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.

The effects of vitamin D supplementation on inflammatory biomarkers in patients with abnormal glucose homeostasis: A systematic review and meta-analysis of randomized controlled trials.

FINDINGS: on the level of inflammatory cytokines following vitamin D supplementation among individuals with abnormal glucose homeostasis (AGH) are controversial. Therefore, the present study was conducted on AGH patients to assess the impact of vitamin D on inflammatory cytokines such as CRP, TNF-α and IL-6. A systematic search up to September 2020 was performed through PubMed and Scopus databases. All clinical studies which evaluated the effect of oral vitamin D supplementation on inflammation in patients with AGH were included. The random-effects model was applied to obtain pooled results. For dose-response analysis, we used a fractional polynomial model. Overall, 38 studies, with 46 effect sizes, were included in this study. Combining effect sizes, we found that vitamin D considerably decrease serum concentrations of CRP (weight mean difference (WMD): - 0.67 mg/l; 95%CI: - 0.92, - 0.43; P < 0.001), IL-6 (WMD: -1.93 pg/mL; 95%CI: -2.80, -1.07; P < 0.001) and TNF-α (WMD: -0.81 pg/mL; 95%CI: -1.59, -0.03; P = 0.04). In the dose-response analysis, we failed to find any correlation between dosage of supplements and inflammatory biomarkers concentrations. Summarizing earlier studies, we demonstrated that circulating concentrations of inflammatory cytokines such as CRP, TNF-α, and IL-6 might be decreased following vitamin D supplementation among individuals with AGH.

Effect of glutamine supplementation on cardiometabolic risk factors and inflammatory markers: a systematic review and meta-analysis.

BACKGROUND: Evidence exists that glutamine plays multiple roles in glucose metabolism, insulin sensitivity, and anti-inflammatory effects. This systematic review and meta-analysis of controlled trials aimed to assess the effect of glutamine supplementation on cardio-metabolic risk factors and inflammatory markers. METHODS: The processes of systematic reviews and meta-analyses were performed according to the PRISMA checklist. PubMed, Web of Sciences, Cochrane library, and Scopus databases were search for relevant studies without time or language restrictions up to December 30, 2020. All randomized clinical trials which assessed the effect of glutamine supplementation on "glycemic indices", "level of triglyceride, "and "inflammatory markers" were included in the study. The effect of glutamine supplementation on cardio-metabolic risk factors and inflammatory markers was assessed using a standardized mean difference (SMD) and 95% confidence interval (CI). Heterogeneity between among studies was assessed using Cochran Q-statistic and I-square. Random/fixed-effects meta-analysis method was used to estimate the pooled SMD. The risk of bias for the included trials was evaluated using the Cochrane quality assessment tool. RESULTS: In total, 12 studies that assessed the effect of glutamine supplementation on cardio-metabolic risk factors were included in the study. Meta-analysis showed that glutamine supplementation significantly decreased significantly serum levels of FPG [SMD: - 0.73, 95% CI - 1.35, - 0.11, I2: 84.1%] and CRP [SMD: - 0.58, 95% CI - 0.1, - 0.17, I2: 0%]. The effect of glutamine supplementation on other cardiometabolic risk factors was not statistically significant (P > 0.05). CONCLUSION: Our findings showed that glutamine supplementation might have a positive effect on FPG and CRP; both of which are crucial as cardio-metabolic risk factors. However, supplementation had no significant effect on other cardio-metabolic risk factors.

Intake of Camelina Sativa Oil and Fatty Fish Alter the Plasma Lipid Mediator Profile in Subjects with Impaired Glucose Metabolism - A Randomized Controlled Trial.

n-3 and n-6 polyunsaturated fatty acids (PUFAs) and their lipid mediator metabolites are associated with inflammation. We investigated the effect of dietary intake of plant- and animal-derived n-3 PUFAs and fish protein on the circulatory concentrations of lipid mediators. Seventy-nine subjects with impaired fasting glucose who completed the controlled dietary intervention after randomization to the fatty fish (FF, n=20), lean fish (LF, n=21), Camelina sativa oil (CSO, n=18) or control group (n=20) for 12 weeks were studied. Lipid mediator profiling from fasting plasma samples before and after the intervention was performed by liquid chromatography-mass spectrometry (LC-MS/MS). The FF diet increased concentrations of 18-hydroxyeicosapentaenoic acid (18-HEPE) and 4- and 17-hydroxydocosahexaenoic acid (4-, 17-HDoHE) derived from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), respectively. Concentrations of lipid mediators derived from α-linolenic acid (ALA) increased and arachidonic acid (AA) derived 5-iso prostaglandin F2α-VI decreased in the CSO group. There were no significant changes in lipid mediators in the LF group. The dietary intake of both plant and animal-based n-3 PUFAs increased circulatory concentrations of lipid mediators with potential anti-inflammatory properties.

Effect of Konjac Mannan Oligosaccharides on Glucose Homeostasis via the Improvement of Insulin and Leptin Resistance In Vitro and In Vivo.

Functional oligosaccharides, particularly konjac mannan oligosaccharides (KMOS), can regulate glucose metabolism. However, the molecular mechanisms involved in the hypoglycemic effect of KMOS remain largely unknown. Here, the effect of KMOS supplementation on glucose homeostasis was evaluated in both high-fat diet (HFD)-fed C57BL/6J mice and high-glucosamine-induced HepG2 cells. KMOS supplementation remarkably ameliorated the fasting blood glucose, glucose tolerance, and insulin tolerance of HFD-fed mice. Abnormalities of triglyceride and glycogen metabolism in the liver induced by the HFD were reversed by KMOS supplementation. The insulin signaling pathway was activated by KMOS, with stimulation of GLUT2 membrane translocation and glucose uptake in HepG2 cells via the AMPK pathway. Moreover, KMOS suppressed p-mTOR expression and stimulated the GSK-3ß/CREB pathway via the AMPK pathway. KMOS significantly upregulated leptin receptor expression and downregulated PTP1B and SOCS3 levels in the liver and brain, with a decreased serum leptin concentration. Phosphorylation of JAK2 and STAT3 in the liver was activated by KMOS supplementation, while the expressions of Sirt1, Tfam, and Pgc1-α in the brain were elevated. Conclusively, KMOS attenuated HFD-induced glucose metabolism dysfunction through the regulation of insulin resistance and leptin resistance. This finding indicates that KMOS have potential value as an anti-hyperglycemic dietary supplement.

Use of an Extract of Annona muricata Linn to Prevent High-Fat Diet Induced Metabolic Disorders in C57BL/6 Mice.

Annona muricata Linn, commonly known as graviola, is one of the most popular plants used in Brazil for weight loss. The aim of this study is to evaluate the therapeutic effects of three different doses (50 mg/kg, 100 mg/kg, and 150 mg/kg) of aqueous graviola leaf extract (AGE) supplemented by oral gavage, on obese C57BL/6 mice. Food intake, body weight, an oral glucose tolerance test (OGTT), an insulin sensitivity test, quantification of adipose tissue cytokines, weight of fat pads, and serum biochemical and histological analyses of the liver, pancreas, and epididymal adipose tissue were measured. AGE had an anti-inflammatory effect by increasing IL-10 at doses of 50 and 100 mg/kg. Regarding the cholesterol profile, there was a significant decrease in LDL-cholesterol levels in the AGE 150 group, and VLDL-cholesterol and triglycerides in the AGE 100 and 150 groups. There was an increase in HDL cholesterol in the AGE 150 group. The extract was able to reduce the adipocyte area of the epididymal adipose tissue in the AGE 100 and 150 groups. According to the histological analysis of the liver and pancreas, no significant difference was found among the groups. There were no significant effects of AGE on OGTT and serum fasting glucose concentration. However, the extract was effective in improving glucose tolerance in the AGE 150 group.

Curcumin or combined curcuminoids are effective in lowering the fasting blood glucose concentrations of individuals with dysglycemia: Systematic review and meta-analysis of randomized controlled trials.

Curcuminoids have received considerable attention as therapeutical adjuvants in the treatment of dysglycemia. The purpose of this meta-analysis was to evaluate whether the supplementation of turmeric extract, curcuminoids and/or isolated curcumin is more effective than placebo in decreasing fasting blood glucose (FBG) in adults. MEDLINE, CENTRAL, ScienceDirect and gray literature databases were searched. Randomized controlled trials with the following criteria were included: (1) studied individuals older than 18 years, supplemented with curcumin, curcuminoids and/or turmeric extract (2) had a follow-up ≥4 weeks (3) used a placebo group. Titles and abstracts were screened and potentially eligible articles were retrieved. The primary outcome was FBG. The secondary outcomes were HbA1c and HOMA-IR. Eleven studies were included. In the overall analysis, turmeric, curcuminoids and curcumin supplementation led to a decrease in FBG (-8.88, 95% CI: [-5.04 to -2.72] mg/dL, p = 0.005). Supplementation of curcuminoids and/or curcumin decreased the concentrations of HbA1c (-0.54, 95% CI: [-1.09 to -0.002] %, p = 0.049) but were not able to decrease HOMA-IR (-1.26, 95% CI: [-3.71 to -1.19], p = 0.31). Sensitivity analyses revealed that baseline FBG was an important covariate. Heterogeneity was high in the overall analyses and there was evidence of publication bias. Supplementation of isolated curcumin or combined curcuminoids were both effective in lowering the FBG concentrations of individuals with some degree of dysglycemia, but not in non-diabetic individuals. Isolated curcumin lead to significant decreases of the HbA1c compared to placebo.

The effects of lutein on cardiometabolic health across the life course: a systematic review and meta-analysis.

BACKGROUND: The antioxidant lutein is suggested as being beneficial to cardiometabolic health because of its protective effect against oxidative stress, but evidence has not systematically been evaluated. OBJECTIVE: We aimed to evaluate systematically the effects of lutein (intake or concentrations) on cardiometabolic outcomes in different life stages. DESIGN: This is a systematic review with meta-analysis of literature published in MEDLINE, Embase, Cochrane Central, Web of Science, PubMed, and Google Scholar up to August 2014. Included were trials and cohort, case-control, and cross-sectional studies in which the association between lutein concentrations, dietary intake, or supplements and cardiometabolic outcomes was reported. Two independent investigators reviewed the articles. RESULTS: Seventy-one relevant articles were identified that included a total of 387,569 participants. Only 1 article investigated the effects of lutein during pregnancy, and 3 studied lutein in children. Furthermore, 31 longitudinal, 33 cross-sectional, and 3 intervention studies were conducted in adults. Meta-analysis showed a lower risk of coronary heart disease (pooled RR: 0.88; 95% CI: 0.80, 0.98) and stroke (pooled RR: 0.82; 95% CI: 0.72, 0.93) for the highest compared with the lowest tertile of lutein blood concentration or intake. There was no significant association with type 2 diabetes mellitus (pooled RR: 0.97; 95% CI: 0.77, 1.22), but higher lutein was associated with a lower risk of metabolic syndrome (pooled RR: 0.75; 95% CI: 0.60, 0.92) for the highest compared with the lowest tertile. The literature on risk factors for cardiometabolic diseases showed that lutein might be beneficial for atherosclerosis and inflammatory markers, but there were inconsistent associations with blood pressure, adiposity, insulin resistance, and blood lipids. CONCLUSIONS: Our findings suggest that higher dietary intake and higher blood concentrations of lutein are generally associated with better cardiometabolic health. However, evidence mainly comes from observational studies in adults, whereas large-scale intervention studies and studies of lutein during pregnancy and childhood are scarce.

Statin action favors normalization of the plasma lipidome in the atherogenic mixed dyslipidemia of MetS: potential relevance to statin-associated dysglycemia.

The impact of statin treatment on the abnormal plasma lipidome of mixed dyslipidemic patients with metabolic syndrome (MetS), a group at increased risk of developing diabetes, was evaluated. Insulin-resistant hypertriglyceridemic hypertensive obese males (n = 12) displaying MetS were treated with pitavastatin (4 mg/day) for 180 days; healthy normolipidemic age-matched nonobese males (n = 12) acted as controls. Statin treatment substantially normalized triglyceride (-41%), remnant cholesterol (-55%), and LDL-cholesterol (-39%), with minor effect on HDL-cholesterol (+4%). Lipidomic analysis, normalized to nonHDL-cholesterol in order to probe statin-induced differences in molecular composition independently of reduction in plasma cholesterol, revealed increment in 132 of 138 lipid species that were subnormal at baseline and significantly shifted toward the control group on statin treatment. Increment in alkyl- and alkenylphospholipids (plasmalogens) was prominent, and consistent with significant statin-induced increase in plasma polyunsaturated fatty acid levels. Comparison of the statin-mediated lipidomic changes in MetS with the abnormal plasma lipidomic profile characteristic of prediabetes and T2D in the Australian Diabetes, Obesity, and Lifestyle Study and San Antonio Family Heart Study cohorts by hypergeometric analysis revealed a significant shift toward the lipid profile of controls, indicative of a marked trend toward a normolipidemic phenotype. Pitavastatin attenuated the abnormal plasma lipidome of MetS patients typical of prediabetes and T2D.

Comparison of the postprandial effects of purple-fleshed and yellow-fleshed potatoes in healthy males with chemical characterization of the potato meals.

The aim of the current study was to characterize the anthocyanin content and composition of a purple potato landrace cultivar (Solanum tuberosum 'Synkeä Sakari') and to compare the postprandial effects of purple-fleshed potatoes, yellow-fleshed potatoes and bilberries in potato starch on postprandial glycemia and insulinemia in healthy males. The purple potato meal caused smaller insulinemia than the yellow potato meal (iAUC 120 min 1347 and 2226, respectively, p = 0.012 and iAUC 240 min 1448 and 2403, p = 0.007) or the bilberry meal (iAUC 120 min 1920, p = 0.027). The purple potato meal caused a smaller plasma glucose at 40 min postprandially compared with the yellow potato meal (p = 0.044). The results of this study suggest that anthocyanin-containing purple-fleshed potatoes influence the postprandial insulinemia positively. Since potatoes are the world's largest non-grain commodity, replacing yellow-fleshed potatoes with purple-fleshed potatoes as staple food could have large potential in maintaining public health.

Procyanidins improve some disrupted glucose homoeostatic situations: an analysis of doses and treatments according to different animal models.

This review analyses the potential beneficial effects of procyanidins, the main class of flavonoids, in situations in which glucose homeostasis is disrupted. Because the disruption of glucose homeostasis can occur as a result of various causes, we critically review the effects of procyanidins based on the specific origin of each type of disruption. Where little or no insulin is present (Type I diabetic animals), summarized studies of procyanidin treatment suggest that procyanidins have a short-lived insulin-mimetic effect on the internal targets of the organism, an effect not reproduced in normoglycemic, normoinsulinemic healthy animals. Insulin resistance (usually linked to hyperinsulinemia) poses a very different situation. Preventive studies using fructose-fed models indicate that procyanidins may be useful in preventing the induction of damage and thus in limiting hyperglycemia. But the results of other studies using models such as high-fat diet treated rats or genetically obese animals are controversial. Although the effects on glucose parameters are hazy, it is known that procyanidins target key tissues involved in its homeostasis. Interestingly, all available data suggest that procyanidins are more effective when administered in one acute load than when mixed with food.

The effects of adjuvant insulin therapy among pregnant women with IGT who failed to achieve the desired glycemia levels by diet and moderate physical activity.

OBJECTIVE: Evaluation of adjuvant insulin therapy effects on glycemic control, perinatal outcome and postpuerperal glucose tolerance in impaired glucose tolerance (IGT) pregnant women who failed to achieve desired glycemic control by dietary regime. METHODS: A total of 280 participants were classified in two groups: Group A patients continued with dietary regime and Group B patients were treated with adjuvant insulin therapy. Glycemic control was assessed by laboratory and ultrasonograph means. Pregnancy outcomes were evaluated by prevalence of pregnancy induced hypertension (PIH), high birth weight, neonatal hypoglycemia and caesarean section rates. Postpuerperal glucose tolerance was assessed by oral glucose tolerance test (oGTT). RESULTS: All laboratory and ultrasound indicators of glycemic control had significantly lower values in Group B. Group A women were more likely to develop the EPH (Edema, Proteinuria, Hypertension) syndrome, 20% versus 7.86% (p = 0.003). High birth weight occurred more frequently in Group A, but the difference was not significant (p = 0.197). Higher rate of caesarean delivery was in Group A than in Group B, 16.43% versus 26.43% (p = 0.041). The difference in neonatal hypoglycemia was not significant (p = 0.478). Pathological oGTT results were observed in 73 Group A patients and in 15 Group B patients. CONCLUSION: Lower caesarean section rates and the EPH syndrome incidence are the benefits of adjuvant insulin therapy in IGT patients.

A diet high in fatty fish, bilberries and wholegrain products improves markers of endothelial function and inflammation in individuals with impaired glucose metabolism in a randomised controlled trial: the Sysdimet study.

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.

Caloric restriction and L-carnitine administration improves insulin sensitivity in patients with impaired glucose metabolism.

BACKGROUND: Reduced circulating and tissue carnitine levels, possibly leading to impaired mitochondrial function, have been postulated to be involved in the pathogenesis of insulin resistance. However, whether L-carnitine administration may improve insulin sensitivity in patients with impaired fasting glucose (IFG) or type 2 diabetes mellitus (DM-2) is still controversial. The aim of the study was to explore the role of L-carnitine supplementation in influencing insulin sensitivity. METHODS: A randomized controlled study involving adult outpatients was designed. Adult patients referred to the outpatient clinic and within 10 days of the diagnosis of IFG or DM-2 were consecutively enrolled. Exclusion criteria were concomitant antidiabetic therapy and modifications of lifestyle during the previous 4 weeks. Patients were randomly assigned to receive a hypocaloric diet for 10 days (group C; n = 8) or the same dietetic regimen in addition to oral L-carnitine (2 g twice daily) supplementation (group LC; n = 8). Oral glucose tolerance test (OGTT), fasting plasma insulin levels, and homeostasis model assessment of insulin resistance (HOMA-IR) were assessed at the beginning and end of the study. Data were statistically analyzed using the Student t test for paired and unpaired data. RESULTS: OGTT at 2 hours improved in both groups. Only in the L-carnitine-supplemented group did plasma insulin levels and HOMA-IR significantly decrease when compared to baseline values. CONCLUSIONS: Considering the role of caloric restriction in increasing the intestinal uptake of carnitine, the results suggest that oral L-carnitine administration, when associated with a hypocaloric feeding regimen, improves insulin resistance and may represent an adjunctive treatment for IFG and DM-2.

Coffee and caffeine consumption reduce the risk of elevated serum alanine aminotransferase activity in the United States.

BACKGROUND & AIMS: Based on experimental and epidemiologic studies, we investigated whether coffee and caffeine consumption reduced the risk of elevated alanine aminotransferase (ALT) activity in persons at high risk for liver injury in a national, population-based study. METHODS: Participants were 5944 adults in the Third US National Health and Nutrition Examination Survey, 1988-1994, with excessive alcohol consumption, viral hepatitis, iron overload, overweight, or impaired glucose metabolism. Liver injury was indicated by abnormal serum ALT activity (>43 U/L). RESULTS: Elevated ALT activity was found in 8.7% of this high-risk population. In unadjusted analysis, lower ALT activity was associated with increasing consumption of coffee ( P = .001) and caffeine ( P = .001). Multivariate logistic regression analyses showed that the risk of elevated ALT activity declined with increasing intake of coffee ( P for trend = .034) and caffeine ( P < .001). Comparing persons who drank more than 2 cups per day with noncoffee drinkers, the odds ratio was .56 (95% confidence interval, .31-1.0). Comparing persons in the highest caffeine quintile with the lowest, the odds ratio was .31 (95% confidence interval, .16-.61). These relationships were consistent across subgroups at risk for liver injury and were relatively unchanged when analyses included the entire population or when limited to persons without impaired liver function or right upper quadrant pain. Fasting insulin concentrations did not mediate the effects. CONCLUSIONS: In this large, national, population-based study, among persons at high risk for liver injury, consumption of coffee and especially caffeine was associated with lower risk of elevated ALT activity.