BACKGROUND: Exercise is a critical treatment modality in persons with Type II Diabetes Mellitus (T2DM), however people with this disease experience chronic fatigue and a decreased exercise capacity, which affects their ability or willingness to participate in physical activity. Studies suggest that this exercise intolerance may be partly due to a reduced exercising muscle blood flow (MBF), and in particular to a reduced ability of red blood cells (RBCs) to evoke ATP-mediated vasodilation and an increase in MBF as they traverse areas of high O2 demand. Additional evidence suggests that caffeine may attenuate this impairment by enhancing the release of ATP from RBCs. HYPOTHESIS: Persons with T2DM would have reduced Forearm Blood Flow (FBF), oxygen consumption (VO2), and exercise tolerance responses to exercise compared to control (CON) subjects, and caffeine would attenuate these impairments. METHODS: T2DM (n = 4) and CON (n = 4) participants performed rhythmic forearm handgrip exercise at an intensity equivalent to 17.5 kg until “task failure” or 20 minutes of exercise was reached, after having consumed either a caffeine (5mg/kg; Caff) or placebo (Pl) capsule. FBF (Doppler and Echo ultrasound of the brachial artery), VO2 and lactate efflux (deep venous blood sampling), forearm vascular conductance (FVK), mean arterial pressure (MAP) and heart rate (HR) were quantified for each minute of exercise. RESULTS: Steady state FBF was similar across groups and treatment conditions (mean ± SE ml/min; CONCaff 553.80 ± 82.35, CONPl 583.42 ± 112.62, T2DMCaff 523.33 ± 105.39, T2DMPl 569.08 ± 134.20, NS), and this was due to similar MAP and FVK (across groups and treatment conditions, NS). VO2 and Time to Task Failure (TTF) were not different between groups and treatment conditions (NS), although TTF tended to be improved with caffeine versus placebo (10.00 ± 2.02 vs 8.24 ± 1.79 min, P=0.295). There was a strong positive relationship between FBF and TTF (r2=0.763; P=0.005). CONCLUSIONS: In the exercise model utilized, persons with T2DM do not have impaired cardiovascular responsiveness or reduced exercise tolerance, and caffeine does not provide any benefit. Differences in exercising MBF may be an underlying mechanism regarding differences in exercise tolerance. / Thesis (Master, Kinesiology & Health Studies) -- Queen's University, 2009-09-16 16:19:42.537

Ensaio clinico randomizado, constituído por 82 adultos com Diabetes Mellitus tipo 2, desenvolvido em Pachuca, Hidalgo no México, cujo objetivo foi avaliar os efeitos da utilização do protocolo Staged Diabetes Management no controle metabólico (pressão arterial sistólica e diastólica, índice de massa corporal, glicemia de jejum e capilar, hemoglobina glicada, colesterol total, HDL, LDL, triglicérides), conhecimento da doença e cuidados. A população constituiu-se pelas pessoas atendidas no período de junho a dezembro de 2007. Formaram-se dois grupos, aleatoriamente, um intervenção e outro controle. O grupo intervençao recebeu atenção de uma equipe multiprofissional, de acordo com as diretrizes do protocolo MDE e intervenções educativas grupais durante oito semanas, com carga horária de 16 horas e dois seguimentos trimestrais. O grupo controle manteve-se conforme rotina do serviço. As avaliações foram realizadas no início do estudo e nos terceiro e sexto meses seguintes. Para o processamento dos dados, utilizou-se o programa estatístico SPSS-15 e para as análises estatísticas, o teste t Student para as variáveis contínuas, qui-quadrado para as variáveis categóricas e o teste Wilks\' lambada para análise de associações inter grupos. A população do estudo ficou constituída por 41 pessoas adultas com DM2, respectivamente nos grupos intervenção e controle. No grupo intervenção houve predominância do sexo feminino (70,7%) enquanto que, no controle, do sexo masculino (51,2%). Em ambos, a faixa etária predominante foi de 50 |- 60 anos; as maiores freqüências foram para escolaridade \"primária\", ocupação \"empregado\" e estado civil \"casado\". Entre os parâmetros do controle metabólico alterados, destacam-se para os grupos, a pressão arterial sistólica perfil glicêmico, colesterol e triglicérides. Antes das intervenções os grupos apresentavam-se semelhanças, exceto para o sexo. Na análise de associações intra grupos, observaram-se mudanças significantes (p<0,005), na seguintes variáveis: entre a primeira e segunda medidas, houve diferenças nos valores da pressão arterial sistólica (t=2, 31, p=0,026); índice de massa corporal (t=5, 21, p=0,001); glicemia capilar (t=7, 06, p=0,001; glicemia plasmática (t=2, 09, p=0,043); hemoglobina glicada (t=4, 26, p=0,001); colesterol (t=3, 78, p=0,001); triglicérides (p=3, 38, p=0,002). Na terceira medida observaram-se diferenças significantes para as variáveis da pressão arterial sistólica (t=3, 61, p=.0001); pressão arterial diastólica (t=2, 42, p=0,002); Índice de Massa Corporal (t=4, 56, p=0,001); glicemia capilar (t=7, 98, p=0,001; glicemia plasmática (t=2, 89, p=0,006); hemoglobina glicada (t=9, 53, p=0,001); colesterol (t=6, 18, p=0,001); triglicérides (t=5, 52, p=0,001). O grupo controle mostrou diferenças significativas após a intervenção, na glicemia capilar e plasmática, porém, as médias são superiores às do grupo intervenção e fora dos parâmetros normais. Observaram-se diferenças significantes nos índices de conhecimentos (t=11.42, p<. 001), destacando-se que, aos três meses, no grupo intervenção houve aumento destes índices. Na análise de associação entre os grupos, observou-se que a variável pressão arterial sistólica, índice de massa corporal, glicemia capilar, hemoglobina glicada, colesterol, LDL e triglicérides, dos grupos intervenção e controle, entre as três medidas estão interagindo, indicando que o comportamento dos grupos não são os mesmos através das medidas. Os resultados do estudo apontaram para efeitos positivos das intervenções propostas no controle metabólico, no entanto, sugerem-se estudos para investigar a relação custo e benefício quando comparados a outros estudos de intervenções junto às pessoas com diabetes mellitus. / This randomized clinical essay was performed with 82 adults with Type II Diabetes Mellitus, in Pachuca, Hidalgo, Mexico. The purpose was to assess the effects that using the Staged Diabetes Management protocol had over metabolic control (systolic and diastolic blood pressure, body mass index, fasting and capillary glucose, glycosylated hemoglobin, total cholesterol, HDL, LDL, triglycerides), knowledge about the disease, and care. The population consisted of people seen from June to December 2007. Two groups, intervention and control, were composed at random. The intervention group was seen by a multiprofessional team, as recommended in the Staged Diabetes Management protocol, and received a total of 16 hours of group interventions during eight weeks, with two quarterly follow-up appointments. The control group was provided with the regular service. Assessments were performed at the beginning of the study and in the third and sixth following months. Data processing was done using the SPSS-15 statistical software, Student t test for statistical analyses, for continuous variable, chi-square, for categorical variables, and the Wilks\' lambada test to analyze intergroup association. Each group was composed of 41 adults with Type 2 Diabetes Mellitus. In the intervention group, most participants were women (70.7%) whereas in the control group, men prevailed (51.2%). In both, the predominant age group was 50 |- 60 years; the highest frequencies were in \"primary education\", \"employed\", and \"married\". Among the parameters for altered metabolic control, special emphasis is given to systolic blood pressure, glucose profile, cholesterol and triglycerides. Prior to the interventions, the groups were similar except in terms of gender. The intragroup association analysis showed there were significant changes (p<0.005) in the following variables, between the firts and second measurements: systolic blood pressure (t=2.31, p=0.026); body mass index (t=5.21, p=0.001); capillary glucose (t=7.06, p=0.001; plasma glucose (t=2.09, p=0.043); glycosylated hemoglobin (t=4.26, p=0.001); cholesterol (t=3.78, p=0.001); triglycerides (p=3.38, p=0.002). In the third measurement it was observed there were significant changes for the variables regarding systolic blood pressure (t=3.61, p=0. 0001); diastolic blood pressure (t=2.42, p=0.002); Body Mass Index (t=4.56, p=0.001); capillary glucose (t=7.98, p=0.001; plasma glucose (t=2.89, p=0.006); glycosylated hemoglobin (t=9.53, p=0.001); cholesterol (t=6.18, p=0.001); triglycerides (t=5.52, p=0.001). The control group showed significant differences after intervention on capillary and plasma glucose; however, the means are above those of the intervention group and not within the normal standards. Significant differences were observed in the knowledge rates (t=11.42, p<<. 001), and it is worth emphasizing that, at three months, in the intervention group, those rates increased. The analysis of the association between the groups showed that there is an interaction among the variables systolic blood pressure, body mass index, capillary glucose, glycosylated hemoglobin, cholesterol, LDL and triglycerides in the intervention. This shows that the groups\' behaviors are not the same. The results revealed that the proposed interventions have positive effects over the metabolic control, however, further studies are needed in order to analyze cost effectiveness in comparison with other studies of intervention among people with diabetes mellitus.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that function as ligand activated transcription factors. There are three identified isotypes: PPAR alpha, PPAR gamma and PPAR delta, together controlling the expression of genes involved in inflammation, cell differentiation, proliferation, lipid and carbohydrate metabolism and energy homeostasis. The PPARs are potential targets for the treatment of dyslipidaemia, type II diabetes mellitus and the metabolic syndrome. This thesis uses a multi-platform metabolomics approach, 13C-isotope substrate flux analysis, respirometry and transcriptomics to determine the role PPAR delta and PPAR gamma play in metabolic control both in adipose tissue and systemically. To achieve this, the metabolic phenotype of the 3T3-L1 adipocyte cell line was defined to generate a metabolically phenotyped in vitro model of adipose tissue. The importance of fatty acid alpha-oxidation in the differentiation of adipocytes was emphasised The effects of PPAR delta and PPAR gamma activation in white adipose tissue from the ob/ob mouse model of insulin resistance, and in the phenotyped 3T3-L1 adipocyte model, were investigated. PPAR delta activation was distinguished by oxidative catabolism of fatty acids and citric acid cycle intermediates. Conversely, PPAR gamma activation was identified by the sequestration of lipids into adipose tissue. Moreover, to address the systemic influence of PPAR activation, with a focus on the Cori cycle and the interactions of the liver and skeletal muscle, the metabolic changes that occur in these tissues following PPAR delta and PPAR gamma activation in the ob/ob mouse were examined. PPAR delta activation was characterised by the mobilisation and release of triacylglycerols (TAGs) into circulation as an energy source for peripheral tissues whereas PPAR gamma activation was defined by a reduction and sequestration of circulating TAGs. This thesis has better characterised the role of the PPARs as master regulators of metabolism and emphasised their potential as therapeutic targets for metabolic diseases of global importance.

The current study empirically tested four models of type II diabetic patient adherence, including wellness, screening, medication, and treatment adherence. Four mediators were proposed patient understanding, agreement, trust, and motivation were tested for each model. The current study is grounded in patient-centered communication, responding to Street’s (2013) call to model pathways between communication and patient health outcomes. Moreover, the study argues that adherence, for type II diabetic patients should be conceptualized as four distinct clusters of behavior (wellness, screening, medication, and treatment). A sample of (n=817) type II diabetes patients from the U.S. under the care of a medical provider and taking medication for their type II diabetes were surveyed. Findings from the present study indicate that the relationship between patient-centered communication and patient-health outcomes is mediated by proximal outcomes. The results contribute to our understanding or patient-centered communication, patient understanding, agreement, trust, and motivation, and adherence behaviors. Resulted indicated that while three of the four proposed hypotheses were supported, the most commonly studied type of adherence (medication), the relationship between patient-centered communication and medication adherence was not mediated. The current study ends with a discussion and implication of the findings as well as directions for future research

This work details the inhibition of BACE1, BACE2, and SARS-CoV-2 3CLpro through several novel and potent protease inhibitors. Nanomolar potency of BACE1 and BACE2 is achieved with all tested inhibitors, and the S2 subsite has been identified as a BACE2 selectivity determinant. This is supported by the observation that the novel BACE2 mutant, BACE2 L246N, displays increased potency and selectivity over BACE1 against this peptidomimetic scaffold. Nanomolar to micromolar potency of SARS-CoV-2 3CLpro is achieved with the compounds tested in this study. Kinetic data illustrates the allowed substitutions at the P1’, P1, P2, and P4 positions on two scaffolds: ML188 and GC376. Finally, this work presents the high-resolution crystal structures of four inhibitors bound to BACE1 and 12 inhibitors bound to SARS-CoV-2 3CLpro. These structural data help to explain the selectivity determinants of BACE1 and BACE2 and further enable structure-based drug design against these two enzymes for the treatments of Alzheimer's Disease and Type II Diabetes, respectively. Additionally, these structural data illustrate the flexibility of the GC376 scaffold at the P3/P4 position, providing a structural rationale for the observed differences in potency across the different analogs. These structural data further enable structure-based drug design against SARS-CoV-2 3CLpro for the treatment of COVID-19.

Type II diabetes is a significant problem in the United States that had affected almost 10% of the American population and over 13% of African Americans. Although culturally competent diabetes education and treatment programs have been significantly more successful, little is known about the cultural factors affecting type II diabetes in African Americans of Caribbean descent (AACD). The purpose of this qualitative, phenomenological study was to explore the cultural factors relevant to the treatment and prevention of type II diabetes among AACD. The theoretical framework for the study consisted of cultural adaptation theory and the transtheoretical model. Data collection consisted of in-depth, qualitative semistructured interviews. For the first research question, findings indicated that AACD viewed dietary and exercise regimens as challenging to implement. For the second question, findings indicated that AACD viewed medical advice related to diabetes as valuable and helpful, and AACD fully appreciated and perhaps even exaggerated the seriousness of diabetes, a factor that might incentivize preventative behaviors. Findings from the present study could inform new diabetes treatment and education for AACD that addresses specific cultural factors, which could lead to lower diabetes rates for this population.

The incidence of diabetes mellitus and cardiovascular diseases is increasing at a worrisome rate globally. Diabetes mellitus is known to occur due to high blood glucose levels, caused by defects in insulin levels. Adult on-set type II diabetes, which is closely associated with obesity, is reported to be 90-95% of all diabetic cases and linked to diet and lifestyle factors. A large population of the developed and developing countries is now being effected by this epidemic. Natural sources of phenolic antioxidants and inhibitors of digestive enzymes from food sources have potential for low cost dietary management of type II diabetes. Therefore, the main focus of this study was to evaluate, develop and design effective dietary strategies based on a combination of Chilean potatoes and herb synergies for the management of hyperglycemia and hypertension linked to type II diabetes. Antioxidant, antihypertensive and anti-hyperglycemic potentials of Chilean potato (Solanum tuberosum ssp. tuberosum L.), herbs from the Apiaceae (Dill, Ajowan, Fennel, Caraway, Coriander and Anise) and Lamiaceae (Sage and Marjoram) families were evaluated, with a goal to target a new dietary management strategy for early stages of type II diabetes through lowering of hyperglycemia and related complications of hypertension The results indicated a high correlation between total phenolic content and total antioxidant activity in several Chilean potato varieties evaluated, which indicates that certain phenolic compounds may be responsible for high antioxidant activity. Also, certain varieties of Chilean potato had antihypertensive potentials, with ACE inhibition upto 88%. The -glucosidase inhibition relevant for hyperglycemia management for Apiaceae family ranged upto 50% (Dill) for aqueous extracts. A high correlation (r = 0.86) was observed between -glucosidase inhibition and total phenolic content for aqueous extracts of all species investigated in the Apiaceae family. A high rosmarinic acid activity was observed in aqueous extracts of Lamiaceae family, which ranged upto 39.7 mg/g of sample dry weight (DW). This suggests that high phenolic content and associated antioxidant activity found in sage and marjoram is dominated by rosmarinic acid. High enzyme inhibitory activities, reflecting in vitro anti-hyperglycemic and anti-hypertensive potentials indicates that consumption of these food sources in our diet would prove to be beneficial towards our health. Further in vivo studies for type II diabetes-linked functionalities of these natural sources of antioxidants and inhibitors would confirm the human health benefits achieved through dietary intake.

No description available.

Osteoarthritis (OA) is a common and incapacitating joint disease beginning with breakdown of articular cartilage and extending into subchondral bone. At present, the processes through which the disease occurs are poorly understood, and interventions are limited to pain relief and eventual joint replacement. OA is commonly associated with obesity and corresponding pathologies, and as OA is demonstrably not a product of passive erosion of cartilage over time or under increased loads there must needs be some other mechanistic link between the two conditions. We hypothesize that the production of ceramides, a hallmark of the insulin resistance syndrome underlying many obesity-related conditions, acts to induce OA through its pro-inflammatory and pro-apoptotic activities, as well as directly inhibiting intracellular mediators of cartilage production and homeostasis. We demonstrate in Wistar rats that a high-fat, high-sugar (HFHS) diet successfully induces OA and that downregulation of ceramide synthesis through intraperitoneal myriocin administration does not prevent this degradation, and that myriocin in conjunction with a standard chow diet actually induces OA. Alteration in OA biomarkers in this study are discussed. We then tested the efficacy of a topical regimen of wogonin, an anti-inflammatory, anti-oxidative, and potentially analgesic compound in a surgical destabilization model (DMM) of OA in mice and demonstrate its disease modifying anti-OA properties. We further test the efficacy of this compound on the HFHS model previously established and find it successfully ameliorated the morphology and biomarker changes associated with OA; based on this data we hypothesize that inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is the most relevant physiological target of wogonin in a HFHS-induced OA model. Lastly and separately, we seek to clarify conflicting data regarding secondhand smoke (SHS), which observational studies suggest having either deleterious or beneficial effects to preexisting OA. In the first controlled study on the subject we model we demonstrate in a murine DMM model that SHS accelerates cartilage degradation and patterns of biomarker expression characteristic of OA, eliminating the question of any potential benefits of SHS to articular cartilage.

No description available.