Yang Tao. / "November 2000." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2000. / Includes bibliographical references (p. 136-152). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

Gao, Zhibo. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 147-157). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Liu, Xin. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 157-164). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

研究背景和目的 / 高血壓和糖尿病是人群中常見的疾病，兩者常共同存在，其共存的病理生理機制非常複雜，其中腎素血管景張素系統功能紊亂起重要作用。多個研究表明血管緊張素轉化晦抑制劑和血管緊張素II 1 型受體阻滯劑通過調節不同基因的表達，發揮其保護心血管和腎臟功能的效用。然而，目前仍缺乏遠兩類藥物影響全基因表達譜的全面調查。因此，本研究應用全基因表達譜晶片技術，檢測分析了高血壓和糖尿病並發的病人在服用安慰劑、雷米普利(ramipril)和替米沙坦(telmisartan)後的全基因表達譜的變化，從而全面評估了血管緊張素轉化臨抑制劑和血管繁張素II 1 型受體阻滯劑對相關基因的轉錄調控作用。 / 方法 / 11 名患有高血壓和糖尿病的病人(男性5 名)在服用安慰劑最少2 星期后，以隨機吹序接受為期各6 星期的雷米普利和替米沙坦治療，並分別在安慰劑期和2 個藥物治療期結束后提取心A 進行全基因表達譜分析。 / 結果 / 與服用安慰劑時的全基因表達譜相比，雷米普利治療后有267 個基因的表達降低， 99 個基因的表達增強。表達差異幅度為-2.0 至1.3 (P < 0.05) 。表達下降的基因主要與血管平滑肌收縮、炎症反應和氧化壓力相關。表達增強的基因主要與心血管炎症反應負調節相關。基因共表達網絡分析表明， 2 個共表達基因組與雷米普利的降血壓作用相闕， 3 個共表達基因組與肥胖相關。 / 與服用安慰劑時的全基因表達譜相比， 替米拉)、坦治療后有55 個基因表達降低， 158 個基因的表達增強。表達差異幅度為-1. 9 至1.3 (P < 0.05) 。表達增強的基因主要與脂質代謝、糖代謝和抗炎症因子作用相關。基因共表達網絡分析表明， 2 個共表達基因組與替米沙坦對24 小時舒張壓負荷量的作用相關， 2 個共表達基因組則與總膽固醇， 低密度脂蛋白膽固醇和C 反應蛋白相關。 / 結論 / 本論文描述了高血壓和2 型糖尿病病患全基因組表達的總體模式及經藥物治療後表達譜的相應改變， 為今後進一步研究腎素血管緊張素系統抑制劑和高血壓、糖尿病發展進程的相互作用提供了方向。 / Background and aim: Pathophysiological mechanisms underpinning the coexistence of hypertension and type 2 diabetes are complex systemic responses involving dysregulation of the renin-angiotensin system (RAS). We conducted this study to investigate the genome wide gene expression changes in patients with both hypertension and diabetes at three treatment stages, including placebo, ramipril and telmisartan. This study aimed to obtain a panoramic view of interactions between gene transcription and antihypertensive therapy by RAS inhibition. / Methods: 11 diabetic patients (S men) with hypertension were treated with placebo for at least 2 weeks followed by 6 weeks randomised crossover treatment with ramipril Smg daily and telmisartan 40mg daily, respectively. Total RNA were extracted from leukocytes at the end of placebo and each treatment period, and were hybridized to the whole transcript microarray. The limma package for R was used to identify differentially expressed genes between placebo and the 2 active treatments. The weighted gene coexpression network analysis (WGCNA) was applied to identify groups of genes (modules) highly correlated to a common biological function in pathogenesis and progression of hypertension and diabetes. / Results: There were 267 genes down-regulated and 99 genes up-regulated with ramipril. Fold changes of gene expression were ranged from -2.0 to 1.3 (P < 0.05). The down-regulated genes were involved in vascular signalling pathways responsible for vascular smooth muscle contraction, inflammation and oxidative stress. The up-regulated genes were associated with negative regulation of cardiovascular inflammation. The WGCNA identified 17 coexpression gene modules related to ramipril. The midnight blue (57 genes, r < -0.44, P < 0.05) and magenta (190 genes, r < -0.44, P < 0.05) modules were significantly correlated to blood pressure differences between placebo and ramipril. / There were 55 genes down-regulated and 158 genes up-regulated with telmisartan. Fold changes of gene expression were ranged from -1.9 to 1.3 (P < 0.05). The down-regulated genes were mainly associated with cardiovascular inflammation and oxidative stress. The up-regulated genes were associated with lipid and glucose metabolism and anti-inflammatory actions. The WGCNA identified 8 coexpression gene modules related to telmisartan. The black (56 genes, r = 0.46, P = 0.03) and turquoise (1340 genes, r = -0.48, P = 0.02) modules were correlated with diastolic blood pressure load. The blue (1027 genes) module was enriched with genes correlated with total cholesterol (r = - 0.52, P = 0.01), LDL-C (r = - 0.58, P = 0.004), and hsCRP (r = -0.57, P = 0.006). The green module (272 genes) was significantly correlated with LDL-C (r = - 0.44, P = 0.04) and hsCRP (r = - 0.59, P = 0.004). / Conclusion: Genome wide gene expression profiling in this study describes the general pattern and treatment responses in patients with hypertension and type 2 diabetes, which suggests future directions for further investigations on the interaction between actions of the RAS blockers and disease progression. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Deng, Hanbing. / "December 2011." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 198-256). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese. / Declaration --- p.i / Publications --- p.ii / Abstract --- p.iv / 論文摘要 --- p.vi / Acknowledgements --- p.viii / Table of Contents --- p.x / List of tables --- p.xiv / List of figures --- p.xv / List of appendices --- p.xvii / List of abbreviations --- p.xviii / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Overview --- p.1 / Chapter 1.2 --- Epidemiology --- p.6 / Chapter 1.2.1 --- Epidemiology of hypertension --- p.9 / Chapter 1.2.2 --- Epidemiology of type 2 diabetes --- p.10 / Chapter 1.3 --- Aetiology --- p.13 / Chapter 1.3.1 --- Ageing --- p.13 / Chapter 1.3.1.1 --- Age-induced artery stiffness --- p.14 / Chapter 1.3.1.2 --- Age-related endothelial dysfunction --- p.14 / Chapter 1.3.2 --- The renin-angiotensin system (RAS) --- p.16 / Chapter 1.3.2.1 --- The local RAS --- p.20 / Chapter 1.3.2.2 --- The RAS and insulin resistance --- p.22 / Chapter 1.3.2.3 --- The RAS and inflammation --- p.26 / Chapter 1.3.2.4 --- The RAS and oxidative stress --- p.28 / Chapter 1.3.3 --- Obesity --- p.31 / Chapter 1.3.3.1 --- Obesity and renin-angiotensin system (RAS) --- p.33 / Chapter 1.3.3.2 --- Obesity and insulin resistance --- p.36 / Chapter 1.3.3.3 --- Obesity and oxidative stress --- p.38 / Chapter 1.3.3.4 --- Obesity and sympathetic nervous system (SNS) --- p.38 / Chapter 1.4 --- Pharmacogenomics of antihypertensive therapy --- p.39 / Chapter 1.4.1 --- Angiotensin-converting enzyme inhibitors (ACEIs) --- p.41 / Chapter 1.4.2 --- Angiotensin II type 1 receptor blockers (ARBs) --- p.43 / Chapter Chapter 2 --- Aim --- p.59 / Chapter Chapter 3 --- Methods --- p.60 / Chapter 3.1 --- Subjects --- p.60 / Chapter 3.1.1 --- Subject recruitment protocol --- p.60 / Chapter 3.1.2 --- Definition of type 2 diabetes --- p.62 / Chapter 3.1.3 --- Definition of obesity --- p.62 / Chapter 3.1.4 --- Definition of dyslipidaemia --- p.63 / Chapter 3.2 --- Study design and procedure --- p.64 / Chapter 3.2.1 --- Blood pressure assessments --- p.65 / Chapter 3.2.2 --- Anthropometric measurements --- p.68 / Chapter 3.2.3 --- Medical history, life style and side effect evaluation --- p.68 / Chapter 3.2.4 --- RNA isolation --- p.68 / Chapter 3.2.5 --- RNA quality assessment --- p.70 / Chapter 3.2.6 --- Oligonucleotide microarrays --- p.71 / Chapter 3.2.7 --- DNA extraction --- p.75 / Chapter 3.2.8 --- Biomedical measurements --- p.76 / Chapter 3.2.8.1 --- Glycosylated haemoglobin Alc (HbA₁c) --- p.77 / Chapter 3.2.8.2 --- Fasting plasma glucose (FP G) --- p.77 / Chapter 3.2.8.3 --- Fasting insulin --- p.77 / Chapter 3.2.8.4 --- Plasma urate --- p.77 / Chapter 3.2.8.5 --- High sensitive C-reactive protein (hsCRP) --- p.78 / Chapter 3.2.8.6 --- Fasting plasma triglycerides (TG) --- p.78 / Chapter 3.2.8.7 --- Fasting plasma cholesterols --- p.78 / Chapter 3.2.8.8 --- Renal and liver functions --- p.78 / Chapter 3.2.8.9 --- Urinary parameters --- p.79 / Chapter 3.3 --- Statistical Analysis --- p.79 / Chapter 3.3.1 --- Statistical analysis of clinical and biomedical data --- p.79 / Chapter 3.3.2 --- Analysis of microarray data --- p.80 / Chapter 3.3.2.1 --- Raw data assessment --- p.80 / Chapter 3.3.2.2 --- Data normalisation --- p.92 / Chapter 3.3.2.3 --- Data filtering --- p.96 / Chapter 3.3.2.4 --- Linear models for assessment of differential expression --- p.96 / Chapter 3.3.2.5 --- Weighted gene coexpression network analysis --- p.101 / Chapter 3.3.2.6 --- Network visualisation and gene ontology analysis --- p.102 / Chapter 3.3.3 --- Sample size calculation --- p.103 / Chapter Chapter 4 --- Results --- p.104 / Chapter 4.1 --- Demographic and biomedical characteristics at baseline --- p.104 / Chapter 4.1.1 --- Hypertension and diabetes status at baseline --- p.108 / Chapter 4.1.2 --- Prevalence of dyslipidaemia --- p.108 / Chapter 4.1.3 --- Prevalence of obesity --- p.109 / Chapter 4.1.4 --- Prevalence of metabolic syndrome --- p.109 / Chapter 4.1.5 --- Inflammation markers --- p.110 / Chapter 4.2 --- Blood pressure response to the RAS blockers --- p.110 / Chapter 4.2.1 --- Clinic blood pressure --- p.110 / Chapter 4.2.2 --- 24-hour ambulatory blood pressure --- p.112 / Chapter 4.3 --- Biomedical characteristics --- p.118 / Chapter 4.4 --- Compliance, side effects and adverse events --- p.120 / Chapter 4.5 --- Gene expression differences between treatments --- p.121 / Chapter 4.5.1 --- Gene expression differences between placebo and ramipril --- p.121 / Chapter 4.5.1.1 --- Expression changes in genes related to regulation of transcription with ramipril --- p.122 / Chapter 4.5.1.2 --- Expression changes with ramipril in genes related to molecular mechanism of cardiovascular changes in hypertension --- p.125 / Chapter 4.5.1.3 --- Expression changes in genes related to blood pressure with ramipril --- p.128 / Chapter 4.5.1.4 --- Expression changes in genes related to fatty acid metabolism with ramipril --- p.130 / Chapter 4.5.1.5 --- Expression changes in genes related to inflammation with ramipril --- p.130 / Chapter 4.5.1.6 --- Expression changes in genes related to oxidative stress with ramipril --- p.133 / Chapter 4.5.1.7 --- Power estimation --- p.133 / Chapter 4.5.2 --- Gene expression differences between placebo and telmisartan --- p.135 / Chapter 4.5.2.1 --- Changes in regulation oftranscription with telmisartan --- p.137 / Chapter 4.5.2.2 --- Expression changes in genes related to glucose metabolism with telmisartan --- p.141 / Chapter 4.5.2.3 --- Expression changes in genes related to lipid metabolism with telmisartan --- p.143 / Chapter 4.5.2.4 --- Expression changes in genes related to inflammation with telmisartan --- p.143 / Chapter 4.5.2.5 --- Power estimation --- p.145 / Chapter 4.5.3 --- WGCNA for comparison between placebo and ramipriI --- p.147 / Chapter 4.5.3.1 --- Midnight blue module and clinical responses to ramipril --- p.152 / Chapter 4.5.3.2 --- Magenta module and blood pressure responses to ramipril --- p.154 / Chapter 4.5.3.3 --- Yellow module and clinical responses to ramipril --- p.158 / Chapter 4.5.3.4 --- Red module and clinical responses to ramipril --- p.161 / Chapter 4.5.3.5 --- Salmon module and clinical responses to ramipril --- p.163 / Chapter 4.5.4 --- WGCNA for comparison between placebo and telmisaItan --- p.168 / Chapter 4.5.4.1 --- Diastolic blood pressure load and gene coexpression modules --- p.168 / Chapter 4.5.4.2 --- Lipids, hsCRP and gene coexpression modules --- p.172 / Chapter Chapter 5 --- Discussion --- p.176 / Chapter 5.1 --- Gene expression changes related to ramipril --- p.177 / Chapter 5.1.1 --- Gene expression changes and blood pressure reduction by ramipri1 --- p.177 / Chapter 5.1.2 --- Gene expression changes and vascular protection by ramipri1 --- p.181 / Chapter 5.1.3 --- Obesity and gene expression changes by ramipril --- p.183 / Chapter 5.2 --- Gene expression changes related to telmisartan --- p.185 / Chapter 5.2.1 --- Blood pressure and coexpressed gene modules with telmisartan --- p.185 / Chapter 5.2.2 --- Lipid metabolism and gene expression changes by telmisartan --- p.187 / Chapter 5.2.3 --- Glucose metabolism and gene expression changes by telmisartan --- p.189 / Chapter 5.2.4 --- hsCRP and gene expression changes by telmisartan --- p.190 / Chapter 5.3 --- Limitations of this study and future directions of research --- p.191 / Chapter Chapter 6 --- Conclusion --- p.194 / References --- p.198 / Appendices --- p.257

BACKGROUND AND OBJECTIVES: Type 2 diabetes mellitus (T2DM) is a complex disease with genetic predisposition and histopathological characterization. Pancreatic islet amyloidosis, hyaline arteriolosclerosis, and diabetic glomerulopathy are histopathological hallmarks of T2DM at autopsy examination. The associations of genetic variants with diabetic amyloidosis, arteriosclerosis and glomerulopathy have not been fully elucidated. Several candidate genes including apolipoprotein E (ApoE), insulin degrading-enzyme (IDE) and glucose transporter-1 ( GLUT1) have been reported to increase risk of T2DM in human studies although results are not always consistent. Capitalizing on the pathological hallmarks of T2DM, I used autopsy specimens to investigate the risk associations of polymorphisms of ApoE (rs429358 and rs7412), IDE (rs6583813) and GLUT1 (rs710218) genes with clinical features and specific pathological changes in diabetic kidney and pancreas. I further explored the mechanisms of these associations by evaluating the histopathological changes and protein expression in pancreas and kidney. / CONCLUSIONS: These findings suggest that genetic factors have important effects in the development of tissue-specific changes and chronic complications in T2DM. Islet amyloidosis, arteriosclerosis and glomerulosclerosis in T2DM may share common pathogenetic processes as suggested by the coexistence of chaperone proteins, amyloid P and ApoE. Genetic--pathologic correlation studies are useful in advancing our understanding of the mechanisms of complex diseases such as T2DM. / METHODS AND MATERIALS: Genomic DNA was extracted from white blood cell-concentrated paraffin embedded formalin fixed spleen tissues. Genotyping for ApoE, IDE and GLUT1 polymorphisms was determined by polymerase chain reaction (PCR) and ligase detection reaction (LDR). The pathological changes were blindly assessed in pancreatic and kidney tissues of autopsy specimens. Protein expression of these genes was examined by immunostaining and quantified by using Metamorph image analysis system. / RESULTS: In a consecutive study population of 3693 autopsy specimens containing 328 T2DM and 209 control cases, the respective frequencies of genotypes were as follows: 1) TT of GLUT1 rs710218: 11.2% vs. 11.3%; 2) ApoE epsilon2: 19.4% vs. 10.9%; 3) ApoE epsilon4: 12.1% vs. 9.1% and 4) C carriers of IDE rs6583813: 51.2% vs. 47.9%. The key genotype-phenotype correlations were as follows. 1) In the T2DM cases, GLUT1 rs710218 IT genotype carriers (0% in TT genotype vs. 59.1% in AA genotype, P=0.0407) were less likely but ApoE epsilon 2 allele carriers (57.1% in epsilon2 allele carriers vs. 23.5% in epsilon3 allele carriers P=0.0382) were more likely to have diabetic glomerular hypertrophy than referential group. ApoE epsilon2 carriers showed increased glomerular ApoE protein expression with the immunoreactivity found mainly in the mesangial regions and nodular lesions. On the other hand, ApoE epsilon 3/epsilon4 cases had diffuse ApoE expression in glomerular capillaries. 2) ApoE epsilon4 carriers were more likely to have islet amyloidosis than non-carriers (62.5% in epsilon4 allele carriers vs. 23.6% in epsilon 3 allele carriers P=0.0232). There was immunolocalization of the chaperone proteins, amyloid P and ApoE in both islet amyloid deposits and arterial walls with hyaline arteriolosclerosis. 3) In T2DM cases, IDE rs6583813 C allele carriers had higher prevalence of vascular disorders [hypertension (67.4% vs. 43.6%, P=0.0332), death due to cardiovascular disease (58.1% vs. 25.6%, P=0.0479) and cerebral vascular accident (CVA) (20.9% vs. 2.4%, P=0.0412)1 than T allele carriers. / Guan, Jing. / Adviser: Chan Chung Ngor Juliana. / Source: Dissertation Abstracts International, Volume: 73-02, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 175-192). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Zhang, Ji. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2009. / Includes bibliographical references (leaves 100-104). / Abstracts in English and Chinese. / Chapter CHAPTER 1. --- Introduction / Chapter 1.1. --- Introduction of genetic association studies --- p.1 / Chapter 1.1.1. --- Application of genetic association studies in complex diseases --- p.3 / Chapter 1.1.2. --- Application of genetic association studies in type-2 diabetes --- p.4 / Chapter 1.2. --- Study design of genetic association studies --- p.7 / Chapter 1.3. --- Overview of statistical approaches in association studies --- p.10 / Chapter 1.3.1. --- Preliminary analyses --- p.10 / Chapter 1.3.1.1. --- HardýؤWeinberg equilibrium testing --- p.10 / Chapter 1.3.1.2. --- Inference of missing genotype data --- p.12 / Chapter 1.3.1.3. --- SNP tagging --- p.14 / Chapter 1.3.2. --- Single-point and multipoint tests for association --- p.15 / Chapter 1.4. --- Other relevant methods employed in this study --- p.20 / Chapter 1.4.1. --- Self-Organizing Maps (SOM) with further classification by K-means clustering --- p.20 / Chapter 1.4.2. --- Random forests --- p.27 / Chapter 1.5. --- Main objectives of this study --- p.31 / Chapter CHAPTER 2. --- Materials and methods / Chapter 2.1. --- Study cohort --- p.32 / Chapter 2.2. --- Study design --- p.34 / Chapter 2.2.1. --- Construction of sample sets for each stage using SOM and K-means clustering --- p.34 / Chapter 2.2.2. --- Stage 1 analysis by random forests --- p.37 / Chapter 2.2.3. --- Stage 2 analysis by chi-square test --- p.42 / Chapter 2.2.4. --- Two-stage genetic association study by chi-square test --- p.43 / Chapter 2.2.5. --- Comparison of results: random forests plus chi-square test versus chi-square test --- p.43 / Chapter 2.2.6. --- Validation of results in the whole sample set by allelic chi-square test --- p.44 / Chapter 2.2.7. --- Extensions of the study: cumulative effects of candidate SNPs on risk of type-2 diabetes --- p.45 / Chapter CHAPTER 3. --- Results / Chapter 3.1. --- Effects of sample classification by SOM and K-means clustering --- p.50 / Chapter 3.2. --- Genetic associations in stage 1 --- p.64 / Chapter 3.3. --- Genetic associations in stage 2 and validation of results --- p.69 / Chapter 3.4. --- Cumulative effects of candidate SNPs on risk of type-2 diabetes --- p.76 / Chapter CHAPTER 4. --- Discussion / Chapter 4.1. --- Overall strategy --- p.81 / Chapter 4.1.1. --- Effects of SOM and K-means clustering --- p.82 / Chapter 4.1.2. --- Effects of random forests in the first stage of association study --- p.83 / Chapter 4.1.3. --- Comparison of our method with traditional chi-square test --- p.84 / Chapter 4.1.4. --- Joint effects of candidate SNPs selected by the hybrid method --- p.86 / Chapter 4.2. --- Biological significance of candidate SNPs --- p.88 / Chapter 4.2.1. --- Gene CDKAL1 --- p.89 / Chapter 4.2.2. --- Gene KIAA1305 --- p.90 / Chapter 4.2.3. --- Gene DACH1 --- p.91 / Chapter 4.2.4. --- Gene FUCA1 --- p.92 / Chapter 4.2.5. --- Gene KCNQ1 --- p.93 / Chapter 4.2.6. --- Gene SLC27A1 --- p.94 / Chapter 4.3. --- Limits and improvement of this study --- p.96 / Chapter 4.4. --- Conclusion --- p.99 / REFERENCES --- p.100

Os polimorfismos do gene TCF7L2 têm sido fortemente associados com risco de desenvolvimento de diabetes mellitus em populações de diversas origens étnicas. No presente estudo, investigou-se se esta associação se confirma em diferentes populações brasileiras e qual seu efeito sobre o desempenho de um modelo de predição de risco de diabetes mellitus quando a informação genética foi acrescentada às variáveis clínicas e laboratoriais iniciais. Concluiu-se que, apesar de haver sido confirmado a associação do polimorfismo rs7903146 ao diabetes tipo 2 na população brasileira, a inclusão desta informação no modelo teve desempenho equivalente ao modelo baseado unicamente em variáveis clínicas. / Recently, polymorphisms of gene TCF7L2 have been strongly associated with Type 2 Diabetes risk in populations of diverse genetic backgrounds. In this study we investigated if this association is present in different Brazilian populations and how the inclusion of genetic information to a diabetes risk prediction model based on clinical and laboratorial variables would affect its would affect its performance. We concluded that, even though the TCF7L2 rs7903146 polimorphism is associated to Type 2 Diabetes risk in the Brazilian population, that inclusion of such information to a diabetes risk prediction model based on clinical variables lead to equivalent performance.

Os polimorfismos do gene TCF7L2 têm sido fortemente associados com risco de desenvolvimento de diabetes mellitus em populações de diversas origens étnicas. No presente estudo, investigou-se se esta associação se confirma em diferentes populações brasileiras e qual seu efeito sobre o desempenho de um modelo de predição de risco de diabetes mellitus quando a informação genética foi acrescentada às variáveis clínicas e laboratoriais iniciais. Concluiu-se que, apesar de haver sido confirmado a associação do polimorfismo rs7903146 ao diabetes tipo 2 na população brasileira, a inclusão desta informação no modelo teve desempenho equivalente ao modelo baseado unicamente em variáveis clínicas. / Recently, polymorphisms of gene TCF7L2 have been strongly associated with Type 2 Diabetes risk in populations of diverse genetic backgrounds. In this study we investigated if this association is present in different Brazilian populations and how the inclusion of genetic information to a diabetes risk prediction model based on clinical and laboratorial variables would affect its would affect its performance. We concluded that, even though the TCF7L2 rs7903146 polimorphism is associated to Type 2 Diabetes risk in the Brazilian population, that inclusion of such information to a diabetes risk prediction model based on clinical variables lead to equivalent performance.

Introdução: O gene TCF7L2 (Transcription Factor 7-Like 2) codifica o fator de transcrição de mesmo nome que, tem importante papel na via Wnt de sinalização intra celular. A via Wnt é constituída por proteínas de integração e ligação dos processos de diferenciação e multiplicação celulares, interagindo com os fatores TCF, e ativando a expressão de genes relacionados ao TCF7L2, sendo este amplamente expresso em vários tecidos. Dados epidemiológicos atuais não deixam dúvidas quanto à forte associação de polimorfismos do gene TCF7L2 com o diabetes tipo 2 (DM2) em diferentes etnias. Apesar de serem pouco conhecidos os mecanismos que envolvem o gene TCF7L2 no DM2, tem sido bem demonstrada a associação do alelo T no rs7903146 com redução da secreção de insulina, redução do efeito das incretinas, principalmente do GLP-1, aumento na secreção de glucagon e a longo prazo, redução da meia vida da célula beta. Em vista destas evidências, aventamos a hipótese de que pacientes com DM2 portadores da variante rs7903146 do gene TCF7L2, ao ser tratados com GLP-1 mimético, poderiam responder de forma peculiar. Objetivos: Avaliar a resposta hormonal pancreática antes e após tratamento com GLP-1 mimético em indivíduos com DM2 portadores da variante rs7903146 do gene TCF7L2. Pacientes e Métodos: Foram genotipados162 indivíduos com DM2 portadores da variante rs7903146 do gene TCF7L2: idade (57,0 &#177; 7,6) anos, IMC (30,5 &#177; 5,1) kg/m2. Dessa amostra, 56 pacientes foram divididos em dois grupos conforme o genótipo, sendo 26 CC x 30 CT/TT, e a seguir tratados com Exenatide durante oito semanas. Os testes de refeição foram realizados antes e após o tratamento, para avaliação das concentrações plasmáticas de: Glicose (mg/dl), Insulina (&#956;U/dl), Pró-insulina (pmol/L), Peptideo-c (ng/ml); Glucagon (pg/ml) e GLP-1(pmol/L). Foram comparadas as áreas sob as curvas e os pontos das curvas durante o teste. Análise estatística por ANOVA com dois fatores e medidas repetidas, nível de significância maior que 5%. Resultados: A distribuição genotípica CC x CT x TT foi 41,4% x 47,5% x 11,1% respectivamente. A influência do alelo T na resposta pancreática durante o teste da refeição mostrou que as concentrações plasmáticas de insulina, pró-insulina e peptídeo-c foram maiores no grupo CT/TT do que no CC (p<0,05) mas, não houve diferença na secreção do glucagon, GLP-1 e na glicemia entre os grupos (NS).Com relação à influência do alelo T na resposta ao tratamento verificou-se que o grupo CT/TT apresentou maior redução da secreção de insulina (p<0,005), peptídeo-c (p<0,05) e pró-insulina (p<0,001) do que o grupo CC durante o teste da refeição após o tratamento. Observou-se diminuição da glicemia, do glucagon e do GLP-1 de forma semelhante em ambos os grupos. Além disso, houve diminuição semelhante do peso e da hemoglobina glicosilada em ambos os grupos. Discussão: Os resultados do presente estudo mostraram que a presença do alelo T em indivíduos com DM2 esteve associada à maior secreção de insulina, pró-insulina e peptídeo-c em relação aos não portadores, com semelhantes concentrações séricas de glucagon e glicose em resposta ao teste da refeição. Este dado demonstra que a função da célula &#946; dos portadores da variante rs7903146 apresenta características diferentes dos não portadores. Após o tratamento com Exenatide, os indivíduos com DM2 e genótipo CT/TT, apresentaram valores estatisticamente menores de insulina, pró-insulina e peptídeo-c do que o grupo CC. Os efeitos do GLP-1 na glicemia pós-prandial são atribuídos a mecanismos de supressão do glucagon, lentificação do esvaziamento gástrico e também a efeitos insulinotrópicos e decorrentes de aumento na sensibilidade periférica à insulina. Além disso, já foi demonstrado que o Exenatide aumenta a captação de glicose de forma insulino-independente em músculo esquelético, pelo estímulo dos transportadores de glicose. Portanto, acredita-se que as características da resposta observada após o tratamento nos portadores do alelo T correspondem ao efeito do Exenatide na célula &#946; melhorando o processamento da pró-insulina, peptídeo-c e insulina e ao aumento da captação periférica da glicose. Sugere-se que esse processo seja resultante da melhor interação com os receptores de GLP-1, tanto em fígado, músculo esquelético e pâncreas. Conclusões: Os dados sugerem que indivíduos com DM2 portadores do alelo T no rs7903146 do gene TCF7L2 apresentam mais benefícios do tratamento com Exenatide, pois a secreção de insulina, pró-insulina e peptídeo-c foram condizentes com maior qualidade na função de célula &#946; nesse grupo após o tratamento. Além disso, o presente estudo proporcionou adicionais evidências clínicas de que os problemas que associam o TCF7L2 ao DM2 estão relacionados à tolerância periférica a glicose. / Introduction:The TCF7L2 gene (Transcription Factor 7-Like 2) encodes the transcription factor of the same name that has an important role in the intracellular Wnt signaling. The Wnt pathway is composed of connecting and integrating proteins of cell proliferation and differentiation process by interacting with TCF factors, and activating the expression of genes related to TCF7L2, which is widely expressed in several tissues. Current epidemiological data leave no doubt as to the strong association of polymorphisms of the TCF7L2 gene with type 2 diabetes (T2DM) in different ethnic groups. Although they are poorly known mechanisms involving TCF7L2 gene in DM2 the association of the T allele of rs7903146 with reduced insulin secretion, reducing effect of incretins, mainly GLP-1, increase in glucagon secretion and long-term reduction in the half-life of the beta cell, have been well demonstrated. In view of this evidences, we hypothesized that patients with DM2 carriers of the variant rs7903146 of the TCF7L2 gene, being treated with GLP-1 mimetic, could respond in a peculiar way. Objectives: Evaluating the pancreatic hormone response before and after treatment with GLP-1 mimetic in individuals with T2DM carriers of rs7903146 variant of TCF7L2 gene. Patients and Methods: We genotyped 162 individuals with T2DM patients with the variant rs7903146 gene TCF7L2: age ( 57.0 &#177; 7.6 ) years old, BMI ( 30.5 &#177; 5.1 ) kg/m2. From this sample, 56 patients were divided into two groups according to the genotype, 26 x 30 CC CT / TT, and then treated with exenatide for eight weeks. Meal tests were conducted before and after treatment to evaluate plasma concentrations of: Glucose ( mg / dl) Insulin ( U / dL ) Proinsulin (pmol / L), C-peptide (ng / ml) , Glucagon (pg / ml) and GLP-1 (pmol / L). The areas under the curves and the points of the curves were compared during the test. Statistical analysis by ANOVA with two factors and repeated measures, significance level greater than 5%. Results: The genotype distribution CC x CT x TT was 41.4% vs. 47.5% vs. 11.1 % respectively. The influence of the T allele in the pancreatic response during the test meal showed that plasma insulin concentrations, pro-insulin and c-peptide were higher in the CT / TT than in CC (p <0.05) but no difference in the glucagon secretion, GLP-1 and glucose in both groups (NS). Regarding to the influence of the T allele in response to treatment has been found that the group CT / TT presented greater reduction in insulin secretion (p <0.005) c-peptide (p <0.05) and proinsulin (p <0.001) than in CC group during the test meal after treatment. There was a decrease in blood glucose, glucagon and GLP-1 similarly in both groups. In addition, there was a similar decrease in weight and glycosylated hemoglobin in both groups. Discussion: The results of this study showed that the presence of the T allele in individuals with T2DM was associated with higher insulin secretion, proinsulin and c-peptide compared to non-carriers, with similar serum concentrations of glucagon and glucose in response to the test meal. This data demonstrates that the function of &#946; cells of carriers of the variant rs7903146 shows different features from non-carriers. After treatment with Exenatide, individuals with T2DM and genotype CT / TT, showed statistically lower values of insulin, proinsulin and c-peptide than the CC group. The effects of GLP-1 on postprandial glycemia mechanisms are attributed to suppression of glucagon, retardation of gastric emptying and also the insulinotropic effects and resulting increase in peripheral sensitivity to insulina. In addition, it was demonstrated that the Exenatide increases glucose uptake independent of insulin in skeletal muscle, the stimulation of glucose transporters way. Therefore, it is believed that the characteristics of the response observed after treatment in patients with the T allele corresponds to the effect of Exenatide in &#946; cell improving the processing of proinsulin, insulin and c-peptide and increasing peripheral glucose uptake. It is suggested that this process is best resulting from the interaction with the GLP-1 receptor in both liver, skeletal muscle and pancreas. Conclusions: These data suggest that individuals with T2DM patients with T allele in rs7903146 of TCF7L2 presents more benefits of treatment with Exenatide, because the secretion of insulin, proinsulin and c-peptide were consistent with higher quality in &#946; cell function in that group after treatment. Moreover, this study provided further evidence that the clinical problems associated with T2DM and TCF7L2 are related to peripheral glucose tolerance.

Introdução: O gene TCF7L2 (Transcription Factor 7-Like 2) codifica o fator de transcrição de mesmo nome que, tem importante papel na via Wnt de sinalização intra celular. A via Wnt é constituída por proteínas de integração e ligação dos processos de diferenciação e multiplicação celulares, interagindo com os fatores TCF, e ativando a expressão de genes relacionados ao TCF7L2, sendo este amplamente expresso em vários tecidos. Dados epidemiológicos atuais não deixam dúvidas quanto à forte associação de polimorfismos do gene TCF7L2 com o diabetes tipo 2 (DM2) em diferentes etnias. Apesar de serem pouco conhecidos os mecanismos que envolvem o gene TCF7L2 no DM2, tem sido bem demonstrada a associação do alelo T no rs7903146 com redução da secreção de insulina, redução do efeito das incretinas, principalmente do GLP-1, aumento na secreção de glucagon e a longo prazo, redução da meia vida da célula beta. Em vista destas evidências, aventamos a hipótese de que pacientes com DM2 portadores da variante rs7903146 do gene TCF7L2, ao ser tratados com GLP-1 mimético, poderiam responder de forma peculiar. Objetivos: Avaliar a resposta hormonal pancreática antes e após tratamento com GLP-1 mimético em indivíduos com DM2 portadores da variante rs7903146 do gene TCF7L2. Pacientes e Métodos: Foram genotipados162 indivíduos com DM2 portadores da variante rs7903146 do gene TCF7L2: idade (57,0 &#177; 7,6) anos, IMC (30,5 &#177; 5,1) kg/m2. Dessa amostra, 56 pacientes foram divididos em dois grupos conforme o genótipo, sendo 26 CC x 30 CT/TT, e a seguir tratados com Exenatide durante oito semanas. Os testes de refeição foram realizados antes e após o tratamento, para avaliação das concentrações plasmáticas de: Glicose (mg/dl), Insulina (&#956;U/dl), Pró-insulina (pmol/L), Peptideo-c (ng/ml); Glucagon (pg/ml) e GLP-1(pmol/L). Foram comparadas as áreas sob as curvas e os pontos das curvas durante o teste. Análise estatística por ANOVA com dois fatores e medidas repetidas, nível de significância maior que 5%. Resultados: A distribuição genotípica CC x CT x TT foi 41,4% x 47,5% x 11,1% respectivamente. A influência do alelo T na resposta pancreática durante o teste da refeição mostrou que as concentrações plasmáticas de insulina, pró-insulina e peptídeo-c foram maiores no grupo CT/TT do que no CC (p<0,05) mas, não houve diferença na secreção do glucagon, GLP-1 e na glicemia entre os grupos (NS).Com relação à influência do alelo T na resposta ao tratamento verificou-se que o grupo CT/TT apresentou maior redução da secreção de insulina (p<0,005), peptídeo-c (p<0,05) e pró-insulina (p<0,001) do que o grupo CC durante o teste da refeição após o tratamento. Observou-se diminuição da glicemia, do glucagon e do GLP-1 de forma semelhante em ambos os grupos. Além disso, houve diminuição semelhante do peso e da hemoglobina glicosilada em ambos os grupos. Discussão: Os resultados do presente estudo mostraram que a presença do alelo T em indivíduos com DM2 esteve associada à maior secreção de insulina, pró-insulina e peptídeo-c em relação aos não portadores, com semelhantes concentrações séricas de glucagon e glicose em resposta ao teste da refeição. Este dado demonstra que a função da célula &#946; dos portadores da variante rs7903146 apresenta características diferentes dos não portadores. Após o tratamento com Exenatide, os indivíduos com DM2 e genótipo CT/TT, apresentaram valores estatisticamente menores de insulina, pró-insulina e peptídeo-c do que o grupo CC. Os efeitos do GLP-1 na glicemia pós-prandial são atribuídos a mecanismos de supressão do glucagon, lentificação do esvaziamento gástrico e também a efeitos insulinotrópicos e decorrentes de aumento na sensibilidade periférica à insulina. Além disso, já foi demonstrado que o Exenatide aumenta a captação de glicose de forma insulino-independente em músculo esquelético, pelo estímulo dos transportadores de glicose. Portanto, acredita-se que as características da resposta observada após o tratamento nos portadores do alelo T correspondem ao efeito do Exenatide na célula &#946; melhorando o processamento da pró-insulina, peptídeo-c e insulina e ao aumento da captação periférica da glicose. Sugere-se que esse processo seja resultante da melhor interação com os receptores de GLP-1, tanto em fígado, músculo esquelético e pâncreas. Conclusões: Os dados sugerem que indivíduos com DM2 portadores do alelo T no rs7903146 do gene TCF7L2 apresentam mais benefícios do tratamento com Exenatide, pois a secreção de insulina, pró-insulina e peptídeo-c foram condizentes com maior qualidade na função de célula &#946; nesse grupo após o tratamento. Além disso, o presente estudo proporcionou adicionais evidências clínicas de que os problemas que associam o TCF7L2 ao DM2 estão relacionados à tolerância periférica a glicose. / Introduction:The TCF7L2 gene (Transcription Factor 7-Like 2) encodes the transcription factor of the same name that has an important role in the intracellular Wnt signaling. The Wnt pathway is composed of connecting and integrating proteins of cell proliferation and differentiation process by interacting with TCF factors, and activating the expression of genes related to TCF7L2, which is widely expressed in several tissues. Current epidemiological data leave no doubt as to the strong association of polymorphisms of the TCF7L2 gene with type 2 diabetes (T2DM) in different ethnic groups. Although they are poorly known mechanisms involving TCF7L2 gene in DM2 the association of the T allele of rs7903146 with reduced insulin secretion, reducing effect of incretins, mainly GLP-1, increase in glucagon secretion and long-term reduction in the half-life of the beta cell, have been well demonstrated. In view of this evidences, we hypothesized that patients with DM2 carriers of the variant rs7903146 of the TCF7L2 gene, being treated with GLP-1 mimetic, could respond in a peculiar way. Objectives: Evaluating the pancreatic hormone response before and after treatment with GLP-1 mimetic in individuals with T2DM carriers of rs7903146 variant of TCF7L2 gene. Patients and Methods: We genotyped 162 individuals with T2DM patients with the variant rs7903146 gene TCF7L2: age ( 57.0 &#177; 7.6 ) years old, BMI ( 30.5 &#177; 5.1 ) kg/m2. From this sample, 56 patients were divided into two groups according to the genotype, 26 x 30 CC CT / TT, and then treated with exenatide for eight weeks. Meal tests were conducted before and after treatment to evaluate plasma concentrations of: Glucose ( mg / dl) Insulin ( U / dL ) Proinsulin (pmol / L), C-peptide (ng / ml) , Glucagon (pg / ml) and GLP-1 (pmol / L). The areas under the curves and the points of the curves were compared during the test. Statistical analysis by ANOVA with two factors and repeated measures, significance level greater than 5%. Results: The genotype distribution CC x CT x TT was 41.4% vs. 47.5% vs. 11.1 % respectively. The influence of the T allele in the pancreatic response during the test meal showed that plasma insulin concentrations, pro-insulin and c-peptide were higher in the CT / TT than in CC (p <0.05) but no difference in the glucagon secretion, GLP-1 and glucose in both groups (NS). Regarding to the influence of the T allele in response to treatment has been found that the group CT / TT presented greater reduction in insulin secretion (p <0.005) c-peptide (p <0.05) and proinsulin (p <0.001) than in CC group during the test meal after treatment. There was a decrease in blood glucose, glucagon and GLP-1 similarly in both groups. In addition, there was a similar decrease in weight and glycosylated hemoglobin in both groups. Discussion: The results of this study showed that the presence of the T allele in individuals with T2DM was associated with higher insulin secretion, proinsulin and c-peptide compared to non-carriers, with similar serum concentrations of glucagon and glucose in response to the test meal. This data demonstrates that the function of &#946; cells of carriers of the variant rs7903146 shows different features from non-carriers. After treatment with Exenatide, individuals with T2DM and genotype CT / TT, showed statistically lower values of insulin, proinsulin and c-peptide than the CC group. The effects of GLP-1 on postprandial glycemia mechanisms are attributed to suppression of glucagon, retardation of gastric emptying and also the insulinotropic effects and resulting increase in peripheral sensitivity to insulina. In addition, it was demonstrated that the Exenatide increases glucose uptake independent of insulin in skeletal muscle, the stimulation of glucose transporters way. Therefore, it is believed that the characteristics of the response observed after treatment in patients with the T allele corresponds to the effect of Exenatide in &#946; cell improving the processing of proinsulin, insulin and c-peptide and increasing peripheral glucose uptake. It is suggested that this process is best resulting from the interaction with the GLP-1 receptor in both liver, skeletal muscle and pancreas. Conclusions: These data suggest that individuals with T2DM patients with T allele in rs7903146 of TCF7L2 presents more benefits of treatment with Exenatide, because the secretion of insulin, proinsulin and c-peptide were consistent with higher quality in &#946; cell function in that group after treatment. Moreover, this study provided further evidence that the clinical problems associated with T2DM and TCF7L2 are related to peripheral glucose tolerance.