Type 2 diabetes mellitus (T2DM), presents a significant health burden globally, affecting millions of individuals, especially in the elderly population. While its association with cardiovascular diseases and cognitive impairments is well-documented, further research on the precise influence of glucose control on cognitive outcomes in elderly T2DM patients is necessary. This scoping review aims to address this gap by investigating the impact of HbA1c levels representing glycemic control on the risk of developing cognitive impairments in elderly patients with T2DM. A literature search was conducted on MEDLINE and eligible studies involved T2DM patients aged 60 or older, with documented cognitive function and glycemic status. Screening and selection processes were conducted following PRISMA guidelines, and three relevant articles were selected for review. Most of the findings suggest a possible association between higher HbA1c levels and cognitive decline. Such results provide valuable insights regarding medical approaches focusing on glucose control that could be created to prevent and delay cognitive decline in T2DM patients.

Coronary artery disease (CAD), Hypertension (Ht) and Type 2 Diabetes Mellitus (T2DM) are all global health problems. This is particularly evident amongst South Asian population groups. The conventional risk factors do not fully explain the higher prevalence of these diseases among South Asians. The endothelial Nitric Oxide Synthase (eNOS) gene is responsible for the production of Nitric Oxide (NO), which may contribute to the physiology of all three disease states. Endothelial dysfunction (which is characterised by a reduction in basal NO) has been shown to be present in, or prior to all three diseases. Numerous variations exist within the eNOS gene, of these variations three have been shown to have a possible functional effect. The first is the Glu298Asp polymorphism within the exon region of the gene, resulting in an amino acid substitution of Glutamate (Glu) to Aspartate (Asp). The second, known as the T-786C polymorphism, is a thymine to cytosine mutation at position -786 in the promoter region. Finally a VNTR polymorphism in Intron 4 causes either a 4 27bp repeat or a 5 27bp repeat. It is hypothesised that these variations could have an effect on the ability of eNOS to produce NO and thus may increase the risk or contribute to the development of the diseases. Previous studies on these variants have shown conflicting results and further studies are warranted to understand and confirm the role of eNOS gene polymorphisms in cardio-metabolic diseases. There is very limited research into the distributions of these genetic variants and their interaction in diseases processes in North Indian populations. Objectives: 1. To analyse through a case control study three different polymorphisms of the eNOS gene for possible association with Coronary Artery Disease (CAD), Hypertension (Ht) and Type 2 Diabetes Mellitus (T2DM) in North Indian population groups. 2. To statistically evaluate descriptive statistics including; age, gender, smoking, dietary behaviours and lipid parameters for possible influence on disease and potential interaction with genetic polymorphisms. 3. To evaluate linkage disequilibrium between the three eNOS variants and carryout haplotype analysis to work out haplotype risk in different diseases. 4. To analyse through a case control study the deletion variant of the Angiotensin-converting enzyme (ACE) gene for possible association with Coronary Artery Disease (CAD), Hypertension (Ht) and Type 2 Diabetes Mellitus (T2DM) in North Indian population groups. 5. To determine a possible interactive effect of the eNOS polymorphisms with the ACE polymorphism. Subjects and Methods: The Glu298Asp and Intron 4 variants were genotyped using a PCR-RFLP technique, the T-786C variant was genotyped using a real time-PCR technique. The ACE deletion variant was also genotyped using a standard PCR technique. The genotyping was undertaken in a total of 457 CAD patients and 220 matched controls from Lucknow, Uttar Pradesh in North India, 319 T2DM patients and 307 matched controls from Punjab, North India and 210 Ht and 162 matched controls, also from Punjab, North India. Results: CAD: The Glu298Asp was significantly associated with CAD among smokers (TT+GT vs. GG OR=2.84 (CI: 1.61-5.0), p<0.001). The Intron 4 variant was also significantly associated with CAD in a smoking dependent manner (4aa+4ab vs. 4bb OR=0.56 (CI: 0.33-0.96). The T-786C variant showed no overall influence on CAD risk. There was also evidence for both synergistic and haplotypic effects of the eNOS gene on CAD status (haplotype G-C-4b OR=4.76 (CI: 1.43-15.78), p<0.001). The ACE genetic variant was confirmed to be a strong independent risk factor for CAD under a dominant model (OR=2.18 (CI: 1.46-3.25), p<0.001). There was no evidence for an interactive effect between the ACE deletion and any of the three eNOS variants incorporated in the current study. Ht: The Glu298Asp variant was not shown to increase Ht risk, with a reduced risk association found under a recessive model (OR=0.316 (CI:0.089-1.116)), p=0.061). The T-786C variant s role in disease remained unclear with the findings showing a non significant increased risk. The Intron 4 variant was also shown to increase Ht risk, in a non significant manner. Sufficiently powered studies would be required to clarify these possible associations. The combined analysis, using logistic regression and haplotype analysis revealed no significant associations, but there was a possible protective effect of the T-C-4b haplotype (OR=0.46 (CI: 0.21-1.01), p=0.054). The ACE gene variant was confirmed to be a strong independent risk factor for Ht under a recessive model (OR=1.81 (CI: 1.20-2.74), p=0.01). Again there was no evidence for an interactive effect between the ACE deletion and any of the three eNOS variants in hypertension. T2DM: The Glu298Asp variant was found to be associated with T2DM under a dominant model, the protective effect remained significant following adjustment for conventional risk factors and other gene variants (OR=0.407 (CI: 0.231-0.717), p=0.002). The T-786C variant showed no overall influence on T2DM risk. The Intron 4 variant also found no overall influence. Haplotype analysis found the T-T-4b was found to be significantly protective for T2DM (OR=0.41 (CI: 0.26-0.65), p=0.0002). Finally the ACE gene variant was confirmed to be a risk factor for T2DM under a dominant model (OR=2.62 (CI: 1.51-4.54), p=0.001). Overall Conclusions: To conclude, this study successfully identified the frequency of three eNOS gene variants and the ACE deletion variant in three complex diseases within north Indian populations. There is a clear role of the eNOS gene in all three diseases and consequently the genetic variants have susceptible/protective associations. The association with disease was found to be present at an individual level, in association with risk factors and at a haplotypic level. These findings warrant further studies to confirm and untangle the genetics of complex diseases and genetic risk profiles calculations which will contribute to the field of medical genomics/personalised medicare and interventions among North Indian populations.

The prevalence of childhood obesity and Type 2 Diabetes Mellitus (T2DM) has increased during recent decades. T2DM is accompanied with functional changes in the islets of Langerhans, which can be identified early in the pathogenesis. The aim of this thesis was to explore how metabolic changes caused by obesity early in life relate to islet function prior to overt T2DM. To address this, Uppsala Longitudinal Study of Childhood Obesity (ULSCO) was established (paper I). Initially, the association between palmitate and insulin secretion was investigated using a translational approach with obese and lean normoglycemic juveniles and isolated human islets (paper II). Secondly, dynamics of islet-hormones insulin and glucagon, and gut-hormones glucagon like-peptide 1 (GLP-1) and glicentin (paper III) and magnetic resonance imaging of pancreatic fat fraction (PFF) (paper IV) were studied in association to glucose tolerance and beta-cell function. Finally, a novel method of analysing shape features of oral glucose tolerance test (OGTT) curves was introduced and evaluated (paper V). Obese subjects had high prevalence of prediabetes and metabolic syndrome (MetS) (paper I). In obese pre-pubertal children with elevated palmitate levels, hyperinsulinemia was observed (paper II). In contrast, obese pubertal adolescents with similar palmitate levels showed moderate insulin levels during OGTT with delayed first phase insulin response. To explore mechanisms for these variations, isolated human islets were exposed to palmitate for different time periods in vitro. After 2 days accentuated insulin response was observed. Impaired beta-cell function and apoptosis were evident after 7 days, however. Hyperglucagonemia and disturbed GLP-1 and glicentin levels were associated with obesity and glycaemic status, with fasting glicentin being predictive of prediabetes (paper III). Furthermore, PFF was increased in obese subjects and associated to MetS and visceral adipose tissue, but not to beta-cell function (paper IV). OGTT curves were converted into geometric centres, centroids, which correlated with differences in glucose tolerance (paper V). In conclusion, the islet function in obese children was associated with elevated levels of palmitate, but not pancreatic fat. Fasting palmitate and glicentin levels, as well as centroid analyses of OGTT curves, could potentially identify obese children at risk of prediabetes and subsequent T2DM.

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are aging-associated diseases that have rising prevalence in all industrialized countries. AD is a neurodegenerative disease characterized by progressive loss of cognitive functions. It is a complex disease which formation involves both genetic factors and environmental factors. The most important marker associated with this disease is the risk allele ε4 in APOE gene. From the latest genome-wide association study emerged another ten candidate genes. As the most significant from those genes appears the minority G allele of rs744373 polymorphism in the gene BIN1. AD is connected with many metabolic and immune disorders. To the markers of interest belongs also the new parameter visfatin which can act as a pro-inflammatory cytokine. T2DM is a chronic disease characterized by raised levels of blood glucose, which is also characterized by neurological disorders. In the case of both of these diseases can be found a large number of metabolic disorders. One of the most important disorders is insulin resistance. This thesis consists of two parts - the biochemical and genetic one. The biochemical part of the thesis studies the visfatin level in patients with AD and healthly control and studies whether visfatin is related to AD. In this part of the...

O objetivo desse estudo foi avaliar o impacto da atenção farmacêutica em desfechos clínicos e na qualidade de vida de pacientes portadores de diabete melito tipo 2 (DM2) atendidos em um hospital de nível terciário de atenção à saúde. O estudo foi clínico controlado randomizado com 70 pacientes portadores de DM2, com mais de 45 anos, em uso de insulina e hemoglobina glicada (HbA1c) 8%. Os pacientes do grupo controle (GC) (n=36) receberam tratamento usual e os do grupo intervenção (GI) (n=34) receberam acompanhamento farmacoterapêutico individualizado e educação para o DM2. A amostra total foi composta principalmente por mulheres (61,4%), com uma média de idade aproximada de 61 anos e tempo de DM2 de cerca de 14 anos, sendo que os grupos eram homogêneos quanto a essas características (p>0,05). Após seis meses de intervenção, os conhecimentos sobre o diabetes e sobre os medicamentos aumentaram significativamente no GI, de 9,91±2,69 para 15,74±3,03 e de 4,47±0,84 para 6,58±1,29, respectivamente, ambos permanecendo inalterados no GC. A adesão ao tratamento farmacológico, para o GI, segundo o questionário Morisky-Green e o Questionário de Adesão a Medicamentos passou de 17,6% para 70,6% e de 29,4% para 52,9%, respectivamente (p<0,05), permanecendo inalterada no GC. Houve aumentos significativos na realização correta das técnicas de aplicação de insulina e de monitorização de glicemia capilar ao final após a intervenção. No início do estudo, a média de HbA1c era para o GC 9,61±1,38 e, para o GI 9,78±1,55 (p>0,05). Após a intervenção, a média de HbA1c do GI diminuiu significativamente para 9,21±1,41, o que não ocorreu para o GC (9,53±1,68) (p>0,05). Ao final do estudo houve melhora significativa da qualidade de vida relacionada ao diabete no GI enquanto que para o GC esse desfecho piorou significativamente. A atenção farmacêutica resultou em melhora significativa de desfechos clínicos e humanísticos dos pacientes com DM2 após seis meses de intervenção / The aim of this study was to evaluate the impact of a pharmaceutical care program on health outcomes and quality of life in patients with type 2 diabetes mellitus (T2DM) attending in a tertiary care center. The study was a randomized controlled, parallel-group trial with a 6-month follow-up carried out with 70 adults (45 years of age) with T2DM, taking insulin, with an HbA1c 8%. Patients in control group (CG) (n=36) received usual care and for those patients in intervention group (IG) (n=34) an individualized pharmacotherapeutic care plan and diabetes education were provided. Total sample was composed primarily of women (61,4%), with mean age of 61 years and duration of T2DM of 14 years and these characteristics were similar in the groups (p>0,05). After a 6-month follow-up, diabetes knowledge and medication knowledge significantly improved in IG, from 9,75±2,69 to 15,74±3,03 and from 4,47±0,84 to 6,58±1,29, respectively, and both outcomes remained unchanged in the CG. Adherence to medication for the IG according to the Morisky-Green questionnaire and to the Questionário de Adesão a Medicamentos varied, respectively, from 17,6% in baseline to 70,6% at end of the study and from 29,4% to 52,9% (p<0,05), with no changes in CG. There were significant improvements in the correct execution of insulin injections and home blood glucose monitoring techniques in the IG at the end of the study. At the beginning of the study HbA1c mean values were 9,61±1,38 in the CG and 9,78±1,55 in the IG (p>0,05). After the intervention, HbA1c mean values was reduced significantly to 9,21±1,41 in the IG and remained unchanged in the CG (9,53±1,68) (p>0,05). After the intervention the diabetes related quality of life significantly improved in IG while it worsened significantly in the CG. Pharmaceutical care resulted in significant improvement in health outcomes in patients with T2DM after 6-month follow-up

O zinco é um elemento-traço essencial que está envolvido em diferentes processos metabólicos. Possui função antioxidante, uma vez que faz parte da estrutura da enzima superóxido dismutase (CuZn-SOD), atua na restrição da produção endógena de radicais livres e, na estabilização da estrutura de membranas. Diabéticos geralmente apresentam deficiência de zinco, além de possuírem um grau aumentado de estresse oxidativo, que é gerado pela própria doença. Portanto o presente estudo teve como objetivo verificar se a suplementação com zinco em pacientes com diabetes mellitus do tipo 2 poderia melhorar as características indicativas de dano oxidativo. O estudo realizado foi duplo cego, sendo administrado zinco aminoquelado (20mg/dia) e placebo, durante 6 meses, sendo os parâmetros do estudo avaliados antes e depois da suplementação, para que fosse possível se observar as mudanças nos parâmetros indicativos do estresse oxidativo. Na avaliação antropométrica, se verificou peso, estatura, medidas da cintura e bioimpedância elétrica. Foi feita a avaliação dos parâmetros glicêmicos e lipídicos, do mineral zinco, bem como dos indicadores de estresse oxidativo, incluindo os óxidos de colesterol e os autoanticorpos anti-LDL eletronegativa. A avaliação alimentar foi realizada por meio do registro de consumo alimentar. Como resultados, podemos ressaltar alta prevalência de sobrepeso/obesidade. Após a suplementação, as concentrações do zinco no plasma e eritrócito tiveram um leve aumento, passando de 68±10 para 72,9±13&#181;g/dL, e de 40,7±6,2 para 43±6,8&#181;gZn/gHb, respectivamente, entretanto, este aumento não foi estatisticamente significativo. Também não foram encontradas diferenças significativas nas concentrações dos autoanticorpos anti-LDL eletronegativa e do total dos óxidos de colesterol, apesar de existir tendência de melhora destes parâmetros. / Zinc is an essential trace element that is involved with a variety of metabolic processes. It has an antioxidant function as it is part of the superoxidedismutase (CuZn-SOD) enzyme. It works in the restriction of the free-radicals endogenous production and in the membrane structure stabilization. Diabetic people often present zinc deficiency, besides of having an augmented degree of oxidative stress, which is generated by the own disease. Therefore, the present study had as objective to verify if the zinc supplementation would better the indicating characteristics of oxidative damage to type 2 diabetes mellitus patients. The study done was double-blind, with the administration of zinc chelate (20mg/day) and placebo, during 6 months. The study parameters were assessed both before and after the supplementation, in order to be possible for one to observe changes in the indicating oxidative stress parameters. In the antropometric evaluation, it was verified the weight, height, the measure of the waistline and the electric bioimpedance. It was evaluated the glicemic and fat parameters, zinc, as well as the oxidative stress indicators, which included the oxysterols and the electronegative anti-LDL autoantibody. The alimentary evaluation was done by means of the feed consumption registration. As a result, it could be highlighted the predomination of overweigh/obesity. After supplementation, the zinc concentrations in the plasma and erythrocyte showed a slight increase, from 68±10 to 72,9±13mg/dL, and from 40,7±6,2 to 43±6,8mgZn/gHb, respectively. However, this increase was not statically significative. Besides that, it was not found significative differences in the concentration of the electronegative anti-LDL autoantibody and of the oxysterols totals, despite of a trend in improvement of those parameters.

INTRODUÇÃO: O polimorfismo dentro do gene TCF7L2, rs7903146, é, até o momento, o marcador genético mais significantemente associado ao risco de diabetes mellitus tipo 2, sendo também associado à doença arterial coronariana. Contudo, pouco ainda se conhece sobre o papel funcional desse polimorfismo na patologia dessas doenças. O objetivo desse projeto foi investigar esse papel funcional, no fenótipo de células vasculares de músculo liso de 92 indivíduos, usando abordagens de comparação de níveis de expressão gênica e de comparação de correlações de expressão gênica, de modo que tais comparações fossem representadas visualmente como redes de interação gênica. MÉTODOS: Inicialmente, foram comparados os níveis de expressão de 41 genes (genes que possuem ou estão perto de variantes genéticas associadas ao diabetes mellitus tipo 2 e outros genes relacionados às vias de sinalização de diabetes mellitus tipo 2 ou às vias de proliferação celular) entre indivíduos com o alelo associado ao risco de diabetes mellitus tipo 2 (CT e TT) e indivíduos sem o alelo de risco (CC) do rs7903146. Com a finalidade de se observar se os genes estavam se relacionando de modo diferente entre os grupos genotípicos, foram comparados os padrões de correlação de expressão dos 41 genes. RESULTADOS: Quanto às comparações de níveis de expressão entre os grupos, cinco formas de splicing do gene TCF7L2 e os genes CDKAL1, IGF2BP2, JAZF1, CDKN2B, CAMK1D, JUN, CDK4, ATP2A2, e FKBP1A apresentaram níveis de expressão significativamente diferentes. Quanto às comparações de correlação de expressão entre os grupos, os genes RXR?, CALM1, CALR e IGF2BP2 foram os que mostraram os mais diferentes padrões de correlação com os outros genes. CONCLUSÃO: Deste modo, o alelo de risco analisado é apontado como tendo influência em cis na regulação da expressão de determinadas formas de splicing do gene TCF7L2 em células vasculares de músculo liso; além de parecer influenciar nas expressões e nas interações de genes relacionados à homeostase glicolítica e/ou proliferação celular. Sendo assim, através de nossas análises identificaram-se possíveis candidatos-alvos no tratamento de redução do risco em indivíduos com alto risco de desenvolvimento de diabetes mellitus tipo 2 e de doença arterial coronariana, especialmente os indivíduos que possuem os genótipos de risco analisados do gene TCF7L2 / INTRODUCTION: The SNP within the TCF7L2 gene, rs7903146, is, to date, the most significant genetic marker associated with type 2 diabetes mellitus risk, well as being associated with coronary artery disease. Nonetheless, its functional role in these diseases pathology is poorly understood. The aim of the present study was to investigate this role, in vascular smooth muscle cells from 92 patients undergoing aortocoronary bypass surgery, using expression levels and expression correlation comparison approaches, which were visually represented as gene interaction networks. METHODS: Initially, the expression levels of 41 genes (seven TCF7L2 splice forms and other 40 relevant genes) were compared between rs7903146 wild-type (CC) and type 2 diabetes mellitus risk (CT + TT) genotype groups. Next, the expression correlation patterns of the 41 genes were compared between genotypic groups in order to observe if the relationships between genes were different. RESULTS: Five TCF7L2 splice forms and CDKAL1, IGF2BP2, JAZF1, CDKN2B, CAMK1D, JUN, CDK4, ATP2A2 and FKBP1A genes showed significant expression differences between groups. RXR?, CALM1, CALR and IGF2BP2 genes were pinpointed as showing the most different expression correlation pattern with other genes. CONCLUSION: Therefore, type 2 diabetes mellitus risk alleles appear to be influencing TCF7L2 splice form\'s expression in vascular smooth muscle cells; besides it can be influencing expression and interactions of genes related to glucose homeostasis and/or cellular proliferation. Thereby, through our analysis were identified possible treatment target candidates for risk reduction in individuals with high-risk of developing type 2 diabetes mellitus and coronary artery disease, especially individuals harboring TCF7L2 risk genotypes

No tratamento do diabetes mellitus tipo 2, busca-se a otimização do controle glicêmico para evitar as complicações da doença. Quando a combinação mais utilizada (sulfoniluréia e biguanida) falha em manter o controle glicêmico, um terceiro agente é associado, podendo ser a insulina ou outro hipoglicemiante oral. O objetivo deste estudo foi comparar os efeitos da sitagliptina (droga inibidora da enzima dipeptidil-peptidase-4) com os da insulina NPH ao deitar, como terceira droga no tratamento do diabetes mellitus tipo 2, em pacientes inadequadamente controlados com glibenclamida e metformina. Trinta e cinco pacientes, com dados clínicos, demográficos e laboratoriais semelhantes, foram randomizados para receber sitagliptina (grupo Sitagliptina, n= 18) ou insulina NPH ao deitar (grupo Insulina, n= 17) e reavaliados após 24 semanas. Amostras sanguíneas foram coletadas para dosagens de hemoglobina glicada (HbA1c), colesterol total e frações, ácido úrico, transaminases, proteína C reativa (PCR) e grelina em jejum. No teste de tolerância à dieta de 500 calorias, foram determinadas as concentrações de glicose, triglicérides, ácidos graxos livres (AGL), peptídeo glucagon-símile tipo 1 ativo (GLP-1a), glucagon, peptídeo C, pró-insulina e insulina. Monitorização ambulatorial da pressão arterial e ecocardiografia com Doppler tecidual também foram realizados. Decorridas 24 semanas, ambos os tratamentos promoveram reduções semelhantes das concentrações de HbA1c. A insulina NPH ao deitar foi superior à sitagliptina, ao promover redução da glicemia de jejum e das concentrações de triglicérides após a refeição. Diminuição das concentrações de glucagon pós-prandiais e aumento das concentrações de GLP-1 ativo de jejum e após a refeição foram observados somente no grupo Sitagliptina. Concentrações de peptídeo C não se alteraram após o tratamento com sitagliptina, porém diminuíram após a terapia com insulina. Os dois tratamentos reduziram as concentrações de pró-insulina pós-prandiais e de grelina de jejum. Nenhum deles alterou as concentrações de PCR, colesterol, ácido úrico e enzimas hepáticas, exceto a de fosfatase alcalina, que diminuiu em ambos os grupos. Peso, índice de massa corpórea, relação cintura/quadril e pressões arteriais sistólicas e diastólicas permaneceram inalterados. Avaliação cardíaca, realizada em 29 pacientes, mostrou disfunção diastólica do ventrículo esquerdo (DDVE), sinal pré-clínico da cardiomiopatia diabética, em 53 % e 64 % dos pacientes que foram incluídos nos grupos Sitagliptina e Insulina, respectivamente. Melhora da função diastólica de VE foi observada em 40,0% (6/15) dos pacientes do grupo Sitagliptina e em 7,0% (1/14) dos pacientes do grupo Insulina (p=0,049). Esta melhora da função cardíaca pareceu não depender do controle glicêmico, da PA e do status inflamatório. Concluindo, ambos os tratamentos foram efetivos, promovendo redução semelhante da HbA1c. Ambas as drogas parecem melhorar a função das células b, observada pela diminuição das concentrações de pró-insulina. A insulina NPH ao deitar foi mais efetiva na redução da glicemia de jejum e das concentrações de triglicérides após a refeição. Entretanto, melhora na função diastólica de VE foi superior no grupo Sitagliptina. Assim, o inibidor da DPP-4 parece ser uma droga promissora para a prevenção da cardiomiopatia diabética / The main goal of the treatment of type 2 diabetes mellitus is to achieve normal glucose levels in order to prevent diabetic complications. When two oral agents (sulfonylurea plus biguanide) fail to maintain target-level control, a third oral agent must be added or insulin must be started. The aim of this study was to compare sitagliptin, a dipeptidyl-peptidase-4 enzyme inhibitor, with bedtime NPH insulin as a third-line agent in type 2 diabetes mellitus patients inadequately controlled with metformin plus glyburide combined therapy. Thirty-five patients with similar clinical, demographic and basal laboratory characteristics were randomized to receive sitagliptin (Sitagliptin group, n=18) or bedtime NPH insulin (Insulin group, n=17) and reassessed after 24 weeks. Fasting blood samples were collected for determinations of glycated hemoglobin (HbA1c), total- LDL- and HDL-cholesterol, uric acid, liver enzymes, C-reactive protein and ghrelin levels. Determinations of blood glucose, triglycerides, free fatty acids, active glucagon-like peptide 1 (GLP-1), glucagon, C-peptide, pro-insulin and insulin levels was made during the meal tolerance test. Ambulatory blood pressure monitoring and tissue Doppler echocardiography were also performed. After 24 weeks, both treatments resulted in similar HbA1c levels. Bedtime NPH insulin was superior to sitagliptin in reducing fasting plasma glucose and postprandial triglyceride levels. Decreased postprandial glucagon and increased active GLP-1 levels were only observed in the Sitagliptin group. C-peptide levels did not change after treatment with sitagliptin, but decreased following insulin therapy. Both treatments reduced postprandial pro-insulin and fasting ghrelin levels. Neither treatment changed C-reactive protein, cholesterol, uric acid or liver enzymes, except alkaline phosphatase, which decreased in both. Weight, body mass index, waist-hip ratio and systolic and diastolic blood pressures remained unchanged. Cardiac evaluation was performed in 29 patients and showed basal left ventricular diastolic dysfunction, the pre-clinical signal of diabetic cardiomyopathy, in 53% and in 64% of patients in the Sitagliptin and Insulin group, respectively. Left ventricular diastolic function improved in 40% (6/15) of patients receiving sitagliptin and in 7% (1/14) of patients receiving bedtime NPH insulin (p= 0.049). This improvement did not seem to be influenced by glycemic control, blood pressure or inflammatory status. In conclusion, both treatments were effective in reducing HbA1c and seemed to similarly improve b-cell function, as shown by reduced pro-insulin levels. Bedtime NPH insulin was more effective in reducing fasting plasma glucose and postprandial triglyceride levels. However, improvement in left ventricular diastolic function was higher in the Sitagliptin group. Therefore, sitagliptin seems to be a promising drug for the prevention of diabetic cardiomyopathy

O diabetes mellitus (DM) é definido como doença metabólica, caracterizado pela hiperglicemia, causada pela disfunção da secreção de insulina, atividade da insulina ou ambas. É classificado em quatro classes clínicas i) diabetes mellitus tipo 1 (DM1), ii) diabetes mellitus tipo 2 (DM2), iii) diabetes mellitus gestacional (DMG), iv) outros tipos específicos. Dentre os genes conhecidos por influenciarem o mecanismo de produção e liberação de insulina no organismo humano, o gene da insulina (INS) é o mais bem caracterizado nas classes clínicas do DM. A região promotora do gene INS tem sido alvo de estudo em diversas amostras populacionais do mundo, devido a sua capacidade de modular os níveis de expressão de insulina no timo e no pâncreas, de acordo, com a classe alélica que compõe o genótipo do indivíduo. Localizada a 596pb acima do sítio de transcrição do gene da insulina, é estruturada em alelos minissatélites distribuídos in tandem (ACAGGGGTGTGGGG). O alelo classe I (30 - 60 repetições) tem sido associado com predisposição ao DM1, enquanto o alelo classe III (120 - 170 repetições) tem efeito de proteção ao DM1, no entanto, esse alelo tem apresentado correlação ao DM2, à obesidade em crianças e jovens e, aumento de riscos cardiovasculares. O presente trabalho tem como objetivo analisar o polimorfismo da região promotora do gene da insulina sobre os fenótipos do DM e a possível influência desse em características demográficas, clínicas e laboratoriais desses pacientes. Foram analisados 189 pacientes com DM1, 116 pacientes com DM2, 68 pacientes com DMG e 339 indivíduos controle da região de Ribeirão Preto, SP. O DNA genômico foi extraído por salting-out, seguido da amplificação e digestão enzimática do fragmento referente a região promotora do gene INS, o qual contém na sequência downstream, o polimorfismo -23HphI, cujo desequilíbrio de ligação (r2 1) com o polimorfismo INSVNTR, permite inferir os genótipos por intermédio da análise do polimorfismo -23HphI. Observamos que o alelo classe I e o genótipo classe I : classe I estão relacionados à predisposição ao DM1, enquanto o alelo classe III, predominantemente em homozigose, está associado à proteção ao DM1. Em relação ao DM2, o genótipo classe I : classe III foi associado à susceptibilidade a doença e, nenhum genótipo foi correlacionado ao DMG. De acordo com os dados demográficos, clínicos e laboratoriais, variáveis como gênero e pigmentação da pele têm influenciado na frequência do polimorfismo INSVNTR em pacientes com DM1, como por exemplo, a maior frequência de homens com genótipo classe I : classe I no conjunto DM1. Em contrapartida, nesse mesmo grupo de pacientes, o genótipo classe III : classe III evidenciou maior susceptibilidade ao desenvolvimento de retinopatia (p=0,0020; OR= 0,05333; 95% I.C. 0,007839 - 0,3629). Em pacientes com DM2, a comparação entre gêneros evidenciou maior frequência do genótipo classe III : classe III em mulheres. E, em relação ao DMG, os genótipos de classe I : classe I e classe I : classe III estavam associados ao menor nível de glicose no plasma sanguíneo em relação as pacientes que exibiam o genótipo classe III : classe III. Esse é o primeiro estudo de associação do polimorfismo INS-VNTR comparando as três principais classes clínicas de DM oriundas de uma mesma amostra geográfica, sendo evidenciado um perfil genotípico padrão de susceptibilidade de acordo com o tipo de DM. / Diabetes mellitus (DM) is defined as a metabolic disorder characterized by hyperglycemia caused by impaired insulin secretion, insulin activity or both. It is classified into four clinical classes i) type 1 diabetes mellitus (T1DM), ii) type 2 diabetes mellitus (T2DM), iii) gestational diabetes mellitus (GDM), iv) other specific types. Among the genes known to influence the mechanism of production and release of insulin, the insulin gene (INS) has been well characterized in disease susceptibility. The INS promoter has been studied in different worldwide populations due to its ability to modulate expression levels of insulin in the thymus and pancreas, in accordance with the type of diabetes. The major polymorphic site is located 596bp upstream from the translation initiation site of the INS gene and it is structured into minisatellite alleles (ACAGGGGTGTGGGG). The shorter class I alleles (30 60 repeats) confers predisposition to DM1 and the longer class III (120 170 repeats) confers protection to DM1; however, the latter allele has also shown to be correlated with DM2, obesity in children and juvenile individuals, and increased cardiovascular risks. This study aims to analyze the association of a polymorphic site at promoter region of the INS gene with diabetes phenotypes, with the purpose of evaluating this region as a possible genetic marker of the disease, and the possible influence on demographic, clinical and laboratory features in a sample of the urban Brazilian population. We analyzed 189 T1DM patients, 116 T2DM patients, 68 GDM patients and 339 healthy individuals from the region of Ribeirão Preto, SP. DNA extraction was performed using a salting-out procedure, followed by amplification and restriction enzyme digestion of the fragment relating to INS gene promoter, which contains another polymorphism, -23HphI, which is in perfect linkage disequilibrium (r2 1) with the INS-VNTR, making it an useful genetic marker. We observed that the class I allele and class I : class I genotype are associated with predisposition to T1DM, whereas, class III allele, predominantly in homozygosity, is associated to T1DM protection. In relation to T2DM, the class I : class III genotype has been associated with susceptibility to disease. Finally, no genotype was correlated with GDM. Data stratification according to demographical, clinical and laboratory variables, indicated that gender, skin color seemed to influence the frequency of the INS-VNTR polymorphism; i. e., the class I : class I genotype was more frequent in male T1DM patients. On the other hand, the presence of the class III : class III genotype was associated with susceptibility the development of retinopathy (p=0,0020; OR= 0,05333; 95% I.C. 0,007839 - 0,3629). In T2DM patients, a trend association was observed between the class III : class III genotype with female diabetic patients. In relation to GDM, the genotypes class I : class I and class I : class III were associated with decreased glucose levels in relation to patients exhibiting the class III : class III genotype. This is the first study of the INS-VNTR polymorphism encompassing the major types if DM patients from the same geographical region, which showed a differential pattern of susceptibility according to the underlying type of DM.

O diabetes mellitus tipo 1 (DM1) tem etiologia autoimune, enquanto o diabetes mellitus tipo 2 (DM2) e o diabetes mellitus gestacional (DMG) são considerados como distúrbios metabólicos. Neste trabalho, foi realizada análise do transcriptoma das células mononucleares do sangue periférico (do inglês, peripheral mononuclear blood cells - PBMCs), obtidas de pacientes com DM1, DM2 e DMG, realizando análises por module maps a fim de comparar características patogênicas e aspectos gerais do tratamento com anotações disponíveis de genes modulados, tais como: a) análises disponíveis a partir de estudos de associação em larga escala (do inglês genome-wide association studies GWAS); b) genes associados ao diabetes em estudos clássicos de ligação disponíveis em bancos de dados públicos; c) perfis de expressão de células imunológicas fornecidos pelo grupo ImmGen (Immunological Project). Foram feitos microarrays do transcriptoma total da plataforma Agilent (Whole genome onecolor Agilent 4x44k) para 56 pacientes (19 DM1, 20 DM2 e 17 DMG). Para a compreensão dos resultados foram aplicados filtros não-informativos e as listas de genes diferencialmente expressos foram obtidas por análise de partição e análise estatística não-paramétrica (rank products), respectivamente. Posteriormente, análises de enriquecimento funcional foram feitas pelo DAVID e os module maps construídos usando a ferramenta Genomica. As análises funcionais contribuíram para discriminar os pacientes a partir de genes envolvidos na inflamação, em especial DM1 e DMG. Os module maps de genes diferencialmente expressos revelaram: a) genes modulados exibiram perfis de transcrição típicos de macrófagos e células dendríticas, b) genes modulados foram associados com genes previamente descritos como genes de complicação ao diabetes a partir de estudos de ligação e de meta-análises; c) a duração da doença, obesidade, número de gestações, níveis de glicose sérica e uso de medicações, tais como metformina, influenciaram a expressão gênica em pelo menos um tipo de diabetes. Esse é o primeiro estudo de module maps mostrando a influência de padrões epidemiológicos, clínicos, laboratoriais, imunopatogênicos e de tratamento na modulação dos perfis transcricionais em pacientes com os três tipos clássicos de diabetes: DM1, DM2 e DMG. / Type 1 diabetes (T1D) is an autoimmune disease while type 2 (T2D) and gestational diabetes (GDM) are considered as metabolic disturbances. We performed a transcriptome analysis of peripheral mononuclear blood cells obtained from T1D, T2D and GDM patients, and we took advantage of the module map approach to compare pathogenic and treatment features of our patient series with available annotation of modulated genes from i) genome-wide association studies; ii) genes provided by diabetes meta-analysis in public databases, iii) immune cell gene expression profiles provided by the ImmGen project. Whole genome one-color Agilent 4x44k microarray was performed for 56 (19 T1D, 20 T2D, 17 GDM) patients. Noninformative filtered and differentially expressed genes were obtained by partitioning and rank product analysis, respectively. Functional analyses were carried out using the DAVID software and module maps were constructed using the Genomica tool. Functional analyses contributed to discriminate patients on the basis of genes involved in inflammation, primarily for T1D and GDM. Module maps of differentially expressed genes revealed that: i) modulated genes exhibited transcription profiles typical of macrophage and dendritic cells, ii) modulated genes were associated with previously reported diabetes complication genes disclosed by association and meta-analysis studies, iii) disease duration, obesity, number of gestations, glucose serum levels and the use of medications, such as metformin, influenced gene expression profiles in at least one type of diabetes. This is the first module map study to show the influence of epidemiological, clinical, laboratory, immunopathogenic and treatment features on the modulation of the transcription profiles of T1D, T2D and GDM patients.