Cree traditional medicine and type 2 diabetes : an ethnobotanical and pharmacological study

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Integrase, the central DNA flap and human immunodeficiency virus type 1 nuclear import

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

A Québec mystery unveiled : the quest to understand hereditary sensory and autonomic neuropathy type 2

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Molecular and functional studies of human immunodeficiency virus type 1 accessory protein

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Factors of Inflammation in Haitian Americans and African Americans with and without Type 2 Diabetes

Chronic low-grade inflammation has been implicated in the processes leading to the development of type 2 diabetes (T2D) and its progression. Non-Hispanic Blacks bear a disproportionate burden of T2D and are highly susceptible to inflammation. This cross-sectional study assessed and compared the serum levels of established adipocytokines; interleukin-6 (IL-6), C-reactive protein (CRP), leptin, and novel adipocytokines; chemerin and omentin in Haitian and African Americans with and without T2D. The relationships of these adipocytokines with metabolic syndrome (MetS), anthropometric and HOMA2 measures by ethnicity and diabetes status were also assessed. Serum levels of IL-6, CRP, leptin, chemerin and omentin were determined by the ELISA method. HOMA2 measures were calculated for insulin sensitivity (HOMA2-IS) and insulin resistance (HOMA2-IR). Analyses of available data for 230 Haitian Americans and 241 African Americans (240 with and 231 without T2D) for the first study showed that Haitian Americans with and without MetS had lower levels of IL-6 and CRP compared to African Americans with and without MetS (P Ethnic-specific diabetes intervention and treatment programs must be designed to target Haitian Americans and African Americans as separate unique groups, in order to reduce the burden of T2D among the non-Hispanic Black community. Further research is needed to gain better understanding of the role of inflammation and T2D in this population.

Peroxisome Proliferator-Activated Receptor-γ Coactivator 1-α (PPARGC1A) Genetic Associations with Type 2 Diabetes in Three Ethnicities

Genetic heterogeneity, lifestyle factors, gene-gene or gene-environment interactions are the determinants of T2D which puts Hispanics and populations with African ancestry at higher risk of developing T2D. In this dissertation, the genetic associations of PPARGC1A polymorphisms with T2D and its related phenotypes (metabolic markers) in Haitian Americans (cases=110, controls=116), African Americans (cases=120, controls=124) and Cuban Americans (cases=160, controls=181) of South Florida were explored. Five single nucleotide polymorphisms of gene PPARGC1A were evaluated in each ethnicity for their disease association. In Haitian Americans, rs7656250 (OR= 0.22, pp=0.03) had significant protective association with T2D but had risk association in African Americans for rs7656250 (OR=1.02, p=0.96) and rs4235308 (OR=2.53, p=0.03). We found that in Haitian American females, both rs7656250 (OR=0.23, pp=0.03) had protective association with T2D. In African American females, rs7656250 (OR=1.14, p=0.78) had risk association whereas in males, it had significant protective effect (OR=0.37, p=0.04). However, the risk association exhibited by rs4235308 was stronger in African American females (OR=2.69, p=0.03) than males (OR=1.16, p=0.72). In Cuban Americans, only rs7656250 showed significant risk association with T2D (OR=6.87, p=0.02) which was stronger in females alone (OR=7.67, p=0.01). We also observed significant differences among correlations of PPARGC1A SNPs and T2D phenotypes. Positive correlation was observed for log Hs-CRP with rs3774907 (pp=0.03) in Cuban Americans respectively. Correlation of log A1C with rs7656250 (p=0.02) was positive in Cuban Americans while it was negative for rs3774907 in Haitian Americans (ppPPARGC1A correlations with T2D and its phenotypes among the three ethnicities studied (ii) the associations of PPARGC1A SNPs showed significant effect modification by sex. The findings suggest that variations in effects of PPARGC1A gene polymorphisms among three ethnicities and between sexes may have biomedical implications for the development of T2D as well as the phenotypes related to T2D.

The relationship among serum levels of manganese superoxide dismutase and mtDNA 8-hydroxy-2'-deoxyguanosine, and dietary antioxidants intake in Type 2 Diabetes

Oxidative stress plays a key role in the development of Type 2 Diabetes (T2D). This cross-sectional study examined the relationship among serum levels of manganese superoxide dismutase (MnSOD), 8-hydroxy-2’-deoxyguanosine (8OHdG), dietary antioxidant intakes and glycemic control in African Americans (n=209) and Haitian Americans (n=234) with and without T2D. African Americans had higher BMI (32.8 vs. 29.3 kg/m2), higher energy intake (2148 vs. 1770 kcal), and were more educated as compared to Haitian Americans; all variables were significant at p < .001. Serum levels of 8OHdG and MnSOD for African Americans (1691.0 ± 225.1 pg/ml, 2538.0 ± 1091.8 pg/ml; respectively) were significantly higher than for Haitian Americans (1626.2 ± 222.9, 2015.8 ± 656.3 pg/ml; respectively). 8OHdG was negatively correlated with MnSOD (r = -.167, p < .001) in T2D. Having T2D was negatively correlated with MnSOD (r = -.337; p < .01) and positively correlated with 8OHdG (r = .500; p < .01). African Americans and Haitian Americans with T2D had fasting plasma glucose (FPG) levels of 143.0 ± 61.0 mg/dl and 157.6 ± 65.5 mg/dl, and A1C of 7.5 ± 1.8 % and 8.4 ± 2.4 %, respectively. African Americans and Haitian Americans without T2D had FPG levels of 95.8 ± 13.2 mg/dl and 98.7 ± 16.9 mg/dl, and A1C of 5.9 ± 0.4% and 6.0 ± 0.5%, respectively. Dietary intakes of vitamin C and vitamin D were negatively correlated with FPG (r = -.21; r = -.19, p < .05) respectively. Carotenoids negatively correlated with A1C (r = -.19, p < .05). Lower levels of MnSOD were associated with lower levels of zinc, r = .10, p < .05, and higher levels of carotenoids r = -.10, p < .05. Higher levels of 8OHdG were associated with lower levels of Vitamin D, r = -.14, p < .01, and carotenoids, r = -.09, p < .05. The results demonstrate greater oxidative mtDNA damage in persons with T2D compared to those without T2D and in African Americans compared with Haitian Americans. The inverse relationship between dietary intake of antioxidants and oxidative stress implies a potential to reduce oxidative stress with diet. African Americans were significantly younger (53.3 vs. 55.6 years), had higher BMI (32.8 vs. 29.3 kg/m2), higher energy intake (2148 vs. 1770 kcal), and were more educated as compared to Haitian Americans; all variables were significant at p < .001. Serum levels of 8OHdG and MnSOD for African Americans (1691.0 ± 225.1 pg/ml, 2538.0 ± 1091.8 pg/ml; respectively) were significantly higher than for Haitian Americans (1626.2 ± 222.9, 2015.8 ± 656.3 pg/ml; respectively). 8OHdG was negatively correlated with MnSOD (r = -.167, p < .001) in T2D. Having T2D was negatively correlated with MnSOD (r = -.337; p < .01) and positively correlated with 8OHdG (r = .500; p < .01). African Americans and Haitian Americans with T2D had fasting plasma glucose (FPG) levels of 143.0 ± 61.0 mg/dl and 157.6 ± 65.5 mg/dl, and A1C of 7.5 ± 1.8 % and 8.4 ± 2.4 %, respectively. African Americans and Haitian Americans without T2D had FPG levels of 95.8 ± 13.2 mg/dl and 98.7 ± 16.9 mg/dl, and A1C of 5.9 ± 0.4% and 6.0 ± 0.5%, respectively. Dietary intakes of vitamin C and vitamin D were negatively correlated with FPG (r = -.21; r = -.19, p < .05) respectively. Carotenoids negatively correlated with A1C (r = -.19, p < .05). Lower levels of MnSOD were associated with lower levels of zinc, r = .10, p < .05, and higher levels of carotenoids r = -.10, p < .05. Higher levels of 8OHdG were associated with lower levels of Vitamin D, r = -.14, p < .01, and carotenoids, r = -.09, p < .05. The results demonstrate greater oxidative mtDNA damage in persons with T2D compared to those without T2D and in African Americans compared with Haitian Americans. The inverse relationship between dietary intake of antioxidants and oxidative stress implies a potential to reduce oxidative stress with diet.

Efficacy and Safety of Cannabidiol and Tetrahydrocannabivarin on Glycemic and Lipid Parameters in Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Pilot Study

OBJECTIVE Cannabidiol (CBD) and D9-tetrahydrocannabivarin (THCV) are nonpsychoactive phytocannabinoids affecting lipid and glucose metabolism in animal models. This study set out to examine the effects of these compounds in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS In this randomized, double-blind, placebo-controlled study, 62 subjects with noninsulin-treated type 2 diabetes were randomized to five treatment arms: CBD (100 mg twice daily), THCV (5 mg twice daily), 1:1 ratio of CBD and THCV (5 mg/5 mg, twice daily), 20:1 ratio of CBD and THCV (100 mg/5 mg, twice daily), or matched placebo for 13 weeks. The primary end point was a change in HDL-cholesterol concentrations from baseline. Secondary/tertiary end points included changes in glycemic control, lipid profile, insulin sensitivity, body weight, liver triglyceride content, adipose tissue distribution, appetite, markers of inflammation, markers of vascular function, gut hormones, circulating endocannabinoids, and adipokine concentrations. Safety and tolerability end points were also evaluated. RESULTS Compared with placebo, THCV significantly decreased fasting plasma glucose (estimated treatment difference [ETD] = 21.2 mmol/L; P < 0.05) and improved pancreatic b-cell function (HOMA2 b-cell function [ETD = 244.51 points; P < 0.01]), adiponectin (ETD = 25.9 3 106 pg/mL; P < 0.01), and apolipoprotein A (ETD = 26.02 mmol/L; P < 0.05), although plasma HDL was unaffected. Compared with baseline (but not placebo), CBD decreased resistin (2898 pg/ml; P < 0.05) and increased glucose-dependent insulinotropic peptide (21.9 pg/ml; P < 0.05). None of the combination treatments had a significant impact on end points. CBD and THCV were well tolerated. CONCLUSIONS THCV could represent a newtherapeutic agent in glycemic control in subjects with type 2 diabetes.

Toxicity profile of bevacizumab in the UK Neurofibromatosis Type 2 cohort

Bevacizumab is considered an established part of the treatment strategies available for schwannomas in patients with Neurofibromatosis Type 2(NF2). In the UK, it is available through NHS National Specialized Commissioning to NF2 patients with a rapidly growing target schwannoma. Regrowth of the tumour on suspension of treatment is often observed resulting in prolonged periods of exposure to bevacizumab to control the disease. Hypertension and proteinuria are common events with bevacizumab use and there are concerns with regards to the long-term risks of prolonged treatment. Dosing, demographic and adverse event(CTCAE 4.03) data from the UK NF2 bevacizumab cohort are reviewed with particular consideration of renal and cardiovascular complications. Eighty patients (48 male:32female), median age 24.5 years (range 11-66years), were followed for a median of 32.7 months (range 12.0–60.2months). The most common adverse events were fatigue, hypertension and infection. A total of 19/80 patients (24%) had either a grade 2 or grade 3 hypertension event and 14/80 patients (17.5%) had proteinuria. Of 36 patients followed for 36 months, 78% were free from hypertension and 86% were free of proteinuria. Logistic regression modeling identified age and induction dosing regime to be predictors of development of hypertension with dose of 7.5mg/kg three weekly and age >30years having higher rates of hypertension. Proteinuria persisted in one of three patients after cessation of bevacizumab. One patient developed congestive heart failure and the details of this case are described. Further work is needed to determine optimal dosing regimes to limit toxicity without impacting on efficacy.

EGFR interacts with the fusion protein of respiratory syncytial virus strain 2-20 and mediates infection and mucin expression.

Respiratory syncytial virus (RSV) is the major cause of viral lower respiratory tract illness in children. In contrast to the RSV prototypic strain A2, clinical isolate RSV 2-20 induces airway mucin expression in mice, a clinically relevant phenotype dependent on the fusion (F) protein of the RSV strain. Epidermal growth factor receptor (EGFR) plays a role in airway mucin expression in other systems; therefore we hypothesized that the RSV 2-20 F protein stimulates EGFR signaling. Infection of cells with chimeric strains RSV A2-2-20F and A2-2-20GF or over-expression of 2-20 F protein resulted in greater phosphorylation of EGFR than infection with RSV A2 or over-expression of A2 F, respectively. Chemical inhibition of EGFR signaling or knockdown of EGFR resulted in diminished infectivity of RSV A2-2-20F but not RSV A2. Over-expression of EGFR enhanced the fusion activity of 2-20 F protein in trans. EGFR co-immunoprecipitated most efficiently with RSV F proteins derived from “mucogenic” strains. RSV 2-20 F and EGFR co-localized in H292 cells, and A2-2-20GF-induced MUC5AC expression was ablated by EGFR inhibitors in these cells. Treatment of BALB/c mice with the EGFR inhibitor erlotinib significantly reduced the amount of RSV A2-2-20F-induced airway mucin expression. Our results demonstrate that RSV F interacts with EGFR in a strain-specific manner, EGFR is a co-factor for infection, and EGFR plays a role in RSV-induced mucin expression, suggesting EGFR is a potential target for RSV disease.

Development and Evaluation of a Computer-Based, Self-Management Tool for People Recently Diagnosed with Type 2 Diabetes

Aim. The purpose of this study was to develop and evaluate a computer-based, dietary, and physical activity self-management program for people recently diagnosed with type 2 diabetes. 
Methods. The computer-based program was developed in conjunction with the target group and evaluated in a 12-week randomised controlled trial (RCT). Participants were randomised to the intervention (computer-program) or control group (usual care). Primary outcomes were diabetes knowledge and goal setting (ADKnowl questionnaire, Diabetes Obstacles Questionnaire (DOQ)) measured at baseline and week 12. User feedback on the program was obtained via a questionnaire and focus groups. Results. Seventy participants completed the 12-week RCT (32 intervention, 38 control, mean age 59 (SD) years). After completion there was a significant between-group difference in the “knowledge and beliefs scale” of the DOQ. Two-thirds of the intervention group rated the program as either good or very good, 92% would recommend the program to others, and 96% agreed that the information within the program was clear and easy to understand. 
Conclusions. The computer-program resulted in a small but statistically significant improvement in diet-related knowledge and user satisfaction was high. With some further development, this computer-based educational tool may be a useful adjunct to diabetes self-management.

The relationship between adipokines and the onset of type 2 diabetes in middle-aged men: The PRIME study

Aims: Epidemiological evidence suggests that adipokines may be associated with the onset of type 2 diabetes, but the evidence to date is limited and inconclusive. This study examined the association between adiponectin and leptin and the subsequent diagnosis of type 2 diabetes in a UK population based cohort of non-diabetic middle-aged men.
Methods: Baseline serum levels of leptin and adiponectin were measured in 1839 nondiabetic men aged 50–60 years who were participating in the prospective populationbased PRIME study. Over a mean follow-up of 14.7 years, new cases of type 2 diabetes were determined from self-reported clinical information with subsequent validation by general practitioners.
Results: 151 Participants developed type 2 diabetes during follow-up. In Cox regression models adjusted for age, men in the top third of the leptin distribution were at increased risk (hazard ratio (HR) 4.27, 95% CI 2.67–6.83) and men in the top third of the adiponectin
distribution at reduced risk (HR 0.24, 95% CI 0.14–0.42) relative to men in the bottom third. However, significance was lost for leptin after additional adjustment for BMI, waist to hip ratio, lifestyle factors and biological risk factors, including C-reactive protein (CRP). Further adjustment for HOMA-IR also resulted in loss of significance for adiponectin.
Conclusions: This study provides evidence that adipokines are associated with men’s future type 2 diabetes risk but not independently of other risk factors.

Fruit and vegetable intake and risk of incident of type 2 diabetes: results from the consortium on health and ageing network of cohorts in Europe and the United States (CHANCES)

BACKGROUND/OBJECTIVES: There is limited information to support definitive recommendations concerning the role of diet in the development of type 2 Diabetes mellitus (T2DM). The results of the latest meta-analyses suggest that an increased consumption of green leafy vegetables may reduce the incidence of diabetes, with either no association or weak associations demonstrated for total fruit and vegetable intake. Few studies have, however, focused on older subjects.

SUBJECTS/METHODS: The relationship between T2DM and fruit and vegetable intake was investigated using data from the NIH-AARP study and the EPIC Elderly study. All participants below the age of 50 and/or with a history of cancer, diabetes or coronary heart disease were excluded from the analysis. Multivariate logistic regression analysis was used to calculate the odds ratio of T2DM comparing the highest with the lowest estimated portions of fruit, vegetable, green leafy vegetables and cabbage intake.

RESULTS: Comparing people with the highest and lowest estimated portions of fruit, vegetable or green leafy vegetable intake indicated no association with the risk of T2DM. However, although the pooled OR across all studies showed no effect overall, there was significant heterogeneity across cohorts and independent results from the NIH-AARP study showed that fruit and green leafy vegetable intake was associated with a reduced risk of T2DM OR 0.95 (95% CI 0.91,0.99) and OR 0.87 (95% CI 0.87,0.90) respectively.

CONCLUSIONS: Fruit and vegetable intake was not shown to be related to incident T2DM in older subjects. Summary analysis also found no associations between green leafy vegetable and cabbage intake and the onset of T2DM. Future dietary pattern studies may shed light on the origin of the heterogeneity across populations.European Journal of Clinical Nutrition advance online publication, 17 August 2016; 

HDL-C and HDL-C/ApoA-I predict long-term progression of glycemia in established type 2 diabetes

OBJECTIVE: Low HDL cholesterol (HDL-C) and small HDL particle size may directly promote hyperglycemia. We evaluated associations of HDL-C, apolipoprotein A-I (apoA-I), and HDL-C/apoA-I with insulin secretion, insulin resistance, HbA1c, and long-term glycemic deterioration, reflected by initiation of pharmacologic glucose control.

RESEARCH DESIGN AND METHODS: The 5-year Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study followed 9,795 type 2 diabetic subjects. We calculated baseline associations of fasting HDL-C, apoA-I, and HDL-C/apoA-I with HbA1c and, in those not taking exogenous insulin (n = 8,271), with estimated β-cell function (homeostasis model assessment of β-cell function [HOMA-B]) and insulin resistance (HOMA-IR). Among the 2,608 subjects prescribed lifestyle only, Cox proportional hazards analysis evaluated associations of HDL-C, apoA-I, and HDL-C/apoA-I with subsequent initiation of oral hypoglycemic agents (OHAs) or insulin.

RESULTS: Adjusted for age and sex, baseline HDL-C, apoA-I, and HDL-C/apoA-I were inversely associated with HOMA-IR (r = -0.233, -0.134, and -0.230; all P < 0.001; n = 8,271) but not related to HbA1c (all P > 0.05; n = 9,795). ApoA-I was also inversely associated with HOMA-B (r = -0.063; P = 0.002; n = 8,271) adjusted for age, sex, and HOMA-IR. Prospectively, lower baseline HDL-C and HDL-C/apoA-I levels predicted greater uptake (per 1-SD lower: hazard ratio [HR] 1.13 [CI 1.07-1.19], P < 0.001; and HR 1.16 [CI 1.10-1.23], P < 0.001, respectively) and earlier uptake (median 12.9 and 24.0 months, respectively, for quartile 1 vs. quartile 4; both P < 0.01) of OHAs and insulin, with no difference in HbA1c thresholds for initiation (P = 0.87 and P = 0.81). Controlling for HOMA-IR and triglycerides lessened both associations, but HDL-C/apoA-I remained significant.

CONCLUSIONS: HDL-C, apoA-I, and HDL-C/apoA-I were associated with concurrent insulin resistance but not HbA1c. However, lower HDL-C and HDL-C/apoA-I predicted greater and earlier need for pharmacologic glucose control.

Alleles that increase risk for type 2 diabetes mellitus are not associated with increased risk for Alzheimer's disease

Although epidemiological studies suggest that type 2 diabetes mellitus (T2DM) increases the risk of late-onset Alzheimer's disease (LOAD), the biological basis of this relationship is not well understood. The aim of this study was to examine the genetic comorbidity between the 2 disorders and to investigate whether genetic liability to T2DM, estimated by a genotype risk scores based on T2DM associated loci, is associated with increased risk of LOAD. This study was performed in 2 stages. In stage 1, we combined genotypes for the top 15 T2DM-associated polymorphisms drawn from approximately 3000 individuals (1349 cases and 1351 control subjects) with extracted and/or imputed data from 6 genome-wide studies (>10,000 individuals; 4507 cases, 2183 controls, 4989 population controls) to form a genotype risk score and examined if this was associated with increased LOAD risk in a combined meta-analysis. In stage 2, we investigated the association of LOAD with an expanded T2DM score made of 45 well-established variants drawn from the 6 genome-wide studies. Results were combined in a meta-analysis. Both stage 1 and stage 2 T2DM risk scores were not associated with LOAD risk (odds ratio = 0.988; 95% confidence interval, 0.972-1.004; p = 0.144 and odds ratio = 0.993; 95% confidence interval, 0.983-1.003; p = 0.149 per allele, respectively). Contrary to expectation, genotype risk scores based on established T2DM candidates were not associated with increased risk of LOAD. The observed epidemiological associations between T2DM and LOAD could therefore be a consequence of secondary disease processes, pleiotropic mechanisms, and/or common environmental risk factors. Future work should focus on well-characterized longitudinal cohorts with extensive phenotypic and genetic data relevant to both LOAD and T2DM.