Type 2 diabetes mellitus (T2DM) is a chronic and debilitating disease contributing to the rise in healthcare associated costs in the United States (ADA, 2013a; USDHHS, 2013). T2DM management is complex and requires an ongoing multi-system approach (Goderis et al., 2010). In this quality improvement project, the DNP student led a team in a family care practice setting through a systematic quality improvement process, the PDSA cycle, for the improvement of performance rates of quality indicators including A1C testing, LDL testing, and performance of comprehensive foot examinations. The QI team developed a multi-component intervention to include utilization of an electronic type 2 diabetes mellitus (T2DM) decision support tool. The expected outcome was to increase current performance rates of A1C testing, LDL testing, and comprehensive foot examinations at a family care practice by at least 10% within four weeks of implementing the intervention. A1C testing improved from a pre-intervention median of 70.97% to a post-intervention median of 91.38%, an increase of 20.41%. LDL testing improved from a pre-intervention median of 74.19% to a post-intervention median of 91.38%, an increase of 17.19%. Comprehensive foot examinations improved from a pre-intervention median of 58.06% to a post-intervention median of 84.48%, an increase of 26.42%. While results demonstrate a trend of improvement, the duration of the intervention was insufficient for statistical significance. The QI project served as a first systematic change process for the family care practice and a model for future change processes at the clinic. This project highlights the DNP's role in utilizing evidence-based research and applying a systematic change model for quality improvement in the primacy care practice setting.

Thesis (MNutr (Interdisciplinary Health Sciences. Human Nutrition))--Stellenbosch University, 2008. / OBJECTIVES: To determine perceived Quality of Life (QOL) of the diabetic patient and to assess whether QOL is associated with diabetes-related markers. DESIGN: This was a descriptive cross sectional study. SETTING: A multiethnic group of type 1 and 2 diabetic patients (n= 68) attending a diabetic clinic in Alberton, South Africa, were evaluated. SUBJECTS OUTCOME MEASURES: QOL was assessed by means of the Audit of Diabetes-Dependant Quality of Life (ADDQoL) questionnaire. Glycaemic control, duration of Diabetes Mellitus (DM), type of DM, diabetic complications, level of education and nutritional status were evaluated. RESULTS: Ninety eight percent of diabetic patients perceived their DM to impact negatively on their QOL (p=0.03). QOL and glycaemic control were significantly (p=0.03) related. QOL and the duration (p=0.80) or type (p=0.77) of DM were not significantly related. QOL ratings were lower in participants who had hypertension and hyperlipidaemia, whereas this trend was not present in those with microvascular complications. There was a trend towards a negative relationship between QOL and weight (p=0.10), BMI (p=0.10) and WC (p=0.41). All 13 individual life domains were significantly related (p < 0.05) to QOL for the group as a whole. Rankings of individual life domains differed between type 1 and type 2 diabetics (p<0.05) as well as between black and white subjects (p<0.05). CONCLUSIONS: These results show that DM impacts on various aspects of QOL and that various population sub-groups perceive their DM to impact differently on their QOL. QOL assessments should therefore form part of DM management and should be culturally sensitive.

Bakgrund Det finns många olika varianter av diabetes men av alla personer som har diagnostiserats med sjukdomen så har 80-90% typ 2 diabetes (T2D). Sjukdomen kan uppstå av ärftliga faktorer och förekommer ofta i äldre åldrar men kan utvecklas i samband med en ohälsosam livsstil. Vid behandling av T2D är en livsstilsförändring viktigast och sker främst genom förändrade kost- och träningssvanor. Traditionellt har länge måttligt intensiv uthållighetsträning (MICT) i 150 min/vecka rekommenderats till målgruppen som träningsform. Syfte Syftet med studien är att undersöka effektiviteten av högintensiv intervallträning som behandling för vuxna människor med typ 2 diabetes eller prediabetes. Metod Studien är en deskriptiv systematisk litteraturöversikt som innebär att tillgänglig forskning sammanställs inom ett specifikt ämnesområde för att skapa förståelse för forskningsområdet. Sökningar har skett i databaserna PubMed och samlingsdatabasen Discovery där MeSH termer och friasökningar har kombinerats för att täcka en så stor del av forskningsfältet som möjligt. Resultat 11 artiklar valdes ut och resultatet delades upp i tre olika kategorier mellan glykemisk kontroll, högintensiv intervallträning (HIIT) i jämförelse med MICT och genomförbarheten av HIIT med self-efficiency theory som utgångspunkt. HIIT gav liknande eller bättre effekter på glykemisk kontroll (HbA1c) jämfört med MICT. I studier där genomförbarheten av ett HIIT protokoll nämns så visade samtliga positiva resultat oavsett interventionens längd. Slutsats Liknande eller bättre förbättringar på glykemisk kontroll går att uppnå genom en lägre träningsvolym än de traditionellt rekommenderade 150 min/vecka med måttlig intensitet och HIIT skulle kunna rekommenderas som behandlingsmetod för typ 2 diabetiker samt personer med prediabtes inom vården.

Despite the importance of muscle in the development of type 2 diabetes, few studies have investigated the effect of polychlorinated biphenyls (PCBs) on muscle energy metabolism. Previous results from our lab suggested that PCB126 exposure induced an indirect negative effect on muscle mitochondrial function. Since PCBs are stored in adipose tissue, we hypothesized that PCB126 alters adipokine secretion which in turn affects muscle metabolism. Objectives. Study the adipose-to-muscle communication in PCB126-induced metabolic defects. Methods. Communication between adipocytes and myotubes was reproduced by exposing C2C12 or mouse primary myotubes to the conditioned medium (CM) of 3T3L1 adipocytes exposed to environmentally relevant PCB126 levels. Results. PCB126 significantly increased adipokine secretion and decreased mitochondrial function, glucose uptake and glycolysis in insulin resistant (IR) but not in insulin sensitive 3T3L1. However, exposure of myotubes to CM of IR 3T3L1 only decreased glucose uptake and insulin sensitivity, without altering myotubes glycolysis or mitochondrial function. Conclusion. Our results suggest that the increased adipokine secretion by adipocytes could explain the decreased muscle glucose uptake and insulin sensitivity when exposed to PCB126.

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.

Human muscle metabolism, the biochemical reactions which lead storage and usage of energy, is complex, but important in understanding human health and disease. Optimal muscle metabolism can help maintain a healthy organism by adequately storing and utilizing energy for subsequent use in contraction and recovery and adaption from contraction and exercise. Dysregulated muscle metabolism can lead to insulin resistance and obesity among other health problems. Flux balance analysis (FBA) and constraint-based modeling have successfully elucidated important aspects of metabolism in single-celled organisms. However, limited work has been done with multicellular organisms. The foci of this dissertation are (1) to show how novel applications of this technique can aid in the investigation of human nutrition and (2) to elucidate metabolic phenotypes associated with the insulin resistance (IR) characteristics of Type 2 Diabetes (T2D). First, for human nutrition a novel steady-state constraint-based model of skeletal muscle tissue was constructed to investigate the effect of amino acid supplementation on protein synthesis. Several in silico supplementation strategies implemented showed that amino acid supplementation could increase muscle contractile protein synthesis, which is consistent with published data on protein synthesis in a post-resistance exercise state. These results suggest that increasing bioavailability of methionine, arginine, and the branched-chain amino acids can increase the flux of contractile protein synthesis. Thus, this dissertation introduces the prospect of using systems biology as a framework to investigate how supplementation and nutrition can affect human metabolism and physiology. Second, given the complexity of metabolism, the cause(s) of the altered muscle metabolism in IR remain(s) unknown. Attempting to elucidate this complexity, the constraint-based modeling framework was expanded upon to develop the first in silico analysis of muscle metabolism under varying nutrient conditions and during transitions from fasted to fed states. Systematic perturbations of the metabolic network identified reactions which mimic IR phenotypes: reduced ATP/creatine phosphate synthesis, reduced TCA cycle flux, and reduced metabolic flexibility. Reduced flux through a single reaction is not sufficient to recapitulate the IR phenotypes, but knockdowns in pyruvate dehydrogenase in combination with either reduced lipid uptake or lipid/amino acid oxidative metabolism do so. These combinations also decrease complete lipid oxidation and glycogen storage. Thus, the computational model also provides a novel tool to identify candidate enzymes contributing to dysregulated metabolism in IR.

Diabetes mellitus (DM) is a significant public health problem that afflicted approximately 29.1 million Americans in 2012 (CDC, 2014). The estimated cost of diabetes in the United States in 2012 was $245 billion, including $176 billion in direct medical costs and $69 billion in reduced productivity (ADA, 2013a). To reach a diagnosis of DM, a clinician generally relies on fasting plasma glucose (FPG), the oral glucose tolerance test (OGTT), and/or the Hemoglobin A1c (HbA1c) test (ADA, 2013b). Current noninsulin antidiabetic medications include sulfonylureas, GLP-1 analogues, DPP-4 inhibitors, biguanides, thiazolidinediones, and SGLT2 inhibitors (Kaiser & Oetjen, 2014). Insulin therapies include basal (long-acting insulin analogues), biphasic (premixed insulin analogues), prandial (short-acting insulin analogues), and basal bolus (a combination of long-acting and short-acting insulin analogues) (Esposito et al., 2012). The aim of this study is to review the existing literature on the cost effectiveness of diabetes interventions to develop a standardized protocol for early type 2 diabetes care that can be delivered through primary care providers. The substantial cost effectiveness of preventative measures, including ad campaigns and outreach programs, has already been established (Mendis & Chestnov, 2013). Screening for impaired glucose tolerance early and implementing lifestyle and pharmacological changes at an early stage are also considered cost effective approaches for the long-term management of diabetes mellitus (Gillies et al., 2008). This study utilizes six cost effectiveness analyses on both clinical and non-clinical interventions to determine a standardized protocol for screening, diagnosing, and treating DM. Noninsulin antidiabetic drugs accounted for 78.4% of the 154.4 million prescriptions for antidiabetic drugs filled in 2012 (Hampp et al., 2014). Approximately half of the noninsulin antidiabetic drugs filled in 2012 was for metformin, whereas roughly a quarter of the same category was for sulfonylureas (Hampp et al., 2014). In decreasing order, long-acting human analog insulin and fast-acting human analog insulin were the most popular insulin variants in the insulin antidiabetic drug market (Hampp et al., 2014). Of the noninsulin antidiabetic drugs, the highest proportion of diabetic patients who achieved the HbA1C target of <7% were those taking sustained release exenatide (a GLP-1 analog) (63.2%) (Esposito et al., 2012). Of the insulin varieties, the highest proportion of diabetic patients who achieved the HbA1C target of <7% were those using basal bolus insulin (50.2%) (Esposito et al., 2012). While there are some concerns about the ability of diabetic patients with chronic kidney disease to clear metformin via renal excretion, extensive clinical experience supports its use in diabetic patients with mild to moderate renal impairment (Inzucchi et al., 2014). From the cost effectiveness studies, lifestyle modification (i.e., changes in diet and exercise) beginning at any age was determined to be a cost-effective approach in preventing and treating DM and may be cost saving for adults between the age of 25 to 44 (Herman et al., 2005). Screening for DM beginning at age 45 and repeating every three years if negative provides the best balance of effectiveness and cost effectiveness (Kahn et al., 2010). As a first-line clinical intervention, metformin was established to be cost-effective as well in treating DM (but less so compared to lifestyle modification) (Herman et al., 2005). Bariatric surgery for diabetics with a BMI greater than or equal to 35 kg/m2 has also been established as cost effective (Hoerger et al., 2010). Next, in considering the ideal frequency of clinical consultations, diabetics with a stable condition (assessed as HbA1c ≤7.5%, blood pressure ≤145 mmHg, and total cholesterol ≤201 mg/dL) can safely be seen by a primary care provider every six months compared to every three months with no noticeable decline in long-term health outcomes (Wermeling et al., 2014). For cases of T2D that cannot be simply controlled with metformin, sulfonylurea has shown that it is overall more cost-effective and effective as a second-line therapy when compared to DPP-4 inhibitors and GLP-1 analogs (Zhang et al., 2014). Cost effectiveness analysis of the long-acting analogue insulin detemir across different countries reveals substantially different cost effectiveness for the medication in terms of both nominal and purchasing power terms (Home et al., 2014). The results of these studies were parsed to establish a long-term clinical protocol for primary care providers in screening, diagnosing, and treating type 2 diabetes. Future studies should focus on integrating cost effectiveness and comparative effectiveness research in implementing even more nuanced clinical decisions through a structured protocol. The cost effectiveness of existing and new interventions--both clinical and non-clinical in nature--will also need to be continuously assessed to ensure that the measurements incorporate the most accurate set of assumptions on costs and effectiveness.

Objectives: To explore how adjustment to type 2 diabetes mellitus (T2DM) can be understood using psychological (in)flexibility, the theoretical model underlying acceptance and commitment therapy (ACT). The specific research questions are: (a) what are participant experiences of adjustment and coping in T2DM? and (b) how can participant experiences be understood in terms of the processes underlying the model of psychological (in)flexibility? Design: This interview study utilised a cross-case qualitative methodology. Methods: Semi-structured interviews were conducted with 11 purposively recruited individuals with a diagnosis of T2DM. Interview transcripts were subjected to an interpretative phenomenological analysis (IPA) methodology. Results: Three primary themes were identified from the IPA: (a) ‘Eating myself into diabetes’: Managing the self in relation to perceived diabetes stigma; (b) My other illness is the real problem: diabetes minimised in the context of co-morbid diagnoses; and (c) Knowledge reduces attachment to the patient-role self-story. Conclusion The interpretation of the qualitative data generated suggests that adjustment to a diagnosis of T2DM is a complex process incorporating intra-individual and systemic factors. Whilst psychological flexibility may be a useful model for understanding and supporting adjustment, interventions are required that also address wider systemic issues such as the integration of care, health-related stigma and relationships with health professionals.

Cardiovascular disease contributes significantly to global morbidity and mortality and is particularly prevalent among individuals with Type 2 diabetes, which is thought to in part be due to the association between diabetes and the metabolic syndrome. Traditional cardiovascular risk prediction scores perform well in the general population but their use in people with Type 2 diabetes is limited as they are thought to underperform in high risk groups. Indeed, the use of any risk prediction in people with Type 2 diabetes is a point of discussion among clinicians as people with diabetes are thought by some to be at immediate high risk of CVD, whereas others view them as having a degree of modifiable risk which can be addressed using risk prediction. In the general population, novel markers such as cIMT and carotid plaque, as well as other potential biomarkers of cardiovascular risk, have been explored as possible adjuncts to risk scores in the prediction of cardiovascular disease. The evidence for their use in general populations has been established, although there have been no firm conclusions with regard to recommendations for their use, which is partly due to the high degree of variability in cIMT measurement. However, the evidence for their use in people with Type 2 diabetes is sparse, despite the use of such markers as surrogate CV endpoints in clinical trials. This thesis aimed to describe the frequency, distribution and change of cIMT and carotid plaque, as well as to explore the relationship of cIMT and carotid plaque with cardiovascular risk factors, prevalent cardiovascular disease and future cardiovascular events in older people with Type 2 diabetes. The association between cIMT, carotid plaque and other novel risk markers was also explored. The analysis was performed using data from the Edinburgh Type 2 Diabetes Study (ET2DS). This study is a large, prospective cohort study of 1066 men and women with Type 2 diabetes, aged 60-75 years at recruitment, living in Edinburgh and the Lothians. cIMT and carotid plaque were measured at year 1 follow up of the study. Variables concerning cardiovascular risk factors used in this thesis were obtained from the data collection performed at baseline and year 1. A mean of 3.5 years of follow up was available for analysis and is complete for the baseline cohort as data linkage was performed. Mean values of cIMT in the ET2DS were comparable with other studies of cIMT in people with Type 2 diabetes and may indeed be higher than cIMT in the general population. Measurement of cIMT by the sonographer was comparable with computer aided measurements. Increasing cIMT was independently associated (although only modestly) with increasing age, male sex and raised systolic blood pressure. Mean cIMT was associated with prevalent vascular disease and was predictive of incident global cardiovascular events and coronary artery events (but not stroke) over and above UKPDS risk factors, although the clinical impact of this on the reclassification of vascular risk (as demonstrated by net reclassification index (NRI)) was limited. There was a high prevalence of carotid plaque, and in particular “high risk” plaque, in the ET2DS. Different measures of carotid plaque were independently associated with several cardiovascular risk factors. Carotid plaque thickness was independently associated, albeit modestly, with increasing age, male sex, duration of diabetes and hypertension, plaque score with increasing age, hypertension, smoking and low BMI, and high risk plaque with hypertension and low BMI. All measures of carotid plaque were associated with prevalent vascular disease. However, despite these associations, carotid plaque did not have any additional predictive value for incident cardiovascular events over and above UKPDS risk factors. Finally, measures of cIMT and carotid plaque in the ET2DS were associated with the biomarkers ankle brachial index (ABI) and NTproBNP. In addition these markers were significantly higher in those individuals with prevalent vascular disease, suggesting a more extensive exploration of the association of these markers in relation to cardiovascular disease in the ET2DS may be warranted. cIMT and carotid plaque are modestly associated with traditional cardiovascular risk factors and prevalent cardiovascular disease in older adults with Type 2 diabetes. cIMT has been shown to be predictive of incident events while carotid plaque was not, in people with Type 2 diabetes, over and above traditional cardiovascular risk factors, although its impact on risk reclassification may only be small. Further evidence is required from the longer follow up of the ET2DS before firm conclusions can be drawn on the usefulness of cIMT and carotid plaque as risk markers in people with Type 2 diabetes. In addition, large collaborative studies could be used to further explore the relationship of carotid plaque, and change in cIMT with incident cardiovascular events, as well as exploring the additive effect of cIMT and plaque on risk prediction.

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.