High-normal serum uric acid predicts macrovascular events in patients with type 2 diabetes mellitus without hyperuricemia based on a 10-year cohort.

BACKGROUND AND AIMS: The upper limits of normal serum uric acid (SUA) or the lower limits of hyperuricemia were frequently set at 420 or 360 µmol/L (7.0 or 6.0 mg/dL). We aimed to explore the association between high-normal SUA (360 ≤ SUA≤420 µmol/L) and incidence of macrovascular and renal events based on a 10-year cohort with type 2 diabetes mellitus (T2DM) to explore which cut-off was more appropriate. METHODS AND RESULTS: A total of 2988 patients with T2DM without hyperuricemia (SUA≤420 µmol/L) were included and followed up. Cox proportional hazards models and restricted cubic spline regression were used to evaluate the relationship between baseline SUA (as continuous and categorical variable) and macrovascular and renal events. Patients were grouped as low-normal (SUA<360 µmol/L) and high-normal groups based on baseline SUA, and the latter group had higher incidence of macrovascular events. Multivariate Cox regression analysis indicated that baseline levels of SUA were significantly associated with cardiovascular (HR = 1.385, 95%CI:1.190-1.613, P < 0.001) and peripheral vascular events (HR = 1.266, 95%CI:1.018-1.574, P = 0.034), and the linear association existed. Moreover, fully adjusted multivariable Cox analyses indicated high-normal SUA increased the risks of cardiovascular (HR = 1.835, 95%CI:1.319-2.554, P < 0.001) and peripheral vascular events (HR = 1.661, 95%CI:1.000-2.760, P = 0.050) compared to low-normal SUA. CONCLUSIONS: Baseline SUA levels were positively associated with cardiovascular and peripheral vascular events, and high-normal SUA increased the risks of these events in patients with T2DM even without hyperuricemia. A threshold value for SUA of 360 µmol/L should be more appropriate in terms of predicting macrovascular events risks compared to the value of 420 µmol/L.

Angiotensin(1-7) attenuates visceral adipose tissue expansion and lipogenesis by suppression of endoplasmic reticulum stress via Mas receptor.

BACKGROUND: White adipose tissue can be classified based on its location as subcutaneous and visceral fat, and the latter accumulation is reported to be more detrimental to metabolism. Endoplasmic reticulum (ER) stress has been demonstrated to regulate lipogenesis. The peptide angiotensin(1-7) [Ang(1-7)], which can be produced from angiotensin II (AngII) by angiotensin-converting enzyme 2 (ACE2), plays its role through Mas receptor, also participates in the regulation of lipid metabolism in adipose tissue, however, whether ER stress is involved in the mechanism remains unclear. Therefore, we aimed to explore the role of Ang(1-7) pathway in regulating visceral adipose tissue expansion and ER stress. METHODS: ACE2 knockout (KO), Mas KO and C57BL/6 J mice were fed with high fat diet. Db/db mice were treated with either normal saline, Ang(1-7) or Ang(1-7) combined with Mas receptor inhibitor A779 using mini osmotic pumps. Fat mass was weighted, fat distribution was evaluated by MRI, and lipid profile and adipokines in epididymal adipose tissue were measured by ELISA kits, and histology of epididymal adipose tissue was also analyzed in multiple animal models. Additionally, differentiated 3T3-L1 cells were pre-loaded with palmitic acid to induce ER stress, then treated with drugs as those administrated to db/db mice. ER stress and lipogenesis related proteins in mice adipose and differentiated 3T3L-1 cells were analyzed by Western blot. RESULTS: ACE2 or Mas KO mice exhibited increased visceral adipose tissue, adipocyte size and protein expression of lipogenesis and ER stress related markers in epididymal adipose tissue compared to wild-type mice. Db/db mice treated with Ang(1-7) displayed decreased visceral fat mass, adipocyte size and protein expression of lipogenesis and ER stress markers in epididymal adipose tissue compared to those treated with normal saline, while A779 partly attenuated these effects. Additionally, Ang(1-7) improved ER stress and lipogenesis markers in differentiated 3T3-L1 cells pre-loaded with palmitic acid. CONCLUSIONS: Our findings indicated that Ang(1-7) attenuated visceral adipose tissue expansion and lipogenesis by suppression of ER stress via Mas receptor. The present study provides a potential perspective for Ang(1-7) for the therapeutics of obesity and related disorders.

Effect of Hemoglobin A1c Trajectories on Future Outcomes in a 10-Year Cohort With Type 2 Diabetes Mellitus.

Background: Hemoglobin A1c (HbA1c) variability may be a predictor of diabetic complications, but the predictive values of HbA1c trajectories remain unclear. We aimed to classify long-term HbA1c trajectories and to explore their effects on future clinical outcomes in a 10-year cohort with type 2 diabetes mellitus (T2DM). Methods: A total of 2,161 participants with T2DM from the Beijing Community Diabetes Study were included. The 10-year follow-up was divided into two stages for the present data analysis. Stage I (from 2008 to 2014) was used to identify the HbA1c trajectories and to calculate the adjusted SD of HbA1c (HbA1c-adjSD), or the coefficient of variation of HbA1c (HbA1c-CV). Stage II (from 2014 to 2018) was used to collect the records of the new occurrence of diabetes-related clinical outcomes. Latent growth mixture models were used to identify HbA1c trajectories. Cox proportional hazards models were used to explore the relationship between HbA1c trajectories, HbA1c-adjSD, or HbA1c-CV and the future outcomes. Results: Three HbA1c trajectories were identified, including low stable (88.34%), gradual decreasing (5.83%), and pre-stable and post-increase (5.83%). Either the risk of death or the chronic complications were significantly higher in the latter two groups compared to the low stable group after adjustment for average HbA1c and other traditional risk factors, the adjusted hazard ratios (HRs) for renal events, composite endpoint, and all-cause death for the pre-stable and post-increase group were 2.83 [95%CI: 1.25-6.41, p = 0.013], 1.85 (95%CI: 1.10-3.10, p = 0.020), and 3.01 (95%CI: 1.13-8.07, p = 0.028), respectively, and the adjusted HR for renal events for the gradual decreasing group was 2.37 (95%CI: 1.08-5.21, p = 0.032). In addition, both univariate and multivariate Cox HR models indicated that participants in the fourth and third quartiles of HbA1c-CV or HbA1c-adjSD were at higher risk of renal events compared to participants in the first quartile. Conclusions: HbA1c trajectories, HbA1c-CV, and HbA1c-adjSD could all predict diabetes-related clinical outcomes. HbA1c trajectories could reflect long-term blood glucose fluctuation more intuitively, and non-stable HbA1c trajectories may predict increased risk of renal events, all-cause death, and composite endpoint events, independent of average HbA1c.

Hemoglobin A1c modifies the association between triglyceride and time in hypoglycemia determined by flash glucose monitoring in adults with type 1 diabetes: implications for individualized therapy and decision-making.

BACKGROUND: We aimed to investigate the associations of flash glucose monitoring (FGM)-derived metrics with lipid profiles and identify potential modifiers of these associations among adults with type 1 diabetes (T1D). METHODS: A cross-sectional study was conducted among 108 Chinese adults with T1D who used FGM for 14 consecutive days. The relationship between FGM-derived metrics and lipid variables and potential modifiers were identified using interaction and subgroup analysis. RESULTS: Serum triglyceride level inversely correlated with time below range (glucose <3.9 mmol/L) and time in range (glucose 3.9-10.0 mmol/L) and positively correlated with time above range (glucose >10.0 mmol/L) (Spearman's r=-0.34, -0.25, 0.34, respectively, all P<0.01). Additionally, triglyceride levels had positive correlation with absolute measures of glycemic variability (GV) but not with the coefficient of variation for glucose (Spearman's r=0.12, P>0.05), a relative measure. Multivariate linear regression analysis adjusting for potential confounders including gender, age, disease duration, body mass index (BMI), daily insulin dose, fasting C-peptide, and dyslipidemia medication use showed that higher triglyceride level independently predicted decrease in time below range and time in range and increase in time above range (all P<0.01). Furthermore, interaction analysis found that the interaction between HbA1c and triglyceride was significant in the time below range (P for interaction =0.034). The association between triglyceride and time below range differed substantially after stratification by HbA1c, which was significant in those with HbA1c <7.0% whereas inconsequential among those with HbA1c ≥7.0%. In those with HbA1c <7.0% (n=44), the area under receiver operating characteristic curve of triglyceride predicting achievement of targets of time below range (<4%) was 0.856 (95% confidence interval 0.688-1.000, P=0.042) with an optimal cutoff value of 0.50 mmol/L (sensitivity 100%, specificity 66.7%, positive predictive value 94.4%). CONCLUSIONS: In adults with T1D, HbA1c may be a potential modifier of the association between triglyceride and time below range, suggesting it might be necessary for those with HbA1c <7.0% accompanied by lower triglyceride levels to set a less intensive glycemic target to minimize risk of hypoglycemia.

Association between glucose fluctuation during 2-hour oral glucose tolerance test, inflammation and oxidative stress markers, and ß-cell function in a Chinese population with normal glucose tolerance.

BACKGROUNDS: Glucose fluctuation (GF) may have detrimental effects in individuals with diabetes; however, clinical data on the association between short-term GF, inflammation/oxidative stress markers, and islet ß-cell function based on a population with normal glucose tolerance (NGT) are insufficient. Therefore, we aimed to explore these associations in a Chinese population of 209 individuals with NGT in a cross-sectional analysis. METHODS: Individuals were categorized based on GF tertiles, calculated as the maximum-minimum glucose levels among four time points (0, 30, 60, 120 min) during 2-hour oral glucose tolerance test (OGTT). Plasma inflammation markers tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), and oxidative stress markers superoxide dismutase (SOD), and 8-oxo-2'-deoxyguanosine (8-oxo-dG) were measured. Islet ß-cell function was estimated according to the disposition index (DI) at the early (30 min) and total (120 min) phase of the OGTT, adjusted for insulin sensitivity. RESULTS: Individuals in the middle and highest tertile of GF had reduced ß-cell function, and increased plasma SOD and TNF-α levels compared with those in the lowest tertile of GF (P<0.05). Multiple linear regression analysis indicated that GF was positively associated with TNF-α, 8-oxo-dG and SOD levels, but negatively associated with ß-cell function, whereas IL-6, TNF-α, 8-oxo-dG and SOD levels were negatively associated with ß-cell function (P<0.05). CONCLUSIONS: GF may increase inflammation and oxidative stress markers in individuals with NGT, which could contribute to reduced ß-cell function. Thus, maintaining glucose stability after a meal may have beneficial effects on delaying ß-cell dysfunction, suggesting that diet and exercise strategies to decrease diet related GF are warranted.

C-Peptide: A Mediator of the Association Between Serum Uric Acid to Creatinine Ratio and Non-Alcoholic Fatty Liver Disease in a Chinese Population With Normal Serum Uric Acid Levels.

Background: The data on the relationship between normal-ranged serum uric acid (SUA), ß-cell function, and non-alcoholic fatty liver disease (NAFLD) are complicated and insufficient. Moreover, uric acid is excreted by kidney, and SUA levels may be affected by renal function. Thus, we introduced a renal function-normalized index [serum uric acid to creatinine ratio (SUA/Cr)] into the study and explored the association between SUA/Cr, C-peptide and NAFLD in a Chinese population with normal SUA levels by a cross-sectional analysis. Materials and Methods: A total of 282 individuals with normal SUA levels and different glucose tolerance status from a diabetes project were included in the study (mean age = 53.7± 10.5 years; women = 64.50%). NAFLD was diagnosed by abdominal ultrasonography (NAFLD, n=86; without NAFLD, n=196). Trapezoid formula was used to calculate area under the curve of C-peptide (AUCCP) from 4 points (including 0, 30,60, and 120min) during 2-h oral glucose tolerance test. Spearman correlation analysis was used to explore the correlation between SUA/Cr, AUCCP and NAFLD risk factors. Multiple logistic regression analysis was used to explore the association between SUA/Cr or AUCCP and NAFLD. Mediation analysis was used to explore whether AUCCP mediated the association between SUA/Cr and NAFLD. Results: Individuals with NAFLD had significantly higher SUA/Cr and AUCCP than those without NAFLD(P<0.05). Spearman correlation analysis showed that both SUA/Cr and AUCCP were significantly associated with many NAFLD risk factors, and SUA/Cr was positively correlated with AUCCP (P<0.05). Multiple logistic regression analysis indicated that SUA/Cr and AUCCP were positively associated with NAFLD incidence (P<0.05). Medication analysis indicated that SUA/Cr had a significant direct effect on NAFLD (ß =0.5854, 95% CI: 0.3232-0.8966), and AUCCP partly mediated the indirect effect of SUA/Cr on NAFLD incidence (ß =0.1311, 95% CI: 0.0168-0.4663). Conclusions: SUA/Cr was positively associated with NAFLD incidence, and AUCCP partly mediated the association in a Chinese population with normal SUA levels. Thus, we should pay more attention to high-normal SUA and C-peptide levels due to their predictive power in NAFLD incidence.

Association Between Leukocyte Mitochondrial DNA Copy Number and Non-alcoholic Fatty Liver Disease in a Chinese Population Is Mediated by 8-Oxo-2'-Deoxyguanosine.

Background: Alterations in mitochondrial DNA are potentially associated with oxidative stress and may be involved in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, the association between mitochondrial DNA copy number (mtDNAcn) and NAFLD was not consistent. In addition, the association between inflammation and NAFLD has not been established yet. The present study, based on a Chinese population of individuals with different glucose statuses, aimed to explore the association between leukocyte mtDNAcn, markers of oxidative stress, and inflammation and NAFLD. Methods: A total of 318 participants from a diabetes project were included. NAFLD was diagnosed by ultrasonography. Leukocyte mtDNAcn was determined by PCR assay. The levels of the inflammation markers tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) and the oxidative stress markers glutathione reductase (GR), superoxide dismutase (SOD), and 8-oxo-2'-deoxyguanosine (8-oxo-dG) were also measured. Results: Participants with NAFLD (n = 105) exhibited significantly higher leukocyte mtDNAcn, IL-6, and 8-oxo-dG (all P < 0.05). Pearson correlation analysis indicated mtDNAcn was negatively associated with age, uric acid, SOD, and TNF-α, but was positively associated with 8-oxo-dG (all P < 0.05). Univariate logistic regression analysis revealed that mtDNAcn was positively associated with NAFLD [odds ratio (OR) = 1.617, 95% confidence interval (CI) = 1.036-2.525; P = 0.034]. However, after adjustment for 8-oxo-dG, this association was no longer statistically significant (OR = 1.534, 95% CI = 0.979-2.403, P = 0.062). Moreover, the stress marker 8-oxo-dG was independently associated with NAFLD after adjustment for mtDNAcn, IL-6, glucose tolerance status, and other conventional NAFLD risk factors (OR = 1.707, 95% CI =1.142-2.550, P = 0.009). Mediation analysis indicated that 8-oxo-dG fully mediated the effect of mtDNAcn on the incidence of NAFLD (direct effect ß = 0.5221, 95% CI = -0.0648 to 1.2504; indirect effect ß = 0.0946, 95% CI = 0.0049-0.2463). Conclusions: In a Chinese population, the association between leukocyte mtDNAcn and NAFLD was fully mediated by high levels of 8-oxo-dG. Thus, oxidative stress may be an important driver of NAFLD, and clinical interventions aimed at decreasing oxidative stress to improve NAFLD warrant further research.

Negative association between antioxidant vitamin intake and non-alcoholic fatty liver disease in Chinese non-diabetic adults: mediation models involving superoxide dismutase.

We aimed to explore the association between antioxidant vitamin intake, oxidative stress related markers and non-alcoholic fatty liver disease (NAFLD) by a cross-sectional analysis. A total of 241 non-diabetic participants from a Chinese rural cohort were included. NAFLD was diagnosed by abdominal ultrasound (NAFLD, n = 71; Non-NAFLD, n = 171). Dietary intake was assessed by a 24-h food recall. Plasma oxidative stress related markers superoxide dismutase (SOD), glutathione reductase (GR) and 8-oxo-2'-deoxyguanosine(8-oxo-dG) were measured. The association between dietary antioxidant vitamin intake, oxidative stress related markers and NAFLD were analysed by Spearman correlation analysis and multiple logistic regression analysis. Mediation models were established to examine whether SOD mediated the association between dietary vitamin A or α-tocopherol intake and NAFLD. Spearman correlation analysis indicated that dietary vitamin A and α-tocopherol intake were positively correlated with SOD (p < .05). Multiple logistic regression analysis found plasma SOD, dietary vitamin A and α-tocopherol intake were inversely associated with NAFLD (all p < .05). Mediation analysis indicated that SOD significantly mediated the indirect effect of dietary α-tocopherol (mediated effect = 13.21% total effect) or vitamin A (mediated effect = 3.12% total effect) intake on NAFLD. Our study indicated that dietary vitamin A and α-tocopherol intake may contribute to protect from NAFLD in Chinese non-diabetics, and the associations were partly mediated by SOD. However, SOD only accounted for a minor percentage of the association between vitamin A intake and NAFLD. Thus, other mechanisms underlying antioxidant vitamin' protective effect on NAFLD need further exploration.

Negative Association between Caloric Intake and Estimated Glomerular Filtration Rate in a Chinese Population: Mediation Models Involving Mitochondrial Function.

BACKGROUND: With the shortening of leukocyte telomere length (LTL) and decrease in the copy number of mitochondrial DNA, mitochondrial dysfunction and oxidative stress are considered important drivers of the aging process. Although previous experimental studies report that caloric intake is associated with age-related renal dysfunction through the changes in mitochondrial function, there are insufficient epidemiological data to establish this association. OBJECTIVE: We aimed to explore the association between caloric intake and renal function and to investigate whether mitochondrial DNA copy number (mtDNAcn) mediated this association by cross-sectional analysis. METHODS: A total of 403 individuals from a Chinese rural cohort (women = 66.50%; mean age = 53.94 ± 10.27 years) with an estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 and with differences in the glucose tolerance status (diabetes, n = 106; prediabetes, n = 125; normal glucose tolerance, n = 172) were included. Dietary data were obtained by a 24-h food recall, and caloric intake was normalized by ideal body weight. The mtDNAcn and LTL were detected using real-time PCR assay. The associations between caloric intake, aging markers, and renal function were analyzed by partial correlation analysis and multiple linear regression analysis. Mediation analysis was applied to examine the role of mtDNAcn in the association between caloric intake and eGFR. RESULTS: Caloric intake was higher while age-adjusted mtDNAcn was lower in individuals with eGFR <90 mL/min/1.73 m2 (n = 140) than in those with eGFR ≥90 mL/min/1.73 m2 (n = 263). After adjusting for multiple factors, linear regression analysis revealed that caloric intake was negatively associated with eGFR and mtDNAcn, while mtDNAcn was positively associated with eGFR. Moreover, mediation analysis indicated that the indirect effect of caloric intake on eGFR through mtDNAcn was significant (ß = -0.0505, 95% confidence interval -0.0931 to -0.0190). CONCLUSIONS: Caloric intake was negatively associated with eGFR in a Chinese population, and the association was partly mediated by decreased mtDNAcn.

Low glucose enhanced metformin's inhibitory effect on pancreatic cancer cells by suppressing glycolysis and inducing energy stress via up-regulation of miR-210-5p.

To explore mechanisms underlying the discrepancy in anti-tumor effects of metformin on pancreatic cancer cells PANC-1 under different glucose conditions. We cultured PANC-1 cells in 25 mM and 5 mM glucose media, then treated with or without metformin. It showed that metformin significantly inhibited proliferation and viability, induced apoptosis of PANC-1 cells, which was more pronounced in low-glucose than in high-glucose group. Metformin up-regulated the expression of miR-210-5p in low glucose, but not in high glucose. miR-210-5p mimic inhibited the viability of PANC-1 cells and further enhanced the inhibitory effect of metformin. miR-210-5p down-regulated the expression of PFKFB2, a predicted target gene of miR-210-5p, reduced the activity of PFK1 and LDH. Metformin significantly inhibited the expression of phosphorylation-PFKFB2(p-PFKFB2) in the low-glucose group and inhibited the LDH activity both in the low and high glucose groups, thus inhibiting anaerobic glycolysis and inducing energy stress. Cells in the high glucose group could make a compensatory adaptation to the energy stress induced by metformin through increasing glucose consumption. However, due to the limited glucose supply and high dependence on anaerobic glycolysis of cells in the low glucose group, they couldn't make effective adaptive compensation. Therefore, cells in the low-glucose group were more vulnerable to the toxicity of metformin. In conclusion, the enhanced inhibitory effect of metformin on PANC-1 cells cultured in low glucose may be due to the up-regulation of the expression of miR-210-5p, then inhibiting anaerobic glycolytic flux and inducing energy stress via repressing the expression of p-PFKFB2 and activity of LDH. ABBREVIATIONS: PC: pancreatic cancer; DM: diabetes mellitus; PFKFB2: 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase2; PFK1: phosphofructokinases; LDH: lactate dehydrogenase; F-2,6-BP: fructose 2,6-bisphosphate.

Relationship between Decreased Serum Superoxide Dismutase Activity and Metabolic Syndrome: Synergistic Mediating Role of Insulin Resistance and ß-Cell Dysfunction.

The interplays of cellular aging and oxidative stress (OS) markers form a complex network, which has been reported to be interrelated with numerous age-related and metabolic diseases, including metabolic syndrome (MS). However, given the multifactorial mechanisms of MS, several important confounders such as dietary factors and the reciprocal effect among these markers have not been considered and adjusted in previous investigations regarding the associations of cellular aging and OS markers with MS and its related metabolic abnormalities. To explicate this, we conducted a cross-sectional study among 533 Chinese adults. All the participants underwent a 75 g oral glucose tolerance test. Dietary data were collected via a 24-hour dietary recall and subsequently analyzed by a registered dietitian using nutrition calculation software. Clinical diagnosis of MS was made according to the revised National Cholesterol Education Program Adult Treatment Panel III criteria (2004) with waist circumference cutoff modified for an Asian population. The leukocyte telomere length, mitochondrial DNA copy number, 8-hydroxy-2-deoxyguanosine, superoxide dismutase (SOD) activity, and glutathione reductase were examined. SOD activity was significantly decreased in MS subjects (62.06 ± 16.89 U/mL vs. 56.25 ± 22.61 U/mL, P = 0.001) and exhibited a descending trend across sequential increase of MS component number (P for trend = 0.031). SOD activity is modestly correlated with glucose indicators and insulin sensitivity and ß-cell function indices and was independently and negatively correlated with the level of triglyceride. An independent association between SOD activity and MS was observed after adjusting for metabolic indicators, dietary factors, cellular aging, and OS markers, as well as insulin sensitivity and ß-cell function indices. However, the statistical significance of the association between SOD activity and MS was attenuated after adjusting for the Matsuda insulin sensitivity index (ISIM) and insulin secretion-sensitivity index-2 (ISSI-2), suggesting a possible mediating effect. Therefore, we conducted a mediation model analysis, which showed that decreased ISIM and ISSI-2 partially and synergistically mediated the contribution of decreased SOD activity to MS. In conclusion, decreased SOD activity is an independent predictor for increased risk of MS, and insulin resistance and ß-cell dysfunction partially mediate the relationship between decreased SOD activity and MS.

Potential Protective Effect of Dietary Intake of Non-α-Tocopherols on Cellular Aging Markers Mediated by Tumor Necrosis Factor-α in Prediabetes: A Cross-Sectional Study of Chinese Adults.

It remains unknown how different glucose tolerance status affects the relationships between dietary intake of different tocopherol isoforms (α-, ß-, γ-, and δ-tocopherol) and cellular aging, oxidative stress, and inflammatory markers. The authors conducted a cross-sectional study among 582 Chinese adults with different glucose tolerance status to explore the association between dietary intake of different tocopherol isoforms and cellular aging, oxidative stress, and inflammatory markers. The inverse correlations between non-α-tocopherols and tumor necrosis factor-alpha (TNF-α) varied substantially across different glucose tolerance status, with the strongest observed in prediabetes (r = -0.33 for ß-/γ-tocopherol, r = -0.37 for δ-tocopherol, p < 0.01), followed by normal glucose tolerance (NGT). While such correlations were abolished in established diabetes. Furthermore, within prediabetes, the strongest inverse correlations between non-α-tocopherols and TNF-α were observed in impaired fasting glucose (IFG) (r = -0.42 for ß-/γ-tocopherol, r = -0.55 for δ-tocopherol, p < 0.01), while such correlations were significantly attenuated in individuals with impaired glucose tolerance (IGT) and IFG+IGT. And mediation model analysis displayed that TNF-α mediated the protective effect of non-α-tocopherols on leukocyte telomere length and mitochondrial DNA copy number, which was uniquely observed in prediabetes, while such mediation effect was statistically nonsignificant in NGT and established diabetes. In conclusion, our findings indicate that dietary intake of non-α-tocopherols might protect against cellular aging markers mediated by TNF-α in prediabetes. Individuals with prediabetes, especially for IFG, might benefit from increasing dietary intake of non-α-tocopherol in alleviating inflammation and cellular aging, which might provide a new dietary avenue for delaying diabetes onset.

Leukocyte Telomere Length Independently Predicts 3-Year Diabetes Risk in a Longitudinal Study of Chinese Population.

Cellular aging markers, including telomere length and mitochondrial function, as well as oxidative stress and inflammation markers influence each other and form a complex network, which is affected in diabetes. However, it remains unknown whether these markers could independently predict future diabetes after adjustment for their mutual effects. We conducted a 3-year longitudinal study in a Chinese cohort that comprised 108 nondiabetic individuals at baseline. The 2-hour 75 g oral glucose tolerance tests were performed at baseline and at 3-year follow-up. At baseline, leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNAcn) in leukocytes were determined using the polymerase chain reaction method. Tumor necrosis factor (TNF-α), interleukin-6, 8-hydroxy-2-deoxyguanosine levels, and superoxide dismutase (SOD) activity were measured by the enzyme-linked immunosorbent assay. Participants who developed diabetes at the 3-year follow-up (n = 28) had shorter LTL and higher levels of TNF-α and SOD activity at baseline. Baseline LTL was found to be independently associated with the development of diabetes at the 3-year follow-up after the adjustment for mtDNAcn, markers of oxidative stress and inflammation, and conventional diabetes risk factors. Our findings suggest that LTL is an independent predictor for 3-year diabetes risk, which might inform timely prevention and treatment of diabetes. Telomere shortening might be involved in the pathogenesis of diabetes independently of conventional diabetes risk factors, mtDNAcn, or oxidative stress and inflammation pathways.