Chromosomal telomere attrition as a mechanism for the increased risk of epithelial cancers and senescent phenotypes in type 2 diabetes

Abstract

Telomeres are the repeat DNA sequences at the end of chromosomes necessary for successful DNA replication and chromosomal integrity. Telomeres shorten at cell division at a rate determined by oxidative DNA damage, and cells are triggered into replicative senescence once telomeres shorten to a critical length. Telomere-related chromosomal maintenance also has a role in carcinogenesis. Type 2 diabetes is characterised by increased oxidative stress, increased oxidative DNA damage, senescent retinal and renal phenotypes, and an increased risk of epithelial malignancy. We suggest that increased oxidative DNA damage and telomere attrition in type 2 diabetes leads to: (1) carcinogenic telomere-dependent chromosomal nonreciprocal translocations, genomic instability, and the development of epithelial cancers; (2) senescent retinal and renal phenotypes (expressed as diabetic retinopathy and nephropathy); and (3) senescent vascular endothelial, monocyte-macrophage and vascular smooth muscle cells (expressed as endothelial dysfunction and accelerated atherogenesis). An adverse intrauterine environment leads to increased feto-placental oxidative stress and feto-placental oxidative DNA damage. We also suggest that intrauterine oxidative DNA damage and telomere shortening is another point at which increased oxidative stress could contribute to a pre-programmed increased risk of senescent phenotypes in adult offspring, characterised by type 2 diabetes and epithelial malignancy. These suggestions can be used to understand early glucose intolerance in the young children of type 1 diabetes pregnancies, poor cancer outcomes in type 2 diabetes, beta cell fatigue in type 2 diabetes and the absence of increased epithelial cancer risk in type 1 diabetes.

The Impact of Type 2 Diabetes on the Development of Hepatocellular Carcinoma in Different Viral Hepatitis Statuses

“…Moreover, type 2 diabetes produces a synergistic effect on liver fibrosis progression in patients with HCV infection (24) and, therefore, increases the risk of hepatocellular carcinoma. Second, liver damage may be exacerbated by oxidative stress and telomere shortening caused by long-term diabetes (26). Telomere shortening limits the proliferative capacity and induces DNA damage, replicative senescence, apoptosis, and chromosomal instability in hepatocytes (1,26).…”

“…Second, liver damage may be exacerbated by oxidative stress and telomere shortening caused by long-term diabetes (26). Telomere shortening limits the proliferative capacity and induces DNA damage, replicative senescence, apoptosis, and chromosomal instability in hepatocytes (1,26). Third, increased insulin levels also stimulate cell growth and DNA synthesis, both of which are involved in carcinogenesis and neoplastic differentiation, by decreasing apoptosis and increasing mitogenesis (27,28).…”

“…The present study provides important implications for public health and clinical practice: that, globally, type 2 diabetes will be an important risk factor for hepatocellular carcinoma, and that the trend of increasing hepatocellular carcinoma will continue as long as type 2 diabetes is epidemic, especially in low-risk countries and in those with a high prevalence of HCV infection. Unfortunately, those infected with HCV are more likely than those not infected to develop type 2 diabetes (26). Therefore, to prevent hepatocellular carcinoma in anti-HCV(+) individuals, it is important to emphasize not only therapeutic intervention for HCV infection (32), but also a change of lifestyle to reduce the development of type 2 diabetes and then reduce its progression into hepatocellular carcinoma (6,21,22).…”

Telomere Length in Prospective and Retrospective Cancer Case-Control Studies

“…Previous experimental studies have indicated that individuals with relatively short mean telomere lengths might have an increased risk of mortality from multiple diseases (20,(29)(30)(31)(32)(33)(34)(35)(36)(37)(38). In particular, five studies have examined the associations between breast cancer risk and mean telomere length (35)(36)(37)(38)(39).…”

Absence of telomere shortening and oxidative DNA damage in the young adult offspring of women with pre-gestational type 1 diabetes

“…Feto-placental telomere attrition is an attractive hypothetical bridge between the adverse intrauterine environment and preprogramming of the offspring towards senescent phenotypes [19][20][21], as an adverse intrauterine environment increases oxidative damage to feto-placental DNA and fetal vascular endothelium [22][23][24]. We have previously suggested that this mechanism could account for a senescent phenotype in the adult offspring of women with type 1 diabetes [25].…”