title: Resveratrol improves insulin sensitivity, reduces oxidative stress and activates the Akt pathway in type 2 diabetic patients. Proposed trial: safety and efficacy of resveratrol for the treatment of non-alcoholic fatty liver disease (NAFLD) and associated insulin resistance in adolescents who are overweight or obese adolescents - rationale and protocol. Resveratrol supplementation improves glycemic control in type 2 diabetes mellitus. Resveratrol Promotes Foot Ulcer Size Reduction in Type 2 Diabetes Patients Antihyperglycemic Effects of Short Term Resveratrol Supplementation in Type 2 Diabetic Patients Six months of resveratrol supplementation has no measurable effect in type 2 diabetic patients. A randomized, double blind, placebo-controlled trial. Administration of resveratrol for 5 wk has no effect on glucagon-like peptide 1 secretion, gastric emptying, or glycemic control in type 2 diabetes: a randomized controlled trial. Resveratrol as Add-on Therapy in Subjects With Well-Controlled Type 2 Diabetes: A Randomized Controlled Trial The effects of resveratrol supplementation on cardiovascular risk factors in patients with non-alcoholic fatty liver disease: a randomised, double-blind, placebo-controlled study. The Impact of Resveratrol Supplementation on Blood Glucose, Insulin, Insulin Resistance, Triglyceride, and Periodontal Markers in Type 2 Diabetic Patients with Chronic Periodontitis One-year supplementation with a grape extract containing resveratrol modulates inflammatory-related microRNAs and cytokines expression in peripheral blood mononuclear cells of type 2 diabetes and hypertensive patients with coronary artery disease. Effects of resveratrol in patients with type 2 diabetes mellitus on skeletal muscle SIRT1 expression and energy expenditure.
abstract: Although resveratrol has widely been studied for its potential health benefits , little is known about its metabolic effects in humans . Our aims were to determine whether the polyphenol resveratrol improves insulin sensitivity in type 2 diabetic patients and to gain some insight into the mechanism of its action . After an initial general examination ( including blood chemistry ) , nineteen patients enrolled in the 4-week-long double-blind study were r and omly assigned into two groups : a resveratrol group receiving oral 2 × 5 mg resveratrol and a control group receiving placebo . Before and after the second and fourth weeks of the trial , insulin resistance/sensitivity , creatinine-normalised ortho-tyrosine level in urine sample s ( as a measure of oxidative stress ) , incretin levels and phosphorylated protein kinase B (pAkt):protein kinase B ( Akt ) ratio in platelets were assessed and statistically analysed . After the fourth week , resveratrol  significantly decreased insulin resistance ( homeostasis model of assessment for insulin resistance ) and urinary ortho-tyrosine excretion , while it increased the pAkt : Akt ratio in platelets . On the other h and , it had no effect on parameters that relate to β-cell function ( i.e. homeostasis model of assessment of β-cell function ) . The present study shows for the first time that resveratrol  improves insulin sensitivity in humans , which might be due to a resveratrol-induced  decrease in oxidative stress that leads to a more efficient insulin signalling via the Akt pathway Non-alcoholic fatty liver ( NAFL ) disease ( NAFLD ) affects 30 % of overweight adolescents and increases the risk of type 2 diabetes mellitus ( T2D ) . Resveratrol is a naturally occurring compound with potential to reverse NAFL and its associated insulin resistance in adults . The use of resveratrol to reduce risk for T2D through its effect on NAFL has not been examined to date in youth . This paper provides a literature review and protocol for a 30 day proof of principle trial of resveratrol in a population of adolescents at risk for T2D . This r and omized double-blind controlled trial is design ed with the primary objective of evaluating a twice daily supplementation of 75 mg of resveratrol for safety and tolerability in overweight and obese adolescent subjects ( 13 to < 18 years of age ) with NAFL . Secondary objectives are to determine the effect size of the intervention on hepatic steatosis and whole body insulin sensitivity .  Adolescents in the intervention arm ( n = 10 ) will receive oral supplementation of resveratrol 75 mg twice daily ( with breakfast and dinner ) for a total daily dose of 150 mg for the duration of 30 days . The comparison group ( n = 10 ) will receive a placebo twice daily for 30 days . Both cases and controls will receive a st and ardized lifestyle intervention program . Subjects in both groups will be followed for an additional 30 days post intervention for total study duration of approximately 60 days . Primary outcome measures include a primary side effect profile determined by participant interview , a side effect profile determined by serum biochemistry and vital signs . Secondary outcome measures include an oral glucose tolerance test , liver and cardiac fat content measured by magnetic resonance spectroscopy , anthropometric measures of overweight/obesity , inflammatory markers , and cardiac function and morphology measured with ultrasonography . Additional outcome measures include serum concentrations of resveratrol , compliance to protocol , physical activity , and nutritional assessment . This study will determine the safety and tolerability of resveratrol in an overweight adolescent population and inform the design of a larger r and omized controlled trial Resveratrol is a naturally occurring polyphenolic compound . Numerous animal studies have been reported on its wide-ranging beneficial effects in the biological system including diabetes mellitus ( DM ) . We hypothesized , therefore , that oral supplementation of resveratrol would improve the glycemic control and the associated risk factors in patients with type 2 diabetes mellitus ( T2DM ) . The present clinical study was therefore carried out to test the hypothesis . Sixty-two patients with T2DM were enrolled from Government Headquarters Hospital , Ootacamund , India , in a prospect i ve , open-label , r and omized , controlled trial . Patients were r and omized into control and intervention groups . The control group received only oral hypoglycemic agents , whereas the intervention group received resveratrol ( 250 mg/d ) along with their oral hypoglycemic agents for a period of 3 months . Hemoglobin A(1c ) , lipid profile , urea nitrogen , creatinine , and protein were measured at the baseline and at the end of 3 months . The results reveal that supplementation of resveratrol for 3 months significantly improves the mean hemoglobin A(1c ) ( means ± SD , 9.99 ± 1.50 vs 9.65 ± 1.54 ; P < .05 ) , systolic blood pressure ( mean ± SD , 139.71 ± 16.10 vs 127.92 ± 15.37 ; P < .05 ) , total cholesterol ( mean ± SD , 4.70 ± 0.90 vs 4.33 ± 0.76 ; P < .05 ) , and total protein ( mean ± SD , 75.6 ± 4.6 vs 72.3 ± 6.2 ; P < .05 ) in T2DM . No significant changes in body weight and high-density lipoprotein and low-density lipoprotein cholesterols were observed . Oral supplementation of resveratrol is thus found to be effective in improving glycemic control and may possibly provide a potential adjuvant for the treatment and management of diabetes Objective . The effect of a proprietary formulation of trans-resveratrol ( t-RSV ) on manifestations of diabetic foot syndrome ( DFS ) was studied in type 2 diabetic patients with newly diagnosed diabetic foot ulcers . Method . Placebo-controlled , examiner-blinded , parallel-group r and omized controlled pilot clinical trial ( ACTRN Clinical Trial Registry number 12610000629033 ) involving 24 patients with DFS ( 15 males and 9 females , average age of 56.4 ± 9.1 years ) divided into the  placebo and RSV-treatment groups was performed . 50 mg of t-RSV or placebo capsules was given to each patient twice a day over a 60-day time period . Results . Reduction in the parameters reflecting diabetic ulcer size was more profound in the RSV group as compared to placebo . RSV-treated patients also had a marginally improved performance in the foot pressure test . A statistically significant decline in the plasma fibrinogen level , but not CRP , was also found in the RSV-treated patients . Some improvement in the plasma lipid profile and fasting glucose levels were not related to RSV-treatment , since they have been seen on both the RSV and placebo groups , revealing the effectiveness of medical supervision and education in the newly diagnosed patients with DFS . Conclusion . t-RSV supplementation promotes reduction of the foot ulcer size and reduces plasma fibrinogen level in type 2 diabetic patients The objective of this study was to examine the effectiveness of resveratrol in lowering blood glucose in the presence of st and ard antidiabetic treatment in patients with type 2 diabetes , in a r and omized placebo-controlled double-blinded parallel clinical trial . A total of 66 subjects with type 2 diabetes were enrolled in this study and r and omly assigned to intervention group which was supplemented with resveratrol at a dose 1 g/day for 45 days and control group which received placebo tablets .  Body weight , blood pressure , fasting blood glucose , haemoglobin A1c , insulin , homeostatic assessment s for insulin resistance , triglycerides , total cholesterol , low density lipoprotein , high density lipoprotein , and markers of liver and kidney damage were measured at baseline and after 45 days of resveratrol or placebo supplementation . Resveratrol treatment significantly decreased systolic blood pressure , fasting blood glucose , haemoglobin A1c , insulin , and insulin resistance , while HDL was significantly increased , when compared to their baseline levels . On the other h and , the placebo group had slightly increased fasting glucose and LDL when compared to their baseline levels . Liver and kidney function markers were unchanged in the intervention group . Overall , this study showed that resveratrol supplementation exerted strong antidiabetic effects in patients with type 2 diabetes The polyphenol resveratrol is considered to exert many beneficial actions , such as antioxidant , anti-inflammatory , insulin-sensitizer and anticancer effects . Its benefits in patients with type 2 diabetes mellitus ( T2DM ) are controversial . Our aims were to determine whether resveratrol supplementation at two different dosages ( 500 and 40mg/day ) for 6 months i ) reduced the concentrations of C-reactive-protein ( CRP ) and ii ) ameliorated the metabolic pattern of T2DM patients .  In the present double-blind , r and omized , placebo-controlled trial , 192 T2DM patients were r and omized to receive resveratrol 500mg/day ( Resv500arm ) , resveratrol 40mg/day ( Resv40arm ) or placebo for 6-months . At baseline and at the trial end , CRP values , anthropometric , metabolic and liver parameters were determined . No serious adverse event occurred . A dose-dependent , though not significant , CRP decrease of 5.6 % ( Resv40arm ) and 15.9 % ( Resv500arm ) was observed vs placebo . We failed to detect significant differences in weight , BMI , waist circumference , and values of arterial blood pressure , fasting glucose , glycated hemoglobin , insulin , C-peptide , free fatty acids , liver transaminases , uric acid , adiponectin , interleukin-6 , in both the Resv500 and Resv40 arms vs placebo . Total cholesterol and triglycerides slightly increased in the Resv500arm . Subgroup analyses revealed that lower diabetes duration ( in both Resv500 and Resv40arms ) , and , in the Resv500arm , younger age , aspirin use and being a smoker were associated with a significantly higher CRP reduction vs placebo . The supplementations with 40mg/day or 500mg/day resveratrol did neither reduce CRP concentrations , nor improve the metabolic pattern of T2DM patients BACKGROUND Resveratrol has been reported to lower glycemia in rodent models of type 2 diabetes associated with the stimulation of glucagon-like peptide 1 ( GLP-1 ) , which is known to slow gastric emptying , stimulate insulin secretion , and suppress glucagon secretion and energy intake . OBJECTIVE We evaluated the effects of 5 wk of resveratrol treatment on GLP-1 secretion , gastric emptying , and glycemic control in type 2 diabetes . DESIGN Fourteen patients with diet-controlled type-2 diabetes [ mean ± SEM glycated hemoglobin ( HbA1c ) : 6.4 ± 0.2 % ( 46.4 ± 2.2 mmol/mol ) ] received resveratrol ( 500 mg twice daily ) or a placebo over two 5-wk intervention periods with a 5-wk washout period in between in a double-blind , r and omized , crossover design . Before and after each intervention period ( 4 visits ) , body weight and HbA1c were measured , and patients were evaluated after an overnight fast with a st and ardized mashed-potato meal labeled with 100 μg (13)C-octanoic acid to measure blood glucose and plasma GLP-1 concentrations and gastric emptying ( breath test ) over 240 min . Daily energy intake was estimated from 3-d food diaries during the week before each visit . RESULTS Fasting and postpr and ial blood glucose and plasma total GLP-1 as well as gastric emptying were similar at each assessment , and the change in each variable from weeks 0 to 5 did not differ between resveratrol and placebo groups . Similarly , changes in HbA1c , daily energy intake , and body weight after 5 wk did not differ between the 2 treatments . CONCLUSIONS In patients with diet-controlled type 2 diabetes , 5 wk of twice-daily 500 mg-resveratrol supplementation had no effect on GLP-1 secretion , glycemic control , gastric emptying , body weight , or energy intake . Our observations do not support the use of resveratrol for improving glycemic control . This trial was registered at www.anzctr.org.au as ACTRN12613000717752 OBJECTIVE To determine whether resveratrol supplementation can improve insulin sensitivity and promote overall metabolic health on top of st and ard diabetes care . RESEARCH DESIGN AND METHODS Seventeen subjects with well-controlled type 2 diabetes ( T2D ) were treated with placebo and 150 mg/day resveratrol ( resVida ) in a r and omized double-blind crossover study for 30 days . The main outcome measure was insulin sensitivity by the hyperinsulinemic-euglycemic clamp technique . RESULTS Hepatic and peripheral insulin sensitivity were not affected by resveratrol treatment . Intrahepatic lipid content also remained unaffected by resveratrol ; however , the change in intrahepatic lipid content correlated negatively with plasma resveratrol levels ( R = −0.68 , P = 0.03 ) . Intramyocellular lipid content increased in type 2 muscle fibers ( P = 0.03 ) , and systolic blood pressure tended to decrease ( P = 0.09 ) upon resveratrol treatment . In addition , resveratrol significantly improved ex vivo mitochondrial function ( state 3 and state U respiration upon malate with octanoyl-carnitine , P < 0.005 ) . Intriguingly , a correlation was found between plasma levels of a metabolite of resveratrol  ( dihydroresveratrol ) and the metformin dose used by the patients ( R = 0.66 , P = 0.005 ) , suggesting an interaction between metformin and resveratrol . It could be speculated that the lack of a  resveratrol-induced insulin-sensitizing effect is caused by this interaction . CONCLUSIONS Resveratrol supplementation does not improve hepatic or peripheral insulin sensitivity . Our results question the generalized value of resveratrol as an add-on therapy in the treatment of T2D and emphasize the need to perform studies in drug-naive patients with T2D or subjects with prediabetes Non-alcoholic fatty liver disease ( NAFLD ) is usually associated with insulin resistance , central obesity , reduced glucose tolerance , type 2 diabetes mellitus and hypertriacylglycerolaemia . The beneficial effects of resveratrol on metabolic disorders have been shown previously . The aim of this study was to evaluate the effects of resveratrol supplementation on cardiovascular risk factors in patients with NAFLD . In this r and omised double-blinded placebo-controlled clinical trial , fifty NAFLD patients were supplemented with either a 500-mg resveratrol capsule or a placebo capsule for 12 weeks . Both groups were advised to follow an energy-balanced diet and physical activity recommendations . resveratrol supplementation reduced alanine aminotransferase ( ALT ) and hepatic steatosis significantly more than placebo ( P0·05 ) . There were no significant changes in blood pressure , insulin resistance markers and TAG in either group ( P>0·05 ) . Our data have shown that 12-week supplementation of 500 mg resveratrol does not have any beneficial effect on anthropometric measurements , insulin resistance markers , lipid profile and blood pressure ; however , it reduced ALT and hepatic steatosis in patients with NAFLD The aim of this study was to investigate the impact of resveratrol supplementation along with non-surgical periodontal treatment on blood glucose , insulin , insulin resistance , triglyceride ( TG ) , and periodontal markers in patients with type 2 diabetes with periodontal disease . In this double-blind clinical trial study , 43 patients with diabetes with chronic periodontitis were participated . Subjects were r and omly allocated to intervention and control groups . The intervention and control groups received either 480 mg/day of resveratrol or placebo capsules ( two pills ) for 4 weeks . Fasting blood glucose , insulin , insulin resistance ( homeostasis model assessment of insulin resistance ) , TGs , and pocket depth were measured in all subjects ' pre-intervention and post-intervention . The mean serum levels of fasting insulin and insulin resistance ( homeostasis model assessment of insulin resistance ) were significantly lower in the intervention group compared with control group ( 10.42 ± 0.28 and 10.92 ± 0.9 ; 3.66 ± 0.97 and 4.49 ± 1.56 , respectively ) . There was a significant difference in the mean pocket depth between intervention and control groups ( 2.35 ± 0.6 and 3.38 ± 0.5 , respectively ) following intervention . No significant differences were observed in the mean levels of fasting blood glucose and TGs between two groups ' post-intervention . It is recommended that resveratrol supplementation may be beneficial as adjuvant therapy along with non-surgical periodontal treatment in insulin resistance and improving periodontal status among patients with diabetes with periodontal disease . Copyright © 2016 John Wiley & Sons , Numerous studies have shown that resveratrol ( RES ) exerts anti-inflammatory effects but human trials evidencing these effects in vivo are limited . Furthermore , the molecular mechanisms triggered in humans following the oral intake of RES are not yet understood . Therefore , the purpose of this study was to investigate the molecular changes in peripheral blood mononuclear cells ( P BMC s ) associated to the one-year daily intake of a RES enriched ( 8 mg ) grape extract ( GE-RES ) in hypertensive male patients with type 2 diabetes mellitus ( T2DM ) . We used microarrays and RT-PCR to analyze expression changes in genes and microRNAs ( miRs ) involved in the inflammatory response modulated by the consumption of GE-RES in comparison to a placebo and GE lacking RES . We also examined the changes in several serobiochemical variables , inflammatory and fibrinolytic markers . Our results showed that supplementation with GE or GE-RES did not affect body weight , blood pressure , glucose , HbA1c or lipids , beyond the values regulated by gold st and ard medication in these patients . We did not find either any significant change on serum inflammatory markers except for a significant reduction of ALP and IL-6 levels . The expression of the pro-inflammatory cytokines CCL3 , IL-1β and TNF-α was significantly reduced and that of the transcriptional repressor LRRFIP-1 increased in P BMC s from patients taking the GE-RES extract . Also , a group of miRs involved in the regulation of the inflammatory response : miR-21 , miR-181b , miR-663 , miR-30c2 , miR-155 and miR-34a were found to be highly correlated and altered in the group consuming the GE-RES for 12 months . Our results provide preliminary evidence that long-term supplementation with a grape extract containing RES downregulates the expression of key pro-inflammatory cytokines with the involvement of inflammation-related miRs in circulating immune cells of T2DM hypertensive medicated patients and support a beneficial immunomodulatory effect in these patients OBJECTIVES The primary aims of the study were to examine the effect of resveratrol on skeletal muscle SIRT1 expression and energy expenditure in subjects with Type 2 diabetes mellitus ( T2DM ) . BACKGROUND Animal and in vivo studies indicate that resveratrol increases SIRT1 expression that stimulates PGC1α activity . Subsequent upregulation of AMPK and GLUT4 expression are associated with improved insulin sensitivity in peripheral tissues . METHODS Ten subjects with T2DM were r and omized in a double-blind fashion to receive 3 g resveratrol or placebo daily for 12 weeks . Secondary outcomes include measures of AMPK , p-AMPK and GLUT4 expression levels , energy expenditure , physical activity levels , distribution of abdominal adipose tissue and skeletal muscle fiber type composition , body weight , HbA1c , plasma lipid subfraction , adiponectin levels , and insulin sensitivity . RESULTS There was a significant increase in both SIRT1 expression ( 2.01 vs. 0.86 arbitrary units [ AU ] , p = .016 ) and p-AMPK to AMPK expression ratio ( 2.04 vs. 0.79 AU , p = .032 ) in the resveratrol group compared with the placebo group . Although the percentage of absolute change ( 8.6 vs. -13.9 % , p = .033 ) and percentage of predicted resting metabolic rate ( RMR ; 7.8 vs. -13.9 % , p = .013 ) were increased following resveratrol , there was a significant reduction in average daily activity ( -38 vs. 43.2 % , p = .028 ) and step counts ( -39.5 vs. 11.8 % , p = .047 ) when compared with placebo . CONCLUSIONS In patients with T2DM , treatment with resveratrol regulates energy expenditure through increased skeletal muscle SIRT1 and AMPK expression . These findings indicate that resveratrol may have beneficial exercise-mimetic effects in patients with T2DM
target: The drug also reduced homeostasis model assessment of insulin resistance ( HOMA-IR ) index , systolic blood pressure , and diastolic blood pressure among participants with T2DM .
  The changes in hemoglobin A1c ( HbA1c ) , low-density lipoprotein cholesterol , and high-density lipoprotein cholesterol were negligible .
  Subgroup analysis comparing the resveratrol supplementation doses of < 100 mg/d versus ≥ 100 mg/d revealed a significant difference in fasting plasma glucose .
  In particular , the latter dose presented more favorable results .
  This meta- analysis provides evidence that supplementation of resveratrol may benefit management of T2DM
background: Although the regular consumption of resveratrol has been known to improve glucose homeostasis and reverse insulin resistance in type 2 diabetes mellitus ( T2DM ) , the reported results are inconsistent .
  Thus , we aim ed to assess the effects of resveratrol on glycemic control and insulin sensitivity among patients with T2DM .