The Genetic Profile from HLA and Non-HLA Loci Allows Identification of Atypical Type 2 Diabetes Patients.

The complex diagnosis and treatment of diabetes highlight the need for markers to define how to monitor patients correctly during the course of their disease. Different studies demonstrate the existence of patients who cannot be clearly classified. We have previously shown that it is possible to differentiate "atypical diabetic patients" based on genotyping the HLA. In this work we show that the analysis of non-HLA related to type 1 diabetes in the INS-VNTR, SNP rs689, and rs3842753 improves the identification of these patients. We genotyped 913 individuals comprising controls from the general population and "classic" and "atypical" diabetic patients. We compared the distribution of these loci and analyzed linkage disequilibrium. The haplotype was in LD for all the SNPs that were evaluated. Regarding their association with the disease, the haplotype IAC was associated with type 1 (odds 2.60, 1.82-3.72, CI 95%) and "atypical diabetes" (odds 1.50, 1.01-2.23, CI 95%), whereas we did not observe an association with type 2 diabetes. Therefore, our results confirm that atypical diabetes is a different entity of the disease where the patient presents with a genetic background of T1D and a T2D phenotype, findings that are likely to be relevant for patient diagnosis and management in the clinic.

The phenotype masks the genotype: A possible new expression of diabetes.

The concept of a new form of diabetes, with signs of both types 1 and 2, has not been often considered, until recently. It is of immense interest to explore the role of the admixture that characterizes the Uruguayan population (higher and different from other Latin America countries) for the presence of such expression of that particular disease. We describe here a child who possibly presents with this expression. He had typical signs of both diabetic conditions: type 1 (young age, positive immunologic and genetic markers, ketoacidosis) and type 2 (obesity [body mass index = 36 kg/m(2)] and acanthosis nigricans). In spite of complying with the established guidelines, therapeutic and nutritional control, quality of life and good metabolic control, the patient's obesity had been continually increasing. Looking for a genetic explanation, we studied three single nucleotide polymorphisms involved in three different metabolic pathways (peroxisome proliferator-activated receptor gamma 2, insulin receptor substrate-1 and uncoupling protein-2) associated with insulin resistance. Our patient showed three mutations, GG, GA, GG, associated with insulin resistance that explains obesity associated with limited response to the commonly used drugs. According to the clinical presentation and the genetic and immunological background, we considered that this patient presents with a new form of diabetes. We have termed this particular disease "hybrid diabetes" because of the involvement of genes associated with both the classical type of diabetes. However, at least in an admixed population such as in Uruguay, clinical classification would not strictly dictate the choice of treatment.

Estudio comparativo de prevalencia del gen de la ECA en muestras de diabéticos y población general / Comparative study on the prevalence of the Angiostatin-converting enzyme gene in diabetic patients and general population samples

Introducción: previamente se ha demostrado que los pacientes diabéticos poseen una incidencia aumentada de patologías micro y macrovasculares. En la exploración de posibles determinantesaparece como candidato atractivo el gen de la enzima convertidora de angiotensina (ECA) el cual presenta de acuerdo al polimorfismo InDel existente, un aumento de la concentración enzimática en sangre asociado a enfermedades vasculares. Objetivo: se plantearon como objetivos establecer la prevalencia del polimorfismo del gen de la ECA, en pacientes diabéticos y comparar las frecuencias con las halladas para la población general demanera de revelar si existe asociación del locus con la diabetes mellitus.Material y método: la población estudiada consistió en 131 individuos con diagnóstico certero de diabetes según criterios de la American Diabetes Association. Se hallaron las frecuencias génicas y genotípicas del polimorfismo InDel del gen de la ECA mediante la técnica de reacción en cadena dela polimerasa (PCR). Resultados: no se encontraron diferencias significativas en la prevalencia del marcador estudiadoentre diabéticos y la población general. Las frecuencias génicas halladas en diabéticos fueron 0,435 para alelo I y 0,565 para alelo D versus 0,440 alelo I y 0,560 alelo D en la población general.Discusión: en suma, este marcador es un factor de riesgo que no está asociado a la diabetes en sí misma, sino que la relación entre este gen y las complicaciones vasculares serían las mismas para diabéticos que para la población general.(AU)

Introduction: we have previously demonstrated that diabetic patients have an increased incidence of micro and macrovascular pathologies. Upon exploration of possible determining factors, the ACE gene appears as an attractive factor, since it presents, according to the existing InDelpolymorphism, an increase of the enzyme concentration in blood associated to vascular diseases.Objective: to establish the prevalence of polymorphism of the ACE gene in diabetic patients, and to compare thefrequencies with those found in the general population, in order to find out whether there is a relationship betweenlocus and diabetes mellitus. Method: the population studied consisted of 131 individuals with a certain diagnosis of diabetes, according to criteria of the American Diabetes Population. We determined InDel polymorhism´s genic and genotypic frequencies in the ACE gene through the polymerase chain reaction (PCR). Results: we failed to find meaningful differences in theprevalence of the marker studied between diabetic patients and the general population. Discussion: to sum up, the present marker is a risk factor that is not associated to diabetes itself; hence the relationship between this gene and vascular complications would be the same in diabetic patients and the general population.(AU)

Introdução: está demonstrado que os pacientes diabéticos apresentam uma maior incidência de patologias microy macrovasculares. Na pesquisa de possíveis determinantes aparece como candidato possível o gen da ECA queapresenta, de acordo ao polimorfismo Índio existente, um aumento da concentração enzimática no sangue associado a patologias vasculares.Objetivo: estabelecer a prevalência do polimorfismo do gen da enzima convertidora de angiotensina (ECA), empacientes diabéticos e comparar as freqüências encontradas com as determinadas para a população em geral para verificar a existência de uma associação do lócus com a diabetes mellitus. Material e método: a população estudada estava composta por 131 indivíduos com diagnóstico confirmadode diabetes de acordo com os critérios da American Diabetes Association. As freqüências gênicas e genotípicas do polimorfismo InDel do gen da ECA foramdeterminadas pela técnica de reação em cadeia da polimerase (PCR). Resultados: nao se encontraram diferenças significativas na prevalên-cia do marcador estudado entre diabéticose a população em geral. As freqüências gênicas encontradas em diabéticos foram 0,435 para alelo I e 0,565para alelo D e, 0,440 alelo I e 0,560 alelo D na população em geral.Discussão: este marcador é um fator de risco que não está associado à diabetes, porém a relação entre este gen e as complicações vasculares seria a mesma para diabéticos que para a população em geral.(AU)

Estudio comparativo de prevalencia del gen de la ECA en muestras de diabéticos y población general / Comparative study on the prevalence of the Angiostatin-converting enzyme gene in diabetic patients and general population samples

Introducción: previamente se ha demostrado que los pacientes diabéticos poseen una incidencia aumentada de patologías micro y macrovasculares. En la exploración de posibles determinantesaparece como candidato atractivo el gen de la enzima convertidora de angiotensina (ECA) el cual presenta de acuerdo al polimorfismo InDel existente, un aumento de la concentración enzimática en sangre asociado a enfermedades vasculares. Objetivo: se plantearon como objetivos establecer la prevalencia del polimorfismo del gen de la ECA, en pacientes diabéticos y comparar las frecuencias con las halladas para la población general demanera de revelar si existe asociación del locus con la diabetes mellitus.Material y método: la población estudiada consistió en 131 individuos con diagnóstico certero de diabetes según criterios de la American Diabetes Association. Se hallaron las frecuencias génicas y genotípicas del polimorfismo InDel del gen de la ECA mediante la técnica de reacción en cadena dela polimerasa (PCR). Resultados: no se encontraron diferencias significativas en la prevalencia del marcador estudiadoentre diabéticos y la población general. Las frecuencias génicas halladas en diabéticos fueron 0,435 para alelo I y 0,565 para alelo D versus 0,440 alelo I y 0,560 alelo D en la población general.Discusión: en suma, este marcador es un factor de riesgo que no está asociado a la diabetes en sí misma, sino que la relación entre este gen y las complicaciones vasculares serían las mismas para diabéticos que para la población general.

Introduction: we have previously demonstrated that diabetic patients have an increased incidence of micro and macrovascular pathologies. Upon exploration of possible determining factors, the ACE gene appears as an attractive factor, since it presents, according to the existing InDelpolymorphism, an increase of the enzyme concentration in blood associated to vascular diseases.Objective: to establish the prevalence of polymorphism of the ACE gene in diabetic patients, and to compare thefrequencies with those found in the general population, in order to find out whether there is a relationship betweenlocus and diabetes mellitus. Method: the population studied consisted of 131 individuals with a certain diagnosis of diabetes, according to criteria of the American Diabetes Population. We determined InDel polymorhism´s genic and genotypic frequencies in the ACE gene through the polymerase chain reaction (PCR). Results: we failed to find meaningful differences in theprevalence of the marker studied between diabetic patients and the general population. Discussion: to sum up, the present marker is a risk factor that is not associated to diabetes itself; hence the relationship between this gene and vascular complications would be the same in diabetic patients and the general population.

Introdução: está demonstrado que os pacientes diabéticos apresentam uma maior incidência de patologias microy macrovasculares. Na pesquisa de possíveis determinantes aparece como candidato possível o gen da ECA queapresenta, de acordo ao polimorfismo Índio existente, um aumento da concentração enzimática no sangue associado a patologias vasculares.Objetivo: estabelecer a prevalência do polimorfismo do gen da enzima convertidora de angiotensina (ECA), empacientes diabéticos e comparar as freqüências encontradas com as determinadas para a população em geral para verificar a existência de uma associação do lócus com a diabetes mellitus. Material e método: a população estudada estava composta por 131 indivíduos com diagnóstico confirmadode diabetes de acordo com os critérios da American Diabetes Association. As freqüências gênicas e genotípicas do polimorfismo InDel do gen da ECA foramdeterminadas pela técnica de reação em cadeia da polimerase (PCR). Resultados: nao se encontraram diferenças significativas na prevalên-cia do marcador estudado entre diabéticose a população em geral. As freqüências gênicas encontradas em diabéticos foram 0,435 para alelo I e 0,565para alelo D e, 0,440 alelo I e 0,560 alelo D na população em geral.Discussão: este marcador é um fator de risco que não está associado à diabetes, porém a relação entre este gen e as complicações vasculares seria a mesma para diabéticos que para a população em geral.

Asociación entre hiperhomocisteinemia, cardiopatía isquémica y diabetes tipo 2

La hiperhomocisteinemia es considerada como un factor de riesgo para las enfermedades vasculares en la población general. Sin embargo, su rol en el desarrollo de la cardiopatía isquémica (CI) no ha sido totalmente dilucidado. El objetivo fue determinar, si existe, en primera instancia una asociación entre la cardiopatía isquémica y los niveles elevados de homocisteína en plasma y posteriormente investigar la posible asociación entre la hiperhomocisteinemia y la diabetes mellitus tipo 2. Se analizó la información de 204 pacientes atendidos en consultorios dependientes del CASMU con una edad promedio de 61,2±10,8 años. Se siguieron los criterios de las guías de Task Force y ADA para el diagnóstico de cardiopatía isquémica y diabetes, respectivamente. Se tomaron valores entre 5-15 µmoles/lt de homocisteína plasmática como normales. Los pacientes fueron clasificados en dos grupos: con cardiopatía isquémica (CCI) y sin cardiopatía isquémica (SCI). En las comparaciones realizadas entre los grupos se observaron diferencias significativas en la distribución de los niveles de homocisteína plasmática entre los individuos CCI y SCI (p<0,001). A su vez, se observó una asociación entre los valores de hiperhomocisteinemia y la CI (OR=2,66). Por otra parte, la ausencia de diferencias significativas entre diabéticos y no diabéticos con CI estaría indicando que la diabetes y la hiperhomocisteinemia serían dos características genéticas independientes o -dicho de otra forma- el hecho de ser diabético no altera la asociación entre la hiperhomocisteinemia y la cardiopatía isquémica.

A high plasmatic level of homocysteine is considered as a risk factor to vascular disease in the general population. However, the role of hyperhomocysteinaemia in the ischaemic heart disease development is not totally elucidated. The aim of our study was to determine in fist place, if in our sample there is an association between homocysteine levels and ischaemic heart disease and subsequently to investigate a possible association of hyperhomocysteinaemia to the presence of diabetes mellitus type 2. We analyzed the information of 204 patients attending to private health centers (depending from CASMU). All patients (61,2 ± 10,8 year olds average) were diagnosed as diabetic type 2 and ischaemic heart disease according to the ADA and Task Force guides criteria respectively. We took 5-15 µmol/l homocysteine plasmatic value as normal. The patients were classified in two groups: with (CCI) and without ischaemic heart disease (SCI). We observed statistical significant differences in the distribution of homocysteine plasmatic levels between: CCI and SCI (p<0,001). We also observed an association between hyperhomocysteinaemia and CI (OR=2,66). In the other hand, non-significant statistical differences between diabetic and non diabetics patient with CI would be indicate that that hyperhomocysteinaemia and diabetes are two independent genetics factors; the diabetes condition do not alter the association between hyperhomocisteinaemia and CI.