fusion. We propose that actin dynamics and α-actinin4 are required for cortical GLUT4 tethering mechanisms, and AS160 contributes to GLUT4 docking/fusion. We confirmed that VAMP2 facilitates GLUT4 fusion, as tetanus toxin-based cleavage did not inhibit peripheral GLUT4 recruitment. Finally, AS160 targets Rab8A and Rab14 in muscle respectively affected GLUT4 availability for membrane fusion, and basal GLUT4 retention. This work will lead to future testing of strategies to selectively enhance vesicle availability, tethering, or surface fusion, for bypassing insulin resistance.

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.