Genética de la diabetes mellitus tipo 1 / Genetic of type 1 diabetes mellitus

Type 1 diabetes (T1D) results from autoimmune-mediated destruction of the pancreatic beta cells, a process that is conditioned by multiple genes and environmental factors. The process that destroys the pancreatic b cells in T1D is mediated by T cells and leads to a complex phenotype influenced by multiple factors. It has been more than 30 years since the publication of the first evidence suggesting the involvement of a specific chromosomal region, HLA, in modulating the risk for T1D. HLA locus has been known for decades to contribute strongly with the attributable to genetic risk. In addition to HLA, many proposed candidate loci have been described that are associated with risk of developing the disease, including the insulin gene (INS), PTPN22,CTLA-4, PD-1, IL2-RA and IFIH1 which together do not contribute more than 15 percent of the risk. This review compiled the data on T1D genes and discusses the major genetic impact of these genetic aspects in T1D etiology.

Validación factorial de un cuestionario para medir la conducta de comer en ausencia de hambre y su asociación con obesidad infantil / A questionnaire to measure eating behavior in the absence of hunger and its association with childhood obesity

Background: It has been observed that some psychological factors tend to stimulate food intake in the absence of hunger in obese children. objective: To evaluate whether obese children have a greater tendency to eat in the absence of hunger, in response to various emotional and environmental factors versus normal weight children. subjects and Methods: Obese patients were selected according to NCHS/CDC2000 (n = 49 and n = 99 for non-obese children), males and females in the age group of 6-12 years who consulted in the UC health network and also children that were evaluated in schools located in southeastern Santiago. The questionnaire "Eating in the absence of hunger" was used, which measures three subscales: external stimuli, fatigue/boredom and negative feelings. results: Factor analysis showed a significant degree of overlap between the "fatigue/boredom" and "negative feelings" subscales. Obese children had higher scores on "external stimuli" versus normal weight children (median 2.7 compared to 1.7, p < 0.001). In the "fatigue/boredom" subscale, scores of 2.5 versus 1.2 (p < 0.001) were obtained, while in "negative feelings", scores reported 2.0 versus 1.2 (p = 0.0013). Conclusions: Obese patients reported higher scores on the questionnaire "Eating in the absence of hunger" than non-obese children, identifying modifiable and educable stimuli that could prevent this eating behavior.

Introducción: Se ha observado que en los niños obesos, algunos factores psicológicos tienden a estimular la ingesta de alimentos en ausencia de hambre. objetivo: Evaluar si los niños obesos presentan mayor tendencia a comer en ausencia de hambre, en respuesta a distintos factores emocionales y ambientales, en comparación con niños normopeso. Pacientes y Método: Se seleccionaron pacientes obesos según NCHS/CDC2000 (n = 49) y normopeso (n = 99) de ambos sexos y con edades entre 6-12 años, que consultaron en forma espontánea en la Red de Salud UC y niños evaluados en colegios del sector suroriente de Santiago. Se aplicó el cuestionario "Comer en ausencia de hambre" que mide tres subescalas: Estímulos externos, cansancio/aburrimiento y sentimientos negativos. resultados: El análisis factorial reveló un importante grado de solapamiento entre las ponderaciones de las subescalas "cansancio/aburrimiento" y "sentimientos negativos". Los niños con obesidad presentaron mayores puntajes en la dimensión "estímulos externos" que los niños normopeso (mediana de 2,7 versus 1,7; p < 0,001). En "cansancio/aburrimiento" se obtuvieron puntajes de 2,5 versus 1,2 (p < 0,001) mientras que en "sentimientos negativos" los puntajes fueron 2,0 versus 1,2 (p = 0,0013). Conclusiones: Los pacientes obesos presentaron mayores puntajes en la encuesta alimentaria "Comer en ausencia de hambre" que los niños normopeso, pudiendo identificarse estímulos modificables y educables que podrían prevenir esta conducta alimentaria.

Hipertrigliceridemias de origen genético / Hypertriglyceridemias of genetic origen

Hypertriglyceridemia (HTG) is defined as plasma triglycerides (TG) > 150 mg/dL, and it is a frequent disease in the general population. When plasma TG reach concentrations > 500 mg/dL (severe HTG), there is usually a genetic defect involved. This defect can involve a single gene or be of polygenic inheritance. In polygenic HTG, the phenotypic expression of the disease is usually associated to the presence of certain diseases such as diabetes, obesity or insulin resistance. The most common known genes associated with monogenic hypertriglyceridemia are LPL and APOC2, but in recent years a few cases caused by mutant APOA5, GPIHBP1 and LMF1, have been identified. Furthermore, genome wide association studies (GWA) have brought up new genes that are related to discrete changes in triglyceride plasma levels of the general population. Among them, it is worth mentioning GCKR, TRIB1, MLXIPL, GALNT2, APOB, APOC2, APOA5, APOE, LPL, ANGPTL3 and NCAN. It is remarkable that most severe hypertriglyceridemias are of polygenic origin, and they could involve a major susceptibility gene. Only in a few cases of severe or very severe HTG (TG > 2.000 mg/dL) the genetic cause is known.

[Leptin-melanocortin system, body weight regulation and obesity]. / Sistema leptina-melanocortinas en la regulación de la ingesta y el peso corporal.

Obesity is a multifactorial disease that is rarely associated to single gene defects. However, due to their direct cause-effect relationships, those genetic defects that cause some forms of monogenic obesity are relevant in the study of mechanisms that contribute to increased energy intake and body fat accumulation. Most of the genes that have been shown to cause monogenic obesity are related to the leptin-melanocortin system. The functionality of this system has been elucidated through natural mutations (Agouti, ob and db) in mice and knock-out models. Mutations related to human monogenic obesity have been described in leptin, leptin receptor, proopiomelanocortin, prohormone convertase 1 or melanocortin receptor 4 genes. Therapy with human recombinant leptin in patients with genetic deficiency of the hormone is an effective medical treatment of obesity, although only applicable to very few families. The use of leptin-melanocortin agonists, drugs to avoid leptin resistance or combinations of treatments with leptin and other satiating peptides are currently being investigated for multifacotiral human obesity.

Sistema leptina-melanocortinas en la regulación de la ingesta y el peso corporal / Leptin-melanocortin system, body weight regulation and obesity

Obesity is a multifactorial disease that is rarely associated to single gene defects. However, due to their direct cause-effect relationships, those genetic defects that cause some forms of monogenic obesity are relevant in the study of mechanisms that contribute to increased energy intake and body fat accumulation. Most of the genes that have been shown to cause monogenic obesity are related to the leptin-melanocortin system. The functionality of this system has been elucidated through natural mutations (Agouti, ob and db) in mice and knock-out models. Mutations related to human monogenic obesity have been described in leptin, leptin receptor, proopiomelanocortin, prohormone convertase 1 or melanocortin receptor 4 genes. Therapy with human recombinant leptin in patients with genetic deficiency of the hormone is an effective medical treatment of obesity, although only applicable to very few families. The use of leptin-melanocortin agonists, drugs to avoid leptin resistance or combinations of treatments with leptin and other satiating peptides are currently being investigated for multifacotiral human obesity (Rev Méd Chile 2009; 137:1225-34).

Estudio multivariado de la evolución de las dimensiones corporales en chilenas mayores de 60 años / Multivariate study of the evolution of body dimensions in elderly Chilean women

Con frecuencia en las investigaciones médicas se requiere analizar datos de tipo longitudinal que no pueden ser analizados por los métodos estadísticos clásicos de series cronológicas. El objetivo de este trabajo es presentar la factibilidad del uso del método exploratorio multivariado STATIS (Structuration des Tableaux A Trois Indices de la Statistique) en un estudio antropométrico de una muestra de 57 mujeres adultas mayores de 60 años (rango: 69-82 años) del Gran Santiago, Chile, que fueron estudiadas en 5 ocasiones durante un período de 30 meses. Las variables de interés son las mediciones antropométricas: peso, talla, circunferencia brazo, circunferencia pantorrilla, circunferencia cintura, circunferencia cadera, altura rodilla; medidas cada 6 meses. Las variables peso, circunferencia de brazo, circunferencia de pantorrilla, circunferencia de cintura y circunferencia de cadera, fueron las más correlacionadas con el primer eje de compromiso y responden fundamentalmente a medidas de composición corporal como adiposidad y masa muscular. El eje 2, caracterizado por la talla y la altura de rodilla, responde al tamaño del esqueleto. Los resultados obtenidos sugieren una evolución cronológica regular en los primeros 24 meses de observación, con un cambio de estructura a los 30 meses del estudio, así como una clasificación de grupos con diferente composición corporal.

Although in medical research the use of longitudinal data to analyze short time periods is frequently required, it does not permit the use of classic statistical methods for chronological series. The objective of this study is to present the possibility and plausibility of using the STATIS method (Structuration des Tableaux A Trois Indices de la Statistique), an explorative method for data analysis, in a study of the body composition of a sample of 57 women over 68 years of age in Santiago, Chile who were observed over a period of 30 months. The variables analyzed (measured every 6 months) were the following anthropometric measurements: weight, height, arm circumference, calf circumference, waist circumference, hip circumference and knee height. The results obtained suggested a regular chronological evolution during the first 24 months of observation with a change in structure after 30 months of the study, thereby classifying subjects according to body composition.

[Genotype-by-nutrition interaction: interpretation of epidemiological studies]. / Interacción entre genotipo y nutrición: interpretación de estudios epidemiológicos.

EpidemiologicaL methods are increasingly used to assess the role of genetic factors and their interaction with environmental factors, in the occurrence of diseases in populations. Nutrition is one of the most relevant components of the interaction between the human being and the environment. Therefore, the interaction between susceptibility genotypes and nutritional risk factors has a great importance in the study of several chronic diseases. The aim of this article is to review different epidemiologic study designs and basic methods of analysis commonly used in the evaluation of the interaction between nutritional and genetic factors. These study designs and analytical methods are equally valid for the assessment of genotype-environment or genotype-genotype interaction.

Interacción entre genotipo y nutrición: interpretación de estudios epidemiológicos / Genotype-by-nutrition interaction: interpretation of epidemiológical studies

Epidemiológica! methods are increasingly used to assess the role of genetic factors and their interaction with environmental factors, in the occurrence of diseases in populations. Nutrition is one of the most relevant components of the interaction between the human being and the environment. Therefore, the interaction between susceptibility genotypes and nutritional risk factors has a great importance in the study of several chronic diseases. The aim of this article is to review different epidemiologic study designs and basic methods of analysis commonly used in the evaluation of the interaction between nutritional and genetic factors. These study designs and analytical methods are equally valid for the assessment of genotype-environment or genotype-genotype interaction.

[Association between tumor necrosis factor-alpha promoter polymorphisms and type 2 diabetes and obesity in Chilean elderly women]. / Asociación entre polimorfismos de la región promotora del gen del factor de necrosis tumoral alfa (TNF-alfa) con obesidad y diabetes en mujeres chilenas.

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) has an increased expression in the adipose tissue of obese subjects and is involved in insulin resistance. AIM: To screen for associations between -308G/A, -238G/A, -376G/A and -163G/A genetic variants of the TNF-alpha gene, diabetes and obesity-related variables. MATERIAL AND METHODS: A group of 263 elderly women aged 60-90 years were recruited. Among them, an oral glucose tolerance test was performed and serum lipids measured in 100 women. TNF-alpha genotypes were determined by polymerase chain reaction (PCR) and analysis of restriction fragment length polymorphisms. RESULTS: No significant differences were found when comparing allele frequencies in TNF-alpha polymorphisms of normal subjects with those having impaired glucose tolerance or type 2 diabetes. After excluding patients with previous diagnosis of diabetes, no significant differences by polymorphism carrier status were found for plasma levels of lipids, glucose and insulin. Additionally, no significant differences were found for the association between variables related to adiposity and the -308G/A polymorphisms. CONCLUSIONS: It is unlikely that polymorphisms in the promoter region of the TNF-alpha gene have a major influence in obesity and diabetes phenotypes in Chilean elderly women.

Asociación entre polimorfismos de la región promotora del gen del factor de necrosis tumoral alfa (TNF-alfa) con obesidad y diabetes en mujeres chilenas / Association between tumor necrosis factor-alpha promoter polymorphisms and type 2 diabetes and obesity in Chilean elderly women

Background : Tumor necrosis factor-alpha (TNF-alpha) has an increased expression in the adipose tissue of obese subjects and is involved in insulin resistance. Aim: To screen for associations between -308G/A, -238G/A, -376G/A and -163G/A genetic variants of the TNF-alpha gene, diabetes and obesity-related variables. Material and methods: A group of 263 elderly women aged 60-90 years were recruited. Among them, an oral glucose tolerance test was performed and serum lipids measured in 100 women. TNF-alpha genotypes were determined by polymerase chain reaction (PCR) and analysis of restriction fragment lenght polymorphisms. Results: No significant differences were found when comparing allele frequencies in TNF-alpha polymorphisms of normal subjects with those having impaired glucose tolerance or type 2 diabetes. After excluding patients with previous diagnosis of diabetes, no significant differences by polymorphism carrier status were found for plasma levels of lipids, glucose and insulin. Additionally, no significant differences were found for the association between variables related to adiposity and the ¡308G/A polymorphisms. Conclusions: It is unlikely that polymorphisms in the promoter region of the TNF-alpha gene have a major influence in obesity and diabetes phenotypes in Chilean elderly women.

Epidemiología genética de la obesidad: estudios familiares / Genetic epidemiology of obesity: Family studies

This review focuses on methodological aspects and main results of different family studies that have been conducted to assess the existence of a genetic contribution in human obesity. A genetic component in the etiology of obesity has been elucidated through specific study designs answering different research questions such as: a) Do obesity aggregate in families? b) Is there a genetic contribution to familial clustering? c) Is it possible to localize chromosomal regions that contain susceptibility genes to obesity? d) Is it possible to estimate the risk for developing obesity depending on the genotype profile in candidate genes? There are sufficient evidences indicating the existence of a moderate familial clustering of obesity defined as body mass index 30 with a stronger aggregation with more extreme values of body mass index. Twin studies have demonstrated that the familial aggregation of obesity has a genetic component and is not only due to cultural or environmental factors clustered in families. Linkage studies have identified markers and genes related to obesity in virtually all human chromosomes. However, some of these linkage studies have produced conflicting results. Discordant results are even more pronounced in case-control studies that evaluate the association between alleles at candidate genes and obesity. Topics related to study design will acquire increasing importance in order to avoid methodological problems related to trait definition, sample sizes, population stratification by ethnicity and other confounding factors.

Perfil de auto anticuerpos y lactancia materna en pacientes diabéticos tipo 1 / Auto-antibody levels and history of breast-feeding in type 1 diabetic patients

Background: Islet cell-specific autoantibodies such as islet cell antibody (ICA), antiinsulin (IAA), anti-glutamic acid decarboxylase (GAD) and anti-tyrosine phosphatase (IA2) can be present in patients with type I diabetes. Breast feeding duration and the early exposure to milk substitutes are environmental factors associated to etiology of type 1 diabetes. Aim To study the frequency of the anti-GAD, anti-IA-2 e ICA antibodies in Chilean type 1 diabetic patients and determine the possible modulator effect of the breast feeding. Patients and methods: One hundred thirty four type I diabetic patients, aged one to 15 years old, were studied at the moment of their diagnosis. Patients were classified according to the duration of exclusive breast feeding. IA-2 and GAD were determined by radio immuno assay and ICA by means of indirect immunofluorescence. Results: Subjects with three months or less and those with more than three months of breast feeding were positive for ICA in 78.8 and 90.6 per cent of cases respectively, for GAD in 75 and 54.6 per cent of cases respectively (p=0.024) and for IA-2 in 73 and 43.8 per cent of cases respectively (p=0.001). All three antibodies were positive in 53.9 and 21.8 per cent of children with less or more than three months of breast feeding (p=0.001). Conclusion: Both IA-2 and GAD antibodies are less frequently positive in type 1 diabetic patients who have been breast fed for more than three months. These findings suggest a possible attenuating role of exclusive breast feeding on pancreatic aggression events in patients with type 1 diabetes

Eventos coronarios tardíos post angioplastía con y sin stent / Late coronary events post angioplasty with and without stent

La angioplastia coronaria transluminal percutánea ha probado ser más efectiva que el tratamiento médico para el control de la cardiopatía coronacia. El uso de stents asociado a angioplastia ha permitido disminuir la reestenosis y los eventos a largo plazo en poblaciones seleccionadas de pacientes, sometidos a angioplastia con y sin stent. Entre agosto de 1993 y julio de 1997, se realizaron 147 angioplastias. El procedimiento fue considerado exitoso en 104 pacientes (70,7 por ciento) los que se separaron en dos grupos: 39 con stent y 65 sin stent. El seguimiento clínico se prolongó por 6,18 meses en promedio con un rango de 1 a 27 meses. Para el análisis estadístico se uso el cuociente de tasa de incidencia (CTI) y regresión de Cox. La incidencia total de eventos coronarios fue de 15,4 por ciento (10,2 por ciento en los pacientes con angioplastia más stent versus 18 por ciento en los pacientes con angioplastia sola (CTI=2,0; p=ns). El evento más frecuente fue la angina inestable (68,7 por ciento). El 31,2 por ciento de los pacientes con eventos requirieron de nueva revascularización. No se registraron muerte ni infartos durante el período de seguimiento. La incidencia de eventos tardíos fue más frecuente en mujeres (22 por ciento) que en hombres (10 por ciento), luego de ajustar por sexo, edad y presencia de diabetes. El uso de stent se asocia a una disminución no estadísticamente significativa de eventos coronarios al largo plazo en casuística de pacientes no seleccionados

La epidemiología molecular en el estudio de enfermedades crónicas con base genética y nutricional / Molecular epidemiology in the study of multifactorial diseases with genetic and nutritional basis

La epidemiología genética puede ser definida como el estudio del papel de los factores genéticos y su interacción con factores ambientales en la ocurrencia de las enfermedades en poblaciones humanas. La epidemiología molecular es una disciplina relacionada con la epidemiología genética, que se caracteriza por la utilización de técnicas de biología molecular en la evaluación de la susceptibilidad genética y de los factores de riesgo de tipo ambiental que actúan sobre la tasa de incidencia de las enfermedades. La interacción entre genética y ambiente es uno de los problemas fundamentales de estudio tanto para los genetistas como para los epidemiólogos. Desde este punto de vista, el tipo de nutrición es uno de los factores de riesgo modificables. En un futuro próximo, estudios epidemiológicos de base poblacional o de base familiar, asumirán un rol de creciente importancia en la estimación de la asociación genética-enfermedad y la interacción genética-nutrición en enfermedades crónicas de etiología multifactorial

Relación entre leptina e insulina sanguíneas en mujeres chilenas obesas y no obesas / Relationship between leptin and insulin blood levels in obese and lean chilean women

Background: Leptin, a product of ob gene and insulin blood levels, are proportional to the amount of adipose tissue. Insulin could have an independent regulatory effect on leptin secretion. Aim: To assess the relationship between serum leptin and plasma insulin levels in obese and lean Chilean women. Material and methods: One hundred forty five women, aged 20 to 60 years old, were studied. Weight, height, waist and hip circumference, fasting blood glucose, insulin and leptin levels were measured. Insulin resistance was assessed using the homeostasis model assessment. The relationship between different variables was determined using multiple linear regression, variance analysis and non parametric correlation. Results: Leptin serum concentrations were positively correlated with body mass index, insulin plasma levels and degree of insulin resistance. The association of leptin with insulin was independent of body mass index and persisted after adjustments by body fat distribution and age. Conclusions: Insulin and insulin resistance are associated to high blood leptin levels and this association is independent of the degree of adiposity and body fat distribution

Asociación obesidad y leptina en tres poblaciones aborígenes de Chile / Body mass index and leptin levels in 3 Chilean aborigin populations

Background: Although there is a clear relationship between body mass index and leptin levels, few authors have addressed the possible influence of ethnic factors on these levels. Aim: To measure serum leptin in three different Chilean aboriginal populations. Subjects and methods: Fasting serum leptin and insulin levels were measured by radioimmunoassay in 345 rural mapuche individuals, 247 rural aymara subjects and 162 urban mapuche subjects. A body mass index of 27.5 kg/m2 was used as cutoff point to classify study subjects. Results: Among the three ethnic groups, women had serum leptin levels three times higher than men. In all three ethnic groups, there was a significant association between leptin levels, body mass index and gender (r2= 0.32 and 0.5 p <0.001, in rural mapuche, r2= 0.32 and 0.5 p <0.001, in aymara and r2= 0.24 and 0.49, p <0.001 in urban mapuche populations). No differences in leptin levels were observed for the interaction between age and insulin. The increments per quartile in leptin levels were lower among mapuche than aymara individuals. Conclusions: Rural mapuche individuals have a high frequency of obesity. However their leptin levels are lower than those of aymara or urban mapuche populations. The higher leptin levels observed in urban mapuche subjects could be due to environmental influences

Prevalencia de obesidad, hipertensión arterial y dislipidemia en grupos aborígenes rurales de Chile / Prevalence of obesity, hypertension and serum lipid profiles in chilean rural aboriginal communities

Background: Chilean aboriginal ethnic groups (mapuche and aymaras) have a very low prevalence rate of type 2 diabetes. The investigation of a possible relationship between this low prevalence of diabetes and obesity, hypertension and serum lipid profiles in both groups is worthwhile. Aim: To study the prevalence of obesity, hypertension and lipid profile in two chilean aboriginal communities. Subjects and Methods: The prevalence of obesity, hypertension, fasting serum total cholesterol, HDL cholesterol, triglycerides, glucose, insulin, leptin and oral glucose tolerance test were measured in 345 mapuche (106 male) and 247 aymara (100 male) individuals. Results: Sixty three percent of mapuche women, 37.9 percent of mapuche men, 39.7 percent of the aymara women and 27.0 percent of aymara men had a body mass index over 27 kg/m2. Twenty percent of mapuche men, 18.0 percent of mapuche women, 9.0 percent of aymara men and 4.8 percent of the aymara women had high blood pressure values. Serum HDL cholesterol was below 35 mg/dl in 16 percent of mapuche women, 14 percent of mapuche men, 25 percent of the aymara women and 27 percent of aymara men. No differences in total cholesterol levels were observed between mapuches and aymaras. Conclusion: Mapuche women have higher prevalence of obesity and high blood pressure than aymara women. Low serum HDL cholesterol has a higher prevalence among aymara individuals