Reversal of Insulin Resistance in Overweight and Obese Subjects by trans-Resveratrol and Hesperetin Combination-Link to Dysglycemia, Blood Pressure, Dyslipidemia, and Low-Grade Inflammation.

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.

Roles of microRNAs in carbohydrate and lipid metabolism disorders and their therapeutic potential.

MicroRNAs (miRNAs) are small (∼21 nucleotides), endogenous, non-coding RNA molecules implicated in the post-transcriptional gene regulation performed through target mRNA cleavage or translational inhibition. In recent years, several investigations have demonstrated that miRNAs are involved in regulating both carbohydrate and lipid homeostasis in humans and other organisms. Moreover, it has been observed that the dysregulation of these metabolism-related miRNAs leads to the development of several metabolic disorders, such as type 2 diabetes, obesity, nonalcoholic fatty liver, insulin resistance, and hyperlipidemia. Hence, in this current review, with the aim to impulse the research arena of the micro-transcriptome implications in vital metabolic pathways as well as to highlight the remarkable potential of miRNAs as therapeutic targets for metabolic disorders in humans, we provide an overview of the regulatory roles of metabolism-associated miRNAs in humans and murine models.

Branched-chain amino acid metabolism, insulin sensitivity and liver fat response to exercise training in sedentary dysglycaemic and normoglycaemic men.

AIMS/HYPOTHESIS: Obesity and insulin resistance may be associated with elevated plasma concentration of branched-chain amino acids (BCAAs) and impaired BCAA metabolism. However, it is unknown whether the insulin-sensitising effect of long-term exercise can be explained by concomitant change in BCAAs and their metabolism. METHODS: We included 26 sedentary overweight and normal-weight middle-aged men from the MyoGlu clinical trial, with or without dysglycaemia, for 12 weeks of supervised intensive exercise intervention, including two endurance and two resistance sessions weekly. Insulin sensitivity was measured as the glucose infusion rate (GIR) from a hyperinsulinaemic-euglycaemic clamp. In addition, maximum oxygen uptake, upper and lower body strength and adipose tissue depots (using MRI and spectroscopy) were measured, and subcutaneous white adipose tissue (ScWAT) and skeletal muscle (SkM) biopsies were harvested both before and after the 12 week intervention. In the present study we have measured plasma BCAAs and related metabolites using CG-MS/MS and HPLC-MS/MS, and performed global mRNA-sequencing pathway analysis on ScWAT and SkM. RESULTS: In MyoGlu, men with dysglycaemia displayed lower GIR, more fat mass and higher liver fat content than normoglycaemic men at baseline, and 12 weeks of exercise increased GIR, improved body composition and reduced liver fat content similarly for both groups. In our current study we observed higher plasma concentrations of BCAAs (14.4%, p = 0.01) and related metabolites, such as 3-hydroxyisobutyrate (19.4%, p = 0.034) in dysglycaemic vs normoglycaemic men at baseline. Baseline plasma BCAA levels correlated negatively to the change in GIR (ρ = -0.41, p = 0.037) and [Formula: see text] (ρ = -0.47, p = 0.015) after 12 weeks of exercise and positively to amounts of intraperitoneal fat (ρ = 0.40, p = 0.044) and liver fat (ρ = 0.58, p = 0.01). However, circulating BCAAs and related metabolites did not respond to 12 weeks of exercise, with the exception of isoleucine, which increased in normoglycaemic men (10 µmol/l, p = 0.01). Pathway analyses of mRNA-sequencing data implied reduced BCAA catabolism in both SkM and ScWAT in men with dysglycaemia compared with men with normoglycaemia at baseline. Gene expression levels related to BCAA metabolism correlated positively with GIR and markers of mitochondrial content in both SkM and ScWAT, and negatively with fat mass generally, and particularly with intraperitoneal fat mass. mRNA-sequencing pathway analysis also implied increased BCAA metabolism after 12 weeks of exercise in both groups and in both tissues, including enhanced expression of the gene encoding branched-chain α-ketoacid dehydrogenase (BCKDH) and reduced expression of the BCKDH phosphatase in both groups and tissues. Gene expression of SLC25A44, which encodes a mitochondrial BCAA transporter, was increased in SkM in both groups, and gene expression of BCKDK, which encodes BCKDH kinase, was reduced in ScWAT in dysglycaemic men. Mediation analyses indicated a pronounced effect of enhanced SkM (~53%, p = 0.022), and a moderate effect of enhanced ScWAT (~18%, p = 0.018) BCAA metabolism on improved insulin sensitivity after 12 weeks of exercise, based on mRNA sequencing. In comparison, plasma concentration of BCAAs did not mediate any effect in this regard. CONCLUSION/INTERPRETATION: Plasma BCAA concentration was largely unresponsive to long-term exercise and unrelated to exercise-induced insulin sensitivity. On the other hand, the insulin-sensitising effect of long-term exercise in men may be explained by enhanced SkM and, to a lesser degree, also by enhanced ScWAT BCAA catabolism. Graphical abstract.

Screening for Glucose Perturbations and Risk Factor Management in Dysglycemic Patients With Coronary Artery Disease-A Persistent Challenge in Need of Substantial Improvement: A Report From ESC EORP EUROASPIRE V.

OBJECTIVE: Dysglycemia, in this survey defined as impaired glucose tolerance (IGT) or type 2 diabetes, is common in patients with coronary artery disease (CAD) and associated with an unfavorable prognosis. This European survey investigated dysglycemia screening and risk factor management of patients with CAD in relation to standards of European guidelines for cardiovascular subjects. RESEARCH DESIGN AND METHODS: The European Society of Cardiology's European Observational Research Programme (ESC EORP) European Action on Secondary and Primary Prevention by Intervention to Reduce Events (EUROASPIRE) V (2016-2017) included 8,261 CAD patients, aged 18-80 years, from 27 countries. If the glycemic state was unknown, patients underwent an oral glucose tolerance test (OGTT) and measurement of glycated hemoglobin A1c. Lifestyle, risk factors, and pharmacological management were investigated. RESULTS: A total of 2,452 patients (29.7%) had known diabetes. OGTT was performed in 4,440 patients with unknown glycemic state, of whom 41.1% were dysglycemic. Without the OGTT, 30% of patients with type 2 diabetes and 70% of those with IGT would not have been detected. The presence of dysglycemia almost doubled from that self-reported to the true proportion after screening. Only approximately one-third of all coronary patients had completely normal glucose metabolism. Of patients with known diabetes, 31% had been advised to attend a diabetes clinic, and only 24% attended. Only 58% of dysglycemic patients were prescribed all cardioprotective drugs, and use of sodium-glucose cotransporter 2 inhibitors (3%) or glucagon-like peptide 1 receptor agonists (1%) was small. CONCLUSIONS: Urgent action is required for both screening and management of patients with CAD and dysglycemia, in the expectation of a substantial reduction in risk of further cardiovascular events and in complications of diabetes, as well as longer life expectancy.

Update on Diabetes Mellitus and Glucose Metabolism Alterations in Prader-Willi Syndrome.

PURPOSE OF REVIEW: This review summarizes our current knowledge on type 2 diabetes mellitus (T2DM) and glucose metabolism alterations in Prader-Willi syndrome (PWS), the most common syndromic cause of obesity, and serves as a guide for future research and current best practice. RECENT FINDINGS: Diabetes occurs in 10-25% of PWS patients, usually in adulthood. Severe obesity is a significant risk factor for developing of T2DM in PWS. Paradoxically, despite severe obesity, a relative hypoinsulinemia, without the expected insulin resistance, is frequently observed in PWS. The majority of PWS subjects with T2DM are asymptomatic and diabetes-related complications are infrequent. Long-term growth hormone therapy does not adversely influence glucose homeostasis in all ages, if weight gain does not occur. Early intervention to prevent obesity and the regular monitoring of glucose levels are recommended in PWS subjects. However, further studies are required to better understand the physiopathological mechanisms of T2DM in these patients.

Pediatric Post-Cardiac Arrest Care: A Scientific Statement From the American Heart Association.

Successful resuscitation from cardiac arrest results in a post-cardiac arrest syndrome, which can evolve in the days to weeks after return of sustained circulation. The components of post-cardiac arrest syndrome are brain injury, myocardial dysfunction, systemic ischemia/reperfusion response, and persistent precipitating pathophysiology. Pediatric post-cardiac arrest care focuses on anticipating, identifying, and treating this complex physiology to improve survival and neurological outcomes. This scientific statement on post-cardiac arrest care is the result of a consensus process that included pediatric and adult emergency medicine, critical care, cardiac critical care, cardiology, neurology, and nursing specialists who analyzed the past 20 years of pediatric cardiac arrest, adult cardiac arrest, and pediatric critical illness peer-reviewed published literature. The statement summarizes the epidemiology, pathophysiology, management, and prognostication after return of sustained circulation after cardiac arrest, and it provides consensus on the current evidence supporting elements of pediatric post-cardiac arrest care.

Prevention of Cardiovascular Diseases in Children and Adolescents.

The atherosclerotic alterations that are the basis of cardiovascular diseases can start already in childhood. For this reason the prevention of cardiovascular diseases should be undertaken very early both in the general population and, in a targeted manner, in subjects at cardiovascular risk. Preventive strategies should include measures to encourage physical activity and correct eating habits and to reduce exposure to pollutants. The main actors responsible for carrying out these preventive interventions are the local and national political authorities. Moreover, particular attention should be paid to the first thousand days of life starting from conception, to prevent unfavorable epigenetic modifications. In addition to initiatives aimed at the general population, interventions should be planned by the medical community to assess the individual risk profile. The current obesity epidemic has in fact made it relatively frequent even among children and adolescents to find some cardiovascular risk factors known in adults such as arterial hypertension, dyslipidemia, glucose metabolism disorders and increased of uric acid values. The purpose of this review is to indicate lines of intervention for cardiovascular prevention in children and adolescents.

Hydration, Arginine Vasopressin, and Glucoregulatory Health in Humans: A Critical Perspective.

Glucoregulatory diseases, such as type 2 diabetes are currently a key public health priority. Public health messages have started to include the addition of water in their dietary guidelines. Such guidelines however are not based on causal evidence pertaining to the health effects of increased water intake, but rather more heavily based upon non-causal or mechanistic data. One line of thinking linking fluid intake and health is that hypohydration induces elevated blood concentrations of arginine vasopressin (AVP). Research in the 1970s and 1980s implicated AVP in glucoregulation, supported by observational evidence. This important area of research subsequently appeared to stop until the 21st century during which interest in hypertonic saline infusion studies, animal AVP receptor knockout models, dietary and genetic associations, and human interventions manipulating hydration status have resurged. This narrative review briefly describes and critically evaluates the usefulness of the current AVP-glucoregulatory research. We offer suggestions on how to test the independent glucoregulatory effects of body water changes compared to elevated circulating AVP concentrations, such as investigating hydration manipulations using 3,4-Methylenedioxymethamphetamine. Whilst much research is still needed before making firm conclusions, the current evidence suggests that although AVP may be partially implicated in glucoregulation, more ecologically valid models using human participants suggests this effect might be independent of the hydration status. The key implication of this hypothesis if confirmed in future research is that manipulating the hydration status to reduce circulating AVP concentrations may not be an effective method to improve glucoregulatory health.

Prolonged effectiveness of 12-month exercise-plus-diet intervention in Japanese adults at risk of impaired glucose or lipid metabolism.

BACKGROUND AND OBJECTIVES: To investigate the prolonged effects of a 12-month exercise-plus-diet intervention in Japanese adults at risk of impaired glucose or lipid metabolism. METHODS AND STUDY DESIGN: A total of 180 participants were randomly divided into an intervention group (n=94), and a control group (n=86). An exercise-plus- diet intervention was conducted on the intervention group for 12 months. The effects were evaluated by questionnaire, physical examinations, and blood tests at baseline, 3 months, 12 months (the end of intervention), and 24 months (one year after the end of intervention). The control group took only the same examinations as the intervention group. RESULTS: At the end of the 12-month intervention, body weight, waist circumference, fasting glucose, HbA1c, triglycerides, and LDL-cholesterol were improved in the intervention group compared to the control group (all p<0.05). One year after the end of the intervention, body weight, waist circumference, fasting glucose, triglycerides, and LDL-cholesterol were still decreased in the intervention group compared to the control group (all p<0.05), especially among non-overweight participants. Among overweight persons, only body weight in the intervention group was lower than the control group. The personal behaviours of physical activity and diet in the intervention group were also improved. CONCLUSIONS: The 12-month exercise-plus-diet programs were found to be effective in improving glucose and lipid metabolism, as well as personal behaviour one year after completion of the intervention.

Delays in Seeking General Medical Services and Measurable Abnormalities Among Individuals With Serious Mental Illness.

OBJECTIVE: The study explored the association of delays in seeking general medical care with elevated blood pressure and metabolic abnormalities among individuals with serious mental illness. METHODS: Association of delays in medical care with blood pressure, serum hemoglobin A1c (HbA1C), and lipids was assessed among patients at two inner-city community mental health centers. RESULTS: Of 271 participants, 62% reported delays in seeking general medical care due to attitudinal and financial barriers. Care delay was associated with abnormalities in measured blood pressure (adjusted odds ratio [AOR]=2.14, p=.029) and HbA1c (AOR=3.18, p=.026). Care delay was not associated with abnormalities in lipid profiles. CONCLUSIONS: This study found that delays in seeking general medical care are common and are associated with clinical markers linked with common medical conditions. The results may help to explain the elevated morbidity and mortality associated with serious mental illness.

Blood Glucose Disorders and Access to Health Care Services Among Adults Aged 30 to 69 Years in Chi Linh, Hai Duong, Vietnam.

Planning for control of diabetes in Vietnam needs valid information about the burden of diseases in general population. This study employed a cross-sectional design among population aged 30 to 69 years to measure the burden of type 2 diabetes and gaps in access to health care to explore the negative effects of rapid economic growth and urbanization in Chi Linh in recent years. A total of 594 adults were interviewed and had their fasting blood glucose tested. Results indicated that the prevalence of impaired fasting glycaemia was 11.8% and of diabetes was 12.1%. Only 16.8% diabetes cases detected in this study were diagnosed before, indicating a high level of unmet needs for detecting/managing diabetes in Chi Linh population. Significant associated factors with abnormal blood glucose included age and body mass index level. Without effective intervention programs for diabetes control and management, its burden will continue raising in the coming years. Chi Linh need to strengthen the diagnostic/treatment services at primary health care levels to ensure that people at early stage of raised blood pressure, raised blood glucose can be detected and provided with proper management to avoid serious complications, and to reduce hospital overload at central level.

Glucose Metabolism Abnormalities in Cushing Syndrome: From Molecular Basis to Clinical Management.

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.

Analysis of "never events" following adult cardiac surgical procedures in the United States.

BACKGROUND: This study was conducted to determine the risk factors, nature, and outcomes of "never events" following open adult cardiac surgical procedures. Understanding of these events can reduce their occurrence, and thereby improve patient care, quality metrics, and cost reduction. METHODS: "Never events" for patients included in the Nationwide Inpatient Sample who underwent coronary artery bypass graft, heart valve repair/replacement, or thoracic aneurysm repair between 2003-2011 were documented. These events included air embolism, catheter-based urinary tract infection (UTI), pressure ulcer, falls/trauma, blood incompatibility, vascular catheter infection, poor glucose control, foreign object retention, wrong site surgery and mediastinitis. Analysis included characterization of preoperative demographics, comorbidities and outcomes for patients sustaining never events, and multivariate analysis of predictive risk factors and outcomes. RESULTS: A total of 588,417 patients meeting inclusion criteria were identified. Of these, never events occurred in 4377 cases. The majority of events were in-hospital falls, vascular catheter infections, and complications of poor glucose control. Rates of falls, catheter based UTIs, and glucose control complications increased between 2009-2011 as compared to 2003-2008. Analysis revealed increased hospital length of stay, hospital charges, and mortality in patients who suffered a never event as compared to those that did not. CONCLUSIONS: This study establishes a baseline never event rate after cardiac surgery. Adverse patient outcomes and increased resource utilization resulting from never events emphasizes the need for quality improvement surrounding them. A better understanding of individual patient characteristics for those at risk can help in developing protocols to decrease occurrence rates.

Reducing the prevalence of dysglycemia: is the time ripe to test the effectiveness of intervention in high-risk individuals with elevated 1 h post-load glucose levels?

Identifying the earliest time point on the prediabetic continuum is critical to avoid progressive deterioration in ß-cell function. Progressively rising glucose levels even within the "normal range" occur considerably late in the evolution to diabetes thus presenting an important opportunity for earlier diagnosis, treatment, and possible reversal. An elevated 1 h postprandial glucose level, not detected by current diagnostic standards, may provide an opportunity for the early identification of those at risk. When the 1 h post-load glucose level is elevated, lifestyle intervention may have the greatest benefit for preserving ß-cell function and prevent further progression to prediabetes and diabetes. In view of the considerable consistent epidemiologic data in large disparate populations supporting the predictive capacity of the1 h post-load value for predicting progression to diabetes and mortality, the time is therefore ripe to evaluate this hypothesis in a large, prospective multicenter randomized trial with lifestyle intervention.

Continuous glucose monitoring in China: Then, now and in the future.

Glucose monitoring is a key component in assessing glucose metabolic disturbance, evaluating therapeutic outcomes and guiding treatment regimens. For decades, continuous glucose monitoring (CGM) was one of the dreams of patients with diabetes and diabetologists. In this article, the research progress, opportunities and challenges of the use of CGM technology are reviewed.

Testosterone and depressive symptoms among men in the Diabetes Prevention Program.

OBJECTIVE: We examined associations between intensive lifestyle intervention (ILS) and changes in testosterone and associations with mood among middle-aged men. DESIGN: Secondary analysis of men (n=886) participating in the Diabetes Prevention Program which randomized glucose-intolerant, overweight men to ILS, metformin, or placebo between 1996 and 1999. MAIN OUTCOME MEASURES: Changes in testosterone between baseline and 1-year follow-up asnd associations of these changes with mood measures (Beck Depression Inventory [BDI-II], Beck Anxiety Inventory [BAI]). RESULTS: Median baseline testosterone was 10.98nmol/l and 44% (n=385) had testosterone<10.41nmol/l or 300ng/dl. Testosterone increases were greater among men randomized to ILS vs. metformin vs. placebo (1.15nmol/l vs. -0.12nmol/l vs. -0.27nmol/l, p<0.001). The association between changes in testosterone and mood differed by study arm (p<0.001 for interaction); there were no significant associations between changes in testosterone and mood changes among men in the ILS or placebo arms. Among men in the metformin arm, increases in testosterone were significantly associated with decreases in BDI-II (improved depressive symptoms) (ß-coefficient -0.2336, p=0.0002) indicating a 0.23 decrease in BDI-II for every 1nmol/l increase in testosterone and decreases in BAI (improved anxiety symptoms) (ß-coefficient -0.2147, p=0.0014). Similar patterns were observed for bioavailable testosterone. CONCLUSIONS: Among overweight middle-aged men with glucose-intolerance, ILS increased endogenous testosterone slightly but without significant improvements in mood. Metformin did not increase testosterone, but among metformin users, testosterone increases were associated with improvements in mood. Thus, interventions that increase endogenous testosterone may not also improve mood.

Screening for Abnormal Blood Glucose and Type 2 Diabetes Mellitus: U.S. Preventive Services Task Force Recommendation Statement.

DESCRIPTION: Update of the 2008 U.S. Preventive Services Task Force (USPSTF) recommendation on screening for diabetes in asymptomatic adults. METHODS: The USPSTF reviewed the evidence on screening for impaired fasting glucose, impaired glucose tolerance, and type 2 diabetes in asymptomatic, nonpregnant adults who are at average or high risk for diabetes and its complications. POPULATION: This recommendation applies to adults aged 40 to 70 years seen in primary care settings who do not have symptoms of diabetes and are overweight or obese. RECOMMENDATION: The USPSTF recommends screening for abnormal blood glucose as part of cardiovascular risk assessment in adults aged 40 to 70 years who are overweight or obese. Clinicians should offer or refer patients with abnormal blood glucose to intensive behavioral counseling interventions to promote a healthful diet and physical activity. (B recommendation).