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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).

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.

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 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.

Abstract Introduction Ageing skeletal muscles become both insulin resistant and atrophic. The hormone glucagon-like peptide 1 (GLP-1) facilitates postprandial glucose uptake as well as augmenting muscle perfusion, independent of insulin action. We thus hypothesized exogenous GLP-1 infusions would enhance muscle perfusion and positively affect glucose metabolism during fed-state clamps in older people. Methods Eight men (71 ± 1 years) were studied in a randomized crossover trial. Basal blood samples were taken before postprandial (fed-state) insulin and glucose clamps, accompanied by amino acid infusions, for 3 hours. Reflecting this, following insertions of peripheral and femoral vessels cannulae and baseline measurements, peripheral IV infusions of octreotide, insulin (Actrapid), 20% glucose, and mixed amino acids; Vamin 14-EF with or without a femoral arterial GLP-1 infusion were started. GLP-1, insulin, and C-peptide were measured by ELISA. Muscle microvascular blood flow was assessed via contrast enhanced ultrasound. Whole-body glucose handling was assayed by assessing glucose infusion rate parameters. Results Skeletal muscle microvascular blood flow significantly increased in response to GLP-1 vs feeding alone (5.0 ± 2.1 vs 1.9 ± 0.7 fold-change from basal, respectively; P = 0.008), while also increasing whole-body glucose uptake (area under the curve 16.9 ± 1.7 vs 11.4 ± 1.8 mg/kg−1/180 minutes−1, P = 0.02 ± GLP, respectively). Conclusions The beneficial effects of GLP-1 on whole-body glycemic control are evident with insulin clamped at fed-state levels. GLP-1 further enhances the effects of insulin on whole-body glucose uptake in older men, underlining its role as a therapeutic target. The effects of GLP-1 in enhancing microvascular flow likely also affects other glucose-regulatory organs, reflected by greater whole-body glucose uptake.

An impaired glucose metabolism, which often leads to the onset of diabetes mellitus (DM), is a common complication of chronic exposure to exogenous and endogenous glucocorticoid (GC) excess and plays an important part in contributing to morbidity and mortality in patients with Cushing syndrome (CS). This article reviews the pathogenesis, epidemiology, diagnosis, and management of changes in glucose metabolism associated with hypercortisolism, addressing both the pathophysiological aspects and the clinical and therapeutic implications. Chronic hypercortisolism may have pleiotropic effects on all major peripheral tissues governing glucose homeostasis. Adding further complexity, both genomic and nongenomic mechanisms are directly induced by GCs in a context-specific and cell-/organ-dependent manner. In this paper, the discussion focuses on established and potential pathologic molecular mechanisms that are induced by chronically excessive circulating levels of GCs and affect glucose homeostasis in various tissues. The management of patients with CS and DM includes treating their hyperglycemia and correcting their GC excess. The effects on glycemic control of various medical therapies for CS are reviewed in this paper. The association between DM and subclinical CS and the role of screening for CS in diabetic patients are also discussed.This article reviews the pathogenesis, epidemiology, diagnosis, and management of glucose metabolism abnormalities associated with hypercortisolism.

BackgroundThe microbiota is emerging as a key factor in the predisposition to insulin resistance and obesity.ObjectiveTo understand the interplay among gut microbiota and insulin sensitivity in multiple tissues.DesignIntegrative multiomics and multitissue approach across six studies, combining euglycaemic clamp measurements (used in four of the six studies) with other measurements of glucose metabolism and insulin resistance (glycated haemoglobin (HbA1c) and fasting glucose).ResultsSeveral genera and species from the Proteobacteria phylum were consistently negatively associated with insulin sensitivity in four studies (ADIPOINST, n=15; IRONMET, n=121, FLORINASH, n=67 and FLOROMIDIA, n=24). Transcriptomic analysis of the jejunum, ileum and colon revealed T cell-related signatures positively linked to insulin sensitivity. Proteobacteria in the ileum and colon were positively associated with HbA1c but negatively with the number of T cells. Jejunal deoxycholic acid was negatively associated with insulin sensitivity. Transcriptomics of subcutaneous adipose tissue (ADIPOMIT, n=740) and visceral adipose tissue (VAT) (ADIPOINST, n=29) revealed T cell-related signatures linked to HbA1c and insulin sensitivity, respectively. VAT Proteobacteria were negatively associated with insulin sensitivity. Multiomics and multitissue integration in the ADIPOINST and FLORINASH studies linked faecal Proteobacteria with jejunal and liver deoxycholic acid, as well as jejunal, VAT and liver transcriptomic signatures involved in the actin cytoskeleton, insulin and T cell signalling. Fasting glucose was consistently linked to interferon-induced genes and antiviral responses in the intestine and VAT. Studies in Drosophila melanogaster validated these human insulin sensitivity-associated changes.ConclusionThese data provide comprehensive insights into the microbiome-gut-adipose-liver axis and its impact on systemic insulin action, suggesting potential therapeutic targets.Cite Now

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.

Background The prevention of type 2 diabetes is a globally recognised health care priority, but there is a lack of rigorous research investigating optimal methods of translating diabetes prevention programmes, based on the promotion of a healthy lifestyle, into routine primary care. The aim of the study is to establish whether a pragmatic structured education programme targeting lifestyle and behaviour change in conjunction with motivational maintenance via the telephone can reduce the incidence of type 2 diabetes in people with impaired glucose regulation (a composite of impaired glucose tolerance and/or impaired fasting glucose) identified through a validated risk score screening programme in primary care. Design Cluster randomised controlled trial undertaken at the level of primary care practices. Follow-up will be conducted at 12, 24 and 36 months. The primary outcome is the incidence of type 2 diabetes. Secondary outcomes include changes in HbA1c, blood glucose levels, cardiovascular risk, the presence of the Metabolic Syndrome and the cost-effectiveness of the intervention. Methods The study consists of screening and intervention phases within 44 general practices coordinated from a single academic research centre. Those at high risk of impaired glucose regulation or type 2 diabetes are identified using a risk score and invited for screening using a 75 g-oral glucose tolerance test. Those with screen detected impaired glucose regulation will be invited to take part in the trial. Practices will be randomised to standard care or the intensive arm. Participants from intensive arm practices will receive a structured education programme with motivational maintenance via the telephone and annual refresher sessions. The study will run from 2009–2014. Discussion This study will provide new evidence surrounding the long-term effectiveness of a diabetes prevention programme conducted within routine primary care in the United Kingdom. Trial registration Clinicaltrials.gov NCT00677937

Glucose levels in blood must be constantly maintained within a tight physiological range to sustain anabolism. Insulin regulates glucose homeostasis via its effects on glucose production from the liver and kidneys and glucose disposal in peripheral tissues (mainly skeletal muscle). Blood levels of glucose are regulated simultaneously by insulin-mediated rates of glucose production from the liver (and kidneys) and removal from muscle; adipose tissue is a key partner in this scenario, providing nonesterified fatty acids (NEFA) as an alternative fuel for skeletal muscle and liver when blood glucose levels are depleted. During sleep at night, the gradual development of insulin resistance, due to growth hormone and cortisol surges, ensures that blood glucose levels will be maintained within normal levels by: (a) switching from glucose to NEFA oxidation in muscle; (b) modulating glucose production from the liver/kidneys. After meals, several mechanisms (sequence/composition of meals, gastric emptying/intestinal glucose absorption, gastrointestinal hormones, hyperglycemia mass action effects, insulin/glucagon secretion/action, de novo lipogenesis and glucose disposal) operate in concert for optimal regulation of postprandial glucose fluctuations. The contribution of the liver in postprandial glucose homeostasis is critical. The liver is preferentially used to dispose over 50% of the ingested glucose and restrict the acute increases of glucose and insulin in the bloodstream after meals, thus protecting the circulation and tissues from the adverse effects of marked hyperglycemia and hyperinsulinemia.