OBJECTIVE -Telomeres are DNA sequences necessary for DNA replication, which shorten at cell division at a rate related to levels of oxidative stress. Once shortened to a critical length, cells are triggered into replicative senescence. Type 2 diabetes is associated with oxidative DNA damage, and we hypothesized that telomere shortening would characterize type 2 diabetes.RESEARCH DESIGN AND METHODS -We studied 21 male type 2 diabetic subjects (mean age 61.2 years, mean HbA 1c 7.9%) selected to limit confounding effects on telomere length and 29 matched control subjects. Telomere length was measured in peripheral venous monocyte and T-cells (naïve and memory) by fluorescent in situ hybridization and oxidative DNA damage by flow cytometry of oxidized DNA bases. Peripheral insulin resistance (homeostasis model assessment) and high-sensitivity C-reactive protein (hsCRP) were measured.RESULTS -Mean monocyte telomere length in the diabetic group was highly significantly lower than in control subjects (4.0 [1.1] vs. 5.5 [1.1]; P Ͻ 0.0001), without significant differences in lymphocyte telomere length. There was a trend toward increased oxidative DNA damage in all diabetes cell types examined and a significant inverse relationship between oxidative DNA damage and telomere length (r ϭ Ϫ0.55; P ϭ 0.018) in the diabetic group. Telomere length was unrelated to plasma CRP concentration or insulin resistance.CONCLUSIONS -Monocyte telomere shortening in type 2 diabetes could be due to increased oxidative DNA damage to monocyte precursors during cell division. This data suggests that monocytes adhering to vascular endothelium and entering the vessel wall in type 2 diabetes are from a population with shorter telomeres and at increased risk of replicative senescence within vascular plaque. Diabetes Care 29:283-289, 2006T elomeres are tandem repeats of the DNA sequence TTAGGG extending over 6 -15 kb at the end of eukaryotic chromosomes and are necessary for both successful DNA replication and chromosomal integrity (1-3). Telomeres in somatic human cells shorten by 30 -200 bp each cell division, and once shortened to a critical length, cells are triggered into replicative senescence, an irreversible cell cycle block in G0/G1 (1-5) where cells function differently (1,2,5,6) and are more likely to undergo apoptosis if exposed to increased oxidative insult (7). Rates of telomere shortening, and therefore telomere length, are highly dependent on oxidatively induced strand breaks in telomeric DNA and on cellular oxidant balance (1)(2)(3)5,6,8,9), and we and others have shown that lymphocyte DNA from subjects with type 2 diabetes is characterized by increased susceptibility to oxidative damage (10 -12). Telomeric DNA is particularly prone to oxidative damage at the GGG sequence (13,14), and it is probable that oxidatively induced single-and double-strand DNA breaks in people with type 2 diabetes (10 -12) would translate into accelerated telomere shortening and a progression to replicative senescence (1-3). Many of the dysf u n c t i o n s...

The normal degree of intra- and interindividual variation in gene transcription profiles of healthy human tissues has not been extensively investigated. In the study described here, microarrays were employed to analyze gene transcription in peripheral blood mononuclear cells prepared from serial blood samples that had been obtained, at weekly intervals, from apparently healthy human volunteers. Transcript levels for the majority of genes examined were found to be remarkably consistent within samples from a single donor. Conversely, marked differences were observed in samples obtained from different donors. Genes that exhibited differential expression dependent on sex, age, body mass index, and the presence of varying proportions of different leukocyte subsets were identified. These results emphasize the important contributions of genetic and environmental factors, as well as varying representation of different cell types, in determining the overall gene transcriptional profiles of human tissues. However, the study also provides evidence that, within an individual, the gene transcription profiles of sampled tissues can be comparatively stable over time.

Background Epidemiological evidence suggests that consumption of cruciferous vegetables is associated with reduced risk of prostate cancer progression, largely attributed to the biological activity of glucosinolate degradation products, such as sulforaphane derived from glucoraphanin. Because there are few therapeutic interventions for men on active surveillance for prostate cancer to reduce the risk of cancer progression, dietary approaches are an appealing option for patients. Objective We evaluated whether consumption of a glucoraphanin-rich broccoli soup for 1 y leads to changes in gene expression in prostate tissue of men with localized prostate cancer. Methods Forty-nine men on active surveillance completed a 3-arm parallel randomized double-blinded intervention study for 12 mo and underwent transperineal template biopsy procedures and dietary assessment at the start and end of the study. Patients received a weekly 300 mL portion of soup made from a standard broccoli (control) or from 1 of 2 experimental broccoli genotypes with enhanced concentrations of glucoraphanin, delivering 3 and 7 times that of the control, respectively. Gene expression in tissues from each patient obtained before and after the dietary intervention was quantified by RNA sequencing followed by gene set enrichment analyses. Results In the control arm, there were several hundred changes in gene expression in nonneoplastic tissue during the 12 mo. These were associated with an increase in expression of potentially oncogenic pathways including inflammation processes and epithelial–mesenchymal transition. Changes in gene expression and associated oncogenic pathways were attenuated in men on the glucoraphanin-rich broccoli soup in a dose-dependent manner. Although the study was not powered to assess clinical progression, an inverse association between consumption of cruciferous vegetables and cancer progression was observed. Conclusion Consuming glucoraphanin-rich broccoli soup affected gene expression in the prostate of men on active surveillance, consistent with a reduction in the risk of cancer progression. This trial was registered at clinicaltrials.gov as NCT01950143.