Introdução: O diabetes mellitus tipo 2 (DM2) representa cerca de 90% dos tipos de diabetes e vem atingindo de forma cada vez mais intensa a população adulta e atualmente também jovens e até crianças. Uma dieta hipercalórica, aliada ao sedentarismo tem sido junto com a predisposição genética os principais desencadeantes das complicações crônicas associadas com o DM2. Infelizmente, são essas complicações que levam ao grande aumento da morbidade e mortalidade que pode chegar até 80% nesta doença, sendo que as principais são as de natureza micro e macrovascular. Complicações microvasculares compreendem a retinopatia diabética (RD), a nefropatia diabética (ND) e a neuropatia periférica (NP), enquanto que as complicações macrovasculares compreendem a doença cardiovascular (DCV), a doença arterial periférica (DAP) e o acidente vascular cerebral (AVC). Pacientes com DM2 em sua fase inicial já podem apresentar um quadro protrombótico que só tende a piorar com a progressão da doença. Esse quadro protrombótico é resultante principalmente do processo inflamatório e da disfunção endotelial. Polimorfismos genéticos relacionados com as diferentes fases da hemostasia podem contribuir para o aumento ou diminuição no risco de formação de trombos arteriais e venosos que podem afetar a micro e macrovasculatura destes indivíduos. Objetivos: Investigar a influência de polimorfismos envolvidos com a hemostasia como fatores de risco para o desenvolvimento de complicações crônicas micro e macrovasculares em pacientes com DM2. Metodologia: Foi realizado um estudo de caso controle aninhado em uma coorte de pacientes DM2 não relacionados provenientes de um estudo multicêntrico no sul do Brasil. Os pacientes DM2 foram divididos em 2 grupos de estudo. Para o grupo com complicação macrovascular estudou-se 404 pacientes DM2. Casos para a complicação macrovascular foram definidos como tendo cardiopatia isquêmica (CI), acidente vascular cerebral isquêmico (AVCI) ou DAP enquanto que controles foram definidos como pacientes com pelo menos 5 anos de DM2 e sem a respectiva complicação. Para o estudo das complicações microvasculares 393 pacientes com DM2 foram estudados. Os casos foram definidos como tendo RD, ND ou neuropatia sensório distal (NSD). Controles para a complicação microvascular foram pacientes com pelo menos 10 anos de DM2 e sem a respectiva complicação. Os polimorfismos estudados foram testados em duplicata utilizando-se a PCR seguida de RFLP quando necessário. Foram investigados nove polimorfismos assim distribuídos: Na fase da coagulação foram estudados cinco polimorfismos (FGB rs1800790, F2 rs1799963, FV rs6025 F7 rs5742910 e F13A rs5985); dois (PLAT rs4646972 e PAI-1 rs1799768) na fase da fibrinólise e um (ITGB3 rs5918) na fase plaquetária. O polimorfismo da MTHFR rs1801133 envolvido com a hiperhomocisteínemia é considerado um fator de risco para DCV e por isso foi incluído. Para a análise estatística foi utilizado o teste do χ2 para a comparação das frequências genotípicas e alélicas. Os polimorfismos com diferença significativa foram testados na regressão de Poisson com variância robusta ajustado pelas variáveis de confusão. Para as complicações microvasculares também foi utilizado o teste do χ2 com análise de resíduo ajustado. Resultados: O polimorfismo do receptor plaquetário ITGB3 rs5918 apresentou associação com os desfechos AVCI e DAP. Para o desfecho AVCI o genótipo 176TC mostrou associação significativa [(PR = 2.04(1.11-3.73); P = 0.021], enquanto que para a DAP a associação foi com o genótipo 176CC [PR = 1.90(1.29-2.81); P = 0.001]. Em relação às complicações microvasculares o único polimorfismo que mostrou associação foi o PAI-1 rs1799768. Neste caso, o polimorfismo demonstrou ter uma associação inesperada para o alelo 4G como um fator de proteção quando comparamos pacientes com e sem ND [PR = 0.71(0.57-0.89); P = 0.003]. Porém, quando foi estratificado o grupo de pacientes com ND de acordo com a severidade, foi possível demonstrar usando a análise de resíduo ajustado do teste do χ2 que havia uma diminuição significativa na frequência do alelo 4G somente no estágio mais avançado da doença renal (P = 0.009; AR = -2.95) o que sugere o seu envolvimento com uma maior taxa de mortalidade na ND. Também foi possível mostrar que o alelo de risco 4G está significativamente associado com a cardiopatia isquêmica nos indivíduos com ND (P = 0.03; AR = 2.5). Conclusões: Os pacientes com DM2 portadores do alelo de risco 176C do polimorfismo ITGB3 rs5918 apresentam um risco significativamente aumentado de desenvolver AVCI e DAP, enquanto que os portadores do alelo de risco 4G do polimorfismo PAI-1 rs1799768 provavelmente apresentem maior risco de desenvolver ND. Além disso, os portadores do alelo 4G e que tem ND apresentaram um risco significativamente aumentado de desenvolverem CI. / Introduction: Type 2 diabetes mellitus (T2DM) represents approximately 90% of the diabetes types, increasingly affecting the adult population and nowadays also occurring in young adults and children. Hypercaloric diets, sedentarism and genetic predisposition are the main triggering factors of chronic complications associated to T2DM. Unfortunately, these are the complications that lead to a considerable increase in morbidity and mortality, which may reach 80%, with the main complications being of micro- and macrovascular nature. The microvascular complications are diabetic retinopathy (DR), diabetic nephropathy (DN) and peripheral neuropathy (PN). The macrovascular complications include cardiovascular disease (CVD), peripheral arterial disease (PAD) and stroke. In the initial T2DM stage, patients may present a prothrombotic state that tends to worsen as the disease evolves. This prothrombotic state results mainly from the inflammatory process and from the endothelial dysfunction. Genetic polymorphisms related to the different stages of hemostasis may play a role in the increase or decrease of the risk of arterial and venous thrombus, which may affect the micro- and the macrovasculature of these individuals. Objectives: To investigate the influence of the polymorphisms related to hemostasis as risk factors for the development of micro- and macrovascular complications in T2DM patients. Methods: A nested case-control study was conducted with a cohort of unrelated T2DM patients from a multicenter study made in southern Brazil. T2DM patients were divided in two groups. The macrovascular complication group included 404 T2DM patients. Macrovascular complications were defined according to the presence of the following criteria: ischemic heart disease (IHD), ischemic stroke (IS) or PAD. The control group was formed by patients who had had T2DM for at least five years but without the respective complications. The microvascular complication group included 393 T2DM patients. Microvascular complications were defined based on the presence of the following criteria: DR, DN, or distal sensory neuropathy (DSN). The controls used in the investigation of the microvascular complications were patients who had T2DM for at least 10 years, without the respective complications. The polymorphisms investigated were analyzed by PCR with RFLP, when necessary. In total, nine polymorphisms were studied. Five polymorphisms (FGB rs1800790, F2 rs1799963, FV rs6025, F7 rs5742910 and F13A1 rs5985) were investigated for the coagulation stage, two (PLAT rs4646972 and PAI-1 rs1799768) for the fibrinolysis stage, and one (ITGB3 rs5918) for the platelet stage. The polymorphism MTHFR rs1801133, associated to hyperhomocysteinemia, which is considered a risk factor for IHD, was also investigated. The statistical analysis used the χ² test to compare genotypic and allelic frequencies. The polymorphisms presenting significant differences were tested using the Poisson regression with robust variance adjusted for the confounding variables. The χ² test with the analysis of adjusted residues was also used for microvascular complications. Results: The polymorphism of the platelet receptor ITGB3 rs5918 was associated with the outcomes IS and PAD. Considering IS, the genotype 176TC exhibited significant association [(PR = 2.04(1.11-3.73); P = 0.021], while considering PAD the association was with genotype 176CC [PR = 1.90(1.29-2.81); P = 0.001]. Regarding the microvascular complications, the only polymorphism that presented association was PAI-1 rs1799768. In this case, the polymorphism demonstrated an unexpected association with allele 4G as a protection factor when patients with and without DN [PR = 0.71(0.57-0.89); P = 0.003]. However, when the group of patients with DN was stratified in terms of severity, it was possible to demonstrate a significant decrease in 4G allele frequency only n the more advanced stage of the renal disease, using the adjusted residue of the χ2 test (P = 0.009; AR = -2.95), which suggests its involvement with a higher mortality rate in DN. It was also possible to show that the risk allele 4G is significantly associated with ischemic cardiopathy in individuals with DN (P = 0.03; AR = 2.5). Conclusions: The T2DM patients carriers of the risk allele 176C of the polymorphism ITGB3 rs5918 present a significantly increased risk of developing IS and PAD, while carriers of the risk allele 4G of the polymorphism PAI-1 rs1799768 probably present higher risk of developing DN. Apart from this, this group of subjects also presented a significant risk of developing IHD.

Background and Aims: Type 2 diabetes mellitus (T2DM) is a chronic progressive condition characterised by hyperglycaemia due to insulin deficiency with or without insulin resistance. The prevalence of diabetes is increasing rapidly worldwide and it has a significant burden on health care resources with estimated costs of up to 10% of health expenditure in the UK. With an ageing population, people are now living longer with diabetes which consequently leads to increased multimorbidity and polypharmacy. Some previous studies have not assessed the effect of demographic or geographic factors (such as age, gender, UK nation and social deprivation) on the incidence and prevalence of T2DM in the UK over the past decade. In addition, detailed reports on the patterns of comorbidities in T2DM patients are sparse. Patients with T2DM are at a two-fold higher risk for cardiovascular (CV) disease. Some earlier studies assessing the CV risk associated with available therapies have been inconclusive in determining the preferred regimens. This thesis aimed to: i) assess the incidence and prevalence of T2DM in the UK; ii) investigate and compare mortality risk between T2DM patients and patients without diabetes and explore if it explains the observed prevalence rates; iii) examine the patterns of comorbidities in T2DM patients and matched comparators without diabetes; and iv) assess the comparative CV risk associated with second-line diabetes therapies. Methods: All the studies in this thesis used data from the UK Clinical Practice Research Datalink. Access to linked national hospitalisation, deprivation and mortality data was obtained for the individual studies. Annual overall and gender-specific incidence and prevalence of T2DM were calculated for the study period 2004-2014. Rates were standardised by age bands, gender, neighbourhood social deprivation, and UK nation and expressed per 10,000 person-years (PYRs) with 95% confidence intervals (95% CI). For the mortality analysis, T2DM patients (cases) were matched to patients without diabetes (controls) on age, gender and general practice. Annual mortality rates for the matched T2DM and patients without diabetes were calculated and compared. Cox regression analysis was used to examine the effect of important covariates on the risk for all-cause mortality in the matched cohort and calculate hazard ratios (HR) and 95% CI. The multimorbidity profile in T2DM cases and matched controls, registered in English general practices, were also examined. Annual prevalence rates of 18 physical and mental health comorbidities were determined between 2004 and 2014 using linked primary care and hospitalisation records. For the CV risk analysis, patients prescribed a second-line medication after greater than or equal to90days of metformin monotherapy between 1998 and 2011 were identified. Using a retrospective cohort study design, inverse probability of treatment-weighted time-varying Cox regression models were used to estimate HRs and 95% CI for developing a major CV event (myocardial infarction, stroke, acute coronary syndrome, unstable angina, coronary revascularisation, or CV death) associated with second-line therapies after adjusting for clinically important CV risk factors. Results: The prevalence of T2DM nearly doubled from 320.62 (95% CI: 318.83; 322.41) in 2004 to 526.36 per 10,000 PYR (95% CI: 523.81; 528.91) in 2014, whereas the incidence was relatively stable with overall rate of 43.07 per 10,000 PYR (95% CI: 40.06; 46.09). Gender-specific incidence and prevalence rates were markedly higher in men than women. Between 2004 and 2014, the prevalence increased from 380.31 (95% CI: 377.48; 383.13) to 625.45 (95% CI: 621.37; 629.52) in men and from 268.56 (95% CI: 266.22; 270.90) to 437.28 (95% CI: 433.94; 440.62) in women. Overall, older individuals, men, and residents in the most deprived locations were more likely to have T2DM. Wales and Northern Ireland had higher prevalence rates than the other UK nations. In the all-cause mortality analysis, 20,312 (11.5%) patients with T2DM died, as compared with 79,951 (9.1%) controls. The adjusted survival model showed that patients with T2DM were at significantly greater risk for mortality in comparison with patients without diabetes (HR: 1.26, 95% CI: 1.20; 1.32). Mortality rates decreased over time in both cases and controls. The multimorbidity study showed that comorbidities were more prevalent in patients diagnosed with T2DM in comparison with patients without diabetes. The number of patients with two comorbidities increased between 2004 and 2014. The prevalence of cardiovascular disease (CVD) in T2DM patients was double that of matched control patients. DPP-4 inhibitors, thiazolidinediones and sulphonylureas add-on therapies to metformin were the most commonly-prescribed second-line therapies. The time-varying survival models showed that DPP-4 inhibitors (HR: 0.78, 95% CI: 0.55; 1.11) and thiazolidinediones (HR: 0.68, 95% CI: 0.54; 0.85) add-on therapies were associated with lower risk for major CVD compared to sulphonylurea add-on therapy when all added to initial metformin. Conclusions: The prevalence of T2DM is increasing rapidly in the UK. Patients with T2DM are at significantly greater risk for mortality than patients without diabetes. However, with the declining mortality rates over the past decade, patients are now living longer to develop comorbidities. CVD was the most prevalent comorbidity in T2DM cases in comparison with people without diabetes. This is important as CVD is the main cause of mortality in patients with T2DM. Thiazolidinedione combination with metformin was associated with significantly lower CV risk in comparison with sulphonylurea add-on therapies to metformin. Lower, but non-statistically significant, risks were also found with DPP-4 inhibitors add-on therapies. These real-world findings add to the existing knowledge on the epidemiology of T2DM, provide novel insight on the patterns of multimorbidity in these patients and clinically relevant evidence on the CV risk associated with commonly-prescribed second-line regimens. Future larger studies are needed to confirm the observed CV benefits associated with antidiabetic therapies.

Introdução: O diabetes mellitus (DM) é uma condição prevalente, de alto custo e associada a várias complicações. Apesar dos potenciais benefícios do rastreamento para DM em indivíduos de alto risco, o rastreamento ainda é controverso. Em 2001, o Brasil realizou um programa Nacional de rastreamento para DM, convidando todos os indivíduos a partir dos 40 anos de idade a participar. Objetivos: Este estudo tem como objetivos descrever a implementação do programa de rastreamento; estimar sua efetividade e impacto populacional; estimar o custo por caso de DM diagnosticado; e avaliar o custoefetividade da estratégia de rastreamento. Métodos: Foi construído um modelo de decisão analítico. Os parâmetros para a fase de rastreamento foram estimados a partir de dados do Ministério da Saúde e estudo de seguimento de uma amostra de 90,106 participantes do rastreamento. As etapas de diagnóstico e vinculação de casos de DM aos serviços de saúde foram avaliadas em uma sub-amostra de 4,906 indivíduos com rastreamento positivo. Custos do programa e custos do DM foram estimados (em R$, US$ e Int$ para o ano de 2001). Para a análise de custo-efetividade, o modelo de decisão analítico foi incorporado a um modelo de Markov de progressão do DM.Foram estimados os custos e benefícios (em anos de vida salvos e anos de vida ajustados para qualidade - AVAQ) durante toda a vida para cada caso de DM. Fontes adicionais de dados incluíram dados de inquéritos nacionais, DATASUS, Instituto Brasileiro de Geografia e Estatística (IBGE) e literatura. O horizonte de análise foi da vida toda e assumiu a perspectiva do Sistema Único de Saúde (SUS). Não foram considerados custos de perda de produtividade. Taxa de desconto de 5% foi aplicada aos custos e benefícios futuros. Foi calculada a razão de custoefetividade adicional do rastreamento populacional, comparado à ausência de programa de rastreamento. Resultados: Dos 22.069.095 de testes de rastreamento realizados, 3.417.106 resultaram positivos. Foi estimado que aproximadamente 346 mil novos casos de DM foram diagnosticados e 320 mil novos casos foram incorporados ao SUS. Foi necessário rastrear 64 indivíduos para diagnosticar 1 caso de DM. O custo total federal do programa de rastreamento foi de R$39 milhões (US$16,5 milhões; Int$50 milhões). O custo porcada caso de DM diagnosticado foi de R$136 (US$58; Int$175). A razão de custo-efetividade do programa de rastreamento foi estimada em R$ 15.216 (US$ 6.475; Int$ 19.608) por ano de vida salvo ou R$ 14.164 (US$ 6.027; Int$ 18.252) por AVAQ. Conclusões: O programa de rastreamento realizado no Brasil foi uma iniciativa inédita, efetivo na mobilização de municípios e da população. Apesar dos altos custos, o custo por caso de DM diagnosticado foi inferior ao relatado por outros países. A razão de custo-efetividade foi semelhante à estimada por simulações do rastreamento seletivo em indivíduos de alto risco. Considerando evidências recentes de efetividade do tratamento precoce na redução de complicações e mortalidade por DM, análises de sensibilidade deverão ser realizadas considerando a variação destes parâmetros. Estes resultados são importantes para tomadores de decisão, em especial em países considerando estratégias de rastreamento para DM. / Introduction: Diabetes mellitus (DM) is a common and costly disorder associated with major complications. Despite the rationale for screening high-risk individuals, direct evidence on the effectiveness of diabetes population screening has not been demonstrated. In 2001 Brazilian citizens aged 40 or older were invited to participate in a nationwide population screening program for DM. Objectives: The objectives of this study are to evaluate the initial impact of the program, estimate the cost per DM case diagnosed, and conduct a cost-effectiveness analysis of the Brazilian nationwide screening program considering lifetime disease progression. Methods: A decision analytic model with a screening phase and a diagnostic phase was developed. Model parameters considered data from National screening program and from a follow-up study of 90,106 screenees. To describe the actions taken for positive screenees, a sub-sample of 4,906 positive screenees was actively followed up through home interviews. Program cost data (in R$, US$ and Int$ considering 2001 exchange rates) and disease costs were estimated. For the cost-effectiveness analysis, the decision analytic model was incorporated into a Markov model of DM disease progression. Lifetime costs and benefits for individuals newly diagnosed with DM were estimated. Additional sources of data included national registries, surveys, and data from the literature. The analysis considered the health care system perspective and lifetime horizon. Productivity losses were not considered. Discount rate of 5% was considered in the base-case analysis.The incremental cost-effectiveness ratio was estimated comparing screening program with no screening program. Results: Of a total of 22,069,905 tests performed, an estimated 3,417,106 were positive. Approximately 345,000 new DM cases were diagnosed, and 320,000 were incorporated into the healthcare system. The number of screening tests needed to detect one case of DM was 64. Total screening program costs were R$ 39 million (US$ 16.5 million or Int$ 50 million). The cost per new DM case diagnosed was R$ 136 (US$ 58 or Int$ 175). Results were sensitive to proportion of individuals returning for diagnostic confirmation. Compared with no screening, the incremental cost for population screening was estimated as R$ 15,261 (US$ 6,475; Int$ 19,608) per life-year saved, and R$ 14,164 (US$ 6,027; Int$ 18,252) per QALY. Conclusions: This pioneering nationwide population-based screening conducted through primary healthcare services was effective in mobilizing municipalities andpopulation. Despite significant overall costs, cost per new DM case diagnosed was lower than described by other countries. Cost-effectiveness ratios of the Brazilian Nationwide population screening program incorporating long-term disease management are similar to those estimated for selective screening of high risk population based on modeling studies. Considering recent evidence on effectiveness of DM treatment in reducing complications and mortality, sensitivity analysis should be conducted considering different parameter estimates. These data provides invaluable information for decision makers, especially to other countries planning screening programs for early diagnosis of DM.

Introdução: O diabetes mellitus tipo 2 (DM2) representa cerca de 90% dos tipos de diabetes e vem atingindo de forma cada vez mais intensa a população adulta e atualmente também jovens e até crianças. Uma dieta hipercalórica, aliada ao sedentarismo tem sido junto com a predisposição genética os principais desencadeantes das complicações crônicas associadas com o DM2. Infelizmente, são essas complicações que levam ao grande aumento da morbidade e mortalidade que pode chegar até 80% nesta doença, sendo que as principais são as de natureza micro e macrovascular. Complicações microvasculares compreendem a retinopatia diabética (RD), a nefropatia diabética (ND) e a neuropatia periférica (NP), enquanto que as complicações macrovasculares compreendem a doença cardiovascular (DCV), a doença arterial periférica (DAP) e o acidente vascular cerebral (AVC). Pacientes com DM2 em sua fase inicial já podem apresentar um quadro protrombótico que só tende a piorar com a progressão da doença. Esse quadro protrombótico é resultante principalmente do processo inflamatório e da disfunção endotelial. Polimorfismos genéticos relacionados com as diferentes fases da hemostasia podem contribuir para o aumento ou diminuição no risco de formação de trombos arteriais e venosos que podem afetar a micro e macrovasculatura destes indivíduos. Objetivos: Investigar a influência de polimorfismos envolvidos com a hemostasia como fatores de risco para o desenvolvimento de complicações crônicas micro e macrovasculares em pacientes com DM2. Metodologia: Foi realizado um estudo de caso controle aninhado em uma coorte de pacientes DM2 não relacionados provenientes de um estudo multicêntrico no sul do Brasil. Os pacientes DM2 foram divididos em 2 grupos de estudo. Para o grupo com complicação macrovascular estudou-se 404 pacientes DM2. Casos para a complicação macrovascular foram definidos como tendo cardiopatia isquêmica (CI), acidente vascular cerebral isquêmico (AVCI) ou DAP enquanto que controles foram definidos como pacientes com pelo menos 5 anos de DM2 e sem a respectiva complicação. Para o estudo das complicações microvasculares 393 pacientes com DM2 foram estudados. Os casos foram definidos como tendo RD, ND ou neuropatia sensório distal (NSD). Controles para a complicação microvascular foram pacientes com pelo menos 10 anos de DM2 e sem a respectiva complicação. Os polimorfismos estudados foram testados em duplicata utilizando-se a PCR seguida de RFLP quando necessário. Foram investigados nove polimorfismos assim distribuídos: Na fase da coagulação foram estudados cinco polimorfismos (FGB rs1800790, F2 rs1799963, FV rs6025 F7 rs5742910 e F13A rs5985); dois (PLAT rs4646972 e PAI-1 rs1799768) na fase da fibrinólise e um (ITGB3 rs5918) na fase plaquetária. O polimorfismo da MTHFR rs1801133 envolvido com a hiperhomocisteínemia é considerado um fator de risco para DCV e por isso foi incluído. Para a análise estatística foi utilizado o teste do χ2 para a comparação das frequências genotípicas e alélicas. Os polimorfismos com diferença significativa foram testados na regressão de Poisson com variância robusta ajustado pelas variáveis de confusão. Para as complicações microvasculares também foi utilizado o teste do χ2 com análise de resíduo ajustado. Resultados: O polimorfismo do receptor plaquetário ITGB3 rs5918 apresentou associação com os desfechos AVCI e DAP. Para o desfecho AVCI o genótipo 176TC mostrou associação significativa [(PR = 2.04(1.11-3.73); P = 0.021], enquanto que para a DAP a associação foi com o genótipo 176CC [PR = 1.90(1.29-2.81); P = 0.001]. Em relação às complicações microvasculares o único polimorfismo que mostrou associação foi o PAI-1 rs1799768. Neste caso, o polimorfismo demonstrou ter uma associação inesperada para o alelo 4G como um fator de proteção quando comparamos pacientes com e sem ND [PR = 0.71(0.57-0.89); P = 0.003]. Porém, quando foi estratificado o grupo de pacientes com ND de acordo com a severidade, foi possível demonstrar usando a análise de resíduo ajustado do teste do χ2 que havia uma diminuição significativa na frequência do alelo 4G somente no estágio mais avançado da doença renal (P = 0.009; AR = -2.95) o que sugere o seu envolvimento com uma maior taxa de mortalidade na ND. Também foi possível mostrar que o alelo de risco 4G está significativamente associado com a cardiopatia isquêmica nos indivíduos com ND (P = 0.03; AR = 2.5). Conclusões: Os pacientes com DM2 portadores do alelo de risco 176C do polimorfismo ITGB3 rs5918 apresentam um risco significativamente aumentado de desenvolver AVCI e DAP, enquanto que os portadores do alelo de risco 4G do polimorfismo PAI-1 rs1799768 provavelmente apresentem maior risco de desenvolver ND. Além disso, os portadores do alelo 4G e que tem ND apresentaram um risco significativamente aumentado de desenvolverem CI. / Introduction: Type 2 diabetes mellitus (T2DM) represents approximately 90% of the diabetes types, increasingly affecting the adult population and nowadays also occurring in young adults and children. Hypercaloric diets, sedentarism and genetic predisposition are the main triggering factors of chronic complications associated to T2DM. Unfortunately, these are the complications that lead to a considerable increase in morbidity and mortality, which may reach 80%, with the main complications being of micro- and macrovascular nature. The microvascular complications are diabetic retinopathy (DR), diabetic nephropathy (DN) and peripheral neuropathy (PN). The macrovascular complications include cardiovascular disease (CVD), peripheral arterial disease (PAD) and stroke. In the initial T2DM stage, patients may present a prothrombotic state that tends to worsen as the disease evolves. This prothrombotic state results mainly from the inflammatory process and from the endothelial dysfunction. Genetic polymorphisms related to the different stages of hemostasis may play a role in the increase or decrease of the risk of arterial and venous thrombus, which may affect the micro- and the macrovasculature of these individuals. Objectives: To investigate the influence of the polymorphisms related to hemostasis as risk factors for the development of micro- and macrovascular complications in T2DM patients. Methods: A nested case-control study was conducted with a cohort of unrelated T2DM patients from a multicenter study made in southern Brazil. T2DM patients were divided in two groups. The macrovascular complication group included 404 T2DM patients. Macrovascular complications were defined according to the presence of the following criteria: ischemic heart disease (IHD), ischemic stroke (IS) or PAD. The control group was formed by patients who had had T2DM for at least five years but without the respective complications. The microvascular complication group included 393 T2DM patients. Microvascular complications were defined based on the presence of the following criteria: DR, DN, or distal sensory neuropathy (DSN). The controls used in the investigation of the microvascular complications were patients who had T2DM for at least 10 years, without the respective complications. The polymorphisms investigated were analyzed by PCR with RFLP, when necessary. In total, nine polymorphisms were studied. Five polymorphisms (FGB rs1800790, F2 rs1799963, FV rs6025, F7 rs5742910 and F13A1 rs5985) were investigated for the coagulation stage, two (PLAT rs4646972 and PAI-1 rs1799768) for the fibrinolysis stage, and one (ITGB3 rs5918) for the platelet stage. The polymorphism MTHFR rs1801133, associated to hyperhomocysteinemia, which is considered a risk factor for IHD, was also investigated. The statistical analysis used the χ² test to compare genotypic and allelic frequencies. The polymorphisms presenting significant differences were tested using the Poisson regression with robust variance adjusted for the confounding variables. The χ² test with the analysis of adjusted residues was also used for microvascular complications. Results: The polymorphism of the platelet receptor ITGB3 rs5918 was associated with the outcomes IS and PAD. Considering IS, the genotype 176TC exhibited significant association [(PR = 2.04(1.11-3.73); P = 0.021], while considering PAD the association was with genotype 176CC [PR = 1.90(1.29-2.81); P = 0.001]. Regarding the microvascular complications, the only polymorphism that presented association was PAI-1 rs1799768. In this case, the polymorphism demonstrated an unexpected association with allele 4G as a protection factor when patients with and without DN [PR = 0.71(0.57-0.89); P = 0.003]. However, when the group of patients with DN was stratified in terms of severity, it was possible to demonstrate a significant decrease in 4G allele frequency only n the more advanced stage of the renal disease, using the adjusted residue of the χ2 test (P = 0.009; AR = -2.95), which suggests its involvement with a higher mortality rate in DN. It was also possible to show that the risk allele 4G is significantly associated with ischemic cardiopathy in individuals with DN (P = 0.03; AR = 2.5). Conclusions: The T2DM patients carriers of the risk allele 176C of the polymorphism ITGB3 rs5918 present a significantly increased risk of developing IS and PAD, while carriers of the risk allele 4G of the polymorphism PAI-1 rs1799768 probably present higher risk of developing DN. Apart from this, this group of subjects also presented a significant risk of developing IHD.

abstract: Type 2 diabetes mellitus (T2DM) is a chronic disease affecting more than ten percent of the U.S. adults. Approximately 50 percent of people with diabetes fail to achieve glycemic targets of A1C levels below seven percent. Poor glycemic control disproportionately affects minority populations such as Korean Americans (KAs). Successful diabetes self-management requires a comprehensive approach that takes into account depression, sleep, and acculturation to achieve good glycemic control. Therefore, the purposes of this study were to: 1) describe the levels of glycemic control, depressive symptoms, sleep quality and duration, and acculturation; 2) examine an association of depressive symptoms with glycemic control; 3) identify mediational roles of sleep quality and sleep duration of less than 6 hours between depressive symptoms and glycemic control; and 4) explore a moderation role of acculturation between depressive symptoms and glycemic control in KAs with T2DM. This is a cross-sectional, descriptive correlational study. A total of 119 first generation KAs with T2DM were recruited from Korean communities in Arizona. A1C levels, the Center for Epidemiological Studies Depression Scale, the Pittsburgh Sleep Quality Index, the Suinn-Lew Asian Self-Identity Acculturation scale, the International Physical Activity Questionnaire, and the Berlin Questionnaire were measured. Descriptive statistics, multiple regression analyses, path analyses, and the Sobel tests were conducted for data analyses of this study. Poor glycemic control (A1C ≥ 7 %), high depressive symptoms (CES-D ≥ 16), poor sleep quality (PSQI > 5), and short sleep duration (< 6 hours) were prevalent among KAs with T2DM. The mean score of acculturation (2.18) indicated low acculturation to Western culture. Depressive symptoms were revealed as a significant independent predictor of glycemic control. Physical activity was negatively associated with glycemic control, while cultural identity was positively related to glycemic control. Sleep quality and sleep duration of less than 6 hours did not mediate the relationship between depressive symptoms and glycemic control. Acculturation did not moderate the association between depressive symptoms and glycemic control. Diabetes self-management interventions of a comprehensive approach that considers depressive symptoms, sleep problems, and cultural differences in minority populations with T2DM are needed. / Dissertation/Thesis / Doctoral Dissertation Nursing and Healthcare Innovation 2017

abstract: Curcumin is an active ingredient of Curcuma longa (Turmeric) and is studied extensively for its antioxidant, anti-inflammatory, anti-bacterial, anti-viral, and anti-cancer properties. The purpose of this study was to examine the effects of turmeric on blood glucose and plasma insulin levels. The study utilized a placebo-controlled, randomized cross-over design with participants serving as their own control. Eight glucose tolerant healthy participants completed the full study. Three-weeks washout period was kept in between six-weeks. Prior to the test meal day, participants were asked to eat a bagel with their evening dinner. During the day of the test meal, participants reported to the test site in a rested and fasted state. Participants completed mashed potato meal tests with 500 mg of turmeric powder or placebo mixed in water, followed by 3 weeks of 500 mg turmeric or placebo supplement ingestion at home. During this visit blood glucose finger picks were obtained at fasting, 30, 60, 90, and 120 min post-meal. Blood plasma insulin at fasting and at 30 min after the test meal were also obtained. During week 4, participants reported to the test site in a rested and fasted state where fasting blood glucose finger pricks and blood plasma insulin were measured. During week 5 to 7, participants were given a washout time-period. During week 8, entire process from week 1 to 4 was repeated by interchanging the groups. Compared to placebo, reduction in postprandial blood glucose and insulin response were non-significant after ingestion of turmeric powder. Taking turmeric for 3 weeks had no change in blood glucose and insulin levels. However, taking turmeric powder supplements for 3 weeks, showed a 4.4% reduction in blood glucose. Change in insulin at 30 min were compared with baseline insulin level showing no significant change between placebo and turmeric group. Fasting insulin after 3-weeks consumption of turmeric did not show any significant change, but showed a larger effect size (0.08). Future research is essential to examine the turmeric powder supplement benefits over a long period of time in healthy adults and whether it is beneficial in preventing the occurrence of type 2 diabetes. / Dissertation/Thesis / Masters Thesis Nutrition 2017

abstract: According to the ADA (American Diabetes Association), diabetes mellitus is one of the chronic diseases with the highest mortality rate. In the US, 25 million are known diabetics, which may double in the next decade, and another seven million are undiagnosed. Among these patients, older adults are a very special group with varying physical capabilities, cognitive functions and life expectancies. Because they run an increased risk for geriatric conditions, Type 2 diabetes treatments for them must be both realistic and systematic. In fact, some researchers have explored older adults’ experiences of diabetes, and how they manage their diabetes with new technological devices. However, little research has focused on their emotional experiences of medical treatment technology, such as mobile applications, tablets, and websites for geriatric diabetes. This study will address both elderly people's experiences and reactions to devices and their children's awareness of diabetes. It aims to find out how to improve the diabetes treatment and create a systematic diabetes mobile application that combines self-initiated and assisted care together. / Dissertation/Thesis / Masters Thesis Design 2017

Philosophiae Doctor - PhD / Diabetes is a chronic, metabolic disease that requires lifelong medical management, health education and self-management. According to a World Health Organisation report, there is a global increase in the prevalence of diabetes and even more so in the low-and middle-income countries, specifically Nigeria, which has the highest number of people with diabetes in the African region of the World Health Organisation. As a global issue, the positive health outcomes of diabetes are tied to health education and self-management of the disease and using the health resources of nations. However, in the context of limited resources in Nigeria, there is a need for improvement of health education in self-management of Type 2 diabetes. Health education that is provided in some Nigerian health facilities is reported to be unstructured, without patients’ active participation, not tailored to the needs and the interests of the patients and limited collaboration between multi-disciplinary professionals. In this context, the aim of the study was to develop a structured health education programme for self-management of patients with Type 2 diabetes, to facilitate the quality of the lives of these patients .An adapted intervention mapping framework provided a structured process for development of an evidenced based programme. A mixed method approach was followed. In the first phase of the study an exploratory descriptive qualitative research design was followed. A purposive sampling approach was used in selecting (i) participants, who were patients with Type 2 diabetes and (ii) health-care professionals working in two health-care institutions in Benin City, Edo State, Nigeria. In phase 1, Step1 of the research was a situation analysis, which consisted of conducting 30 semi-structured interviews with patients; observation of nurses providing health education; and five focus group discussions with health-care professionals (nurses, dieticians and social workers). Qualitative data analysis was accomplished through using Tesch’s (1990) steps of analysis to identify themes and categories. The situation analysis revealed, firstly, that there was a lack in the knowledge and self-management of Type 2 diabetes among patients. Secondly, that the health-care professionals acknowledged their collective role in health education and were burdened with the patients who were non-adherent to self-management. The result also revealed the necessity to change from a traditional teaching method to a structured educational process that is patient-centred. The second phase of the research was the stage of developing the educational programme through collaboration with the stakeholders (health-care professionals and patients with Type 2 diabetes) using the findings from the data-analysis of the first phase supported with literature. In phase 2, Step 2 was to develop matrices from the data analysis in Phase 1 for the programme. Step 3 added theory-based intervention methods and practical applications to the preliminary program and in Step 4 the programme was described. This was followed in Step 5 by preparing health-care professionals for offering the programme to patients and implementing and evaluating the programme. The evaluation of the programme was by means of a quantitative pilot study in which a pre-post-test in a quasi-experiment was conducted with 28 patients and qualitative interviews after the program and post intervention interviews with the participants. The evaluation showed that the program was effective in meeting its objectives. In Step 6 a plan for the adoption, implementation, sustainability and evaluation of future implementations was developed.

INTRODUÇÃO:. A dislipidemia diabética é um dos principais fatores de risco para doença arterial coronária (DAC) O uso de uma nanoemulsão LDL-símile para avaliar clearance do éster de colesterol(EC) e colesterol livre(CL) do intravascular mostrou uma remoção acentuada do CL e um maior depósito em vasos sanguíneos de indivíduos com DAC avançada. OBJETIVOS: Identificar em DM2 a cinética plasmática do CL e EC; se há diferença na cinética de CL e EC em DM2 assintomáticos para DAC com e sem aterosclerose subclínica. MÉTODOS: Estudou-se 12 DM2 e 09 controles pareados para idade e sexo. A aterosclerose subclínca foi avaliada pela presença de Calcificação na artéria coronária (CAC). A Nanoemulsão artificial LDLsímile com dupla marcação radioativa 14C-EC, 3H-CL foi utilizada para o estudo cinético do colesterol, sendo injetada nos participantes e amostras de sangue foram coletadas durante 24 horas para mensuração da radioatividade. Remoção dos lípides da circulação foi calculada por análise compartimental. Mediu-se a taxa de esterificação do 3H-CL no plasma e avaliou-se a capacidade in vitro da HDL de receber lípides a partir das LDL-símile. RESULTADOS: Os diabéticos tiveram IMC, CA e CA/CQ maior que os controles, respectivamente: 31,9 ± 4,6 vs. 27,1± 2,4, p<0,05; 104,9 ± 9,8 vs. 94,2 ± 7,3, p<0,05; 0,98 ± 0,09 vs.0,89 ± 0,06, p<0,01. A glicemia de jejum (171 ± 96 vs. 83 ± 7,5 mg/dl, p <0,05) e hemoglobina glicada (8,9 ± 2,1 vs. 5,6 ± 0,4%, p<0,05) também foram maiores no DM2. A concentração de colesterol total, LDL, HDL, Triglicérides e apolipoproteínas A1,B e E não diferiu entre os grupos. A Taxa fracional de remoção (TFR)14C-EC foi 22% maior DM2 que nos controles (0,07 ± 0,02 vs. 0,05 ± 0,01 h-1, p<0.01). A TFR3H- CL foi semelhante entre os dois grupos, bem como a esterificação. A presença de CAC no grupo DM2 não alterou a remoção de EC e CL nesses pacientes. In vitro a capacidade da HDL em receber EC (4,2 ± 0,8vs. 3,5 ± 0,6 %, p=0,03) e TG (6,8 ± 1,6 vs. 5,0 ± 1,1, p=0.03) foi maior nos DM2. CONCLUSÕES: A remoção acelerada do 14C-EC na população DM2 e a remoção semelhante do 3H-CL quando comparado com grupo controle, pode sinalizar alterações na gênese da dislipidemia diabética. O fato dos DM2 com CAC assintomática não apresentam alterações na remoção de colesterol livre sinaliza uma provável relação do CL com a instabilidade da placa aterosclerótica. / INTRODUTION: The diabetic dyslipidemia is one of the most important risk factor in the development of coronary artery disease (CAD). The LDL-like nanoemulsion is being used to study the clearance of cholesteryl ester(CE) and free cholesterol(FC) from intravascular in patients with advanced CAD and it was shown a higher removal of FC and higher deposit in vases. OBJECTIVE: The aim of this study is to analyze the plasma kinetics of FC and CE in Type 2 Diabetes Mellitus (T2DM); and identify if there are any differences in the removal of FC in the presence of subclinical atherosclerosis in asymptomatic patients with T2DM. METHODS: It was studied 12 T2DM and 09 controls paired by age and gender. The LDL-like nanoemulsion labeled with radioactive: 14C- cholesterol ester (CE), 3H-cholesterol free (CF) was used on plasma kinetics. The nanoemulsion was injected intravenously in all participants and blood sample was collected over 24 hours for radioactivity measurement. The intravascular lipid removal was calculated through compartmental analysis. The intravascular esterification of FC contained in the nanoemulsion was calculated. The ability of HDL to received lipids from LDL-simile were observed in vitro essays. Coronary Calcium Score was detected to identify subclinical atherosclerosis. RESULTS: T2DM patients had a bigger BMI, waist and waist/hip than control, respectively 31.9 ± 4.6 vs. 27.1± 2.4, p<0.05; 104.9 ± 9.8 vs. 94.2±7.3, p<0.05; 0.98± 0.09 vs. 0.89 ± 0.06,p<0.01. Fasting glycemia (171 ± 96 vs. 83 ± 7.5 mg/dl, p <0.05) and glycated hemoglobin( 8.9 ± 2.1 vs. 5.6 ± 0.4%,p<0.05) was higher in T2DM, and there was no differences in the concentration of Total cholesterol, HDL, LDL, Triglycerides and apolipoproteins A1, B and E concentrations. The Fractional Clearance rate (FCR) 14C CE in T2DM was 22% bigger than control ( 0.07 ± 0.02 vs. 0.05± 0.01 h-1, p<0.01). FCR 3H-CF was similar between the groups. The CAC in T2DM did not show differents TFR in CE and FC in these group. In Both groups there was no statistical difference in FC esterification rate. The HDL ability to received CE (4.2 ± 0,8vs. 3.5 ± 0,6 %, p=0,03) and TG (6.8 ± 1.6 vs. 5.0 ± 1.1, p=0.03) from LDL-like nanoemulsion was higher in T2DM. CONCLUSIONS: The higher removal of 14C-CE and similar removal of FC in T2DM can be related to the genese of the diabetic dyslipidemia. The similar removal of FC between the control group and T2DM asymptomatic CAD, with and without subclinical atherosclerosis, could possibly signalize to the relation of FC and the atherosclerotic plaque stability.

Diabetes mellitus é considerado um importante problema de saúde pública, que, pelas conseqüências decorrentes de suas complicações e tratamento, poderá afetar a qualidade de vida das pessoas acometidas. Os conceitos trazidos pela literatura sobre Qualidade de Vida têm enfocado a percepção das pessoas sobre suas experiências e satisfação em relação a determinadas áreas que compõem a natureza humana. Nas últimas décadas tem crescido o interesse de obter indicadores para avaliar os resultados de intervenções clínicas, de modo a garantir maior resolutividade dos problemas de saúde. Neste contexto surgem os estudos de Qualidade de Vida Relacionada à Saúde, que se constituem em um modelo multidimensional para incluir os vários aspectos da vida humana, no qual a pessoa é fonte primária de informação, para expressar as conseqüências da enfermidade e do tratamento, na sua vida diária. A literatura traz instrumentos gerais e específicos para avaliar a qualidade de vida em relação à saúde. Entendemos que os instrumentos específicos poderão trazer informações direcionadas a realidade que se pretende atuar. Entre os instrumentos específicos de qualidade de vida das pessoas com diabetes, identificou-se o instrumento D-39 para avaliar a qualidade de vida das pessoas com diabetes mellitus. Desta forma, o presente estudo teve como objetivos adaptar o D-39 para a língua portuguesa e desenvolver uma primeira fase do processo de validação, em um estudo piloto. Trata-se de um estudo transversal, de caráter metodológico, com análise psicométrica na simulação do teste de campo para a validade (face, constructo) e a confiabilidade da versão adaptada em uma amostra de brasileiros com diabetes mellitus tipo 2. Este instrumento é composto por 39 itens divididos em cinco domínios (Controle do diabetes, Ansiedade e preocupação, Sobrecarga social, Funcionamento sexual e Energia e mobilidade). O presente estudo foi conduzido em Unidade Básica de Saúde em uma amostra de conveniência, composta por 52 pessoas com diabetes mellitus tipo 2. O processo de adaptação seguiu os seguintes passos metodológicos: tradução do D-39 para a língua portuguesa; avaliação por um Comitê de Juízes; \"back-translation\" da versão para o inglês, comparação das duas versões em inglês; análise semântica dos itens; préteste da versão adaptada e aplicação da versão final em português entre os participantes. Encontramos predomínio de pessoas do sexo feminino (65,4%), convivendo em companhia 9 conjugal ou com filhos (75%), idade entre 45 e 84 anos, média de 62,8 anos (DP=8,6) e baixa escolaridade (71,1%). Em relação à doença, o tempo médio de duração foi de 9,15 anos (DP=4,2); 23 participantes não faziam uso de insulina (23/52; 44,2%) e 29 faziam (29/52; 55,8%). Quanto às comorbidades, identificamos que 84,6% das pessoas apresentavam sobrepeso e obesidade; o valor médio da pressão arterial sistólica foi de 136,15 mmHg (DP=22) e da diastólica 80,57 mmHg (DP=13,34). Na versão adaptada do instrumento D-39, as respostas variaram de 1 a 7; o intervalo possível, para a soma dos 39 itens variou de 49 a 217, e quanto maior o valor, pior a avaliação da qualidade de vida. Obtivemos uma média total do instrumento de 152,5 (DP=38,6). Para a validade de constructo, verificamos a convergência e a divergência entre os itens do D-39. O D-39 possibilitou discriminar entre as pessoas que faziam e as que não faziam uso de insulina. Houve correlações moderadas entre os domínios Controle do diabetes e Ansiedade e Preocupação (0,52), Controle do diabetes e Funcionamento Sexual (0,55), Ansiedade e Preocupação e Energia e Mobilidade (0,46), Sobrecarga Social e Funcionamento Sexual (0,58), Sobrecarga Social e Energia e Mobilidade (0,56), Funcionamento Sexual e Energia e Mobilidade (0,60), e correlação forte entre os domínios Controle do diabetes e Energia e Mobilidade (0,64). A consistência interna, representada pelo alfa de Cronbach, mostrou resultados significantes para o total do instrumento (0,91) e valores variando de 0,58 a 0,85 entre os domínios. Diante dos resultados podemos concluir que a versão adaptada para o português do D-39 mostrou atender aos critérios de validade e confiabilidade exigidos para um instrumento de avaliação da QVRS, mantendo as propriedades da versão original. / Diabetes mellitus is considered an important public health problem which for the decurrent consequences of its complications and treatment, could affect the life quality of the attacked people. The concepts carried by the literature about the Life Quality have focused the perception of the people about their experiences and satisfaction regarding to certain areas which compose the human nature. In the last decades, a major interest concerning to the achievement of new indicators for the results of the evaluation of the clinical intervention have increased in such way to ensure a major resolutivity of the heath problems. In this context appears studies of Health-Related Quality Life related to health which constitute in a multidimensional model to include the several human life aspects, in which the person is primary source of information to express the disease and treatment consequences in his daily life. The literature brings specific instruments to evaluate the health-related quality life. We understand that the specific instruments could bring focused informations on the reality which is intended to act. Among the specific intruments of quality of the people with diabetes, it was identified the instrument D-39 to evaluate the life quality of the people with diabetes mellitus. In this way, the aim of this study was to adapt to Portuguese and to develop a prime phase of the validation process in a pilot study. It deals with a transversal study with a methodological character with psychometric analysis in the simulation of the field test for the validity (face and construct) and the reliability of the adapted version in a sample of Brazilians with Type 2 diabetes mellitus. This instrument is composed of 39 items divided in five domains (Diabetes Control, Anxiety and Preoccupation, Social Burden, Sexual Behavior and Energy and Mobility). This study was performed in Basic Health Unity in a convenience sample, composed by 52 people with Type 2 diabetes mellitus. The adaptation process followed the following methodological steps: translation of the D-39 to Portuguese; evaluation by a Committee of Judges; \"back-translation\" of the version to english, comparison of both English versions; semantical analysis of the items; pre-test of the adapted version and application of the final version in Portuguese among the participants. It was found predominance of female people (65,4%), living together partners with conjugal bonds or with children (75%), age between 45 and 84 years of age, average = 62,8 anos (DP = 8,6) and low scholarity (71,1%). The average time of disease was 9,15 years (DP = 4,2); concerning to the 11 treatment 23 participants did not use insulin (23/52; 44,2%) and 29 participants used insulin (29/52; 55,8%). Concerning to the comorbities it was identified that 84,6% of the people were overweight and obesity; the average valor systolic arterial pressure was 136,15 mmHg (DP=22) and diastolic arterial pressure 80,57 mmHg (DP=13,34). In the adapted version of the instrument D-39, the answers varied from 1 to 7; the possible interval, for the 39 items varied from 49 to 217, and how much the larger value is, the worse the evaluation of the quality life will be. It was obtained average total average of the instrument of (152,5 DP = 38,6). For the construct validity, it was verified the convergence and the divergency among the items of the D-39. The D-39 it made possible to discriminate well among the people who used and those who did not use the insulin. It had moderate correlations among the domains Diabetes Control and Anxiety and Preoccupation (0,52), Diabetes Control and Sexual Behavior (0,55), Anxiety and Preoccupation and Energy and Mobility (0,46), Social Burden and Sexual Behavior (0,58), Social Burden and Energy and Mobility (0,56), Sexual Behavior and Energy and Mobility (0,60) and strong correlation among the domains Diabetes Control and Energy and Mobility (0,64). The internal consistency, represented by Cronbach\'s alpha, showed significant results for the total of the instrument (0,91) and values varying from 0,58 to 0,85 among the domains. According to these results, it was concluded that the adapted version to Portuguese of the D- 39 answer the validity and reliability criterion and required for an evaluation instrument of the Health-Related Quality of Life (HRQL), maintaining the properties of the original version.