acase@tulane.edu / Study aim: This study aimed to assess the individualized treatment goals (A1C, Blood Pressure, LDL-C) for patients with type 2 diabetes mellitus (T2DM), which lead to optimal health outcomes by different treatment strategies. Background and significance: The evidences in medical guidelines came from clinical trials with highly selected patients, whereas the treatment goals may differ in some subgroups. Additionally, considerable confusions on treatment target has resulted from recent changes in guidelines. So, there is a critical need to examine heterogeneity in optimal goals that lead to the most efficacious treatment options. Methods: A retrospective longitudinal study was conducted for veterans with T2DM by using US Veterans Affairs (VA) Administrative Database (Jan 2005 and Dec 2015). Longitudinal medical records were prepared for each 6-month cycle and multivariate longitudinal regression was used to estimate the risk of microvascular and macrovascular complication events and mortality. Second-degree polynomial and splines were applied in the model to identify the optimal goals in their associations with lowest risk of clinical outcomes by controlling the demographic characteristics, medical history, and medications. Results: 124,651 patients with T2DM were selected, with 62.68 years old (SD=10.96) and 6.72 (SD=6.68) follow-up years at average. In general population, A1C=6.06, LDL-C=106.10 and BP=137.90/98.00 were associated with lowest mortality risk. As of achieving lowest risk of microvascular and macrovascular complication, the optimal goals were A1C=6.81, LDL-C=109.10; and A1C=6.76, LDL-C=111.65, SBP=130.60 respectively. The optimal goals differed between age and racial subgroups. Lower SBP for younger patients and lower LDL-C for blacks were identified with better health outcomes. Conclusions: Individualized treatment goals were identified and multi-faceted treatment strategies targeting hypertension, hyperglycemia and hyperlipidemia may improve health outcome in veterans with T2DM. In addition to general ADA recommended goals, health system may examine their own large, more diverse patients with T2DM for better quality of care. / 1 / Qian Shi

There is substantial evidence of the elevated risk of cancer among individuals with type 2 diabetes. Very little is known, however, about the role that antidiabetic therapies play in this relationship. The objective of this program of research was to examine whether there is a therapeutic risk associated with antidiabetic therapies that increase circulating insulin levels, such as sulfonylureas and exogenous insulin, or a therapeutic benefit associated with antidiabetic therapies that reduce insulin resistance, such as metformin and the glitazones. This objective was achieved through four related population-based cohort studies using the administrative databases from Saskatchewan Health. The first study looked at the effect of the older antidiabetic therapies metformin and sulfonylureas on cancer mortality. The focus of the second study was to explore more closely the effect of metformin and sulfonylurea by using a time-varying Cox regression to define drug exposures. The third study looked more closely at the effect of exogenous insulin therapy and cancer mortality, and the last study focused on the more recently available antidiabetic therapy the glitazones and cancer mortality. We found that individuals with type 2 diabetes exposed to sulfonylurea monotherapy had a significantly increased risk of cancer-related mortality, compared to patients exposed to metformin. We also observed a dose-response gradient with exogenous insulin therapy and cancer mortality, whereby individuals exposed to higher levels of insulin had a higher risk of cancer mortality. In the last study, we found that the newer class of antidiabetic therapies, the glitazones, were associated with a decreased risk of cancer mortality. These finding add further support that antidiabetic therapies may play a moderating role in the relationship between type 2 diabetes and cancer outcomes. However, it is unclear whether the increased risk of cancer mortality we observed was related to a toxic effect of sulfonylureas and exogenous insulin or a protective effect of metformin and glitazones, or due to some unmeasured effect related to both choice of drug therapy and cancer risk. Future research should incorporate a non-diabetes control cohort for comparison and examine the more proximal outcome measure cancer incidence. / Epidemiology

Compared to other Canadians, Aboriginal people suffer disproportionately from Type 2 diabetes and its complications. In an attempt to fill gaps in services for Aboriginal people to support better management of diabetes and to prevent further complications, the West Side Community Clinic launched a monthly outreach diabetes education program using an informal hands-on approach to learning about meal planning and other forms of diabetes management. The purpose of this qualitative study was to determine the impact that the program has had on the participants' health and well-being through the stories they shared in a group or individual interview. Out of the core group of 30 women, most of them Aboriginal, eleven participated in the group interview and five women participated in individual interviews.<p>Findings reveal that the program's impact on participants' health and well-being is embedded within the context of their lives. Diabetes is managed within multiple life realities in an individual, a familial and a community context. The women report learning management skills and sharing support among participants and staff of Diabetes Morning; and altered health status such as regulated blood glucose levels and weight loss. Opportunities for change include more programming like Diabetes Morning, more often, more information, access to low-cost diabetes-friendly foods, communication with health care practitioners, and integrating knowledge on a day-to-day basis. Domains for outcome indicators and contextual indicators are suggested for the program.

HSV-2 may have adverse consequences in HIV. I evaluated the impact of HSV-2 co-infection on (highly active antiretroviral therapy)-untreated HIV infection in a systematic review of observational studies (study 1) and a retrospective cohort (study 2). I further evaluated whether HSV reactivation rates in co-infected persons differ by use of suppressive cART (study 3). Study 1 found modest evidence that HSV-2 seropositivity may be associated with accelerated progression to opportunistic infection or clinical AIDS, but not with increased HIV viral load. Some evidence suggests that HSV-2 disease activity is associated with increased HIV viral load and decreased CD4 counts. Study 2 compared rates of CD4 count change by HSV-2 status (Focus HerpeSelect ELISA) among 218 patients with a past period of ART-untreated follow-up using mixed linear regression models. No significant difference in the rate of CD4 count change was observed in HSV-2 seropositives at +13.6 cells/mm3/year (p=0.12) in univariate analysis, and -4.5 cells/mm3/year (p=0.68) in analysis adjusted for sex, HSV-1, oral and genital HSV symptoms, immigrant status, and immigrant*time interaction. These findings support the need for carefully designed and executed studies of HSV-2 suppression as an adjunctive management strategy for HIV disease, but raise questions regarding the exact mechanism of negative synergy between these viruses and the relative importance of HSV-2 latency and replication in driving these effects. In Study 3, 44 cART-naïve and 41 treated (HIV RNA<50 copies/mL) HIV+ adults with HSV-1 and/or 2 co-infection collected oral, genital and anal swabs daily for 28 days. Negative binomial models were used to quantify the relationship between cART and HSV shedding (Roche LightCycler HSV1/2). Overall HSV shedding was low, at a median (IQR) of 3.6% (0, 14.3%) of days. No relationship was seen between cART and HSV-1 or 2 shedding in univariate (RR=1.55, 95%CI=0.83,2.87) or multivariate analysis adjusted for sex, baseline CD4, recent immigrant status, and time since HIV diagnosis (aRR=1.05, 95%CI=0.43,2.58). Null results were also observed for HSV-1 and HSV-2 considered separately. That HSV shedding persists despite cART suggests that trials of anti-HSV drugs for improving HIV outcomes may be warranted in such patients.

Studies show that insulin induced activation and assembly of insulin receptor substrate-1 (IRS1) and phosphatidylinositol-3-kinase (PI3K), within remodelled actin structures is critical for GLUT4 translocation to the cell surface in muscle cells. This study identifies the F-actin binding protein, nexilin, as a novel IRS1 binding partner. Insulin stimulates nexilin to dissociate from IRS1 and interact with actin. Nexilin knockdown has no effect on insulin-stimulated IRS1 tyrosine phosphorylation, but does enhance insulin-stimulated IRS1-PI3K interaction, increasing PIP3 formation, PKB activation and glucose uptake. This study also shows that nexilin overexpression may have an inhibitory effect on PKB phosphorylation and glucose uptake in adipocytes. These findings suggest nexilin is a negative regulator of IRS1 action on PI3K and insulin-stimulated dissociation of IRS1-nexilin allows the formation of IRS1-PI3K complexes in cytoskeletal-membrane compartments. Nexilin also specifically associates with the PH domain of IRS1, and not IRS2, suggesting a mechanism for signaling specificity of these isoforms.

Studies show that insulin induced activation and assembly of insulin receptor substrate-1 (IRS1) and phosphatidylinositol-3-kinase (PI3K), within remodelled actin structures is critical for GLUT4 translocation to the cell surface in muscle cells. This study identifies the F-actin binding protein, nexilin, as a novel IRS1 binding partner. Insulin stimulates nexilin to dissociate from IRS1 and interact with actin. Nexilin knockdown has no effect on insulin-stimulated IRS1 tyrosine phosphorylation, but does enhance insulin-stimulated IRS1-PI3K interaction, increasing PIP3 formation, PKB activation and glucose uptake. This study also shows that nexilin overexpression may have an inhibitory effect on PKB phosphorylation and glucose uptake in adipocytes. These findings suggest nexilin is a negative regulator of IRS1 action on PI3K and insulin-stimulated dissociation of IRS1-nexilin allows the formation of IRS1-PI3K complexes in cytoskeletal-membrane compartments. Nexilin also specifically associates with the PH domain of IRS1, and not IRS2, suggesting a mechanism for signaling specificity of these isoforms.

Purpose: The prevalence of diabetes (DM) is increasing globally with type 2 diabetes (T2DM) being primarily responsible for this alarming trend. Age and DM have been associated with an increased prevalence of AR cataract in earlier studies but T2DM has not been considered separately from type 1 diabetes. Furthermore, study results have been inconsistent in terms of whether nuclear sclerosis (NS), cortical cataract (CC) or posterior subcapsular (PSC) are specifically associated with DM. The purpose of this thesis was to provide Canadian data on these issues while considering the limitations found in earlier studies in terms of variable age group selection and cataract definition. Logistic regression analysis was extended beyond risk analysis to model the prevalence of AR cataract across the human age range. Finally, as statins are commonly prescribed for patients with T2DM, the impact of using this pharmaceutical on AR cataract prevalence was investigated. Methods: A file review of over 6397 clinic files was performed to create the Waterloo Eye Study (WatES) database. Abstracted data included patient age and sex, the presence of early to late AR cataract (NS, CC, PSC or related lens extraction-LE), systemic health diagnoses including a diagnosis of T2DM or type 1 diabetes, and any medication used. Data quality was looked at through repeatability with double-entry of files and calculation of missing data rates. Comparisons were done between the study population demographics (age and sex) and those available on the general population and representative Canadian optometric patients. Prevalence of AR cataract was determined for the entire study group and for yearly age-groups. The probability of AR cataract generated from logistic regression analysis was used to model the prevalence of AR cataract over the entire age range of patients. Similar functions were determined for T2DM and non-diabetic (ND) subgroups and then again after further subdividing them into patients who did and did not use statins. The age of 50% prevalence of AR cataract were determined for each of these functions. Distribution rates of mixed and uniform cataract were calculated and compared for the T2DM and ND subgroups. Age of first lens extraction and differences in LE rates were also determined for these groups. Multivariable logistic regression analysis was done to determine odds ratios (OR) for associations between variables (patient age, being female, having a diagnosis of T2DM, smoking, systemic hypertension, and statin use) and the outcome of AR cataracts or its subtypes. Results: Data abstraction repeatability was found to be high and missing data rates were found to be low. While significant differences existed between the demographics of the general population and this clinic population, the sex and age distributions were comparable to optometric practices in Canada. The overall prevalence of AR cataract, NS, CC,and PSC in this population was 35.3%, 28.8%, 9.9%, and 3.6% respectively. The yearly prevalence of AR cataract in this population was found to increase in a sigmoid trend over the course of the human age span that began to rise after 38 years of age and approached 100% by 75 years of age. When modelled into a probability of cataract function, 50% prevalence of AR cataract occurred at 56.6 years of age. T2DM was reported in 452 WatES patients; 97% of whom were over 38 years of age. The probability of 50% AR cataract, NS, and CC prevalence occurred almost four years earlier in the T2DM subgroup compared to those without diabetes. PSC was much less prevalent and did not reach 50% levels, but the age of 10% prevalence was eight year earlier in the T2DM group compared to the ND group. Patients with T2DM had more mixed cataract, a higher rate of LE and an earlier age of first LE than non-diabetics. Statin use was reported in 761 patients; 96% who were over 38 years of age. Statin use was 3.5 times more common in patients with T2DM compared to non-diabetics. When the diabetic subgroups were further subdivided by those who do and do not use statins, the age of 50% probability of AR cataracts was now almost eight years earlier in the T2DM patients using statins compared to the ND patients who did not. The probability functions were similar between T2DM patients not using statins and ND patients who did report statin use. Having a diagnosis of T2DM was significantly associated with early to late NS and CC when controlling for statin use, whereas statin use was significantly associated with NS and PSC when controlling for a diagnosis of T2DM. Conclusions: AR cataract, T2DM and statin use were prevalent conditions in this clinic population, especially over 38 years of age. Modelling the prevalence of AR cataract over a broad age range could assist predicting cataract in Canadian optometric patients. A diagnosis of T2DM resulted in an earlier development of all three cataract subtypes, resulting in increased rates of LE and mixed cataract. However, the association was only significant for NS and CC when controlling for statin use. Given the frequent use of statins in patients with T2DM, the significant association found between statin use and increased risk of AR cataract warrants further study.

Compared to other Canadians, Aboriginal people suffer disproportionately from Type 2 diabetes and its complications. In an attempt to fill gaps in services for Aboriginal people to support better management of diabetes and to prevent further complications, the West Side Community Clinic launched a monthly outreach diabetes education program using an informal hands-on approach to learning about meal planning and other forms of diabetes management. The purpose of this qualitative study was to determine the impact that the program has had on the participants' health and well-being through the stories they shared in a group or individual interview. Out of the core group of 30 women, most of them Aboriginal, eleven participated in the group interview and five women participated in individual interviews.<p>Findings reveal that the program's impact on participants' health and well-being is embedded within the context of their lives. Diabetes is managed within multiple life realities in an individual, a familial and a community context. The women report learning management skills and sharing support among participants and staff of Diabetes Morning; and altered health status such as regulated blood glucose levels and weight loss. Opportunities for change include more programming like Diabetes Morning, more often, more information, access to low-cost diabetes-friendly foods, communication with health care practitioners, and integrating knowledge on a day-to-day basis. Domains for outcome indicators and contextual indicators are suggested for the program.

Adiposity has been shown to secrete bioactive cytokines and growth factor known as adipocytokines, they can contribute to obesity, diabetes and complications of diabetes. Visfatin is a novel adipocytokine, and it was shown to exert insulin-mimetic effects in stimulating glucose transport and induced triglyceride accumulation in preadipocytes and triglyceride synthesis from gluvose. Visfatin plasma levels are increased in morbid obesity and type 2 diabetes mellitus. These finding indicate that visfatin may play a role in the association between visceral obesity and increased metabolic risk, visfatin gene suggested that genetic variation in the visfatin gene may, indeed, have a minor effect on visceral and subcutaneous visfatin messenger RNA expression profiles and parameters of glucose and insulin metabolism. In this study, we explored the relationships between the plasma level of visfatin and genetic single nucleotide polymorphisms (SNPs) of visfatin gene in type 2 diabetes mellitus (T2DM) with and without macrovascular disease. Plasma visfatin was found to be elevated significantly in T2DM with macrovascular disease patients. Moreover, waist to hip ratio was independently associated with plasma visfatin level. There were statistically significant differences in visfatin -948 G/T genetic variants distribution between T2DM with macrovascular disease and the T2DM control group. The visfatin -948 G/T heterozygotes showed higher mean high-density lipoprotein cholesterol than the carriers of the G allele. The results of the current study indicated that plasma visfatin levels were associated with macrovascular complications in type 2 diabetes. However, the definite roles of visfatin in the pathogenesis of insulin resistance, glucose and lipid metabolism are unclear. The observation of changes in the plasma concentrations of visfatin seen in T2DM and T2DM with macrovascular diseases may exert beneficial effects in understanding roles of visfatin in physiologic activity and metabolic disorder. Further studies are needed to elucidate the mechanisms behind visfatin overexpression in humans.

Thèse d'exercice : Médecine : Nancy 1 : 2009. / Titre provenant de l'écran-titre.