Lymphocytes of Type 2 Diabetic Women Carry a High Load of Stable Chromosomal Aberrations

Abstract

OBJECTIVE-Diabetes is associated with an increased risk of death in women. Oxidative stress due to chronic hyperglycemia leads to the generation of reactive oxygen species and loss of chromosomal integrity. To clarify whether diabetes is a premature aging syndrome, we determined telomere erosion dynamics and occurrence of structural chromosomal aberrations in women of the Ludwigshafen Risk and Cardiovascular Health (LURIC) Study.RESEARCH DESIGN AND METHODS-Telomere lengths and karyotypes were examined in peripheral blood mononuclear cells. Regarding these parameters, surviving and deceased type 2 diabetic women of the LURIC study were compared with nondiabetic LURIC women with or without coronary heart disease and with healthy female control subjects.RESULTS-Significantly enhanced telomere attrition was seen in all LURIC subjects compared with healthy control subjects. Although the average telomere-length loss is equivalent to well Ͼ10 years of healthy aging, telomere erosion was not associated with outcome within the LURIC cohort. However, strikingly high numbers of stable chromosomal aberrations were found in type 2 diabetic women but not in LURIC disease control subjects or in healthy individuals. Furthermore, within the younger agegroups, deceased type 2 diabetes patients had significantly more marker chromosomes than the surviving type 2 diabetic patients.CONCLUSIONS-All women at high risk for cardiovascular death have accelerated telomere erosion, not caused by type 2 diabetes per se but likely linked to other risk factors, including dyslipidemia. By contrast, the occurrence of marker chromosomes is associated with type 2 diabetes and is a novel risk factor for type 2 diabetes-related early death. Diabetes 57:2950-2957, 2008 T ype 2 diabetes is characterized by increased morbidity and all-cause mortality (1,2). The combination of excess caloric intake and reduced physical activity leading to obesity, dyslipidemia, and hypertension increases the risk for diabetes and coronary heart disease (CHD). Recent data show that among diabetic men, the mortality rate has decreased significantly, whereas in diabetic women, no such trend was found (3). The all-cause mortality rate difference between diabetic and nondiabetic women is considerable. Therefore, the combination of diabetes with multiple risk factors identifies women at particularly high risk (2,4).The relative risk for morbidity and mortality in women with diabetes is increased compared with nondiabetic control subjects (2,5). Diabetes may therefore be regarded as a premature aging syndrome in which the overall metabolic shift leads to genotoxic stress that results in loss of chromosomal integrity (rev. in 6). Oxidative stress plays a crucial role in the pathogenesis of type 2 diabetes and in diabetes-associated complications. The generation of reactive oxygen species (ROS) is a common downstream mechanism whereby multiple by-products of glucose and (pro)inflammatory molecules exert adverse effects (7-11). DNA damage and telomere attrition can serve as marke...

Vitamin B6 and Diabetes: Relationship and Molecular Mechanisms

“…It was shown that tissues from diabetic rats and the urine of T1D and T2D patients have increased levels of 8-Oxo-7,8-dihydro-2 -deoxyguanosine (8-oxodG), a sensitive marker of reactive oxygen species (ROS)-induced DNA damage [127][128][129]. In addition, diabetic patients have a higher frequency of sister chromatid exchange than healthy subjects [130,131]. Another study reported high levels of stable chromosomal aberrations in peripheral lymphocytes associated with T2D, and directly correlated with the risk of early diabetes-related death [131].…”

“…In addition, diabetic patients have a higher frequency of sister chromatid exchange than healthy subjects [130,131]. Another study reported high levels of stable chromosomal aberrations in peripheral lymphocytes associated with T2D, and directly correlated with the risk of early diabetes-related death [131]. Moreover, an elevated frequency of micronuclei was found in T2D patients with no microvascular or macrovascular complications [132].…”

Oxidative protein modification and chromosomal instability among type 2 diabetics in Osogbo, Nigeria

“…Due to increased relative risk of morbidity and mortality among individuals with diabetes as compared with apparently healthy non-diabetes controls, diabetes can be viewed as a premature aging syndrome that affects the overall metabolic shift leading to genotoxic stress and loss of chromosomal integrity [8]. Alterations in genomic system occur when the process of oxidative DNA lesions/damage overwhelms the DNA repair mechanism, leading to accumulation of unrepaired damaged DNA in the system.…”

Avaliação das alterações nucleares e cromatínicas em linfócitos do sangue periférico de portadores de diabetes

“…A condição hiperglicêmica prévia parece desempenhar papel crucial neste processo (EL-OSTA et al, 2008;BEREZIN, 2016). Estudos com enfoque em linfócitos na presença do diabetes têm sido desenvolvidos com o intuito de entender as mudanças que podem ocorrer em nível de cromatina (MIAO et al, 2008;SIMAR et al, 2014), bem como outros processos como danos ao DNA (PEREIRA et al, 2013), perda de integridade cromossômica (BOEHM et al, 2008) e expressão gênica (MIAO et al, 2012) nestas células.…”

“…, em que os núcleos de linfócitos do Grupo 1 apresentaram uma maior compactação da cromatina, pelo fato de ter ocorrido uma diminuição de núcleos com cromatina menos compacta, portanto, há que se considerar que os núcleos deste grupo se mostraram com cromatina mais compacta. Já no Grupo 2, a diminuição geral das áreas nucleares foi integridade cromossômica(BOEHM et al, 2008). Neste contexto existe a possibilidade de que um aumento no conteúdo de DNA possa contribuir para atender a demanda transcricional da célula, visto que um aumento da produção metabólica poderia de certo modo atuar compensando a quantidade aumentada de moléculas danificadas nãofuncionais ou até mesmo funcionar como um mecanismo de proteção ao estresse oxidativo ou a mutações.…”