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Aims/hypothesis Low-grade inflammation and endothelial dysfunction may play a role in the pathogenesis of type 2 diabetes and cardiovascular disease. We evaluated whether a diet high in fatty fish, bilberries and wholegrain products (Healthy Diet) improves biomarkers reflecting inflammation and endothelial dysfunction in individuals with impaired glucose metabolism. Methods We recruited individuals with impaired glucose metabolism and features of the metabolic syndrome into a 12 week, parallel design, dietary intervention trial conducted at the Department of Clinical Nutrition, University of Eastern Finland (Kuopio, Finland). Randomisation was performed by matching according to sex and medians of age, BMI and fasting plasma glucose of the study population at screening. The primary endpoint in the present study was the change in plasma inflammatory markers and the measurements were performed blinded to group assignment. High-sensitivity (hs) C-reactive protein (CRP) and E-selectin responses were also analysed separately in participants not using statins ( n  = 76). Results Altogether, 131 individuals were assigned to either the Healthy Diet ( n  = 44), a whole-grain-enriched diet (WGED) ( n  = 42) or a control ( n  = 45) diet, and 104 participants (mean ± SD: age 59 ± 7 years; BMI 31.1 ± 3.5 kg/m 2 ) who had completed the study, were analysed (Healthy Diet n  = 36, WGED n  = 34 and control diet n  = 34). Plasma E-selectin decreased only in the Healthy Diet group. This occurred in all group participants ( p  < 0.05) and also after excluding participants using statins ( p  < 0.05). Plasma hsCRP levels decreased in the Healthy Diet (median −17%, p  < 0.05) and WGED (median −27%, p  < 0.01) groups in participants not using statins. Controlling for confounding factors, including BMI or insulin sensitivity, did not alter the results. A greater increase in plasma concentration of very-long-chain n -3 fatty acids and in the intake of fibre during the study was associated with a greater decrease in plasma E-selectin ( p  < 0.05). The intake of test breads consumed during the Healthy Diet and WGED interventions was inversely associated with the change in hsCRP levels ( p  < 0.001). Conclusions/interpretation Our results suggest that the combined effect of fatty fish, bilberries and wholegrain products may improve endothelial dysfunction and inflammation in overweight and obese individuals at high risk of developing diabetes. Trial registration: ClinicalTrials.gov NCT00573781 Funding: The study was funded by the Academy of Finland (117844 and 118590 [to M. Uusitupa]; 131460 [to K. Poutanen]; 130469 [to H. Mykkänen] and 131593 [to V. D. F. de Mello]); the Kuopio University Hospital (5106, 5168, 5254 [to M. Uusitupa]); the Finnish Diabetes Research Foundation; the Sigrid Juselius Foundation; the Nordic Centre of Excellence on ‘Systems biology in controlled dietary interventions and cohort studies’ (SYSDIET; 070014); and the European Commission in the Communities 6th Framework Programme, Project HEALTHGRAIN (FOOD-CT-2005-514008).

The discovery of RNAs (for example, messenger RNAs, non-coding RNAs) in sperm has opened the possibility that sperm may function by delivering additional paternal information aside from solely providing the DNA 1 . Increasing evidence now suggests that sperm small non-coding RNAs (sncRNAs) can mediate intergenerational transmission of paternally acquired phenotypes, including mental stress 2 , 3 and metabolic disorders 4 – 6 . How sperm sncRNAs encode paternal information remains unclear, but the mechanism may involve RNA modifications. Here we show that deletion of a mouse tRNA methyltransferase, DNMT2, abolished sperm sncRNA-mediated transmission of high-fat-diet-induced metabolic disorders to offspring. Dnmt2 deletion prevented the elevation of RNA modifications (m 5 C, m 2 G) in sperm 30–40 nt RNA fractions that are induced by a high-fat diet. Also, Dnmt2 deletion altered the sperm small RNA expression profile, including levels of tRNA-derived small RNAs and rRNA-derived small RNAs, which might be essential in composing a sperm RNA ‘coding signature’ that is needed for paternal epigenetic memory. Finally, we show that Dnmt2-mediated m 5 C contributes to the secondary structure and biological properties of sncRNAs, implicating sperm RNA modifications as an additional layer of paternal hereditary information. Zhang et al. report that tRNA methyltransferase Dnmt2 is required for sperm small-non-coding-RNA-mediated transmission of paternal metabolic disorders to the offspring.

For many years, cardiovascular disease (CVD) has been the leading cause of death around the world. Often associated with CVD are comorbidities such as obesity, abnormal lipid profiles and insulin resistance. Insulin is a key hormone that functions as a regulator of cellular metabolism in many tissues in the human body. Insulin resistance is defined as a decrease in tissue response to insulin stimulation thus insulin resistance is characterized by defects in uptake and oxidation of glucose, a decrease in glycogen synthesis, and, to a lesser extent, the ability to suppress lipid oxidation. Literature widely suggests that free fatty acids are the predominant substrate used in the adult myocardium for ATP production, however, the cardiac metabolic network is highly flexible and can use other substrates, such as glucose, lactate or amino acids. During insulin resistance, several metabolic alterations induce the development of cardiovascular disease. For instance, insulin resistance can induce an imbalance in glucose metabolism that generates chronic hyperglycemia, which in turn triggers oxidative stress and causes an inflammatory response that leads to cell damage. Insulin resistance can also alter systemic lipid metabolism which then leads to the development of dyslipidemia and the well-known lipid triad: (1) high levels of plasma triglycerides, (2) low levels of high-density lipoprotein, and (3) the appearance of small dense low-density lipoproteins. This triad, along with endothelial dysfunction, which can also be induced by aberrant insulin signaling, contribute to atherosclerotic plaque formation. Regarding the systemic consequences associated with insulin resistance and the metabolic cardiac alterations, it can be concluded that insulin resistance in the myocardium generates damage by at least three different mechanisms: (1) signal transduction alteration, (2) impaired regulation of substrate metabolism, and (3) altered delivery of substrates to the myocardium. The aim of this review is to discuss the mechanisms associated with insulin resistance and the development of CVD. New therapies focused on decreasing insulin resistance may contribute to a decrease in both CVD and atherosclerotic plaque generation.

Metabolomic screening of fasting plasma from nondiabetic subjects identified α-hydroxybutyrate (α-HB) and linoleoyl-glycerophosphocholine (L-GPC) as joint markers of insulin resistance (IR) and glucose intolerance. To test the predictivity of α-HB and L-GPC for incident dysglycemia, α-HB and L-GPC measurements were obtained in two observational cohorts, comprising 1,261 nondiabetic participants from the Relationship between Insulin Sensitivity and Cardiovascular Disease (RISC) study and 2,580 from the Botnia Prospective Study, with 3-year and 9.5-year follow-up data, respectively. In both cohorts, α-HB was a positive correlate and L-GPC a negative correlate of insulin sensitivity, with α-HB reciprocally related to indices of β-cell function derived from the oral glucose tolerance test (OGTT). In follow-up, α-HB was a positive predictor (adjusted odds ratios 1.25 [95% CI 1.00–1.60] and 1.26 [1.07–1.48], respectively, for each standard deviation of predictor), and L-GPC was a negative predictor (0.64 [0.48–0.85] and 0.67 [0.54–0.84]) of dysglycemia (RISC) or type 2 diabetes (Botnia), independent of familial diabetes, sex, age, BMI, and fasting glucose. Corresponding areas under the receiver operating characteristic curve were 0.791 (RISC) and 0.783 (Botnia), similar in accuracy when substituting α-HB and L-GPC with 2-h OGTT glucose concentrations. When their activity was examined, α-HB inhibited and L-GPC stimulated glucose-induced insulin release in INS-1e cells. α-HB and L-GPC are independent predictors of worsening glucose tolerance, physiologically consistent with a joint signature of IR and β-cell dysfunction.

Evidence from observational and intervention studies has shown a high intake of tree nuts is associated with a reduced risk of cardiovascular disease (CVD), mortality from type 2 diabetes (T2DM), and all-cause mortality. However, there is limited data regarding their effects on indicators of cardiometabolic risk other than hypercholesterolemia, and little is known about the demonstrable health benefits of pecans (Carya illinoensis (Wangenh.) K.Koch). We conducted a randomized, controlled feeding trial to compare the effects of a pecan-rich diet with an isocaloric control diet similar in total fat and fiber content, but absent nuts, on biomarkers related to CVD and T2DM risk in healthy middle-aged and older adults who are overweight or obese with central adiposity. After 4 weeks on a pecan-rich diet, changes in serum insulin, insulin resistance (HOMA-IR) and beta cell function (HOMA-β) were significantly greater than after the control diet (p < 0.05). Pecan consumption also lowered the risk of cardiometabolic disease as indicated by a composite score reflecting changes in clinically relevant markers. Thus, compared to the control diet, the pecan intervention had a concurrent and clinically significant effect on several relevant markers of cardiometabolic risk.

In this study, serum levels of retinol-binding protein 4, a molecule secreted by adipocytes, correlated with the magnitude of insulin resistance in subjects with obesity, impaired glucose tolerance, or type 2 diabetes and in nonobese, nondiabetic subjects with a strong family history of type 2 diabetes. Levels of this molecule appear to be elevated in serum before the development of frank diabetes and might be used to identify insulin resistance and associated cardiovascular risk factors. Levels of retinol-binding protein 4 appear to be elevated in serum before the development of frank diabetes and might be used to identify insulin resistance and associated cardiovascular risk factors. Type 2 diabetes is caused by resistance to insulin action in multiple tissues, accompanied by failure of the pancreatic beta cells to compensate sufficiently by increased insulin secretion. 1 Measurement of insulin resistance provides an early and strong predictor of type 2 diabetes. 2 Even in the absence of hyperglycemia or diabetes, insulin resistance constitutes an important risk factor for cardiovascular disease and early death. 3 Obesity, which has reached epidemic proportions worldwide, is a major cause of insulin resistance. 4 However, insulin resistance does not develop in all obese persons, and genetic background contributes strongly to insulin resistance, even in nonobese persons. 5 In . . .

Background The triglyceride glucose (TyG) index has been suggested as a simple surrogate marker of insulin resistance. However, there are limited data regarding the association between the TyG index and arterial stiffness in adults. Therefore, we evaluated the relationship between the TyG index and arterial stiffness as measured based on brachial ankle pulse wave velocity (baPWV) in Korean adults. Methods A total of 3587 subjects were enrolled in this study. Anthropometric and cardiovascular risk factors were measured. The TyG index was calculated as ln[fasting triglycerides(mg/dl) × fasting glucose(mg/dl)/2], and the insulin resistance index of homeostasis model assessment (HOMA-IR) was estimated. Arterial stiffness was determined by measuring baPWV. Results The subjects were stratified into four groups based on the TyG index. There were significant differences in cardiovascular parameters among the groups; the mean baPWV increased significantly with increasing TyG index. According to the logistic regression analysis after adjusting for multiple risk factors, the odds ratio (95% CI) for increased baPWV (> 75th percentile) for the highest and lowest quartiles of the TyG index was 2.92 (1.92–4.44) in men and 1.84 (1.15–2.96) in women, and the odds ratio for increased baPWV for the highest and lowest quartiles of the HOMA-IR was 1.80 (1.17–2.78) in men and 1.46 (1.06–2.47) in women, respectively. Conclusion The TyG index is more independently associated with increased arterial stiffness than HOMA-IR in Korean adults.

Background Estimate glucose disposal rate (eGDR), Chinese visceral adiposity index (CVAI), triglyceride-glucose (TyG), TyG-body mass index (TyG-BMI), metabolic score for insulin resistance (METS-IR), and atherogenic index of plasma (AIP) are considered surrogate indexes of insulin resistance (IR). There is a lack of studies comparing the predictive values of different IR surrogate indexes for stroke risk among individuals with abnormal glucose metabolism. This study aimed to investigate the relationships between six IR surrogate indexes and stroke risk in individuals with abnormal glucose metabolism, evaluate their predictive abilities for stroke risk. Methods Data from the China Health and Retirement Longitudinal Study (CHARLS) were analysed in this study. Multivariate logistic regression models were applied to analyse the relationships of IR surrogate indexes with stroke risk. The dose-response relationships between IR surrogate indexes and stroke risk were explored using restricted cubic splines. The areas under the curve (AUCs) of IR surrogate indexes were calculated by receiver operating characteristic (ROC) analysis. Results After adjusting for potential confounders, we observed that each standard deviation (SD) increase in eGDR was associated with a reduced risk of stroke, with an adjusted odds ratio (OR) of 0.746 [95% confidence interval (CI): 0.661–0.842]. In contrast, each SD increase in CVAI, TyG, TyG-BMI, METS-IR, and AIP were associated with an increased risk of stroke, with adjusted ORs (95% CIs) of 1.232 (1.106–1.373), 1.246 (1.050–1.479), 1.186 (1.022–1.376), 1.222 (1.069–1.396), and 1.193 (1.050–1.355), respectively. Dose-response analyses showed that eGDR, CVAI, TyG-BMI and METS-IR were linearly associated with stroke risk ( P nonlinear ≥ 0.05), whereas TyG and AIP were nonlinearly associated with stroke risk ( P nonlinear < 0.05). According to ROC analysis, The AUC of eGDR for predicting stroke risk in the overall population with abnormal glucose metabolism (AUC: 0.612, 95% CI: 0.584–0.640) was significantly higher than that of other indexes. Conclusion The six IR surrogate indexes were closely associated with high risk of stroke in individuals with abnormal glucose metabolism. The eGDR showed promising potential in predicting stroke risk in Chinese middle-aged and elderly populations with abnormal glucose metabolism.

The purpose of the present study was to evaluate the impact of a lifestyle intervention programme, combined with a daily low-glycaemic index meal replacement, on body-weight and glycaemic control in subjects with impaired glucose regulation (IGR). Subjects with IGR were randomly assigned to an intervention group (n 46) and a control group (n 42). Both groups received health counselling at baseline. The intervention group also received a daily meal replacement and intensive lifestyle intervention to promote healthy eating habits during the first 3 months of the study, and follow-up visits performed monthly until the end of the 1-year study. Outcome measurements included changes in plasma glucose, glycated Hb (HbA1c), plasma lipids, body weight, blood pressure and body composition (such as body fat mass and visceral fat area). The results showed that body-weight loss after 1 year was significant in the intervention group compared with the control group ( − 1·8 (sem 0·35) v.− 0·6 (sem 0·40) 2·5 kg, P< 0·05). The 2 h plasma glucose concentration decreased 1·24 mmol/l in the intervention group and increased 0·85 mmol/l in the control group (P< 0·05) compared with their baseline, respectively. A 5 kg body-weight loss at 1 year was associated with a decrease of 1·49 mmol/l in 2 h plasma glucose (P< 0·01). The incidence of normal glucose regulation (NGR) in the two groups was significantly different (P= 0·001). In conclusion, the combination of regular contact, lifestyle advice and meal replacement is beneficial in promoting IGR to NGR.

The dietary supplement, trans-resveratrol and hesperetin combination (tRES-HESP), induces expression of glyoxalase 1, countering the accumulation of reactive dicarbonyl glycating agent, methylglyoxal (MG), in overweight and obese subjects. tRES-HESP produced reversal of insulin resistance, improving dysglycemia and low-grade inflammation in a randomized, double-blind, placebo-controlled crossover study. Herein, we report further analysis of study variables. MG metabolism-related variables correlated with BMI, dysglycemia, vascular inflammation, blood pressure, and dyslipidemia. With tRES-HESP treatment, plasma MG correlated negatively with endothelial independent arterial dilatation (r = −0.48, p < 0.05) and negatively with peripheral blood mononuclear cell (PBMC) quinone reductase activity (r = −0.68, p < 0.05)—a marker of the activation status of transcription factor Nrf2. For change from baseline of PBMC gene expression with tRES-HESP treatment, Glo1 expression correlated negatively with change in the oral glucose tolerance test area-under-the-curve plasma glucose (ΔAUGg) (r = −0.56, p < 0.05) and thioredoxin interacting protein (TXNIP) correlated positively with ΔAUGg (r = 0.59, p < 0.05). Tumor necrosis factor-α (TNFα) correlated positively with change in fasting plasma glucose (r = 0.70, p < 0.001) and negatively with change in insulin sensitivity (r = −0.68, p < 0.01). These correlations were not present with placebo. tRES-HESP decreased low-grade inflammation, characterized by decreased expression of CCL2, COX-2, IL-8, and RAGE. Changes in CCL2, IL-8, and RAGE were intercorrelated and all correlated positively with changes in MLXIP, MAFF, MAFG, NCF1, and FTH1, and negatively with changes in HMOX1 and TKT; changes in IL-8 also correlated positively with change in COX-2. Total urinary excretion of tRES and HESP metabolites were strongly correlated. These findings suggest tRES-HESP counters MG accumulation and protein glycation, decreasing activation of the unfolded protein response and expression of TXNIP and TNFα, producing reversal of insulin resistance. tRES-HESP is suitable for further evaluation for treatment of insulin resistance and related disorders.