Insulina e polimorfismos do gene do receptor de insulina e a suscetibilidade à doença hepática gordurosa não alcoólica / Insulin and insulin receptor gene polymorphisms and susceptibility to nonalcoholic fatty liver disease

ABSTRACT BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is an increasing global health concern defined by excessive hepatic fat content in the absence of excessive alcohol consumption. OBJECTIVE: Given the pivotal role of insulin resistance in NAFLD, we hypothesized that insulin (INS) and insulin receptor (INSR) gene polymorphisms may be associated with NAFLD risk. METHODS: A total of 312 subjects, including 153 cases with biopsy-proven NAFLD and 159 controls were enrolled in this case-control study. Four polymorphisms in INS (rs3842752, rs689) and INSR (rs1052371, rs1799817) genes were genotyped using PCR-RFLP method. RESULTS: The cases with NAFLD were older and had higher BMI, systolic blood pressure, diastolic blood pressure, as well as higher serum levels of aspartate aminotransferase, alanine aminotransferase, and gamma glutamyl transferase than the controls (P<0.001). The "TT" genotype of INSR rs1799817 compared with "CC" genotype occurred more frequently in the controls than the cases with NAFLD and the difference remained significant after adjustment for confounding factors (P=0.018; OR=0.10, 95%CI=0.02-0.76). However, no significant difference was found for INS rs3842752, INS rs689, and INSR rs1052371 gene polymorphisms between the cases with NAFLD and the controls either before or after adjustment for the confounders. CONCLUSION: These findings corroborate the hypothesis that genetic polymorphisms related to insulin resistance play a role in NAFLD susceptibility. Specifically, the INSR rs1799817 "TT" genotype had a protective effect for NAFLD. However, our results remain to be validated in other studies.

RESUMO CONTEXTO: A doença hepática gordurosa não alcoólica (NAFLD) é uma preocupação global crescente da saúde definida pelo excesso de teor de gordura hepática na ausência de consumo excessivo de álcool. OBJETIVO: Dado o papel crucial da resistência à insulina no NAFLD, criou-se a hipótese de que os polimorfismos genéticos da insulina (INS) e do receptor de insulina (INSR) podem estar associados ao risco de NAFLD. MÉTODOS: Um total de 312 indivíduos, incluindo 153 casos com NAFLD comprovado por biópsia e 159 controles foram inscritos neste estudo de caso-controle. Quatro polimorfismos em genes INS (rs3842752, rs689) e INSR (rs1052371, rs1799817) foram genotipados utilizando o método PCR-RFLP. RESULTADOS: Os casos com NAFLD foram mais idosos e apresentaram maior IMC, pressão arterial sistólica, pressão arterial diastólica, bem como níveis séricos mais elevados de aspartato aminotransferase, de alanina aminotransferase e de gama glutamil transpeptidase do que os controles (P<0,001). O genótipo "TT" de INSR rs1799817 em comparação com o genótipo "CC" ocorreu com mais frequência nos controles do que os casos com NAFLD e a diferença permaneceu significativa após ajuste para fatores de confusão (P=0,018; OR=0,10, IC95%=0,02-0,76). No entanto, não foi encontrada diferença significativa para INS rs3842752, INS rs689 e INSR rs1052371 polimorfismos genéticos entre os casos com NAFLD e os controles antes ou depois do ajuste para os fatores de confusão. CONCLUSÃO: Esses achados corroboram a hipótese de que os polimorfismos genéticos relacionados à resistência à insulina desempenham um papel na suscetibilidade do NAFLD. Especificamente, o genótipo INSR rs1799817 "TT" teve um efeito protetor para o NAFLD. No entanto, nossos resultados necessitam ser validados em outros estudos.

Expression of tumor-associated vascular insulin receptor in colorectal cancer and its relationship with tumor pathological features / 浙江大学学报·医学版

OBJECTIVE@#To study the expression of tumor associated vascular insulin receptor (TVIR) in colorectal cancer with or without metabolic syndrome (MS) and its relationship with the pathological features of colorectal cancer.@*METHODS@#The expression of TVIR in 220 colorectal cancer specimens was detected by tissue microarray and immunohistochemistry. The relationships between the expression of TVIR and the pathological features (pathological subtypes, histological grade, invasion depth, lymph node metastasis and TNM stage) of colorectal cancer with/without MS were analyzed.@*RESULTS@#The insulin receptor expression was observed in colorectal cancer tissue or border area between cancer and normal tissue, but not in normal intestinal tissue. The high-expression rates of TVIR in MS group was remarkably lower than that of non-MS group (21.6%vs. 41.0%, @*CONCLUSIONS@#s: High-expression of TVIR is associated with aggressive pathological features such as invasion, lymph node metastasis and high TNM stage of colorectal cancer, especially for those patients without MS. TVIR could be a useful biological marker for prognosis of colorectal cancer.

A digital volumetric tomography (DVT) study in the mandibular molar region for miniscrew placement during mixed dentition

OBJECTIVE: To assess bone thickness for miniscrew placement in the mandible during mixed dentition by using digital volumetric tomograph (DVT). MATERIAL AND METHODS: A total of 15 healthy patients aged 8-10 years old, with early exfoliated mandibular second deciduous molar, were included. DVT images of one quadrant of the mandible were obtained using Kodak extraoral imaging systems and analyzed by Kodak dental imaging software. The error of the method (EM) was calculated using Dahlberg's formula. Mean and standard deviation were calculated at 6 and 8 mm from the cementoenamel junction (CEJ).Paired t-test was used to analyze the measurements. RESULTS: Buccal cortical bone thickness, mesiodistal width and buccolingual bone depth at 6 mm were found to be 1.73 + 0.41, 2.15 + 0.49 and 13.18 + 1.22 mm, respectively; while at 8 mm measurements were 2.42 + 0.34, 2.48 + 0.33 and 13.65 + 1.25 mm, respectively. EM for buccal cortical bone thickness, mesiodistal width and buccolingual bone depth was 0.58, 0.40 and 0.48, respectively. The difference in measurement at 6 and 8 mm for buccal cortical plate thickness (P < 0.05) and buccolingual bone thickness (P < 0.05) was found to be significant, whereas for mesiodistal width it was insignificant (P > 0.05). CONCLUSION: Bone thickness measurement has shown promising evidence for safe placement of miniscrews in the mandible during mixed dentition. The use of miniscrew is the best alternative, even in younger patients. .

OBJETIVO: avaliar, por meio de tomografia volumétrica digital (TVD), a espessura óssea necessária para a instalação de mini-implante na arcada inferior durante a fase de dentição mista. MÉTODOS: um total de 15 pacientes saudáveis, com idades entre 8 e 10 anos, com segundo molar inferior decíduo irrompido recentemente, foram incluídos no presente estudo. Imagens de TVD da hemiarcada inferior foram obtidas utilizando sistemas de imagens extrabucais Kodak. As imagens foram analisadas por meio do programa de imagens Kodak. O erro do método (EM) foi calculado utilizando a fórmula de Dahlberg. Médias e desvios-padrão foram calculados de 6 a 8mm aquém da junção amelocementária. O teste t foi utilizado para a análise das medidas. RESULTADOS: a espessura do osso cortical vestibular, largura mesiodistal e profundidade óssea vestibulolingual, a 6mm, foram de 1,73 + 0,41; 2,15 + 0,49; e 13,18 + 1,22 mm, respectivamente. Já a 8mm, os valores foram de 2,42 + 0,34; 2,48 + 0,33; e 13,65 + 1,25mm. O EM para a espessura do osso cortical vestibular, largura mesiodistal e profundidade óssea vestibulolingual foi de 0,58, 0,40 e 0,48mm, respectivamente. A diferença entre as medidas a 6 e 8mm para a espessura do osso cortical vestibular (p < 0,05) e a espessura óssea vestibulolingual (p < 0,05) foi significativa, embora não tenha sido significativa para a largura mesiodistal (p < 0,05). CONCLUSÃO: a mensuração da espessura óssea demonstra evidências promissoras para a segura instalação de mini-implantes na arcada inferior e na fase de dentição mista. O uso de mini-implantes tem se mostrado a melhor alternativa, mesmo nos casos de pacientes mais jovens. .

Relationship between polymorphism of insulin receptor gene, and adiponectin gene with PCOS

Polycystic ovary syndrome [PCOS] is a complex disease having both genetic and environmental components and candidate genes on obesity and insulin metabolism have been hypothesized to be involved in its etiology. We examined the possible association of adiponectin and insulin receptor gene polymorphisms with PCOS. A total of 186 women with PCOS using NIH criteria and 156 healthy women were recruited. Their samples were genotyped for the polymorphism in exon 17 and 8 of the insulin receptor gene or exon and intron 2 of the adiponectin gene. The distributions of genotypes and alleles of both polymorphisms were not different in women with PCOS and controls. There was no significant differences on the anthropometric and hormonal profiles of various adiponectin and insulin receptor genes polymorphisms among both groups. Adiponectin and insulin receptor gene polymorphisms are not associated with PCOS in a sample of Iranian population

Two Novel Insulin Receptor Gene Mutations in a Patient with Rabson-Mendenhall Syndrome: The First Korean Case Confirmed by Biochemical, and Molecular Evidence

Rabson-Mendenhall syndrome (RMS) is a rare syndrome manifested by extreme insulin resistance with hyperinsulinemia, acanthosis nigricans, tooth dysplasia and growth retardation. Our patient was first noted at the age of 8 months due to pigmentations on skin-folded areas. Initial laboratory tests showed normal fasting glucose (69 mg/dL). Fasting insulin level was severely elevated, up to 554.6 microIU/mL, and c-peptide level was increased, up to 13.81 ng/mL. However, hemoglobin A1c was within normal range (4.8%). He is now 11 yr old. His growth development followed the 5-10th percentile and oral hypoglycemic agents are being administered. The last laboratory results showed insulin 364.1 microIU/mL, C-peptide 4.30 ng/mL, and hemoglobin A1c 7.6%. The boy was a compound heterozygote for the c.90C > A and c.712G > A mutations of the insulin receptor gene, INSR, which are nonsense and missense mutations. In summary, we report the first Korean case of RMS, which was confirmed by two novel mutations of the INSR.

Insulin receptor gene mutations in Iranian patients with type II diabetes mellitus

Patients with diabetes mellitus type II suffer from hyperglycemia because they are not able to use the insulin that they produce, often due to inadequate function of insulin receptors. There are some evidences that this deficiency is inherited in a dominant autosomal manner and leads to the malfunction of the pancreatic beta cells resulting in insulin excretion disorders. In this study, we sought to identify mutations in the insulin receptor [INSR] gene, which can cause insulin resistance in type II diabetic patients. DNA was extracted from peripheral blood cells of the patients [n = 128] diagnosed with type II diabetes. All 22 exons of the INSR gene of the patients were analyzed for mutations running PCR, conformation-sensitive gel electrophoresis and DNA sequencing, consecutively. Approximately 26% of the patients had genetic mutations; however, most of them were not reported. These mutations include exon 2 [His171Asn, Ile172Ser, Cys196Ser and Ser210Arg], exon 3 [Gly227Asp and Gly232Ser], exon 8 [Thr543Ser], exon 9 [a heterozygote was observed with no change in phenylalanine at position 669], exon 13 [two heterozygotes: Arg890Pro with Asn865 remaining unchanged], exon 14 [Ala906Gly and Pro918Trp with Arg902 unchanged], exon 17 [Val1086Glu] and exon 19 [His1157Gln with Thr1172 unchanged]. The lack of similar mutation records in literature and genetic data banks may suggest a geographic pattern for these INSR gene variants in our population

Polimorfismo do gene do receptor de insulina em pacientes com síndrome dos ovários policísticos / Polymorphism in the insulin receptor gene in patients with polycystic ovary syndrome

Introdução: A síndrome dos ovários policísticos (SOP) é uma doença heterogênea caracterizada por anovulação crônica e hiperandrogenismo, freqüentemente associada à resistência insulínica. Vários genes parecem estar envolvidos na predisposição genética da SOP, entre eles, o gene do receptor de insulina (lNSR). Objetivo: Avaliar a freqüência do polimorfismo do gene do receptor de insulina (lNSR), localizado no éxon 17 do cromossomo 19, em pacientes com SOP, e a associação com a sensibilidade à insulina e hiperandrogenismo. Pacientes e Métodos: Foram estudadas 57 pacientes com SOP e 50 mulheres normais com ciclos menstruais regulares sem hiperandrogenismo (grupo controle). Avaliou-se a frequência de genótipos de polimorfismos de nucleotide único (Single Nucleotide Polymorphisms - SNPs), do gene do lNSR nas pacientes com SOP e controles, através da análise de comprimento o fragmento de restrição (Restriction Lengh Fragment Polymorphisms - RFLPs). Para avaliar a sensibilidade à insulina, utilizou-se os seguintes métodos matemáticos: relação da glicemia/insulina de jejum (G/I), Homeostasis Model Assessment (HOMA) e Quantitative Sensitivity Check Index (QUlCKI). Foram considerados normais, G/I maior ou igual 4,5, HOMA menor que 3,8, e QUlCKl maior ou igual 0,34. Resultados: A frequência do genótipo mutado (C/T e T/T), nas pacientes com SOP, não apresentou diferença significativa comparada ao grupo controle. Quanto aos valores de insulinemia, não observamos diferenças entre as pacientes com genótipo mutado (C/T e T/T) e genótipo não-mutado (C/C), tanto no grupo SOP e controle. Conclusão: As frequências do polimorfismo do gene do INSR, localizado no éxon 17 do gene do receptor de insulina, são semelhantes tanto em pacientes com SOP, como em mulheres normais com ciclos menstruais regulares, sem hiperandrogenismo. Estas mutações (C/T e T/T) não influenciam a sensibilidade à insulina, neste grupo de pacientes com SOP...

Polimorfismo do gene do receptor de insulina (INSR) em pacientes com síndrome dos ovários policísticos / Polymorphims of the insulin receptor gene (INSR) in patients with polycystic ovary syndrome

OBJETIVO: Avaliar a freqüência do polimorfismo do gene (INSR), localizado no éxon 17 do cromossomo 19, quanto ao seu envolvimento na predisposição genética da SOP e a associação com a sensibilidade à insulina e hiperandrogenismo. MATERIAL E MÉTODOS: Foram estudadas 57 pacientes com SOP e 50 mulheres normais com ciclos menstruais regulares (controle) quanto à frequência de polimorfismos de nucleotídeo único (Single Nucleotide Polymorphisms–SNPs) do gene INSR, através da análise de comprimento do fragmento de restrição (Restriction Lengh Fragment Polymorphisms-RFLPs). Para avaliar a sensibilidade à insulina, utilizou-se os seguintes métodos matemáticos: relação glicemia/insulina de jejum (G/I), Homeostasis Model Assessment (HOMA) e Quantitative Sensitivity Check Index (QUICKI). Foram considerados normais, G/I maior ou igual a 4,5, HOMA menor que 3,8, e QUICKI maior ou igual a 0,34. RESULTADOS: O polimorfismo (C/T, T/T) na SOP não apresentou diferenças significativas com o grupo controle. Quanto a insulinemia, não observamos diferenças entre as pacientes com genótipos (C/T, T/T) e (C/C). CONCLUSÕES: As frequências do polimorfismo do gene INSR, são semelhantes tanto em pacientes com SOP, como em mulheres normais. Esses genótipos (C/T e T/T) não influenciam a sensibilidade à insulina e o hiperandrogeninsmo na SOP

Mutación G972R del gen IRS-1 en individuos chilenos con enfermedad coronaria y controles / G972R mutation of the IRS-1 gene in chilean individuals with coronary artery disease and controls

El sustrato 1 del receptor de la insulina (IRS-1) es una de las moléculas más importantes en la transducción de señales, que permiten la incorporación de glucosa a la célula. Variaciones genéticas del IRS-1 han sido relacionadas con alteraciones de su función y diversas anormalidades metabólicas. Considerando la escasa información sobre las bases genéticas de las enfermedades cardiovasculares en nuestro país, el objetivo del presente estudio fue determinar la asociación entre la mutación G972R del gen IRS-1 y enfermedad coronaria en individuos de la población de la IX Región (Chile). Estudios de casos y controles, que evaluó 111 individuos (33 a 74 años), con enfermedad coronaria comprobada por angiografía y 116 controles (20 a 68 años). La genotipificación de la mutación G972R fue realizada mediante la técnica de PCR-RFLP. La mutación G972R fue más frecuente en individuos con enfermedad coronaria que en controles (17 por ciento vs. 6 por ciento, p=0,016). La OR asociada a esta mutación fue 3,21 (I.C. 95 por ciento, 1,28 - 8,06, p<0.05). Adicionalmente, el genotipo heterocigoto GR para la mutación G972R fue asociado a niveles más bajos de HDL-C (p=0,048) y a mayores niveles de glucosa (p=0,006) en los individuos controles. La mutación G972R del gen IRS-1 fue asociada a enfermedad coronaria en la población analizada, lo que sugiere un importante rol de IRS-1 en la patogénesis de desordenes metabólicos asociados a EC.