Free fatty acids (FFA) modulate the effectiveness of glucose to suppress endogenous glucose production (EGP), and increased FFA levels contribute importantly to the loss of glucose effectiveness in type 2 diabetes mellitus (T2DM). Elevating FFA levels in nondiabetic (ND) subjects for at least 6h both increases gluconeogenesis (GNG) and impairs glucose effectiveness. Therefore, we wished to define the extent to which an increase in GNG is responsible for the loss of glucose effectiveness and whether EGP can be inhibited in the presence of elevated plasma FFA by inhibiting GNG with ethanol. To determine the effect of inhibiting GNG on glucose effectiveness, EGP ([3-3H]-glucose) was measured during three separate 7h normoglycemic/hyperglycemic pancreatic clamp studies (somatostatin; basal glucagon/GH/insulin replacement) in n=7 ND subjects (1F/6M; age=45±5 yr; BMI=27.6±3.0 kg/m2). Following an initial 210 min interval of euglycemia (5 mmol/l), blood glucose levels were raised to hyperglycemic levels (10 mmol/l) from t=210-420 min. The first pancreatic clamp study was a baseline study with saline infusions (Lip-/Et-). Lipid emulsion (Liposyn 20%) was infused throughout the second and third study types (Lip+ and Lip+/Et+) to increase FFA to T2DM levels (~ 500 mmol/l). In addition to Liposyn, ethanol (Et) was infused during hyperglycemia in the third study type (Lip+/Et+), using a pharmacokinetic algorithm to attain GNG-inhibiting ethanol levels of 80 mg/dl within 20 min. Under baseline conditions, hyperglycemia suppressed EGP by 61%. After raising plasma FFA to T2DM levels, suppression of EGP by hyperglycemia was impaired in Lip+ (34% decrease). During the Lip+/Et+ co-infusion studies the infusion of ethanol enhanced suppression of EGP by hyperglycemia (65.8% decrease, P=0.004 vs. Lip+) and thus restored glucose effectiveness (P=0.6 vs. Lip-/Et-). Thus, our results confirm the striking effects of elevated plasma FFA to impair glucose effectiveness and suggest that increased GNG contributes importantly to this loss of regulation. Inhibiting GNG could be an effective means of lowering EGP and improving glucose effectiveness in T2DM. / Freie Fettsäuren (FFA) modulieren die Fähigkeit von Glukose die endogene Glukoseproduktion (EGP) zu unterdrücken und spielen eine wichtige Rolle bei dem Verlust der Glukoseeffektivität bei Typ-2-Diabetes mellitus (T2DM). Die Erhöhung freier Fettsäuren in Nicht-Diabetikern (ND) für mindestens 6 Stunden steigert die Glukoneogenese (GNG) und beeinträchtigt die Glukoseeffektivität. Ziel dieser Studien war es daher zu erkennen inwiefern die GNG für den Verlust der Glukoseeffektivität verantwortlich ist und ob die EGP in der Gegenwart von erhöhten FFA, durch die Inhibierung der GNG mit Ethanol, gehemmt werden kann. Um die Auswirkung der Hemmung der GNG auf die Glukoseeffektivität zu bestimmen haben wir die EGP ([3-3H]-glucose) während drei verschiedener normoglykämischen/ hyperglykämischen ‘Pancreatic Clamp’ Studien (Infusion von Somatostatin; Ersetzung basaler Konzentrationen von Glukagon, GH, und Insulin) von jeweils 7 Stunden Dauer in n=7 ND Probanden (1W/6M; Alter=45±5 Jahre; BMI=27.6±3.0 kg/m2) gemessen. Nach einer initialen Phase der Euglykämie (Blutglukosekonzentration bei 5 mmol/l; t=0-210 Minuten) wurde für den Zeitintervall t=210-420 Minuten die Blutglukosekonzentration auf 10 mmol/l erhöht. Die erste ‘Pancreatic Clamp’ Studie war eine Kontrollstudie mit Infusion einer NaCl-Lösung (Lip-/Et-). Eine Lipidemulsion (Liposyn 20%) wurde während der zweiten und dritten Studie (Lip+ und Lip+/Et-) infundiert, um die FFA Plasmaspiegel auf Konzentrationen zu erhöhen, die charakteristisch für den T2DM sind (~ 500 mmol/l). In Ergänzung zu Liposyn wurde Ethanol (Et) während der hyperglykämischen Phase der dritten Studie (Lip+/Et+) zugeführt. Mittels eines pharmakokinetischen Algorithmus wurden innerhalb von 20 Minuten Ethanolwerte erreicht die die GNG hemmen (~80 mg/dl). In den Kontrollstudien verminderte sich die EGP um 61% mit Einsetzen der Hyperglykämie. Nach Infusion von Liposyn in den Lip+ Studien verminderte sich die EGP in Folge der Hyperglykämie jedoch nur um 34%. Die GNG wurde rasch durch die Infusion von Ethanol in den Lip+/Et+ Studien gehemmt und verbesserte signifikant die hyperglykämie-induzierte Suppression der EGP (65% Verminderung der EGP, P=0.004 vs. Lip+). Dadurch wurde die normale Glukoseeffektivität wiederhergestellt (P=0.6 vs. Lip-/Et-). Diese Ergebnisse bestätigen die markante Rolle erhöhter Plasma FFA-Spiegel für die Beeinträchtigung der Glukoseeffektivität und deuten auf die Zentrale Rolle der GNG für den Verlust dieser Regulierung hin. Die Inhibierung der GNG könnte eine effektive Maßnahme sein, die EGP bei T2DM zu vermindern und die Glukoseeffektivität wiederherzustellen.

Nachdem sich in den verschiedenen Rio („Rimonabant in obesity“) -Studien bereits die Wirksamkeit des Cannabinoid-1-Rezeptorantagonisten Rimonabant durch Gewichtsreduktion und einer Verminderung des kardiovaskulären Risikos bei den untersuchten Patienten gezeigt hatte, stellte sich die Frage nach dem genauen Wirkprinzip. In unserer Arbeit konnten wir anhand von Versuchen an Ratten mit genetisch induzierter Glukosetoleranzstörung nachweisen, dass Rimonabant nicht nur eine Gewichtsreduktion, sondern auch eine Verbesserung des Lipidprofils bewirkt. Konkret fanden sich bei den behandelten Tieren nach zwei Wochen die atherogenetischen Triglyceride vermindert und das atheroprotektive HDL-Cholesterin im Vergleich zu den Kontrolltieren erhöht. Weiterhin konnten verminderte Mengen an Leukozyten, insbesondere der Neutrophilen und der Monozyten, als Zeugnis einer anti-inflammatorischen Wirkung nachgewiesen werden. Des Weiteren zeigte sich eine geminderte thrombozytäre Aktivität, verdeutlicht durch die reduzierte thrombozytäre Aktivierbarkeit durch Thrombin und die abgeschwächte Adhäsion an Fibrinogen-beschichteten Membranen. Auch lies sich eine Zunahme der VASP-Phosphorylierung als Marker einer gesteigerten Thrombozyten-Inhibition erkennen. Keine signifikanten Wirkungen fanden sich dagegen hinsichtlich des Blutglukosespiegels, des Gesamtcholesterins, der Gesamtzahl der Thrombozyten, und der pro-atherosklerotisch wirkenden Chemokine MCP-1 und RANTES. Schlussfolgernd lässt sich sagen, dass der selektive Cannabinoid-1-Rezeptorantagonist Rimonabant einen viel versprechenden Ansatzpunkt in der Behandlung von übergewichtigen Patienten mit Diabetes mellitus darstellt. Durch die Verbesserung des Lipidprofils, die anti-inflammatorische Wirkung und durch die reduzierte Thrombozytenaktivität, trägt es maßgeblich dazu bei, das kardiovaskuläre Risiko bei dieser Patientengruppe zu senken. / We investigated the effect of rimonabant, an cannabinoid receptor-1 antagonist, on inflammation and enhanced platelet activity in type 2 diabetic zucker rats, an experimental model of impaired glucose tolerance and the metabolic syndrome. Rimonabant was fed for 2 weeks to 3-month-old male obese zucker rats. We found, that rimonabant slowed weight gain in in rats with the metabolic syndrome and neutrophiles and monocytes were lowered by rimonabant. Platelet-bound-fibrinogen was also reduced by rimonabant. Platelets from obese rats were more sensitive to thrombin-induced aggregation and adhesion to fibrinogen, wich were both attenuated by rimonabnt theraby. But rimonabant shows no effect on the pro-inflammatory chemokines RANTES and MCP-1. In conclusion, rimonabant demonstrates positive modulation of circulating neutrophil and monocyte numbers and reduces platelet activation, wich may potentially contribute to a reduction of cardiovascular risk.

Thesis (M.Fam.Med.)--University of the Witwatersrand, Faculty of Health Sciences, 2014. / Background The combined influence of processes of care, lifestyle advice and drug treatment on glycaemic control in Type 2 diabetes in primary care settings is not well documented. Aim To describe the provision of lifestyle advice, selected processes of care and drug treatment to, and assess the influence of these factors on glycaemic control in, a sample of adults with type 2 diabetes mellitus attending the Johan Heyns Community Health Centre in Sedibeng District, Gauteng. Methods A cross-sectional design was used. Participants consisted of 200, consecutively chosen, adult volunteers with type 2 diabetes. Information on demographics, reported receipt of lifestyle advice and anthropomorphic measurements was collected through questionnaire-based interviews. This was followed by a record review of all participants’ clinic files for information on current drug management, co-morbid medical conditions and documentation of processes of care, in the preceding 12 months, in respect of HbA1c, blood pressure (BP), weight, waist circumference (WC) and body mass index (BMI) monitoring. HbA1c values were used to ascertain glycaemic control. Performance of processes of care was assessed in accordance with Society for Endocrinology, Metabolism and Diabetes of South Africa (SEMDSA) guidelines. Parsimonious models for glycaemic control were constructed through multivariate logistic regression. Results Mean age of the sample was 58 years with 58% in the 50-64 year age group. Blacks (88%) and females (63%) were in the majority. Over two-thirds had diabetes for under 10 years and 98% had at least one co-morbid condition, mainly hypertension (92%). Obesity was noted in 65%, while 95% of females and 83% of males had a WC that conferred substantial cardio-metabolic risk. Receipt of advice on any of diet, exercise or weight control from a health professional in the preceding 12 months was reported by 79%, with 67% reporting receipt of advice on all three. Under 2% of patient records met the SEMDSA standard for processes of care for HbA1c, weight, WC and BMI monitoring, while 93% achieved the standard for BP monitoring. Exclusive oral treatment was prescribed in 62%, and the majority of these were on combined metformin and sulphonylurea; 5% were on insulin monotherapy. Optimal glycaemic control (HbA1c < 7%) was noted in only 25% of the sample. On multivariate analyses, the presence of CCF conferred higher odds of controlled glycaemia (OR = 3.17, P = 0.035). Compared with insulin monotherapy, treatment with either combined metformin and insulin (OR = 0.216, P = 0.02), or with the combination of all 3 drug classes ( metformin, sulphonylurea and insulin) (OR = 0.185, P = 0.027), conferred lower odds of glycaemic control. Conclusions This study highlights substantial shortcomings in the compliance with key processes of care and the achievement of optimal glycaemic control for type 2 diabetes mellitus in the current research setting. An inverse association was noted between glycaemic control and the use of combined oral and insulin drug therapy. Measured processes of care and reported receipt of lifestyle advice showed no association with glycaemic control. CCF co-morbidity conferred improved odds of controlled glycaemia.

Background: Type 2 diabetes mellitus (T2DM) is defined by an increase in serum glucose, however, this leads to the belief that only the serum glucose levels need be monitored and treated. Hence many other risk factors such as obesity, lipids and blood pressure which increase the risk of coronary heart disease, myocardial infarction, stroke and peripheral vascular disease are neglected. Consequently, T2DM patients that are at greater risk of developing cardiovascular disease (CVD), are often not receiving optimal comprehensive care. Aims: To identify the treatment gaps of cardiovascular risk factors in patients with T2DM using both national and international current treatment guidelines. Methods: Using a public sector database, data was obtained on the treatment of 666 T2DM patients. Records of patients were selected on the basis of established T2DM diagnoses, receiving oral hypoglycaemic and/or insulin therapy. The following patient data was recorded: demographics (age, gender, ethnicity), systolic blood pressure (SBP), diastolic blood pressure (DBP), glycated haemoglobin (HbA1c), total cholesterol (TC), triglycerides (TG), HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C) , family history, cardiovascular history and all chronic medications. The following parameters were applied to the cohort: SBP <130 mmHg, DBP <80 mmHg. In the event of proteinuria: SBP ≤120 mmHg, DBP ≤70 mmHg. HbA1c <7.0%, TC <4.5 mmol/L, LDL-C <2.5 mmol/L, HDL-C >1.0 mmol/L (males), HDL-C >1.2 mmol/L (females) and TG <1.7 mmol/L. In patients with established CVD, LDL-C target: ≤1.8 mmol/L. Results: The study cohort consisted of 666 T2DM-patients. 55% females. Mean age was 63 years (SD: 11.8), mean HbA1c was 8.7% (SD: 2.4). The mean SBP and DBP readings for the cohort were 133.66 (SD: 19.9) and 78.07 mmHg (SD: 11.6), respectively. Mean LDL-cholesterol was 2.6 mmol/L (SD: 0.9). 26.2% reached HbA1c of ≤7%, 45.8% reached ≤130/80 mm Hg blood pressure targets, 53.8% reached LDL-C of ≤2.5mmol/L and all 3 were reached by 7.5% of the cohort. TC ≤4.5 mmol/L was reached by 53.8%, 60.2% reached TG ≤1.7mmol/L, 58.6% males and 52.8% females reached HDL-C targets of ≥1.0 mmol/L and ≥1.2 mmol/L, respectively. There were 17.9% of patients with CVD reaching targets of LDL-C ≤1.8 mmol/L whilst 16.4% of patients with nephropathy reaching targets of ≤120/70 mm Hg. Almost half (48.2%) were not receiving lipid-lowering therapy, yet would be deemed eligible for therapy. Blood pressure targets may have been better reached with appropriate dosage reductions in addition to the introduction of further antihypertensive combination therapy. CVD was present in 15.5%. Conclusions: T2DM patients are at high-risk for CVD. Many trials have demonstrated the benefits of targeting CVD risk factors (HbA1c, blood pressure, serum lipids) in T2DM. Less than 10% of CVD risk factor targets were reached by the study cohort despite treatment guideline recommendations. The data from the study suggests poor control of modifiable cardiovascular risk factors and significant under treatment of T2DM in clinical practice. Whether improvement lies in the form of therapeutic titration adjustment or an increase in patient education, there needs to be a more aggressive multi-factorial therapeutic approach to treating this high risk group of patients in order to reduce overall morbidity, mortality and improve patient outcomes.

Embora existam vários mecanismos propostos, o papel das moléculas de histocompatibilidade na susceptibilidade ao DM1 ainda não está totalmente esclarecido. Existem várias evidências de que o número de células apresentadoras de antígenos e a densidade de expressão das moléculas de histocompatibilidade nessas células pode influenciar o resultado da resposta imune. Assim, neste estudo, foram avaliadas as porcentagens das células CD3+, CD4+, CD8+, CD19+ e CD14+, coexpressando as moléculas de histocompatibilidade de classe I e II, a densidade de expressão das moléculas de histocompatibilidade de classe I e II nessas populações linfomonocitárias e a correlação entre densidade de expressão dessas moléculas com o perfil imunogenético do DM1. Para esse fim, foram avaliados 20 pacientes com DM1, recentemente diagnosticados, metabolicamente compensados, sendo 12 do sexo masculino. Como controles, foram avaliados 20 indivíduos saudáveis, pareados com os pacientes em termos de idade, sexo e raça, procedentes da mesma região geográfica dos pacientes. A densidade de expressão das moléculas HLA nas diversas subpopulações linfomonocitárias foi avaliada por citometria de fluxo. Os marcadores imunogenéticos foram tipados utilizando-se iniciadores de oligonucleotídeos seqüência específicos. Os resultados foram analisados usando o teste não paramétrico de Mann Whitney U. Foi observado aumento da densidade de expressão das moléculas de histocompatibilidade de classe I em linfócitos T CD3+, CD4+ e CD8+ de pacientes com DM1 quando comparados aos controles. Em relação às moléculas HLA de classe II, o número e a porcentagem dos linfócitos T CD4+, coexpressando as moléculas HLA-DQ de pacientes estavam diminuídos em relação aos controles. Os resultados referentes à correlação do perfil genotípico dos pacientes revelam que pacientes portadores dos alelos HLA-DQB1*02 apresentaram diminuição no número e porcentagem das células CD3+, CD4+, CD8+, CD19+ e CD14+ coexpressando as moléculas HLA-DQ, e ainda, o aumento da densidade de expressão da molécula HLA-DQ nas células CD19+, em relação aos pacientes sem esses alelos. Pacientes com o alelo HLA-DQB1*0302 apresentaram aumento do número de células CD14+ e CD19+ coexpressando as moléculas HLA-DQ, e ainda, o aumento da densidade de expressão dessas molécula nas células CD14+ em relação aos pacientes negativos para esse alelo. Além da instabilidade de ligação dos peptídeos com as moléculas de susceptibilidade ao DM1, este estudo reafirma a importância da densidade de expressão das moléculas de classe II na susceptibilidade ao DM1. / Althougth the role of MHC molecules in the susceptibility to DM1 has not been elucidated, the density of MHC molecules on cell surface may influence the outcome of the immune response. In this study, the number of CD3+, CD4+, CD8+, CD19+ and CD14+ cells coexpressing MHC class I and II, and the correlation between the density of MHC molecules and the immunogenetic profile of DM1 patients were studied. A total of 20 recently diagnosed patients (12 males) and 20 control individuals matched to the patients in terms of age, sex and race were studied. MHC molecules on cell sufaces were evaluated using flow cytometry. MHC aleles were typed using sequence specific probes. Statistical analysis was performed by the non-parametric Mann Whitney-U test. Increased expression of MHC class I molecules was observed in patients T CD3+, CD4+ and CD8+ cells in relation to controls. The number and porcentage of double-positive CD4+/HLA-DQ+ cells were significantly decreased in patients. Compared to DM1 patients who were not typed as HLA-DQB1*02, DM1 patients typed as HLA-DQB1*02 exhibited decreased numbers of CD3+, CD4+, CD8+, CD19+ and CD14+ cells expressing HLA-DQ molecules, whereas the density of HLA-molecules was increased in CD19+ cells. Compared to non-HLA-DQB1*0302 patients, those typed as HLA-DQB1*0302 presented increased number of CD14+ and CD19+ cells expressing HLA-DQ molecules. Besides the instability of peptide ligation with susceptibility molecules, this study stresses the relevance of the density of MHC class II molecules on the susceptibility to DM1.

A polineuropatia é uma complicação freqüente do diabetes melito, sendo causa de alta morbidade entre pacientes diabéticos. Atualmente o tratamento da polineuropatia diabética consiste na prevenção, através do controle glicêmico, e no tratamento sintomático. O estresse oxidativo assume importante papel na patogenia da polineuropatia diabética, justificando-se o uso de anti-oxidantes no seu tratamento. O ácido tiótico é um co-fator essencial no metabolismo dos carboidratos com propriedades anti-oxidantes. O objetivo deste estudo foi avaliar a eficácia do uso de ácido tiótico para o tratamento da polineuropatia diabética em pacientes com diabetes melito tipo II, através de exame neurológico e estudo eletroneurográfico comparativo antes e após o uso da medicação. Foi realizado um estudo duplo-cego, cruzado, comparado com placebo, com duração de 24 meses, configurando-se a formação de quatro grupos de pacientes, os quais receberam: 1) placebo durante todo o estudo; 2) ácido tiótico durante todo o estudo; 3) ácido tiótico por um ano, e depois placebo; e 4) placebo por um ano, e ácido tiótico a seguir, por mais um ano. Foram incluídos doentes com glicemia entre 140 e 260 mg/dl, hemoglobina glicosilada menor ou igual a 10% e polineuropatia periférica diabética em graus leve e moderado. O protocolo constou da avaliação de sintomas neuropáticos, como dor, hipoestesia e parestesias; força muscular em segmentos distais dos membros inferiores; reflexos bicipital, patelar e aquileu bilateralmente, teste de sensibilidade dolorosa, tátil, e vibratória, e condução nervosa. As velocidades e amplitudes dos potenciais evocados foram obtidas através de estimulação bilateral dos seguintes nervos: condução motora dos nervos mediano e tibial posterior; condução sensitiva dos nervos mediano, ulnar e sural. Estas variáveis foram quantificadas segundo uma escala pré-estabelecida, diretamente proporcional à gravidade da neuropatia. O acompanhamento clínico foi realizado trimestralmente, com registro dos níveis glicêmicos e hemoglobina glicosilada. Os pacientes foram submetidos a avaliação neurofisiológica após 12 e 24 meses do início do estudo. De 43 doentes diabéticos incluídos aleatoriamente, 25 apresentavam polineuropatia periférica ao exame eletroneuromiográfico. Destes, 18 adequavam-se aos critérios de inclusão e exclusão. Cinco pacientes foram excluídos ao longo do estudo, sendo 4 por abandono do protocolo, e 1 por efeitos colaterais. O tratamento foi administrado por via oral a 13 pacientes, na dose de 600 mg/dia. A idade dos doentes variou entre 48 e 65 anos, sendo 5 do sexo feminino, e 8 do masculino. Não houve diferença significativa entre a média do controle glicêmico do grupo placebo e do grupo droga. Somente as variáveis exame neurológico e eletroneurográfico adequaram-se à distribuição normal. A análise univariada realizada com sintomas, exame neurológico e eletroneurográfico não demonstrou diferença estatisticamente significante entre os grupos, assumindo-se p>0,05. A análise de co-variância realizada com as variáveis exame neurológico e eletroneurografia demonstrou que o ácido tiótico foi capaz de influenciar favoravelmente a evolução da neuropatia nestes doentes. Não foram observados efeitos colaterais no grupo que fez uso de ácido tiótico / Polyneuropathy is a frequent complication of diabetes mellitus, being a major cause of morbidity among diabetic patients. Besides prevention through glicemic control, treatment of diabetic polyneuropathy is nowadays just symptomatic. Oxidative stress plays an important role in diabetic polyneuropathy pathogeny, justifying the use of antioxidant drugs in its treatment. Thioctic acid is an essential cofactor in carbohydrate metabolism with anti-oxidant properties. The aim of this study was to evaluate thioctic acid efficacy in the treatment of diabetic neuropathy in type II diabetes, through comparative neurological examination and electroneurographic studies before and after drug use. It was a double-blind, crossed, placebo-controlled study, lasting 24-months. Four groups were studied:1) placebo and placebo; 2) thioctic acid and thioctic acid; 3) thioctic acid and placebo, and 4) placebo and thioctic acid. Only patients with glicaemia between 140 and 260 mg/dl, glicosilated hemoglobin under 10% and mild or moderate diabetic peripheral polyneuropathy were included. The protocol consisted of evaluation of neuropathic symptoms, like pain, hipoesthesia and paresthesias; distal lower limbs muscle strength, bicipital, patelar and aquilean reflexes, examination of pain, tactile and vibratory sensibility, and nerve conduction studies. Nerve conduction velocities and amplitudes were obtained though bilateral stimulation of the following nerves: motor conduction of median and posterior tibial; sensitive conduction of median, ulnar and sural nerves. These variables were quantified according to a pre-established scale, directly proportional to neuropathy severity. Clinical follow-up was trimestral, with register of glicemic levels and glicosilated haemoglobin. Patients were submitted to neurophysiologic evaluation after 12 and 24 months. Of 43 diabetic patients randomly assigned, 25 presented peripheral polyneuropathy on electroneurography. 18 fit inclusion and exclusion criteria. Five patients were excluded throughout the study, 4 lost follow-up, and one for side effects. The treatment was administered orally to 13 patients, 600 mg daily. The age of these patients ranged from 48 to 65 years, being 5 female, and 8 male. There was no significant difference in glicaemic control between groups. Only neurological examination and electroneurography had normal distribution. Univariated analysis with symptoms, neurological examination, and electroneurography demonstrated there was no statistically significant difference between placebo and drug groups, assuming p>0,05. Co-variance analysis was done with neurological examination and electroneurography variables, showing that thioctic acid favourably influenced the neuropathy outcome of these patients. No adverse effects were observed in the thioctic acid group

O Diabetes Mellitus Tipo 1 (DM1) é uma doença caracterizada pela destruição das células beta do pâncreas levando à deficiência absoluta da produção de insulina, podendo ser autoimune ou idiopática. Diversos fatores ambientais podem influenciar o desenvolvimento desta patologia, dentre eles incluem-se fatores externos como a nutrição, infecções virais, peso ao nascer, idade materna, crescimento infantil aumentado, estresse e condições socioeconômicas. O objetivo do presente trabalho foi descrever as características bio-sociocomportamentais de indivíduos com Diabetes Mellitus Tipo 1 e a possíveis relações destas características com a ocorrência da patologia. Trata-se de um estudo observacional transversal com 399 indivíduos, sendo 202 com o diagnóstico de DM1 e 197 controles não diabéticos, pareados por sexo, idade e etnia, que responderam a um questionário com perguntas que versaram sobre informações bio-socioecomportamentais, nos intervalos das consultas médicas na Unidade Básica de Saúde Centro Dr. Alpheu de Vasconcelos Sampaio\" e Hospital Estadual de Bauru Dr. Arnaldo Curvêllo. Para análise dos dados utilizou-se o teste do qui-quadrado nas variáveis qualitativas nominais, o teste de Mann-Whitney nas variáveis qualitativas ordinais e o teste t nas variáveis quantitativas, o coeficiente de correlação de Spearman (variáveis qualitativas ordinais) e de Pearson (variáveis quantitativas) para verificar correlação entre variáveis. Adotou-se o nível de significância de 5% (p<0,05) em todos os testes estatístico. Os resultados mostraram que a renda familiar predominante é a de um a três salários mínimos, que o parto cesárea foi o mais evidente nos dois grupos. Com relação ao mês do diagnóstico, notou-se que ocorreu mais na estação de inverno, nos meses de junho e julho e evidenciou que a idade ao diagnóstico tem diminuído nos últimos anos. A infecção viral mais frequente foi a catapora. Quanto à doença periodontal, o estudo mostrou que a maioria desconhece que ela é uma das complicações do diabetes. Verificou-se que o parto normal ou vaginal contribuiram para o não desenvolvimento do DM1, e que o intervalo maior do que 5 anos entre os irmãos e a catapora estiveram associados ao DM1. / Diabetes mellitus type 1 (DM1) is a disease characterized by the destruction of pancreatic beta cells leading to absolute deficiency of insulin production, may be autoimmune or idiopathic. Several environmental factors may influence the development of this pathology among them include external factors such as nutrition, viral infections, birth weight, maternal age, increased infant growth, stress and socioeconomic conditions. The objective of this study was to describe the bio-socio-behavioral characteristics of individuals with Type 1 Diabetes Mellitus and the possible relationship of these characteristics with the occurrence of the disease. This is a cross-sectional observational study of 399 subjects, 202 diagnosed with type 1 diabetes and 197 nondiabetic controls matched for sex, age and ethnicity, who answered a questionnaire with questions that were about bio-socioecomportamentais information in ranges medical consultations in the Basic Health Unit Centre \"Dr. Alpheu Sampaio de Vasconcelos \"and Bauru State Hospital Dr. Arnaldo Curvello. Data analysis used the chi-square test in nominal qualitative variables, the Mann-Whitney test in the ordinal qualitative variables and the\" t \"in quantitative variables, Spearman\'s correlation coefficient (ordinal qualitative variables) and Pearson (quantitative variables) to check correlation between variables. We adopted the significance level of 5% (p <0.05) in all statistical tests. The results showed that the predominant family income is from one to three minimum wages, the cesarean delivery was most evident in both groups. Regarding the month of diagnosis, it was noticed that there was more in the winter season in the months of June and July and showed that the age at diagnosis has decreased in recent years. The most common viral infection was chickenpox. As for periodontal disease, the study showed that most are unaware that it is one of the complications of diabetes. It was found that normal vaginal delivery or contributed to the development of non-DM1, and that the greater range than five years between the brothers and chickenpox were associated with DM1.

Kwan Hon Pong. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2000. / Includes bibliographical references (leaves 115-156). / Abstracts in English and Chinese. / Abstract --- p.i / 摘要 --- p.iii / Abbreviations --- p.v / Acknowledgment --- p.vii / Chapter 1. --- Introduction / Chapter 1.1 --- Diabetes mellitus - general introduction --- p.1 / Chapter 1.1.1 --- Animal models of diabetes --- p.5 / Chapter 1.1.2 --- Streptozotocin-induced diabetes (SID) --- p.6 / Chapter 1.1.2.1 --- Mechanism of the diabetogenic effect of STZ --- p.7 / Chapter 1.1.2.2 --- Administration of STZ --- p.9 / Chapter 1.2 --- Impairment of cognitive function in diabetes mellitus --- p.9 / Chapter 1.3 --- Common mechanisms suggested in diabetic neuropathy --- p.15 / Chapter 1.3.1 --- Polyol pathway activation --- p.15 / Chapter 1.3.2 --- Redox potential alterations --- p.16 / Chapter 1.3.3 --- Nonenzymatic glycation --- p.17 / Chapter 1.3.4 --- PKC alteration --- p.18 / Chapter 1.4 --- Do the common mechanisms of neuropathy induced the cognitive impairment in diabetes --- p.18 / Chapter 1.5 --- Structure and function of the hippocampus --- p.20 / Chapter 1.6 --- The definition and mechanism of learning and memory --- p.21 / Chapter 1.7 --- The mechanisms underlying the early and late phases of LTP in hippocampus --- p.23 / Chapter 1.7.1 --- Perforant and schaffer collaterals pathways --- p.23 / Chapter 1.7.2 --- Mossy fibre pathway --- p.24 / Chapter 1.7.3 --- Late phase of LTP in hippocampus --- p.25 / Chapter 1.8 --- GABAergic interaction in hippocampal plasticity --- p.25 / Chapter 1.9 --- The objective of the project --- p.27 / Chapter 1.10 --- Hypothesis --- p.27 / Chapter 1.10.1 --- The initial role of glutamate receptors --- p.28 / Chapter 1.10.2 --- Involvement of putative retrograde messengers --- p.30 / Chapter 1.10.3 --- The role of GABA receptors --- p.37 / Chapter 1.10.4 --- The role of the CREB --- p.40 / Chapter 2. --- Materials and methods / Chapter 2.1 --- Animals --- p.43 / Chapter 2.1.1 --- Induction of diabetes mellitus --- p.43 / Chapter 2.1.2 --- Insulin therapy --- p.45 / Chapter 2.1.3 --- Sample collection --- p.46 / Chapter 2.2 --- Isolation of total RNA --- p.47 / Chapter 2.3 --- Quantitation of total RNA --- p.51 / Chapter 2.4 --- Reverse transcription --- p.53 / Chapter 2.5 --- PCR --- p.54 / Chapter 2.5.1 --- Preparation of PCR --- p.54 / Chapter 2.5.2 --- Purification of PCR product --- p.60 / Chapter 2.5.3 --- Confirmation of PCR products by DNA sequencing --- p.61 / Chapter 2.5.4 --- PCR analysis --- p.62 / Chapter 2.5.4.1 --- Quantitation of cDNA --- p.62 / Chapter 2.5.4.2 --- Radioactive PCR --- p.65 / Chapter 2.5.4.3 --- cDNA gel electrophoresis --- p.66 / Chapter 3. --- Results / Chapter 3.1 --- Ionotropic glutamate receptor subtypes --- p.72 / Chapter 3.1.1 --- Non-NMDA receptors --- p.72 / Chapter 3.1.1.1 --- AMPA receptors --- p.72 / Chapter 3.1.1.2 --- Kainate receptors --- p.72 / Chapter 3.1.2 --- NMDA receptors --- p.76 / Chapter 3.2 --- Metabotropic glutamate receptor subtypes --- p.79 / Chapter 3.2.1 --- Group I subtype --- p.79 / Chapter 3.2.2 --- Group II subtypes --- p.79 / Chapter 3.3 --- Synthases of retrograde messengers --- p.79 / Chapter 3.4 --- Calcium-related receptors --- p.82 / Chapter 3.5 --- "GABA receptor subtypes (Aαl-4,BRla)" --- p.85 / Chapter 3.6 --- Glutamic acid decarboxylase (GAD) --- p.88 / Chapter 3.7 --- Enzyme genes related to CREB dephosphorylation --- p.88 / Chapter 3.8 --- Effect of insulin therapy on ionotropic glutamate receptor subtypes --- p.91 / Chapter 3.9 --- Effect of insulin therapy on metabotropic glutamate receptor subtypes --- p.91 / Chapter 3.10 --- Effect of insulin therapy on synthases of retrograde messenger --- p.91 / Chapter 3.11 --- Effect of insulin therapy on GAB A receptor subtype --- p.91 / Chapter 4. --- Discussion / Chapter 4.1 --- SID on Glutamate receptor subtypes --- p.96 / Chapter 4.2 --- SID on Calcium-related receptors --- p.105 / Chapter 4.3 --- SID on Synthases of retrograde messengers --- p.106 / Chapter 4.4 --- SID on GABA receptor subtypes --- p.109 / Chapter 4.5 --- SID on enzyme genes related to dephosphorylation of CREB --- p.111 / Chapter 4.6 --- Effect on insulin therapy on gene expression in hippocampus --- p.113 / Chapter 5. --- References --- p.115

Made available in DSpace on 2019-03-30T00:15:03Z (GMT). No. of bitstreams: 0 Previous issue date: 2016-12-15 / Reducing the health expenditure is fundamental to the resources provision, both in developed and developing countries; characterized by a large transition process, healthcare spending is substantial and continues to increase. Worldwide, people with diabetes mellitus (DM) aggravated with diabetic foot (DF) constitute an adverse economic situation to the health system. This research aimed to analyze the hospital cost of people with diabetes mellitus aggravated with diabetic foot comorbidity and the impact to the healthcare system; characterize people with DM that evolve to DF comorbidity; identify the hospitalization time of patients with this comorbidity; and analyze the costs generated by the hospitalization of patients with plantar injury with lack of prevention and self-care with the diabetic foot. Research ethics committee of UNIFOR authorized the study under protocol number 1,602,430 of June 22, 2016. The research universe comprised the medical records of patients with diabetic foot hospitalized in the period from January 1 to December 31, 2015. We selected 79 medical records, representing patients with a hospital stay between seven and 14 days, the usual period of hospitalization for the administration of antibiotic therapy as a first therapeutic plan. Study results revealed a higher prevalence in females, 41 (51.9%); predominantly aged 60-69 years, 26 (32%) patients; and the prevailing hospitalization time was 30-41 days, eight (15%) patients. There was no statistically significant difference between the groups (p=0.771), with the most frequent hospitalization time of 10-19 days, 27 (34.2%) patients, and the mean cost was BRL 13,168.88 ±9,782.52). Analysis of medical records evidenced the severity of this pathology and the predominance occurred in the female elderly with extended hospitalization time, thus resulting in high costs with hospitalization. Therefore, this study enables to conclude that cost reduction occurs through adequate care, mostly avoiding hospitalizations. Early diagnosis and more effective interventions are preventive measures that promote the shortening of the treatment, avoiding the hospitalization of users and reducing the costs with this comorbidity. / A redução do custo em saúde é condição imprescindível à provisão dos recursos, seja em países desenvolvidos ou em desenvolvimento, marcado por processo de grande transição. Os gastos em saúde são considerados de grande monta e em constante crescimento. Dentro do cenário mundial, as pessoas com diabetes mellitus (DM) complicado com pé diabético (PD) representa um quadro econômico desvantajoso ao sistema de saúde. A pesquisa teve como objetivo analisar o custo hospitalar de pessoas com diabetes mellitus complicado com pé diabético e o impacto para o sistema de saúde caracterizar as pessoas com DM com evolução para a comorbidade PD; identificar o tempo internação dos pacientes acometidos com a comorbidade e analisar a relação dos custos gerados pela hospitalização do paciente com lesão plantar com a ausência da prevenção e do autocuidado com o pé diabético. Pesquisa autorizada pelo comitê de ética da UNIFOR, sob parecer número 1.602.430 de 22 de junho de 2016. O universo da pesquisa foi constituído dos prontuários de pacientes com a comorbidade pé diabético internados no período compreendido entre 1º de janeiro a 31 de dezembro de 2015. Foram selecionados 79 prontuários, cujos pacientes tiveram por período de sete a 14 dias, período habitual de internação para a administração de antibioticoterapia como primeiro plano terapêutico. Os resultados do estudo demonstraram maior prevalência no sexo feminino 41 (51,9%); a faixa etária predominante foi entre 60 a 69 anos com 26 (32%) pacientes; o tempo de internamento foi preponderante entre 30 a 41 dias com oito (15%) dos pacientes. Não houve diferença estatisticamente significante entre os grupos (p= 0,771), o tempo de internação mais frequente foi de 10 a 19 dias com 27 (34,2%) e o custo médio foi R$ 13.166,88 ± 9.782, 52. Análise dos prontuários evidenciou a gravidade desta patologia e o predomínio se deu nos idosos com tempo de internação prorrogado resultando elevado custo com internamento. Portanto, infere-se do estudo que a redução dos custos se dá por meio de assistência adequada, evitando sobremaneira hospitalização. A precocidade do diagnóstico e intervenção mais efetiva são condutas de prevenção que promovem o encurtamento do tratamento evitando a hospitalização do usuário e reduzindo os gastos com essa comorbidade.

Made available in DSpace on 2019-03-30T00:25:05Z (GMT). No. of bitstreams: 0 Previous issue date: 2018-02-16 / Type 2 diabetes (T2DM) has a high prevalence and individuals with this disease have increased morbidity and mortality from cardiovascular diseases (CVD). Knowledge about appropriate ways to identify early subjects who are at greater cardiovascular risk (CVR) is very important. This study aimed to evaluate the CVR of diabetic individuals (T2DM) treated at a primary care facility, through the evaluation of traditional risk factors, stratification of CVR by different scores, to determine the concordance between them and the investigation of the associations between biomarkers and CVR. This was a cross-sectional study that evaluated T2DM subjects with no CVD, from which were obtained: traditional CVR factors, systolic (SBP) and diastolic (DBP) blood pressure and anthropometric data. Blood samples were collected for lipid and glycemic profiles, FGF-23, Sdc-1 and VCAM-1. Urine specimens were collected for evaluation of VEGF and KIM-1 and 24 hours samples for albuminuria. The CVR scores were Framingham score - lipids (FRS-lipids) and body mass index (FRS-BMI), SBD/SBC/SBEM score and UKPDS. A total of 128 individuals were included, aged 56 ± 10 years, 68.8% of whom were women, with a T2DM diagnosis time of 7 ± 6 years. The mean SBP was 133 ± 18 mmHg and DBP was 84 ± 13 mmHg, the BMI was 30.9 ± 5.14 Kg/m2 and the waist circumference was 100.98 ± 11.71 cm. Hypertension was found in 68% of individuals, metabolic syndrome in 92.2% and renal disease in 18.2%. The mean HbA1c was 8.28±2.43%, LDL 101.4±33.52 mg/dL, triglycerides 185.83±113.65 mg/dL, non-HDL cholesterol 135.78±38.13 mg/dL. The stratification of CVR by the scores showed higher rates of high risk by FRS-lipids (68.8%), FRS-BMI (78.1%) and SBD/SBC/SBEM score (98.4%). The UKPDS showed a majority of low risk. The degree of concordance between the scores was substantial between FRS-lipids and SBD/SBC/SBEM score (Kappa index 0.71; p = 0.014), moderate between FRS-lipids and FRS-BMI (Kappa index 0.46; p = 0.000) and absent between UKPDS and the other scores. Logistic regression analysis revealed that VCAM-1 is independently associated with high CVR by FRS-lipids and by category coronary artery disease UKPDS. The diabetic subjects evaluated had an unfavorable cardiometabolic profile and unreached therapeutic targets despite high CVR. The moderate concordance between FRS-lipids and FRS-BMI and non-agreement of the UKPDS with the other scores may not reflect the reality, since none of the evaluated scores had been validated in the Brazilian population and also because the applicability of the UKPDS is better in subjects with newly diagnosed T2DM. The evaluation of the biomarkers, which showed an independent association of VCAM-1 with higher risk categories for FRS-lipids and UKPDS, shows the presence of endothelial dysfunction without clinical manifestations in these individuals, which represents even greater CVR for them. We should consider the incorporation of new biomarkers to existing risk scores, so that we can be able to select subjects with the highest CVR that should be treated aggressively and precociously, aiming to achieve better goals and prevention of future CVD. For this, more robust studies, with larger number of diabetic individuals and with greater statistical power need to be performed. / O diabetes tipo 2 (DM2) tem alta prevalência mundial e portadores dessa condição têm alta morbimortalidade por doenças cardiovasculares (DCV). O conhecimento sobre formas mais adequadas de se identificar precocemente aqueles sob maior risco cardiovascular (RCV) é muito importante. Este estudo objetivou avaliar o RCV dos com DM2 atendidos na atenção primária, através da avaliação dos fatores de risco tradicionais, da estratificação de RCV por diferentes escores, para se determinar a concordância entre eles, e da investigação das associações entre biomarcadores e RCV. Tratou-se de um estudo transversal, em indivíduos com DM2 sem DCV, dos quais foram analisados: fatores de RCV tradicionais, pressão arterial sistólica (PAS) e diastólica (PAD) e dados antropométricos. Foram colhidas amostras de sangue, para perfil lipídico, glicêmico, FGF-23, Sdc-1 e VCAM-1 e de urina isolada, para avaliação de VEGF e KIM-1, além de urina de 24 horas, para a albuminúria. Os escores de RCV foram o de Framingham lipídios (ERF lipídios) e índice de massa corpórea (ERF IMC), escore SBD/SBC/SBEM e UKPDS. Foram incluídos 128 diabéticos, com idade de 56 ±10 anos, sendo 68,8% mulheres, com tempo de diagnóstico de DM2 de 7±6anos. A média de PAS foi 133 ±18 mmHg e de PAD foi de 84 ±13 mmHg, a do IMC foi de 30,9 ±5,14 Kg/m2 e a da circunferência abdominal 100,98±11,71cm. Hipertensão foi encontrada em 68% dos indivíduos, síndrome metabólica em 92,2% e doença renal em 18,2%. A HbA1c média foi 8,28 ±2,43%, LDL 101,4 ±33,52mg/dL, triglicerídeos 185,83 ±113,65mg/dL e colesterol não-HDL 135,78 ±38,13 mg/dL. A estratificação de RCV pelos escores mostrou maiores índices de alto RCV pelo ERF lipídios (68,8%), IMC (78,1%) e escore SBD/SBC/SBEM (98,4%). O UKPDS mostrou maioria de baixo risco para qualquer categoria. O grau de concordância mostrou-se substancial entre o ERF lipídios e o escore SBD/SBC/SBEM (índice Kappa 0,71; p=0,014), moderado entre ERF lipídios e ERF IMC (índice Kappa 0,46; p=0,000) e ausente entre o UKPDS e os demais escores. Análise de regressão logística revelou que o VCAM-1 está associado de forma independente com alto RCV pelo ERF lipídios e pelo UKPDS categoria doença arterial coronariana. Os indivíduos com DM2 avaliados apresentavam perfil cardiometabólico ruim e alvos terapêuticos não atingidos, a despeito do alto RCV. A concordância moderada entre o ERF lipídios e o ERF IMC e a não concordância do UKPDS com os outros escores podem não ser reais uma vez que nenhum desses escores fora validado na população brasileira e por ser a aplicabilidade do UKPDS melhor nos com DM2 recém diagnosticada. A associação independente do VCAM-1 com maior risco pelo ERF lipídios e UKPDS mostra presença de disfunção endotelial sem manifestações clínicas, o que traduz RCV ainda maior. Devemos pensar na incorporação de novos biomarcadores, como o VCAM-1, aos escores de risco existentes, de forma a selecionarmos mais precocemente os indivíduos diabéticos com maior RCV que possam ser tratados de forma agressiva e precoce, visando à obtenção de metas e à prevenção de DCV futura. Para tal, estudos mais robustos, com maiores amostras e com maior poder estatístico necessitam ser realizados.