Analysis of pancreatic hormonal response before and after treatment with GLP-1-mimetic in subjects with type 2 diabetes carrying the rs7903146 variant in TCF7L2

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

Percutaneous ethanol injection versus conservative treatment for benign cystic and mixed thyroid nodules

ABSTRACT Objective: To evaluate the efficacy and safety of percutaneous ethanol injection (PEI) in reducing the volume of cystic and mixed thyroid nodules. Materials and methods: A total of 36 patients with nodules treated with PEI and 13 individuals who declined PEI and were followed clinically or received other non surgical treatment (control group). Assessments were performed at baseline (immediately before treatment in the PEI group or evaluation of the nodule on ultrasonography in the control group) at short-term (on average 30 days after the last injection in the PEI group), and long-term (on average 14 months after baseline in the PEI group or 26 months after baseline in the control group). Results: In the PEI group, the mean baseline volume of 10.4 ± 9.8 cm³ reduced at short-term followup to 2.9 ± 3.1 cm³ (67.7 ± 19.9%, p &lt; 0.001) and at long-term follow-up to 2.0 ± 2.5 cm³ (78.2 ± 19.5%, p &lt; 0.01 versus baseline and p = 0.009 versus short-term follow-up). Both types of nodules showed similar degrees of reduction. In the control group, mean volume was 5.8 ± 3.4 cm³ at baseline and 6.2 ± 3.0 cm³ at long-term follow-up (p = 0.507). Compared with the control group, the PEI group showed larger reduction (p &lt; 0.001). Conclusions: PEI is effective in reducing the volume of cystic and mixed benign thyroid nodules, with sustained long-term efficacy and better outcome when compared with conservative therapies. Treatment with PEI is a safe alternative, with minimal, transient and selflimited adverse events. Arch Endocrinol Metab. 2016;60(3):211-

Percutaneous ethanol injection versus conservative treatment for benign cystic and mixed thyroid nodules

ABSTRACT Objective: To evaluate the efficacy and safety of percutaneous ethanol injection (PEI) in reducing the volume of cystic and mixed thyroid nodules. Materials and methods: A total of 36 patients with nodules treated with PEI and 13 individuals who declined PEI and were followed clinically or received other non surgical treatment (control group). Assessments were performed at baseline (immediately before treatment in the PEI group or evaluation of the nodule on ultrasonography in the control group) at short-term (on average 30 days after the last injection in the PEI group), and long-term (on average 14 months after baseline in the PEI group or 26 months after baseline in the control group). Results: In the PEI group, the mean baseline volume of 10.4 ± 9.8 cm³ reduced at short-term followup to 2.9 ± 3.1 cm³ (67.7 ± 19.9%, p &lt; 0.001) and at long-term follow-up to 2.0 ± 2.5 cm³ (78.2 ± 19.5%, p &lt; 0.01 versus baseline and p = 0.009 versus short-term follow-up). Both types of nodules showed similar degrees of reduction. In the control group, mean volume was 5.8 ± 3.4 cm³ at baseline and 6.2 ± 3.0 cm³ at long-term follow-up (p = 0.507). Compared with the control group, the PEI group showed larger reduction (p &lt; 0.001). Conclusions: PEI is effective in reducing the volume of cystic and mixed benign thyroid nodules, with sustained long-term efficacy and better outcome when compared with conservative therapies. Treatment with PEI is a safe alternative, with minimal, transient and selflimited adverse events

Percutaneous ethanol injection versus conservative treatment for benign cystic and mixed thyroid nodules

ABSTRACT Objective To evaluate the efficacy and safety of percutaneous ethanol injection (PEI) in reducing the volume of cystic and mixed thyroid nodules. Materials and methods A total of 36 patients with nodules treated with PEI and 13 individuals who declined PEI and were followed clinically or received other non surgical treatment (control group). Assessments were performed at baseline (immediately before treatment in the PEI group or evaluation of the nodule on ultrasonography in the control group) at short-term (on average 30 days after the last injection in the PEI group), and long-term (on average 14 months after baseline in the PEI group or 26 months after baseline in the control group). Results In the PEI group, the mean baseline volume of 10.4 ± 9.8 cm3 reduced at short-term follow-up to 2.9 ± 3.1 cm3 (67.7 ± 19.9%, p < 0.001) and at long-term follow-up to 2.0 ± 2.5 cm3 (78.2 ± 19.5%, p < 0.01 versus baseline and p = 0.009 versus short-term follow-up). Both types of nodules showed similar degrees of reduction. In the control group, mean volume was 5.8 ± 3.4 cm3 at baseline and 6.2 ± 3.0 cm3 at long-term follow-up (p = 0.507). Compared with the control group, the PEI group showed larger reduction (p < 0.001). Conclusions PEI is effective in reducing the volume of cystic and mixed benign thyroid nodules, with sustained long-term efficacy and better outcome when compared with conservative therapies. Treatment with PEI is a safe alternative, with minimal, transient and self-limited adverse events

Análise comparativa do risco de quedas entre pacientes com e sem diabetes mellitus tipo 2

OBJETIVO: Comparar a frequência e o risco de quedas baseado em teste de mobilidade funcional entre diabéticos e não diabéticos. MÉTODOS: Estudo transversal envolvendo pacientes com e sem diabetes mellitus tipo 2 (DM2) selecionados por amostra de conveniência. Foram incluídos homens e mulheres entre 50 e 65 anos, sendo divididos em: grupo 1 (G1) - com diagnóstico de DM2 < 10 anos, glicemia de jejum &gt; 200 mg/dL no momento da inclusão e prévia; e grupo 2 (G2) - sem diabetes, de mesma faixa etária, e glicemia de jejum < 100 mg/dL. Ambos responderam a questionário estruturado sobre sua saúde, risco de quedas e se submeteram a exame físico e ao Timed Up &amp; Go (TUG), teste de avaliação de mobilidade. Os resultados foram analisados pelo programa Statistical Package for the Social Sciences (SPSS), sendo que o TUG foi categorizado em faixas de risco para quedas. Consideramos risco positivo para todos os que se enquadraram em médio e alto risco. RESULTADOS: Foram avaliados 50 pacientes com DM2 e 68 sem a doença. Não houve diferença estatística entre o número de quedas para os grupos, entretanto os não diabéticos obtiveram melhor desempenho no teste TUG (p = 0,003) quando observadas as categorias de risco descritas. A redução da acuidade visual e a dificuldade para levantar foram mais referidas no G1 (p < 0,05). CONCLUSÃO: Parece haver uma associação entre estado hiperglicêmico e piora da mobilidade, com risco aumentado de quedas, mesmo em pacientes mais jovens e com menor tempo de doença

TCF7L2 correlation in both insulin secretion and postprandial insulin sensitivity

Abstract Background The TCF7L2 rs7903146 variant is strongly associated with type 2 diabetes mellitus (T2DM). However, the mechanisms involved in this association remain unknown and may include extrapancreatic effects. The aim of this study was to perform a metabolic characterization of T2DM patients with and without the TCF7L2 rs7903146 risk T allele and analyze some influences of the TCF7L2 genotype on glucose metabolism. Methods Patients with T2DM (n = 162) were genotyped for the TCF7L2 rs7903146 single nucleotide polymorphism. Individuals with CT/TT and CC genotypes were compared regarding basal serum levels of glucose, glycosylated hemoglobin A1C, HDL, uric acid, insulin, and C-peptide. A subset of 56 individuals was evaluated during a 500-calorie mixed-meal test with measurements of glucose, insulin, proinsulin, C-peptide and glucagon. Additional secondary assessments included determination of insulinogenic index (IGI30), and insulin sensitivity (%S) and resistance (IR) by Homeostatic model assessment (HOMA). Results Patients with the CT/TT genotype showed lower baseline plasma concentrations of C-peptide when compared with those with the CC genotype. Of the 56 individuals who participated in the mixed-meal test, 26 and 30 had the CC and CT/TT genotypes, respectively. CT/TT subjects, compared with CC individuals, had higher post prandial plasma levels of insulin and C-peptide at 30–120 min (p < 0.05) and proinsulin at 45–240 min (p < 0.05). Interestingly CT/TT individuals presented at baseline higher %S (p = 0.021), and lower IR (p = 0.020) than CC individuals. No significant differences in IGI30 values were observed between groups. Conclusions The T2DM individuals carrying the rs7903146 T allele of the TCF7L2 gene presented higher IR pattern in response to a mix-meal test, different of beta cell function at baseline assessed by C-peptide levels which was lower, and Homa-IR was lower when comparing with non-carriers

Reduction of functional mobility and cognitive capacity in type 2 diabetes mellitus

Submitted by Santos Bárbara ([email protected]) on 2015-03-12T16:51:13Z No. of bitstreams: 1 Redução da mobilidade funcional .pdf: 115690 bytes, checksum: bd838fa60f91e88ce2cc55eb0a9a4fd8 (MD5)Approved for entry into archive by Santos Bárbara ([email protected]) on 2015-03-12T16:51:46Z (GMT) No. of bitstreams: 1 Redução da mobilidade funcional .pdf: 115690 bytes, checksum: bd838fa60f91e88ce2cc55eb0a9a4fd8 (MD5)Approved for entry into archive by Santos Bárbara ([email protected]) on 2015-03-17T12:22:30Z (GMT) No. of bitstreams: 1 Redução da mobilidade funcional .pdf: 115690 bytes, checksum: bd838fa60f91e88ce2cc55eb0a9a4fd8 (MD5)Made available in DSpace on 2015-03-17T12:22:30Z (GMT). No. of bitstreams: 1 Redução da mobilidade funcional .pdf: 115690 bytes, checksum: bd838fa60f91e88ce2cc55eb0a9a4fd8 (MD5) Previous issue date: 2014Universidade de São Paulo. Faculdade de Medicina. Programa de Endocrinologia e Metabologia. São Paulo, SP, Brasil. / Universidade Comunitária Regional de Chapecó. Faculdade de Medicina. Chapecó, SC, Brasil.Universidade Comunitária Regional de Chapecó. Faculdade de Medicina. Chapecó, SC, Brasil.Universidade Comunitária Regional de Chapecó. Faculdade de Medicina. Chapecó, SC, Brasil.Fundação Oswaldo Cruz. Instituto Fernandes Figueira. Rio de Janeiro, RJ, Brasil. / Universidade Comunitária Regional de Chapecó. Faculdade de Medicina. Chapecó, SC, Brasil.Universidade de São Paulo. Hospital das Clínicas. Faculdade de Medicina. Laboratório de Carboidratos. Disciplina de Endocrinologia e Metabologia. São Paulo, SP, Brasil.Universidade de São Paulo. Hospital das Clínicas. Faculdade de Medicina. Laboratório de Carboidratos. Disciplina de Endocrinologia e Metabologia. São Paulo, SP, Brasil.Objetivos: Avaliar a mobilidade funcional e sua relação com a capacidade cognitiva em pacientes com diabetes tipo 2 (DM2) entre 50 e 65 anos de idade, e com menos de 10 anos de diagnóstico. Materiais e métodos: Estudo observacional, analítico e transversal envolvendo indivíduos não diabéticos e pacientes com DM2 com controle glicêmico inadequado, selecionados por amostra de conveniência. Em ambos os grupos, foram aplicados questionário estruturado, avaliação cognitiva com Miniexame do Estado Mental (MEEM) e teste do relógio (TDR), além da avaliação de mobilidade funcional pelo teste Timed Up & GO (TUG). Resultados: No TUG os pacientes com DM2 apresentaram tempo médio de 11,27 segundos versus 9,52 segundos nos controles (p = 0,013). A associação entre declínio cognitivo e dismobilidade foi positiva nos indivíduos com DM2 (p = 0,037). No subgrupo que apresentou dismobilidade e declínio cognitivo associados, 18% eram portadores de DM2 e 1,6% era do grupo sem DM2 (p < 0,01). Conclusões: Pacientes com DM2 apresentaram pior mobilidade funcional e desempenho cognitivo, favorecendo a hipótese de que o DM2 influencia a mobilidade funcional e capacidade cognitiva antes do aparecimento de complicações vasculares ou neuropáticas. Esses dados sugerem que a hiperglicemia é um fator agravante no desempenho de atividades que exijam funções mentais como atenção, orientação e memória de trabalho.Objectives: The aim of the present study was to evaluate the functional mobility and its relationship to cognitive ability in patients with type 2 diabetes (T2DM), age between 50 and 65 years and under 10 years of diagnosis. Materials and methods: An observational, analytical and cross-sectional study, involving no diabetic and type 2 diabetic individuals with inadequate glycemic control, selected by convenience sampling. In both groups, were administered structured questionnaire and cognitive assessment with Mini-Mental State Examination (MMSE) and the clock drawing test (CDT), besides assessment of functional mobility by the Timed Up & Go (TUG). Results: In TUG, DM2 patients presented a mean time of 11.27 seconds versus 9.52 seconds (p = 0.013). The association between cognitive decline and decrease of mobility was positive in individuals with T2DM (p = 0.037). In the subgroup that showed decrease of mobility and associated cognitive decline, 18% were patients with DM2 and 1.6% were individuals without T2DM (p < 0.01). Conclusions: Patients with T2DM presented worse functional mobility and cognitive performance, supporting the hypothesis that DM2 influence functional mobility and cognitive ability, regardless of neuropathic or vascular complications. These data suggest that hyperglycemia is an aggravating factor in the performance of activities requiring mental functions such as attention, working memory and orientation