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Geriatr Gerontol Int 2016; 16 (Suppl. 1): 66–74
REVIEW ARTICLE
Telomere attrition and diabetes mellitus Yoshiaki Tamura,1 Kaiyo Takubo,2 Junko Aida,2 Atsushi Araki1 and Hideki Ito1 1
Department of Diabetes, Metabolism, and Endocrinology, Tokyo Metropolitan Geriatric Hospital, and 2Research Team for Geriatric Pathology and Department of Pathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan
Type 2 diabetes mellitus (DM) is a disease characterized by dysfunction of various organs. Recent studies have shown a close relationship between DM and telomere attrition in leukocytes. In patients with DM or impaired glucose tolerance, excessive oxidative stress induces damage to telomeres and shortens their length. Furthermore, it is suggested that telomere length is a good surrogate marker for mortality and diabetic complications in DM patients. We recently found that telomere length in pancreatic β-cells is also shortened in DM patients, potentially leading to an impaired capacity for proliferation and insulin secretion, and accelerated cell death. In contrast, leukocyte telomere length has also been reported in patients with obesity or insulin resistance, both of which are frequently associated with type 2 DM. In an animal model, it has been shown that telomere attrition in adipose tissue induces insulin resistance. Taken together, the available data suggest that hyperglycemia, oxidative stress, and telomere attrition in pancreatic β-cells and adipocytes create a vicious cycle that underlies the pathophysiology of type 2 DM. Inhibition of telomere attrition in various organs, including pancreatic β-cells, could be a new approach for preventing the progression of DM and its complications. Geriatr Gerontol Int 2016; 16 (Suppl. 1): 66–74. Keywords: diabetes mellitus, insulin resistance, oxidative stress, pancreatic β-cell, telomere.
Introduction In developed societies worldwide, there has been an explosive increase of patients with diabetes mellitus (DM). A report from the International Diabetes Federation has shown that there were 387 million individuals with DM in 2014, and that the figure is expected to rise to 592 million by 2035.1 Sustained hyperglycemia is a risk factor for various vascular complications, such as diabetic retinopathy and nephropathy, which significantly compromise the quality of life. Furthermore, medical care for DM is extremely costly; the International Diabetes Federation have reported that adult DM accounts for at least US$612 billion, or 11% of total health spending. Thus, from both an economic and public health viewpoint, control of the current DM “epidemic” is vitally important. DM is divided into two clinical types, type 1 DM (T1DM) and type 2 DM (T2DM). T2DM accounts for
Accepted for publication 22 December 2015. Correspondence: Dr Yoshiaki Tamura MD PhD, Department of Diabetes, Metabolism, and Endocrinology, Tokyo Metropolitan Geriatric Hospital, 35-2 Sakae-cho, Itabashi-ku, 173-0015 Tokyo, Japan. Email:
[email protected]
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the majority of DM patients, and is increasing rapidly in every country. In contrast to T1DM, in which pancreatic β-cells are damaged by an autoimmune process and their insulin secretory capacity is depleted completely, T2DM develops through multiple pathophysiological processes. These include insulin resistance associated with excess adiposity caused by excessive caloric consumption and insufficient exercise, and a relative shortage of insulin secretion from β-cells that is insufficient for systemic demand. The pathophysiology of DM shows an age-related aspect. First, the prevalence of DM increases with age.2 Second, many deleterious events that are associated with aging, such as atherosclerosis and cognitive dysfunction, are exacerbated and occur frequently in DM patients: transition to a high-risk category for cardiovascular diseases occurs approximately 15 years earlier than in individuals without DM,3 and life expectancy in both the Framingham Heart Study cohort in the USA and a Japanese cohort was shown to be shortened by 6–8 years.4,5 Therefore, it is imperative to clarify the mechanism whereby DM accelerates age-related dysfunction in various organs. To date, various key factors related to cellular aging have been identified. One of these is the telomere, a region of repetitive G-rich DNA at the ends of © 2016 Japan Geriatrics Society
Telomere attrition and DM
eukaryote chromosomes that protects the chromosomes from attrition and damage.6 Telomeres shorten with each cell division because of the end replication problem. Telomerase, an enzyme that prevents telomere shortening, consists of telomere reverse transcriptase (TERT) and a telomerase RNA component (TR). Telomerase is abundant in cancer cells and germ cells, but limited in somatic cells.7 When telomeres in a cell shorten beyond the critical threshold, the cell stops dividing. The telomere length of a cell represents how many times the cell has replicated, and thus can be regarded as a marker of cellular senescence. In the past decade, many studies have shown that patients with DM have shorter white blood cell telomeres than non-DM individuals.8,9 In addition, our group have reported quite recently that patients with T2DM also show telomere shortening in pancreatic β-cells.10 These results strongly indicate a close relationship between metabolic derangement and telomere attrition. In the present review, we first present the available evidence for the clinical relationship between telomere attrition and DM, glucose intolerance, and diabetic complications. We then discuss the influence of telomere attrition on the replication, function and survival of pancreatic β-cells, and its effect on adipocytes in relation to insulin resistance, based on our own data and those from studies using model animals with shortened telomeres. In the final section, we propose some possible strategies for prevention or slowing of telomere shortening.
Telomere shortening in leukocytes of patients with DM To date, many reports have described the association between telomere attrition and DM, in both T1DM11 and T2DM.8,9 Recently, in a meta-analysis of articles addressing the association between leukocyte telomere length (LTL) and T2DM, Zhao et al. concluded that there was a significant relationship between telomere shortening and T2DM (OR 1.17, 95%CI 1.002–1.246, P = 0.045, without heterogeneity).12 Such an association between decreased telomere length in leukocytes and T2DM was also found in a meta-analysis carried out by D’Mello (OR 1.37, 95% CI, 1.10–1.72).13 A further study showed that a shorter LTL was associated with a longer duration of DM.14
Mechanism of telomere attrition in patients with DM It is known that oxidative stress plays the key role in telomere attrition in DM patients. In such patients, pro© 2016 Japan Geriatrics Society
duction of reactive oxygen species (ROS) is increased. The causes of ROS overproduction are diverse. Hyperglycemia increases ROS from the mitochondrial electron transport chain. In addition, increased glucose auto-oxidation, activation of the polyol pathway and protein kinase C pathway, and production of advanced glycation end-products also play roles in increasing the level of oxidative stress.15 Such exacerbated oxidative stress accelerates the shortening of telomeres,16 and in fact Sampson et al. have reported that LTL is negatively correlated with the level of 8-hydroxy deoxyguanosine, a marker of oxidative DNA damage, in patients with T2DM.8 In DM, oxidative stress is increased in not only leukocytes, but also pancreatic β-cells, which could result in shortening of β-cell telomeres and subsequent dysfunction of insulin secretion, as discussed below.17 It is suspected that oxidative stress is also increased in adipocytes and muscle cells in patients with DM, and in fact Ay mice, which are characterized by excessive caloric intake resulting in obesity and DM, have higher ROS levels in adipose tissue.18 Furthermore, another report has shown that oxidative stress in muscle fibers might induce telomere shortening.19
Telomere attrition as a risk factor for onset of diabetes LTL is already reduced in individuals with impaired glucose tolerance, and this is recognized as a risk factor for the onset of DM.20 Three prospective cohort studies have investigated the degree to which LTL shortening is a risk factor for DM onset.21–23 The results were diverse, the relative risk being as high as two-fold in two of the studies,21,22 whereas the risk was fairly attenuated in postmenopausal women.23 Willeit et al. carried out a meta-analysis of these three studies and concluded that the relative risk of T2DM onset in subjects who were in the lowest quartile for telomere length was 1.31 relative to those in the top quartile.21 In contrast, Weischer et al. reported that the change in telomere length within a 10-year period was not associated with subsequent onset of DM.24 Further studies are required to clarify the relationship between chronological change in telomere length and the risk of DM.
Telomere attrition in relation to mortality and diabetic complications Many studies examining the relationship between telomere attrition and mortality or progression of diabetic complications in diabetic patients have suggested that telomere length could be a surrogate marker for mortality and morbidity. In a prospective follow-up study of T1DM patients, baseline LTL was associated with all-cause mortality.25 |
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In a cross-sectional study, T2DM patients with microalbuminuria showed a reduction of LTL relative to patients without microalbuminuria,26 whereas LTL did not differ between T1DM patients with and without diabetic nephropathy.27,28 However, a prospective study of T1DM patients showed that reduced LTL was a significant predictor of diabetic nephropathy progression.26 Telomere length is also associated with a risk of macro-vascular complications in diabetic patients.29 Cross-sectional studies of T2DM patients showed that those with previous myocardial infarction or atherosclerotic plaques detected by carotid artery ultrasonography had a more markedly reduced LTL than those without either.20,30 Besides its relationship with vascular complications, telomere shortening was recently shown to be associated with depression31 and periodontitis,32 which are now recognized as new complications of diabetes.
Telomere attrition and β-cell dysfunction Pancreatic β-cells differentiate from precursor cells during the prenatal period, but after birth they are supplied mainly by autoreplication.33 However, it has been shown that the replication capacity of β-cells decreases with aging,34,35 possibly as a result of telomere shortening, and in fact a previous report has shown that telomerase activity is associated with the proliferative capacity of β-cells. Liew et al. reported that both TERT expression and telomerase activity were upregulated in liver-specific insulin receptor-knockout mice, which show an accelerated proliferative capacity of β-cells. In contrast, TERT expression and telomerase activity were reduced in cyclin D2-knockout and β-cell-specific insulin receptor-knockout mice, which show a low β-cell proliferative capacity.36 Despite the difficulty in evaluating the telomere length of human β-cells, we recently succeeded in doing so using the quantitative fluorescence in situ hybridization method, which is highly accurate and reproducible,37 and discovered for the first time that the telomere length of β-cells decreases with age (manuscript submitted). Although there has been no report that proved the direct relationship between proliferative activity and telomerase/TERT expression in human pancreatic β-cells, as the patterns in age-related changes in Ki67 positive cell numbers in the report by Mizukami et al.35 and telomere length of human β-cells in our report seem extremely similar, it is highly assumed that TERT expression and telomerase activity could also be associated in human β-cells. The age-related pattern of telomere shortening of human β-cells is quite characteristic. Compared with our other data of ductal epithelial cells,38 telomere length in β-cells are originally shorter in infancy and decrease more rapidly before adulthood, whereas the reduction speed 68
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according to age is fairly blunted in adulthood. This means that the effect of aging itself on telomere shortening of β-cells in elderly DM patients might be relatively small. In order to clarify the effect of telomere shortening on β cell function, genetically modified animal models have been created and investigated. Kuhlow et al.39 and Guo et al.40 generated mice that were homozygotically (TR –/–) and heterozygotically (TR +/–) null for the TR gene, respectively, and both mouse strains showed reduced telomere length. Both models had impaired insulin secretion, although their insulin sensitivity was not altered. Although both strains showed impaired replication of β-cells, β-cell mass was intact in TR +/– mice, but decreased in TR –/– mice. However, as transduction of the TERT gene was not sufficient to prevent growth arrest of β-cells in cultured human islet cells,41 there might be other pathways independent of telomere shortening that connect aging with impaired β-cell proliferation. It has been reported that human T2DM patients show a reduction of β-cell mass.42 It is thought that accelerated cellular senescence; that is, irreversible arrest of cell growth, and apoptosis, a process of programmed cell death, are involved in this process. In a diet-induced animal model of DM, Sone et al. found that both senescent cells and apoptotic cells in pancreatic islets were increased.43 In that study, however, the proliferative activity of β-cells did not decline soon after the onset of DM. The proliferation and glucosestimulated insulin secretion of β-cells initially increased after 4 months of the diabetogenic diet, whereas both significantly declined after 12 months of the diet.43 Compensatory proliferation and high turnover of β-cells in DM could lead to accelerated β-cell senescence, and in fact at 12 months apoptotic cells in islets detected by Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining were significantly increased. Later, Kagawa et al. investigated the telomere lengths of β-cells in these mice by isolating the cells using a zinc-sensitive fluorescent probe and measuring their telomere length using quantitative polymerase chain reaction.44 They found that β-cell telomeres in mice fed a high-fat diet for 11 months were significantly shorter than those in mice fed a control diet.45 This result showed that telomere attrition in β-cells in DM could lead to accelerated cellular senescence and apoptosis. In Akita mice, a genetic animal model of non-obese DM, apoptotic β-cells are also increased, and a further increase of β-cell apoptosis in these mice with shortened telomeres (TR –/–) generated using an intergenerational strategy was also evident.40 Although the telomere and telomerase regulation is different between humans and rodents, this result suggested that telomere attrition had an additive effect on apoptotic β-cell death in DM. Recently, for the first time, we have measured the © 2016 Japan Geriatrics Society
Telomere attrition and DM
Figure 1 Representative fluorescence in situ hybridization images of specimens from a control and a patient with type 2 diabetes mellitus. (a,c) Islet sections from controls. (b,d) Islet sections from patients with diabetes. (a,b) Insulin-positive cells; β-cells are stained green in the cytoplasm. (c,d) Glucagon-positive cells; α-cells are stained pink in the cytoplasm. (a–d) Telomeres appear red and centromeres appear green in the nuclei. The normalized telomere–centromere ratio, an index of telomere length, was calculated by dividing the signal strength of telomeres by that of centromeres, and further normalized by the respective values for control cells, thus compensating for any variation in staining efficiency. (b,d) The relative signals of telomeres compared with centromeres are significantly weaker than in (a) and (c), respectively. Reproduced from Tamura et al.10 with permission.
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telomere length of pancreatic β- and α-cells using samples obtained from diabetic patients at autopsy, and compared them with those from individuals without DM. We found that telomeres were shortened in both β- and α-cells from DM patients, although the relative degree of attrition was significantly greater in β-cells (Figs 1,2).10 We also found a significant negative correlation between glycated hemoglobin (HbA1c) and β-cell telomere length (Fig. 3). In an autopsy study, Sakuraba et al. found that reduced β-cell mass in patients with DM was correlated with oxidative stress.42 This suggested that accumulated oxidative stress in islets induced telomere attrition in β-cells, subsequently having an additive influence on diabetes-induced accelerated senescence or apoptosis of β-cells. It is speculated that p53, a tumor suppressor gene product, could play a major role in the process connecting telomere shortening with accelerated senescence and apoptotic cell death. It is known that telomere attrition activates p53, and that this could induce both cellular senescence and apoptosis, resulting in cell loss.46 Furthermore, it has recently been shown that p53 in β-cells disturbs mitophagy, the process in which damaged mitochondria are degraded, and that this impairment results in mitochondrial dysfunction and impaired insulin secretion from β-cells.47 Shortened telomeres in β-cells could also induce accumulation of p16/INK4α, a cyclin-dependent kinase inhibitor, leading to cellular senescence.40 However, the mecha© 2016 Japan Geriatrics Society
nisms by which cellular senescence and apoptosis could be induced are highly diverse and complex. It has been reported that there are other pathways through which oxidative stress could induce apoptosis independently of telomere shortening, such as activation of apoptosis signal-regulating kinase 1 and subsequent activation of c-Jun N-terminal kinase/p38 mitogen-activated protein kinase.48 Further studies are required to clarify the mechanisms responsible for increased senescence and apoptosis of β-cells in DM.
Telomere attrition in obesity and insulin resistance Many T2DM patients have associated obesity and insulin resistance, which play a considerable role in the disease pathogenesis. A number of reports have shown a negative correlation between LTL and obesity parameters, such as body mass index, waist-hip ratio and visceral fat accumulation.49 Telomere attrition is also observed in obese individuals with adipocyte hypertrophy.50 It has been shown that ROS production in adipose tissue is increased in obesity, and that this could result in telomere shortening.51 However, only a few studies have investigated the relationship between telomere length in adipose tissue and glucose level or T2DM: one study found a negative correlation between subcutaneous adipose tissue telomere length and glycated hemoglobin (HbA1c);52 |
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(a)
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Figure 2 Telomere lengths of β- and α-cells in autopsy samples from controls and patients with type 2 diabetes mellitus. The normalized telomere–centromere ratio (NTCR) α and NTCRβ indicate NTCR for α and β-cells, respectively. Boxes represent the 25th and 75th percentiles, the bands inside the boxes are medians, and the whiskers are the 5th and 95th percentiles. Reproduced from Tamura et al.10 with permission.
whereas in contrast, another study found that telomeres in visceral adipose tissue were longer in T2DM.53 However, in DM patients, it is highly likely that adipocytes would have shortened telomeres, as senescence-associated β-galactosidase activity, a marker of cellular senescence, is increased.18 Further studies of this issue are warranted. 70
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Figure 3 Correlation between glycated hemoglobin (HbA1c) level and telomere lengths of β- and α-cells in autopsy samples. HbA1c represents the maximum HbA1c value ever recorded in each individual. Clear circles indicate control subjects and solid circles indicate patients with diabetes. Reproduced from Tamura Y et al.10 with permission.
Accumulated evidence now suggests that insulin resistance is also correlated with shortened telomeres. In two cross-sectional studies, one involving middleaged and elderly Caucasian men, and the other involving middle-aged Arabs, LTL was inversely correlated with homeostasis model assessment-insulin resistance, an indicator of insulin resistance.54,55 However, another study showed that in postmenopausal women, the inverse correlation between insulin resistance and LTL was more attenuated than in premenopausal women.56 In a prospective cohort study, although the participants were considerably younger, Gardner et al. reported that © 2016 Japan Geriatrics Society
Telomere attrition and DM
Figure 4 A schematic diagram showing relationships among diabetes mellitus, obesity and telomere attrition.
yearly change in homeostasis model assessment-insulin resistance was negatively correlated with yearly change in LTL.57 Although the causality of insulin resistance and telomere attrition has not been fully clarified, it might be expected that telomere attrition would be a cause, and not merely a marker, of insulin resistance, and that p53 would have a key role in the mechanism. Minamino et al. proved this using fourth-generation TERT-deficient mice (G4) that had shorter telomeres. They observed significant insulin resistance in G4 mice fed a high-fat, high-sucrose diet, whereas insulin sensitivity was not impaired in mice fed a normal diet.18 They also found that adipose tissue of G4 mice fed a high-fat, high-sucrose diet showed high expression of p53, and that removal of fat pads from the mice improved their insulin sensitivity, whereas implantation of fat pads into wild-type mice significantly impaired their insulin sensitivity. In contrast, inhibition of p53 in adipose tissue of diabetic model animals ameliorated their insulin sensitivity.18 Furthermore, a recent in vitro study has shown that inhibition of TERT expression in muscle cells reduced their basal glucose uptake, whereas overexpression of TERT significantly increased their glucose uptake.58 However, this effect of TERT occurs outside the nucleus through direct interaction of TERT with glucose transporters, and the effect of myocyte telomere shortening or elongation on insulin sensitivity should be examined further.
Relationships among DM, obesity and telomere attrition A schematic diagram of the relationships among DM, obesity and telomere attrition is shown in Figure 4. © 2016 Japan Geriatrics Society
Hyperglycemia induces systemic oxidative stress, including β-cells and adipocytes, whereas obesity induces oxidative stress in adipocytes. In both cell types, oxidative stress induces telomere attrition. Telomere attrition in β-cells further induces senescence and loss of β-cells, and impairment of insulin secretion, which leads to hyperglycemia. Telomere attrition in adipocytes further induces insulin resistance, which also leads to hyperglycemia. Thus, two vicious cycles are formed between hyperglycemia and telomere attrition, and p53 plays a crucial role in both processes.
Strategies to reverse telomere attrition and its deleterious effects Normalization of the glucose level might prevent telomere attrition. Uziel et al. reported that good glycemic control attenuated LTL reduction in patients with both T1DM and T2DM.59 Our own study showed that patients with T2DM who had used hypoglycemic agents showed greater reduction of β-cell telomere length than those who had not, but it remains unclear which drug(s) has an ameliorating or deleterious effect on telomere length.10 We have mainly used sulfonylurea for patients with DM.10 In β-cells, sulfonylurea might induce apoptosis,60 but it might also reduce telomere length. In contrast, a very recent report has shown that LTL was significantly increased in T2DM patients who were treated with a dipeptidyl peptidase-4 (DPP-4) inhibitor.61 Other studies have shown that pioglitazone upregulates telomerase activity in vascular cells in mice,62 and that use of statin is associated with a higher LTL value than non-statin use.63 These drugs have an anti-inflammatory effect as well as their effects on |
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glucose or lipid metabolism. Further studies are required to clarify the effects of specific drugs on telomere length. As obesity is another significant risk factor for telomere attrition, it is possible that lifestyle modification could prevent telomere attrition. Ornish et al. have reported that comprehensive lifestyle intervention, including changes in diet, exercise, stress management and social support, resulted in a higher LTL value than that in control subjects.64 A diet-specific, cross-sectional study showed that strict adherence to a Mediterranean diet was associated with longer LTL.65 Mediterranean diet is characterized by a high intake of olive oil, which has an anti-oxidative effect, and this might have contributed to the favorable outcome. With regard to exercise, although only a few studies have investigated its effect on telomere length, a cross-sectional study showed the older endurance-trained athletes had longer muscle telomeres than non-athletes, suggesting a positive effect of exercise on telomere length.66 Stress management might also exert a protective effect; one report has shown that meditation training increased telomerase activity.67 However, as these results were obtained using only leukocytes, it is unclear whether these lifestyle modifications have the same effects on β-cells and adipocytes. The ultimate goal for treatment of disorders related to telomere attrition is direct modification of telomererelated genes. TERT overexpression in cancer-resistant mice improves glucose tolerance.68 However, as aforementioned, transduction of the TERT gene failed to prevent growth arrest of β-cells in cultured human islet cells.41 The other target of gene therapy is p53. In adipocyte-specific p53-deficient mice, insulin resistance induced with a high-fat, high-sucrose diet was attenuated,18 and a recent study has shown that p53-knockout mice treated with streptozocin were resistant to hyperglycemia, the dysfunction of insulin secretion from β-cells being mild.69 These results show that drugs triggering telomerase activation or p53 inhibition in β-cells or adipocytes could have beneficial effects for glucose normalization. However, modification of these genes should be carried out with caution because of their known role in carcinogenesis.
Disclosure statement Dr. AA received lectures fees from MSD K.K., Takeda Pharmaceutical Company Limited., Novaritis Pharma K.K., Eli Lilly Japan K.K., and Nippon Boehringer Ingelheim Co., Ltd.
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