Dependência e heterogeneidade geográfica da Diabetes Mellitus Tipo2 na região de Lisboa: análise de sensibilidade e robustez das estatísticas espaciais

A Diabetes Mellitus Tipo2 é uma doença crónica que afecta sobretudo a população adulta e é responsável por mais de 90% dos casos de diabetes. A sua prevalência tem aumentado rapidamente, implicando elevados custos em saúde. Está normalmente associada a várias co-morbilidades e complicações, constituindo-se uma das principais causas de morbilidade e mortalidade no mundo. Em Portugal, dados dos Observatório Nacional da Diabetes revelam que, em 2012, cerca de 13% da população adulta sofria de diabetes (aproximadamente um milhão de pessoas), sendo a taxa de incidência anual de 500 novos casos por cada 100 000 habitantes. A amostra do estudo incluiu os doentes com DM2 com mais de 20 anos, num total de 205068 utentes registados nos centros de cuidados de saúde primários da ARSLVT e que residem na área de Lisboa e Vale do Tejo. O enfoque desta dissertação não é somente a exploração dos padrões geográficos da DM Tipo2 mas, sobretudo, a análise de sensibilidade e robustez das estatísticas espaciais utilizadas. Os objectivos são fundamentalmente metodológicos e passam pela aplicação de estatísticas espaciais, em ambiente ArcGIS®, GeoDaTM e linguagem de computação estatística R; pela reflexão em torno das medidas de dependência e de heterogeneidade geográfica e ainda pela análise quantitativa da irregularidade da distribuição espacial da DM Tipo2 na região de Lisboa, baseada em decisões decorrentes do estudo da sensibilidade e da robustez das estatísticas espaciais. A estrutura espacial dos dados foi estudada segundo matrizes de vizinhos mais próximos, fazendo variar o número de vizinhos (1 a 20). Uma vez definida a estrutura de vizinhança procurou-se traduzir o grau de similaridade espacial que existe entre áreas que são próximas, utilizando como medida o Índice Global de Moran. A identificação dos clusters espaciais foi feita através da aplicação das estatísticas de Anselin Local Moran´s I e Getis-Ord Gi*. Após aplicação das estatísticas referidas procurou-se avaliar, ao longo dos testes realizados, a percentagem de permanência das freguesias num cluster espacial. Da análise dos resultados, e tendo em conta os objectivos propostos, concluiu-se que o mapeamento de padrões espaciais é pouco sensível à variação dos parâmetros utilizados. As duas ferramentas de análise espacial utilizadas (análise de cluster e outlier - Anselin´s Local Moran´s I e análises de Hot spot - Getis-Ord Gi*), embora muito distintas, geraram resultados muito similares em termos de identificação da localização geográfica dos clusters para todas as variáveis. Desta forma, foi possível identificar alguns clusters, ainda que de um modo geral exista uma aleatoriedade espacial nos dados.

Fucoidan-based particles for diabetes mellitus treatment

Marine organisms are rich in a variety of materials with potential use in Tissue Engineering and Regenerative Medicine. One important example is fucoidan, a sulfated polysaccharide extracted from the cell wall of brown seaweeds.  Fucoidan is composed by L-fucose, sulfate groups and glucuronic acid. It has important bioactive properties such as anti-oxidative, anticoagulant, anticancer and reducing the blood glucose (1). In this work, the biomedical potential of fucoidan-based materials as drug delivery system was assessed by processing modified fucoidan (MFu) into particles by photocrosslinking using superamphiphobic surfaces and visible light. Fucoidan was modified by methacrylation reaction using different concentrations of methacrylate anhydride, namely 8% v/v (MFu1) and 12% v/v (MFu2). Further, MFu particles with and without insulin (5% w/v) were produced by pipetting a solution of 5% MFu with triethanolamine and eosin-y onto a superamphiphobic surface and then photocrosslinking using visible light (2). The developed particles were characterized to assess their chemistry, morphology, swelling behavior, drug release, insulin content and encapsulation efficiency. Moreover, the viability assays of fibroblast L929 cells in contact with MFu particles showed good adhesion and proliferation up to 14 days. Furthermore, the therapeutic potential of these particles using human beta cells is currently under investigation. Results obtained so far suggest that modified fucoidan particles could be a good candidate for diabetes mellitus therapeutic approaches.  

Hind limb ischemia in type 1 diabetic mice as useful tool to evaluate the neovascularization of tissue engineering constructs

Hind-limb ischemia has been used in type 1 diabetic mice to evaluate treatments for peripheral arterial disease or mechanisms of vascular impairment in diabetes [1]. Vascular deficiency is not only a pathophysiological condition, but also an obvious circumstance in tissue regeneration and in tissue engineering and regenerative medicine (TERM) strategies. We performed a pilot experiment of hind-limb ischemia in streptozotocin(STZ)-induced type 1 diabetic mice to hypothesise whether diabetes influences neovascularization induced by biomaterials. The dependent variables included blood flow and markers of arteriogenesis and angiogenesis. Type 1 diabetes was induced in 8-week-old C57BL/6 mice by an i.p. injection of STZ (50 mg/kg daily for 5 days). Hind-limb ischemia was created under deep anaesthesia and the left femoral artery and vein were isolated, ligated, and excised. The contralateral hind limb served as an internal control within each mouse. Non-diabetic ischaemic mice were used as experiment controls. At the hind-limb ischemia surgical procedure, different types of biomaterials were placed in the blood vessels gap. Blood flow was estimated by Laser Doppler perfusion imager, right after surgery and then weekly. After 28 days of implantation, surrounding muscle was excised and evaluated by histological analysis for arteriogenesis and angiogenesis. The results showed that implanted biomaterials were promote faster restoration of blood flow in the ischemic limbs and improved neovascularization in the diabetic mice. Therefore, we herein demonstrate that the combined model of hind-limb ischemia in type 1 diabetes mice is suitable to evaluate the neovascularization potential of biomaterials and eventually tissue engineering constructs.  

Ambulatory blood pressure monitoring and microalbuminuria in normotensive subjects with insulin-dependent diabetes mellitus

OBJECTIVE: To assess the association between microalbuminuria with ambulatory blood pressure monitoring in normotensive individuals with insulin-dependent diabetes mellitus. METHODS: Thirty-seven patients underwent determination of the rate of urinary excretion of albumin through radioimmunoassay and ambulatory blood pressure monitoring. Their mean age was 26.5±6.7 years, and the mean duration of their disease was 8 (1-34) years. Microalbuminuria was defined as urinary excretion of albumin > or = 20 and <200µg/min in at least 2 out of 3 urine samples. RESULTS: Nine (24.3%) patients were microalbuminuric. Ambulatory blood pressure monitoring in the microalbuminuric patients had higher mean pressure values, mainly the systolic pressure, during sleep as compared with that in the normoalbuminuric patients (120.1±8.3 vs 110.8±7.1 mmHg; p=0.007). The pressure load was higher in the microalbuminuric individuals, mainly the systolic pressure load during wakefulness [6.3 (2.9-45.9) vs 1.6 (0-16%); p=0.001]. This was the variable that better correlated with the urinary excretion of albumin (rS=0.61; p<0.001). Systolic pressure load >50% and diastolic pressure load > 30% during sleep was associated with microalbuminuria (p=0.008). The pressure drop during sleep did not differ between the groups. CONCLUSION: Microalbuminuric normotensive insulin-dependent diabetic patients show greater mean pressure value and pressure load during ambulatory blood pressure monitoring, and these variables correlate with urinary excretion of albumin.

Lipoproteína (a) está associada com níveis basais de insulina em pacientes com Diabetes Mellitus tipo 2

FUNDAMENTO: Ainda não foi claramente estabelecido se a resistência/deficiência insulínica leva diretamente à aterogênese ou através de sua associação com outros fatores de risco como os níveis de lipoproteína (a)[Lp(a)]. OBJETIVO: O objetivo do estudo foi estabelecer a relação entre os níveis basais de insulina, lípides e lipoproteína (a) em pacientes com diabetes mellitus (DM) tipo 2. MÉTODOS: Amostras de sangue foram colhidas em jejum e os níveis de insulina, lipoproteína (a), colesterol total (CT), triglicérides (TG), lipoproteína de baixa densidade (LDL-C), lipoproteína de alta densidade (LDL-C), glicose e hemoglobina glicada (HbA1c) foram medidos em 60 pacientes com DM tipo 2 e 28 indivíduos saudáveis. Nós dividimos os pacientes em dois grupos baseados nos níveis basais de insulina: > 10 µIU/ml e < 10 µIU/ml. RESULTADOS: Os níveis de insulina eram mais altos nos indivíduos diabéticos do que nos controles [p < 0,05]. Os níveis de CT (p< 0,01), LDL-C (p< 0,05), razão CT/HDL (p< 0,01), e TG (p< 0,05) eram mais altos e os níveis de HDL- C eram significantemente mais baixos em ambos os grupos de diabéticos, quando comparados aos controles. Os níveis de Lp(a) eram significantemente mais baixos em diabéticos com insulina basal > 10 µIU/ml comparados com aqueles que apresentavam insulina basal < 10 µIU/ml (p < 0.05). A análise de regressão mostrou uma relação significante da Lp(a) com os níveis de insulina (r = 0,262, p < 0,05) e razão Insulina/Glicose(r = 0,257, p < 0,05). CONCLUSÃO: Os níveis de Lp(a) se correlacionam inversamente com os níveis de insulina em pacientes com DM tipo 2. Os níveis de Lp(a) podem ser um dos fatores de risco cardiovascular em pacientes com DM tipo 2 com maior duração da doença. (Arq Bras Cardiol 2009;93(1):28-33)

Resistance Exercise Restores Endothelial Function and Reduces Blood Pressure in Type 1 Diabetic Rats

Background: Resistance exercise effects on cardiovascular parameters are not consistent. Objectives: The effects of resistance exercise on changes in blood glucose, blood pressure and vascular reactivity were evaluated in diabetic rats. Methods: Wistar rats were divided into three groups: control group (n = 8); sedentary diabetic (n = 8); and trained diabetic (n = 8). Resistance exercise was carried out in a squat device for rats and consisted of three sets of ten repetitions with an intensity of 50%, three times per week, for eight weeks. Changes in vascular reactivity were evaluated in superior mesenteric artery rings. Results: A significant reduction in the maximum response of acetylcholine-induced relaxation was observed in the sedentary diabetic group (78.1 &#177; 2%) and an increase in the trained diabetic group (95 &#177; 3%) without changing potency. In the presence of NG-nitro-L-arginine methyl ester, the acetylcholine-induced relaxation was significantly reduced in the control and trained diabetic groups, but not in the sedentary diabetic group. Furthermore, a significant increase (p < 0.05) in mean arterial blood pressure was observed in the sedentary diabetic group (104.9 &#177; 5 to 126.7 &#177; 5 mmHg) as compared to that in the control group. However, the trained diabetic group showed a significant decrease (p < 0.05) in the mean arterial blood pressure levels (126.7 &#177; 5 to 105.1 &#177; 4 mmHg) as compared to the sedentary diabetic group. Conclusions: Resistance exercise could restore endothelial function and prevent an increase in arterial blood pressure in type 1 diabetic rats.

Diabetes Mellitus and Glucose as Predictors of Mortality in Primary Coronary Percutaneous Intervention

Background: Diabetes mellitus and admission blood glucose are important risk factors for mortality in ST segment elevation myocardial infarction patients, but their relative and individual role remains on debate. Objective: To analyze the influence of diabetes mellitus and admission blood glucose on the mortality of ST segment elevation myocardial infarction patients submitted to primary coronary percutaneous intervention. Methods: Prospective cohort study including every ST segment elevation myocardial infarction patient submitted to primary coronary percutaneous intervention in a tertiary cardiology center from December 2010 to May 2012. We collected clinical, angiographic and laboratory data during hospital stay, and performed a clinical follow-up 30 days after the ST segment elevation myocardial infarction. We adjusted the multivariate analysis of the studied risk factors using the variables from the GRACE score. Results: Among the 740 patients included, reported diabetes mellitus prevalence was 18%. On the univariate analysis, both diabetes mellitus and admission blood glucose were predictors of death in 30 days. However, after adjusting for potential confounders in the multivariate analysis, the diabetes mellitus relative risk was no longer significant (relative risk: 2.41, 95% confidence interval: 0.76 - 7.59; p-value: 0.13), whereas admission blood glucose remained and independent predictor of death in 30 days (relative risk: 1.05, 95% confidence interval: 1.02 - 1.09; p-value ≤ 0.01). Conclusion: In ST segment elevation myocardial infarction patients submitted to primary coronary percutaneous intervention, the admission blood glucose was a more accurate and robust independent predictor of death than the previous diagnosis of diabetes. This reinforces the important role of inflammation on the outcomes of this group of patients.

Ernährungsmedizinische Kontrolle des Körpergewichts: Individuelle Einstellung zu verschiedenen Verfahren der Gewichtsreduktion bei Patienten mit Diabetes mellitus

Die ernährungsmedizinische Kontrolle des Körpergewichts bei Patienten mit Typ 1- und Typ 2-Diabetes stand im Vordergrund dieser Studie. Untersucht wurde dabei die individuelle Einstellung der beiden Typen zu verschiedenen Verfahren der Gewichtsreduktion. Es wurden Daten von je 60 Patienten mit Typ 1- und Typ 2-Diabetes für die Studie erhoben. Ausgeschlossen wurden Patienten mit schwerwiegenden Herzschwächen mit Luftnot bei geringen körperlichen Anstrengungen oder ausgeprägter Wassereinlagerung (Ödembildung), schwerwiegende, chronische Infektionserkrankungen mit Fieber, Sepsis, ausgeprägten Entzündungsreaktion, fortgeschrittene Lebererkrankungen und Funktionseinbußen der Nieren, die eine Nierenersatztherapie notwendig macht. Nicht teilnehmen sollten auch Patienten, die dauerhaft systemisch Glukocortikoide nehmen, deren Energiehaushalt durch eine hochgradige Einschränkung ihrer Bewegungsfähigkeit z.B. stark beeinflusst wird oder Patienten des Diabetes Typ 1 oder Typ 2 während einer Schwangerschaft. Die Teilnehmer mit Typ 2-Diabetes fühlen sich signifikant unwohler mit ihrem Körpergewicht und schätzten es auch als zu hoch ein als die Teilnehmer mit Typ 1-Diabetes. Passend zu dem hohen eingeschätzten Krankheitswert des Übergewichts beim Typ 2-Diabetes, assoziierten diese Patienten das Körpergewicht mit früheren wie auch zukünftigen gesundheitlichen Problemen. Obwohl Typ 2-Diabetiker eher Gewichtsabnahmen begannen, waren diese in der Vergangenheit nur mäßig erfolgreich gewesen. Die Änderungsbereitschaft das Gewicht zu reduzieren, bleibt dennoch bei den Teilnehmern mit Typ 2-Diabetes bestehen und zeigte sich ausgeprägter bei diesen Teilnehmern. Hingegen waren die Gewichtsreduktionsversuche bei den Teilnehmern mit Typ 1-Diabetes öfter von Erfolg gekrönt als bei den Teilnehmern mit (...)

PGC1alpha expression is controlled in skeletal muscles by PPARbeta, whose ablation results in fiber-type switching, obesity, and type 2 diabetes.

Mice in which peroxisome proliferator-activated receptor beta (PPARbeta) is selectively ablated in skeletal muscle myocytes were generated to elucidate the role played by PPARbeta signaling in these myocytes. These somatic mutant mice exhibited a muscle fiber-type switching toward lower oxidative capacity that preceded the development of obesity and diabetes, thus demonstrating that PPARbeta is instrumental in myocytes to the maintenance of oxidative fibers and that fiber-type switching is likely to be the cause and not the consequence of these metabolic disorders. We also show that PPARbeta stimulates in myocytes the expression of PGC1alpha, a coactivator of various transcription factors, known to play an important role in slow muscle fiber formation. Moreover, as the PGC1alpha promoter contains a PPAR response element, the effect of PPARbeta on the formation and/or maintenance of slow muscle fibers can be ascribed, at least in part, to a stimulation of PGC1alpha expression at the transcriptional level.

Prevention du diabète de type 2: état des connaissances [Prevention of type 2 diabetes: where do we stand?]

It is anticipated that one out of 3 children born in the year 2000 in the United States may develop diabetes. In Switzerland, a population based study in the city of Lausanne (CoLaus) has shown that about 30% of the participants have abnormal glucose homeostasis, and that the prevalence of obesity in the younger age groups has doubled since 1992. In this review, we describe clinical and biological factors associated with an increased risk to develop diabetes and summarize the most important intervention studies that have shown a beneficial effect in the prevention of diabetes. While life style modifications should be recommended for everybody, the place of pharmacological interventions (oral hypoglycemic agents, blood pressure and cholesterol lowering agents) is more controversial.

Early diabetes and abnormal postnatal pancreatic islet development in mice lacking Glut-2.

Glut-2 is a low-affinity transporter present in the plasma membrane of pancreatic beta-cells, hepatocytes and intestine and kidney absorptive epithelial cells of mice. In beta-cells, Glut-2 has been proposed to be active in the control of glucose-stimulated insulin secretion (GSIS; ref. 2), and its expression is strongly reduced in glucose-unresponsive islets from different animal models of diabetes. However, recent investigations have yielded conflicting data on the possible role of Glut-2 in GSIS. Whereas some reports have supported a specific role for Glut-2 (refs 5,6), others have suggested that GSIS could proceed normally even in the presence of low or almost undetectable levels of this transporter. Here we show that homozygous, but not heterozygous, mice deficient in Glut-2 are hyperglycaemic and relatively hypo-insulinaemic and have elevated plasma levels of glucagon, free fatty acids and beta-hydroxybutyrate. In vivo, their glucose tolerance is abnormal. In vitro, beta-cells display loss of control of insulin gene expression by glucose and impaired GSIS with a loss of first phase but preserved second phase of secretion, while the secretory response to non-glucidic nutrients or to D-glyceraldehyde is normal. This is accompanied by alterations in the postnatal development of pancreatic islets, evidenced by an inversion of the alpha- to beta-cell ratio. Glut-2 is thus required to maintain normal glucose homeostasis and normal function and development of the endocrine pancreas. Its absence leads to symptoms characteristic of non-insulin-dependent diabetes mellitus.

Renal responses to three types of renin-angiotensin system blockers in patients with diabetes mellitus on a high-salt diet: a need for higher doses in diabetic patients?

Objective Activation of the renal renin-angiotensin system in patients with diabetes mellitus appears to contribute to the risk of nephropathy. Recently, it has been recognized than an elevation of prorenin in plasma also provides a strong indication of risk of nephropathy. This study was designed to examine renin-angiotensin system control mechanisms in the patient with diabetes mellitus.Methods We enrolled 43 individuals with type 2 diabetes mellitus. All individuals were on a high-salt diet to minimize the contribution of the systemic renin-angiotensin system. After an acute exposure to captopril (25 mg), they were randomized to treatment with either irbesartan (300 mg) or aliskiren (300 mg) for 2 weeks.Results All agents acutely lowered blood pressure and plasma aldosterone, and increased renal plasma flow and glomerular filtration rate. Yet, only captopril and aliskiren acutely increased plasma renin and decreased plasma angiotensin II, whereas irbesartan acutely affected neither renin nor angiotensin II. Plasma renin and angiotensin II subsequently did increase upon chronic irbesartan treatment. When given on day 14, irbesartan and aliskiren again induced the above hemodynamic, renal and adrenal effects, yet without significantly changing plasma renin. Irbesartan at that time did not affect plasma angiotensin II, whereas aliskiren lowered it to almost zero.Conclusion The relative resistance of the renal renin response to acute (irbesartan) and chronic (irbesartan and aliskiren) renin-angiotensin system blockade supports the concept of an activated renal renin-angiotensin system in diabetes, particularly at the level of the juxtaglomerular cell, and implies that diabetic patients might require higher doses of renin-angiotensin system blockers to fully suppress the renal renin-angiotensin system. J Hypertens 29: 2454-2461 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

Trends in self-reported prevalence and management of hypertension, dyslipidaemia and diabetes in adults in Switzerland, 1992-2007

Purpose: to assess the trends of self-reported prevalence of cardiovascular risk factors (CV RFs: hypertension, dyslipidaemia, diabetes) and their management for period 1992 to 2007 in the Swiss population. Methods: four National health interview surveys conducted between 1992 and 2007 in representative samples of the Swiss population (63,782 subjects overall). Self-reported CV RFs prevalence, treatment and controllevels were computed after weighting. Weights were calculated by raking ratio such that the marginal distribution of the weighted totals conforms to the marginal distribution of the targeted population. Multivariate analysis adjusted on age, sex, education, nationality and SMI was conducted using logistic regression. Results: prevalence of ail CV RFs increased between 1992 and 2007, see table. Although the self-reported prevalence of treatment among subjects with CV RFs increased, and this was confirmed by multivariate analysis: OR for hypocholesterolaemic treatment relative to 1992: 0.64 [0.52-0.78]; 1.39 [1.18-1.65] and 2.00 [1.69-2.36] for 1997, 2002 and 2007, respectively. Still, in 2007, circa 40% of hypertensive, 60% of dyslipidaemic and 50% of diabetic subjects weren't treated. Conversely, an adequate control of CV RFs was reported by treated subjects, with an increase during the study period. This increase was confirmed by multivariate analysis (not shown). Conclusion: the self-reported prevalence of hypertension, dyslipidaemia and diabetes increased between 1992 and 2007 in the Swiss population. Despite a good control of treated subjects, still a significant percentage of subjects with CV RFs are not treated.