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Hindawi Publishing Corporation Evidence-Based Complementary and Alternative Medicine Volume 2013, Article ID 851267, 11 pages http://dx.doi.org/10.1155/2013/851267

Research Article Antihyperglycemic Effects of Short Term Resveratrol Supplementation in Type 2 Diabetic Patients Ali Movahed,1 Iraj Nabipour,1 Xavier Lieben Louis,2,3,4 Sijo Joseph Thandapilly,2,3,4 Liping Yu,2,3 Mohammadreza Kalantarhormozi,1 Seyed Javad Rekabpour,1 and Thomas Netticadan2,3,4 1

Department of Endocrine and Metabolic Diseases, The Persian Gulf Tropical Medicine Research Center, Bushehr, University of Medical Sciences, Bushehr 7514763448, Iran 2 Heart Failure Research Laboratory, Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Research Centre, Winnipeg, MB, Canada R2H 2A6 3 Agriculture and Agri-Food Canada, Winnipeg, MB, Canada R3T 2M9 4 Department of Physiology, University of Manitoba, Winnipeg, MB, Canada R3E 0J9 Correspondence should be addressed to Ali Movahed; amirali 1957@yahoo.com and Thomas Netticadan; tnetticadan@sbrc.ca Received 13 June 2013; Accepted 25 July 2013 Academic Editor: MinKyun Na Copyright Š 2013 Ali Movahed et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The objective of this study was to examine the effectiveness of resveratrol in lowering blood glucose in the presence of standard antidiabetic treatment in patients with type 2 diabetes, in a randomized placebo-controlled double-blinded parallel clinical trial. A total of 66 subjects with type 2 diabetes were enrolled in this study and randomly 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 assessments 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 hand, 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.

1. Background The incidence of diabetes mellitus continues to rise worldwide, and it has far reaching consequences to the quality of human life [1, 2]. Progression of uncontrolled diabetes culminates in microvascular (retinopathy, nephropathy, and neuropathy) and macrovascular (cardiac, cerebral, and peripheral vascular disease) complications and premature death [3, 4]. Among the two forms of diabetes, type 2 diabetes mellitus (T2DM) (formerly called non-insulin-dependent diabetes mellitus) is the most prevalent one and is primarily characterized by insulin resistance and associated hyperglycemia [5–7].

The most recent epidemiological data from the International Diabetes Federation (IDF) has revealed that diabetes currently affects around 371 million people globally and 4.8 million die every year [8]. Moreover, it has been proposed that developing countries will contribute to the majority (77.6%) of the diabetic patients globally, by the year 2030 [9, 10]. Among these countries, Islamic Republic of Iran is one of the countries having the highest prevalence of T2DM [11, 12]. These alarming epidemiological figures demonstrate the need of alternative therapeutic strategies, dietary interventions, and life style modifications, in addition to the existing pharmacological agents to prevent/manage T2DM in these high risk populations.

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2 In the past decade, resveratrol, a naturally occurring polyphenolic compound, found predominantly in grapes and peanuts, has been widely documented in the scientific literature for its beneficial effects in preventing and/or managing several diseases [13, 14]. Over the past 6 years, we have reported potent effects of resveratrol in preventing or reversing cardiac impairment in animal models of hypertension and obesity [5, 15, 16]. In the obese model [5], we also reported that resveratrol reduced hyperglycemia. Several other studies have also reported improvement in metabolic parameters in resveratrol treated animal models of insulin resistance including T2DM [17–20]. Despite the strong evidence for resveratrol generated from preclinical research and its widespread use as a nutritional supplement, well designed human clinical trials investigating the antidiabetic effects of resveratrol are limited. To date, only two human studies have been completed to investigate the potential of resveratrol in T2DM patients [21, 22]. Both studies [21, 22] reported a modest reduction in blood glucose levels, while one showed no effect on insulin levels [22]. Recently, Crandall et al. also showed a slight improvement in insulin sensitivity and postprandial plasma glucose in resveratrol treated prediabetic older adults [23]. However, two human clinical trials investigating the metabolic effects of resveratrol on insulin sensitivity and glucose response in obese subjects reported no clinically significant effect on blood glucose [24, 25]; it must be noted that these studies included relatively healthy (nondiabetic) subjects, and therefore the results cannot be extrapolated to make decisive conclusions regarding the antidiabetic potential of resveratrol. Given the discordant results achieved with resveratrol treatment, further human clinical trials are needed to establish the antidiabetic effects of resveratrol. As stated earlier the increased risk and prevalence of T2DM among Iranians make them an ideal study population to test the efficacy of resveratrol in improving diabetes related metabolic abnormalities. Accordingly, the primary objective of the present study was to examine whether supplementation with resveratrol at a dose 1 g/day would have a clinically apparent blood glucose lowering effect, while the secondary objective was to assess the effects on insulin, metabolic markers, and cardiovascular risk factors. This study will also address whether resveratrol could complement the standard antidiabetic regimen [26] and render added protection in patients with T2DM, in a randomized placebo-controlled, double-blinded parallel clinical trial.

2. Methods 2.1. Subjects and Study Design. The study was approved by the Medical Ethics Committee of Bushehr University of Medical Sciences. The project was also registered with Clinical Trial Registry of Iran (registration no: IRCT201111198129N1). The informed consent was obtained from each patient at the time of enrolment and continued as a process throughout the investigation. Also, the patients had free medical care and consultation during the study period, especially in the case of any adverse reaction or complications.

Evidence-Based Complementary and Alternative Medicine Seventy patients with T2DM who repeatedly visited the Endocrine Clinic of the Persian Gulf Tropical Medicine Research Center, Bushehr University of Medical Sciences, Bushehr, Iran, were enrolled in a randomized placebocontrolled double-blinded single centre clinical trial. The following inclusion criteria were used to recruit the subjects who had T2DM: (1) age between 20 and 65 years, (2) minimum of 6 months on oral hypoglycemic treatment or combination therapy, (3) being not on any antioxidant therapy such as vitamin supplements, and (4) having no allergy to grapes, green tea, and peanuts. Patients with type 1 diabetes, pregnant women, lactating mothers, and patients with severe heart disease, hepatic disease, and renal impairment were excluded from the present study. The patients were randomly assigned to control and intervention groups. 2.1.1. Randomization/Blinding Procedures. Stratified randomization was used to allocate participants to the 2 treatment sequences so that equal numbers of men and women will be allocated to each sequence. Thereafter, randomization of the participants into treatment group and placebo group was done by computer generated numbered sequence codes which were given in opaque envelopes to subjects in the first study visit. Both the clinical team and participants were blinded from the time of randomization until analysis was completed. 2.1.2. Compliance. At each visit (once a week during the intervention period), the participant returned unused capsule bottles. Study compliance was assessed by counting the remaining capsules from the bottle every week. Every participant was asked to complete a questionnaire during each visit to monitor the type of foods consumed during the study, particularly to confirm that they did not have food products that may contain resveratrol. No other assessments were done during these routine visits. 2.2. Treatment Regime. The patients in the intervention group received 500 mg, twice a day (a total of 1 g/day) of resveratrol capsules (99% pure, Biotivia, Bioceuticals International SrI, Italy) for a period of 45 days. The control group received 500 mg twice daily of placebo capsules (totally inert microcellulose, Biotivia, Bioceuticals International SrI, Italy) supplementation for the same period of time. Since the study was also intended to test the effectiveness of resveratrol when administered in conjunction with existing treatments against T2DM, all patients were allowed to continue their existing antidiabetic medications during the course of the study. Oral hypoglycemic agents and insulin were not modified during the course of the study. Among the participants who completed the study, in the control group, 12, 7, 10, and 2 patients were on metformin, glibenclamide, metformin + glibenclamide, and insulin + metformin, respectively. In the intervention group, 9, 10, 12, and 2 patients were on metformin, glibenclamide, metformin + glibenclamide, and insulin + metformin, respectively. Few subjects were also under atorvastatin (đ?‘› = 3), atenolol (đ?‘› = 1), simvastatin (đ?‘› = 1), and lovastin (đ?‘› = 1).

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Evidence-Based Complementary and Alternative Medicine

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Table 2: Anthropometric, clinical, and biochemical parameters for placebo and resveratrol groups before and after resveratrol supplementation. Control/placebo group

Intervention/resveratrol group

Baseline

After 45 days

P value

Baseline treatment

After treatment

P value

76.60 Âą 14.27

76.60 Âą 14.16

0.809

74.26 Âą 11.39

74.48 Âą 11.34

0.712

27.83 Âą 4.21

27.69 Âą 4.15

0.332

27.05 Âą 3.13

27.16 Âą 3.13

0.395

Systolic blood pressure (mmHg)

129.31 Âą 15.16

130.68 Âą 13.21

0.147

129.03 Âą 14.91

121.45 Âą 10.26

<0.0001â&#x2C6;&#x2014;

Diastolic blood pressure (mmHg)

78.58 Âą 15.39

81.55 Âą 5.84

0.279

76.93 Âą 19.54

78.54 Âą 6.35

0.169

Body weight (kg) 2

BMI (kg/m )

151.24 Âą 51.52

161.13 Âą 53.16

0.002

175.74 Âą 49.63

140.80 Âą 39.74

<0.0001â&#x2C6;&#x2014;

Insulin (đ?&#x153;&#x2021;IU/mL)

9.04 Âą 5.35

8.77 Âą 4.16

0.642

10.20 Âą 4.33

5.37 Âą 2.62

<0.0001â&#x2C6;&#x2014;

HbA1c

8.30 Âą 1.43

8.50 Âą 2.46

0.764

8.6 Âą 1.390

7.60 Âą 1.32

<0.0001â&#x2C6;&#x2014;

HOMA-IR

3.20 Âą 2.37

3.43 Âą 1.83

0.423

4.61 Âą 2.77

1.91 Âą 1.17

<0.0001â&#x2C6;&#x2014;

HOMA-đ?&#x203A;˝

36.13 Âą 8.45

35.68 Âą 7.95

0.039

32.15 Âą 5.32

25.80 Âą 4.43

0.009â&#x2C6;&#x2014;

134.69 Âą 45.61

123.13 Âą 43.27

0.145

160.1 Âą 58.96

142.28 Âą 52.61

0.051

Total cholesterol (mg/dL)

168 Âą 41.97

175.34 Âą 41.31

0.424

203.61 Âą 52.70

192.28 Âą 53.13

0.156

HDL-cholesterol (mg/dL)

41.73 Âą 9.52

39.69 Âą 10.83

0.133

41.40 Âą 8.35

46.15 Âą 8.40

0.001â&#x2C6;&#x2014;

LDL-cholesterol (mg/dL)

107.95 Âą 31.67

117.18 Âą 29.88

0.003â&#x2C6;&#x2014;

134.04 Âą 36.18

122.71 Âą 38.19

0.106

SGOT (IU/L)

24.0 Âą 5.47

25.0 Âą 6.71

0.212

26.0 Âą 5.87

26.0 Âą 7.56

0.837

SGPT (IU/L)

19.44 Âą 8.79

21.65 Âą 8.67

0.202

21.45 Âą 7.91

22.61 Âą 9.74

0.365

GGT (IU/L)

30.82 Âą 17.79

29.93 Âą 17.01

0.545

32.12 Âą 15.32

33.38 Âą 17.92

0.441

Fasting glucose (mg/dL)

Triglyceride (mg/dL)

ALP (IU/L) Creatinine (mg/dL)

â&#x2C6;&#x2014;

â&#x2C6;&#x2014;

169.37 Âą 52.63

189.41 Âą 48.38

0.001

185.29 Âą 59.35

190.64 Âą 47.55

0.372

0.92 Âą 0.24

0.97 Âą 0.25

0.281

0.96 Âą 0.24

0.90 Âą 0.21

0.098

Data is presented as means Âą SD. â&#x2C6;&#x2014; đ?&#x2018;&#x192; < 0.05 versus before treatment. HOMA-đ?&#x203A;˝: homeostasis model of assessment for beta cell function; HOMA-IR: homeostasis model of assessment for insulin resistance; HbA1c: Hemoglobin A1c; HDL: high density lipoprotein; LDL: low density lipoprotein; TG: triglyceride; SGOT: serum glutamate oxaloacetate transaminase; SGPT: serum glutamate pyruvate transaminase; GGT: gamma-glutamyltransferase; ALP: alkaline phosphatase.

(SGOT, SGPT, GGT, and ALP) and a kidney function marker (creatinine) were unchanged with resveratrol treatment for 45 days in T2DM patients (when compared with baseline values). At the end of the study, ALP was significantly increased in the control group (Table 2). Glucose levels were significantly reduced with resveratrol treatment in T2DM patients (when compared with baseline levels); patients in control group showed a small but significant increase in glucose levels (Table 2). There was a significant decrease in HbA1c in intervention group when compared to the baseline levels, whereas, there was no change in HbA1c levels in control group (Table 2). Insulin levels in intervention group were significantly decreased when compared to baseline levels, while control group had no change in insulin levels (Table 2). Homeostatic model assessment of insulin resistance (HOMA-IR) and beta cell function (HOMA-đ?&#x203A;˝) showed that both parameters were significantly decreased in intervention group when compared to the baseline levels (Table 2); however, HOMA-IR did not change in control group, while, HOMA-đ?&#x203A;˝ marginally but significantly decreased (Table 2). When compared with baseline, HDL levels were significantly increased in the intervention group. Changes in total

triglycerides, cholesterol, and LDL levels showed a decreasing trend but were not statistically significant (Table 2). However, the control group had increased LDL levels at the end of the study when compared to the baseline levels, while triglycerides, total cholesterol, and HDL were unchanged (Table 2). A comparison of the changes in the anthropometric, clinical, and biochemical measurements during the study period (end of the study period minus baseline) between the intervention and control groups are shown is Table 3. When compared to the controls, a significant decline was observed in systolic blood pressure, HbA1c, HOMA-IR, serum fasting glucose, and insulin, while significant increment was observed in the levels of HDL-C (đ?&#x2018;&#x192; < 0.0001) in the intervention group. When compared to the control group, no significant changes were found for BMI, body weight, diastolic blood pressure, HOMA-đ?&#x203A;˝, levels of total cholesterol, creatinine, and liver enzymes in the subjects supplemented with resveratrol. Subgroup analyses were also done to determine if resveratrol had any additive effect when combined with metformin and glibenclamide. The seven parameters that showed

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8 supplementation. Accordingly, it may be suggested that short term supplementation with a moderate to high dose of resveratrol (1 g/day) as used in the current study may help to markedly lower blood glucose levels. We speculate that, once blood glucose levels are normalized, T2DM patients may be administered a lower dose (less than the 1 g/day) of resveratrol that in conjunction with dietary modifications and appropriate exercise regimen may help maintain lowered blood glucose levels. Whether the use of a lower dose is an effective option in the long term is a question that needs to be tested in an independent clinical trial. A major concern in using higher doses of resveratrol in humans would be the possibility of toxic effects to major organs in the body. However, in a recent well-designed doseresponse study, Brown et al. reported that up to 1 g resveratrol was well tolerated in human subjects and did not result in toxic effects, while 2.5 and 5 grams resulted in some gastrointestinal symptoms [35]. Brown et al. study was conducted on healthy subjects, while another study on older adults showed that 1-2 g/day dosage of resveratrol was well tolerated without any changes in kidney or liver function markers [23]. Our data on organ damage markers also showed that treatment with 1 g resveratrol caused no changes to liver function markers (SGOT, SGPT, GGT, and ALP), as well as a kidney function marker (creatinine) in T2DM patients, indicating that short term resveratrol supplementation at a moderate to high dose had no adverse effects on liver and kidney. However, our study was only for 45 days, and longer studies would be necessary to confirm the safety of resveratrol at different doses. As speculated earlier, use of a lower dose (<1 g) after the 45-day treatment with 1 g resveratrol may eliminate or minimize, if any, resveratrol related toxicity in the long term. On the other hand, it should be mentioned that the control group which was on standard diabetic treatment alone had an increase in alkaline phosphatase (ALP) levels, when compared to the baseline values. Glycated hemoglobin (HbA1c) levels in blood are another stable marker for blood glucose levels [36]. It must be noted that a decrease by one point in HbA1c levels observed in the intervention group is clinically very significant, given that this was achieved with 45 days of treatment. This result is comparable to decrease in HbA1c levels in T2DM patients with metformin (a frontline glycemic control drug) administration [37]. Accordingly, this data provides further evidence for the effectiveness of resveratrol supplementation in maintaining the lowered blood glucose levels during the study period. There was also a striking decrease in insulin levels, along with significant reductions in HOMA-IR and HOMA-đ?&#x203A;˝ in the intervention group, suggesting that addition of resveratrol to standard antidiabetic therapy is beneficial in lowering insulin levels and improving insulin sensitivity and beta cell function in T2DM patients. Brasny´o et al. [22] did not observe any difference in serum insulin values with resveratrol treatment in type 2 diabetic patients, but they noted a significant reduction in HOMA-IR values; a lack of effect of resveratrol on serum insulin values may be attributed to the very low dose of resveratrol (10 mg/day) used in their study. Although HOMA can be used in subjects treated with insulin or in subjects on insulin secretagogues for

Evidence-Based Complementary and Alternative Medicine determining đ?&#x203A;˝-cell function over time [38], our results need to be interpreted with caution. Type 2 diabetes is associated with increased risk of ischemic heart disease, and higher (than normal) LDL cholesterol levels and lower HDL levels, are independent risk factors for ischemic heart disease [39, 40]. Our data shows that HDL levels were significantly increased in the intervention group. The increase in HDL levels by 4.75 mg/dL with resveratrol treatments was comparable to that achieved with nicotinic acid [41]. There were trends towards a decrease, but no significant changes were observed in triglycerides, cholesterol, and LDL levels with resveratrol supplementation, while a significant increase in LDL levels was observed in the control group. Metformin, glibenclamide, and insulin are all known to have beneficial or no effect on the lipid profiles [42]; therefore, other independent factors may have contributed to the observed increase in the control group. Subgroup analyses showed that resveratrol may have an added effect when used in combination with glibenclamide and metformin. However, the power of the current study for subgroup analyses is weak; hence, the results should not be overinterpreted [43].

5. Conclusion and Summary The results of this study clearly demonstrate that resveratrol supplementation in the presence of standard antidiabetic medication has major benefits in T2DM patients, which include a pronounced lowering of blood glucose, HbA1c, insulin levels, and insulin resistance, as well as improvement in HDL levels (Figure 2). Unlike earlier reports [21â&#x20AC;&#x201C;23] which showed mild effects on hyperglycemia and hyperinsulinemia, our study highlights the marked changes and the potential of resveratrol as an antidiabetic molecule. It is also important to note the beneficial effects of resveratrol observed on metabolic parameters, despite the fact that there was no appreciable effect on body weight or body composition. Some of the observed reductions in HbA1c and HDL with resveratrol supplementation are very significant that they can be compared to benefits achieved with front line antidiabetic drugs. Other important observations which stem from this study are that: (a) 1 g/day of resveratrol supplementation for 45 days had no adverse effects in type 2 diabetic patients and (b) resveratrol not only complemented standard antidiabetic medication but also provided added protection (over standard antidiabetic therapy). 5.1. Study Limitations. This is a pilot study which examined the antidiabetic effects of resveratrol over the short term, and only one dose of resveratrol was tested. There was no followup to check the metabolic parameters of the patients after the resveratrol wash-out period. The study lacks the investigation of cellular mechanisms underlying the antidiabetic effects of resveratrol. Extensive toxicological screening was not done on subjects to confirm the safety of resveratrol administration, and the safety of administering 1 g dose of resveratrol over the long term has not been established.

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N UTR IT ION RE S EA RCH XX ( 2 0 12 ) XXX– X XX

Available online at www.sciencedirect.com

w w w. n r j o u r n a l . c o m

Communication

Resveratrol supplementation improves glycemic control in type 2 diabetes mellitus☆ Jayesh Kumar Bhatt a , Sabin Thomas b , Moola Joghee Nanjan a ,⁎ a b

JSS College of Pharmacy, Ootacamund, Tamilnadu, India 643001 School of Pharmacy, The University of Nizwa, Nizwa 616, Sultanate of Oman

ARTI CLE I NFO

A BS TRACT

Article history:

Resveratrol is a naturally occurring polyphenolic compound. Numerous animal studies have

Received 26 November 2011

been reported on its wide-ranging beneficial effects in the biological system including

Revised 7 June 2012

diabetes mellitus (DM). We hypothesized, therefore, that oral supplementation of resveratrol

Accepted 8 June 2012

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

Keywords:

hypothesis. Sixty-two patients with T2DM were enrolled from Government Headquarters

Type 2 diabetes mellitus

Hospital, Ootacamund, India, in a prospective, open-label, randomized, controlled trial.

Resveratrol

Patients were randomized into control and intervention groups. The control group received

Metformin

only oral hypoglycemic agents, whereas the intervention group received resveratrol (250 mg/

Glibenclamide

d) along with their oral hypoglycemic agents for a period of 3 months. Hemoglobin A1c, lipid

Glycated hemoglobin

profile, urea nitrogen, creatinine, and protein were measured at the baseline and at the end of

Human

3 months. The results reveal that supplementation of resveratrol for 3 months significantly improves the mean hemoglobin A1c (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 lowdensity 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. © 2012 Elsevier Inc. All rights reserved.

1.

Introduction

Diabetes mellitus (DM) is a common, serious, chronic, and currently incurable metabolic disorder of worldwide significance. India is identified as the diabetes capital of the world, with the current estimated 50.8 million diabetic patients. The

worldwide prevalence is 285 million in 2010, and by 2030, the number is expected to increase to 438 million. Most will have type 2 DM (T2DM) [1]. The disease is known to be associated with a high risk of microvascular and macrovascular complications and very often leads to premature death. Despite the availability of

Abbreviations: BMI, body mass index; DM, diabetes mellitus; HbA1c, hemoglobin A1c; HDL-C, high-density lipoprotein cholesterol; LDLC, low-density lipoprotein cholesterol; T2DM, type 2 diabetes mellitus. ☆ Duality of interest: The authors declare that there is no duality of interest associated with this manuscript. ⁎ Corresponding author. PG Studies & Research, JSS College of Pharmacy, Ootacamund, Tamilnadu, India 643001. Tel.: +91 0423 2447135; fax: +91 0423 2447135. E-mail address: mjnanjan@gmail.com (M.J. Nanjan). 0271-5317/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.nutres.2012.06.003

Please cite this article as: Bhatt JK, et al, Resveratrol supplementation improves glycemic control in type 2 diabetes mellitus, Nutr Res (2012), doi:10.1016/j.nutres.2012.06.003

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4

Table 3 – Change in the biochemical and clinical variables during the study period (end of the study minus baseline) for the control and intervention groups

.56 .04 ⁎⁎

.36 .01 ⁎⁎ .21 .62 .02 ⁎⁎ .72 ⁎

Variables

Figures in square brackets refer to normal reference range in the laboratory. Values are expressed as means ± SD (Student paired t test was used). ⁎ Not quite significant. ⁎⁎ P < .05. ⁎⁎⁎ P < .001.

.94 .05 ⁎ .42 .02 ⁎⁎

.0002 ⁎⁎ .20 .004 ⁎⁎

127.92 ± 15.37 79.28 ± 9.71 4.33 ± 0.76 (169.17 ± 29.85) 1.71 ± 0.74 (152.39 ± 66.51) 2.26 ± 0.65 (87.51 ± 25.23) 1.32 ± 0.25 (51.25 ± 9.88) 10.60 ± 2.59 (29.71 ± 7.27) 91.93 ± 17.68 (1.04 ± 0.20) 72.3 ± 6.2 7.23 ± 0.62 139.71 ± 16.10 81.42 ± 9.58 4.70 ± 0.90 (183.5 ± 35.16) 1.70 ± 0.63 (151.64 ± 56.92) 2.58 ± 0.83 (99.96 ± 32.18) 1.37 ± 0.27 (53.28 ± 10.78) 11.78 ± 2.11 (33 ± 5.92) 90.16 ± 15.02 (1.02 ± 0.17) 75.6 ± 4.6 7.56 ± 0.46 142.27 ± 12.99 85.72 ± 9.14 5.07 ± 0.90 (197.93 ± 35.22) 1.92 ± 0.56 (171.42 ± 50.25) 2.98 ± 0.79 (115.43 ± 30.66) 1.21 ± 0.24 (46.96 ± 9.51) 10.51 ± 1.33 (29.44 ± 3.73) 87.51 ± 7.95 (0.99 ± 0.09) 77.3 ± 2.9 7.73 ± 0.29 134.51 ± 14.61 78.62 ± 10.86 4.89 ± 0.89 (191.03 ± 34.91) 1.89 ± 0.59 (168.62 ± 53.21) 2.80 ± 0.80 (108.34 ± 31.01) 1.26 ± 0.17 (48.96 ± 6.92) 10.44 ± 1.42 (29.27 ± 3.99) 83.98 ± 9.72 (0.95 ± 0.11) 76.5 ± 3.5 (7.65 ± 0.35)

.0007 ⁎⁎ .0001 ⁎⁎⁎ .007 ⁎⁎

64.94 ± 9.00 24.60 ± 3.62 11.02 ± 3.86 (198.43 ± 69.57) 13.1 ± − 1.9 (9.65 ± 1.54) 63.31 ± 8.92 24.86 ± 2.89 10.83 ± 2.92 (195.03 ± 52.56) 11.7 ± −1.7 (8.92 ± 1.65) 63.10 ± 9.02 24.92 ± 3.05 10.11 ± 2.56 (182 ± 46.22) 11.4 ± −1.9 (8.75 ± 1.56)

Body weight, kg BMI, kg/m2 Fasting blood glucose, mmol/L and (mg/dL) HbA1c, mmol/L [2.4-4.7] and (percentage of total hemoglobin) [3.9-5.1] Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg Total cholesterol, mmol/L [2.59-6.21] and (mg/dL) [100-240] Triglyceride, mmol/L [0.56-1.98] and (mg/dL) [50-175] LDL-C, mmol/L [<2.6] and (mg/dL) [< 100] HDL-C, mmol/L [0.90-1.68] and (mg/dL) [35-65] Urea nitrogen, mmol/L [3.6-17.8] and (mg/dL) [10-50] Creatinine, mmol/L [44.2-114.9] and (mg/dL) [0.5-1.3] Total protein, g/L [63-84] and (g/dL) [6.3-8.4]

Baseline

After 3 mo

.45 .57 .05 ⁎ .15

64.78 ± 9.25 24.66 ± 3.57 11.82 ± 3.58 (212.82 ± 64.52) 13.7 ± − 2 (9.99 ± 1.50)

After 3 mo Baseline

P Control group (n = 29) Variables

Table 2 – Biochemical and clinical variables at baseline and after 3 months for the control and intervention groups

Intervention group (n = 28)

P

.83 .83 .29 .02 ⁎⁎

N UTR IT ION RE S EA RCH XX ( 2 0 12 ) XXX– X XX

BMI (kg/m2) Fasting blood glucose (mg/dL) HbA1c (mmol/L) (percentage of total hemoglobin) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Total cholesterol (mg/dL) Triglyceride (mg/dL) LDL-C (mg/dL) HDL-C (mg/dL) Urea nitrogen (mg/dL) Creatinine (mg/dL) Total Protein (g/dL)

Control group (n = 29)

Intervention group (n = 28)

P

−0.06 ± 0.16 13.07 ± 6.34

− 0.06 ± 0.05 - 14.39 ± 5.05

.99 .0001 ⁎

0.17 ± 0.10

− 0.33 ± 0.04

.0001 ⁎

7.76 ± 1.62

− 11.78 ± 0.73

.0001 ⁎

7.10 ± 1.72

− 2.14 ± 0.13

.0001 ⁎

6.90 ± 0.31

− 14.32 ± 5.31

.0001 ⁎

2.80 7.09 −2 0.17

0.75 − 12.45 − 2.03 − 3.28

9.59 6.95 0.90 1.35

.2768 .0001 ⁎ .95 .0001 ⁎

0.01 ± 0.03 − 0.32 ± 0.16

.0001 ⁎ .0001 ⁎

± ± ± ±

2.96 0.35 2.59 0.26

0.04 ± 0.02 0.08 ± 0.06

± ± ± ±

Values are expressed as means ± SD. Mean values were significantly different from control group (independent sample t test or Mann-Whitney U test). ⁎ P < .0001.

premature death. Indian races and ethnic groups are prone to these complications. Not only hyperglycemia but also disturbances of lipid metabolism are among the major causes of chronic diabetic complications. In the present study, resveratrol supplementation significantly decreases total cholesterol and LDL-C. During the study period, it was observed that the systolic blood pressure in the control group increased significantly, whereas in the intervention group, it decreased significantly. No significant difference was observed in the weight of control and intervention groups, which may be explained by their normal BMI at the time of enrollment. In conclusion, the results of the present study support our hypothesis that resveratrol supplementation improves glycemic control and the associated risk factors in patients with T2DM. The study also suggests that resveratrol could be used as an effective adjuvant therapy [21] with a conventional hypoglycemic regimen to treat T2DM. Our preliminary study provides data about the possible clinical effects of resveratrol supplementation on the glycemic control and cardiovascular risk factors in patients with T2DM and a base for future studies with larger number of patients and longer duration. Further studies on these lines are in progress.

Acknowledgment The authors thank the Indian Council of Medical Research for the award of a Senior Research Fellowship to Jayesh Kumar Bhatt and Biotivia Bioceuticals International, United States, for their generous gift of resveratrol capsules. All authors have

Please cite this article as: Bhatt JK, et al, Resveratrol supplementation improves glycemic control in type 2 diabetes mellitus, Nutr Res (2012), doi:10.1016/j.nutres.2012.06.003

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High-Dose Resveratrol Treatment for 2 Weeks Inhibits Intestinal and Hepatic Lipoprotein Production in Overweight/Obese Men Satya Dash, Changting Xiao, Cecilia Morgantini, Linda Szeto and Gary F. Lewis Arterioscler Thromb Vasc Biol. published online September 26, 2013; Arteriosclerosis, Thrombosis, and Vascular Biology is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright Š 2013 American Heart Association, Inc. All rights reserved. Print ISSN: 1079-5642. Online ISSN: 1524-4636

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Data Supplement (unedited) at: http://atvb.ahajournals.org/content/suppl/2013/09/26/ATVBAHA.113.302342.DC1.html

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Original Article High-Dose Resveratrol Treatment for 2 Weeks Inhibits Intestinal and Hepatic Lipoprotein Production in Overweight/Obese Men Satya Dash,* Changting Xiao,* Cecilia Morgantini, Linda Szeto, Gary F. Lewis Objective—Overproduction of hepatic apolipoprotein B (apoB)-100 containing very low-density lipoprotein particles and intestinal apoB-48 containing chylomicrons contributes to hypertriglyceridemia seen in conditions such as obesity and insulin resistance. Some, but not all, preclinical and clinical studies have demonstrated that the polyphenol resveratrol ameliorates insulin resistance and hypertriglyceridemia. Here, we assessed intestinal and hepatic lipoprotein turnover, in humans, after 2 weeks of treatment with resveratrol (1000 mg daily for week 1 followed by 2000 mg daily for week 2) or placebo. Approach and Results—Eight overweight or obese individuals with mild hypertriglyceridemia were studied on 2 occasions, 4 to 6 weeks apart, after treatment with resveratrol or placebo in a randomized, double-blinded, crossover study. Steadystate lipoprotein kinetics was assessed in a constant fed state with a primed, constant infusion of deuterated leucine. Resveratrol treatment did not significantly affect insulin sensitivity (homeostasis model of assessment of insulin resistance), fasting or fed plasma triglyceride concentration. Resveratrol reduced apoB-48 production rate by 22% (P=0.007) with no significant effect on fractional catabolic rate. Resveratrol reduced apoB-100 production rate by 27% (P=0.02) and fractional catabolic rate by 26% (P=0.04). Conclusions—These results indicate that 2 weeks of high-dose resveratrol reduces intestinal and hepatic lipoprotein particle production. Long-term studies are needed to evaluate the potential clinical benefits of resveratrol in patients with hypertriglyceridemia, who have increased concentrations of triglyceride-rich lipoprotein apoB-100 and apoB-48. Clinical Trial Registration—URL: www.clinicaltrials.gov. Unique identifier: NCT01451918.    (Arterioscler Thromb Vasc Biol. 2013;33:00-00.) Key Words: apolipoproteins B ◼ chylomicrons ◼ intestines ◼ lipoproteins, VLDL ◼ resveratrol

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ncreased production of triglyceride-rich lipoproteins (TRL), in the form of apolipoprotein B (apoB)-100 containing very low-density lipoprotein (VLDL) from the liver and apoB-48 containing chylomicrons from the gut, in conditions such as overweight/obesity and insulin resistance, may contribute to an increased risk of atherosclerotic disease.1,2 Recently, we have shown that, in healthy human volunteers, intestinal secretion of apoB-48–containing TRL particles is regulated by free fatty acids,3 dietary monosaccharides (glucose and fructose),4 and hormones such as insulin5 and glucagon-like peptide-1.6 Individuals with obesity/overweight,2 insulin resistance,7 and type 2 diabetes mellitus8 have increased production of apoB-48 TRL particles. This, along with the well-established overproduction of apoB-100-containing VLDL by the liver,1 contributes to the elevated TRL seen in these individuals. Identifying novel strategies to lower TRL production by the liver and intestine may have clinical benefits in conditions

such as in overweight/obese states. In the present study, we have examined the effect of resveratrol in overweight and obese men with relatively mild metabolic abnormalities. Polyphenol resveratrol, widely available over the counter, has been demonstrated to have numerous beneficial metabolic effects in vitro and in vivo in murine models. In vitro studies in hepatocytes have demonstrated that resveratrol reduces de novo lipogenesis.9 Resveratrol administration in vivo protects mice from diet-induced obesity, insulin resistance, and hepatic steatosis.10,11 Some, but not all,12,13 studies in humans have shown that resveratrol improves insulin sensitivity14–16 and lowers plasma triglyceride.14 The metabolic effects of resveratrol are thought to be mediated at least in part via indirect activation of AMP kinase and the NAD+dependent deacetylase silent mating type information regulation 2 homolog (sirtuin) 1 (SIRT1).17 Adenine monophosphate kinase (AMPK) has multiple effects on lipid metabolism by

Received on: June 10, 2013; final version accepted on: September 15, 2013. From the Department of Medicine, Physiology, and the Banting and Best Diabetes Centre, University of Toronto, Ontario, Canada (S.D., C.X., C.M., L.S., G.F.L.); and Scuola Superiore Sant’Anna, Pisa, Italy (C.M.). *These authors contributed equally to this article. The online-only Data Supplement is available with this article at http://atvb.ahajournals.org/lookup/suppl/doi:10.1161/ATVBAHA.113.302342/-/DC1. Correspondence to Gary F. Lewis, MD, FRCPC, Toronto General Hospital, 200 Elizabeth St, EN12-218, Toronto, Ontario M5G 2C4, Canada. E-mail gary.lewis@uhn.ca © 2013 American Heart Association, Inc. Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org

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DOI: 10.1161/ATVBAHA.113.302342

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Research Design and Methods Participants 8 overweight or obese individuals (BMI range 27-40) with mild to moderate hypertriglyceridemia (TG >1.5, range 1.6-3.9 mmol/l) were recruited via advertisements in the local press. Their demographic and biochemical parameters are shown in Table 1. Participants had no prior medical illnesses and were taking no medications. They underwent a 2-hour, 75 gram oral glucose tolerance test, routine screening blood tests and urinalysis. Those with evidence of diabetes, anemia, coagulopathy, renal dysfunction or impaired liver function tests were excluded. The Human Research Ethics Board of the University Health Network, University of Toronto, approved the study and all subjects gave written, informed consent prior to their participation. Each participant was studied on 2 occasions, 4-6 weeks apart, in a randomized, double blind, crossover trial. They were randomized to receive two weeks of placebo or resveratrol (Transmax, Biotivia Longevity Biologicals, New York, NY) [1g/d (500mg twice per day) for one week, followed by 2g/d (1g twice per day) for the second week] preceding the lipoprotein kinetics study. Each participant was reviewed after one week of treatment to ensure there were no adverse effects and to ensure compliance by pill counting. Lipoprotein kinetic studies Participants were admitted to the Metabolic Test Centre of the Toronto General Hospital after two weeks of treatment. Fasting blood samples were taken for measurement of plasma glucose, insulin and lipids. They had a standardized meal comprising rice, chicken, vegetables and jell-o at 5pm on both occasions. The following day a lipoprotein kinetics

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Journal of Gerontology: MEDICAL SCIENCES Cite journal as: J Gerontol A Biol Sci Med Sci doi:10.1093/gerona/glr235

© The Author 2012. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Pilot Study of Resveratrol in Older Adults With Impaired Glucose Tolerance Jill P. Crandall,1,2,3 Valerie Oram,1 Georgeta Trandafirescu,1,2 Migdalia Reid,1 Preeti Kishore,1,2,3 Meredith Hawkins,1,2,3 Hillel W. Cohen,4 and Nir Barzilai1,2,3 1Division

of Endocrinology, Department of Medicine, 2Diabetes Research and Training Center, 3Institute of Aging Research, and of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York.

4Department

Background.  Resveratrol, a plant-derived polyphenol, has shown promising effects on insulin sensitivity and glucose tolerance in animal models and is also reported to have cardioprotective properties, but human studies are limited. In a pilot study, we tested the hypothesis that resveratrol improves glucose metabolism and vascular function in older adults with impaired glucose tolerance (IGT). Methods.  Ten subjects aged 72 ± 3 years (M ± SD) with IGT were enrolled in a 4-week open-label study of resveratrol (daily dose 1, 1.5, or 2 g). Following a standard mixed meal (110 g carbohydrate, 20 g protein, 20 g fat), we measured 3-hour glucose and insulin area under the curve (AUC), insulin sensitivity (Matsuda index), and secretion (corrected insulin response at 30 minutes). Endothelial function was assessed by reactive hyperemia peripheral arterial tonometry (reactive hyperemia index) before and 90 minutes postmeal. Results did not differ by dose, so data were combined for analysis. Results.  At baseline, body mass index was 29 ± 5 kg/m2, fasting plasma glucose 110 ± 13 mg/dL, and 2-hour glucose 183 ± 33 mg/dL. After 4 weeks of resveratrol, fasting plasma glucose was unchanged, but peak postmeal (185 ± 10 vs 166 ± 9 mg/dL, p = .003) and 3-hour glucose AUC (469 ± 23 vs 428 ± 19, p = .001) declined. Matsuda index improved (3.1 ± 0.5 vs 3.8 ± 0.5, p = .03), and corrected insulin response at 30 minutes was unchanged (0.6 ± 0.1 vs 0.5 ± 0.5, p = .49). There was a trend toward improved postmeal reactive hyperemia index (baseline vs resveratrol postmeal delta −0.4 ± 0.2 vs 0.2 ± 0.3, p = .06). Weight, blood pressure, and lipids were unchanged. Conclusions.  At doses between 1 and 2 g/day, resveratrol improves insulin sensitivity and postmeal plasma glucose in subjects with IGT. These preliminary findings support the conduct of larger studies to further investigate the effects of resveratrol on metabolism and vascular function. Received July 12, 2011; Accepted November 13, 2011 Decision Editor: Luigi Ferrucci, MD, PhD

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ESVERATROL (3,5,4′-trihydroxystilbene) is a plantderived polyphenolic compound mainly known for its antioxidant and phytoestrogenic properties. Interest in this compound has increased in recent years, first from its identification as a chemopreventive agent for skin cancer and subsequently from reports that it activates sirtuins and extends the life span of lower organisms, including rodents (1). Resveratrol has demonstrated promising effects on insulin secretion, insulin sensitivity, and glucose tolerance in a variety of animal models (2,3). Notably, resveratrol prevented the negative metabolic effects of excess calorie intake, improving glucose tolerance, lowering insulin levels, and significantly increasing survival of middle-aged mice (4). Resveratrol has also been shown to increase mitochondrial biogenesis and appears to mimic the beneficial effects of caloric restriction on glucose metabolism (5–7). Resveratrol has also been proposed to have cardioprotective effects. Resveratrol possesses weak activity as a phytoestrogen (8), antioxidant properties (9), and has been shown to both enhance synthesis and decrease inactivation of

the vasorelaxant nitric oxide (10). Resveratrol may also promote vascular relaxation by inhibiting synthesis of the potent vasoconstrictor thromboxane A2 and by other nitric oxide-independent mechanisms (11). However, despite the many health claims made on its behalf and its widespread use as a nutritional supplement, formal studies of resveratrol in humans are very limited and no studies of its metabolic effects have been reported. Further, questions about resveratrol bioavailability, dosing range, and safety also need to be addressed (12–14). We therefore conducted a pilot study of resveratrol treatment as an initial step in assessing its potential to improve glucose tolerance, insulin sensitivity, and vascular function. For this initial investigation, we studied the effects of resveratrol in subjects with impaired glucose tolerance (IGT) who have definite but not-yet-severe metabolic dysregulation, which may be most amenable to intervention. We chose to focus on older adults for two important reasons. First, IGT is in large part an age-related phenomenon, affecting up to 30% of older adults (15) and constitutes a major risk factor for 1

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Address correspondence to Jill P. Crandall, MD, 1300 Morris Park Avenue, Belfer 701, Bronx, NY 10461. Email: jill.crandall@einstein.yu.edu


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CRANDALL ET AL.

the development of both diabetes and cardiovascular disease (16). In addition, although lifestyle modification was exceptionally effective in preventing progression from IGT to diabetes in older participants (age 60–85) in the Diabetes Prevention Program, metformin was not (17), highlighting the need for alternate pharmacologic approaches for older adults with IGT.

Standard Meal Test Subjects were studied following an overnight fast and after a test meal containing 110 g carbohydrate, 20 g protein, and 20 g fat. The meal consisted of standard breakfast foods: cereal, bread, juice, and milk. Blood sampling was performed fasting and 30, 60, 120, and 180 minutes following the meal through an indwelling intravenous catheter. Subjects were instructed to consume a standard meal and snack at home on the night prior to the standard meal test, in order to minimize metabolic variability between tests. The assigned resveratrol dose was administered with the standard meal during the test conducted at the conclusion of the 4-week treatment period. Insulin sensitivity was estimated using homeostasis model assessment (HOMA-IR): insulinfasting (mU/mL) × glucosefasting (mmol/L)/22.5 (19) and also from insulin and glucose levels obtained following the standard meal challenge using the Matsuda index: 10,000/√([fasting plasma glucose × fasting plasma insulin] [mean glucose × mean

Downloaded from http://biomedgerontology.oxfordjournals.org/ at Albert Einstein College of Medicine on January 4, 2012

Methods Adults aged 65 and older were screened with a 75-g oral glucose tolerance test and those with fasting plasma glucose <126 mg/dL and 2-hour glucose ≥140 mg/dL were eligible to enroll. Subjects were excluded if they had a recent cardiovascular event, evidence of significant liver or renal disease; any active cancer; or prior history of estrogen-dependent neoplasm. Because of the possibility of CYP450-related drug interactions (18), treatment with the following drugs was exclusionary: antiepileptics, mexilitene, quinidine, cyclosporine, tacrolimus, HIV protease inhibitors, or high-dose statin therapy (>20 mg atorvastatin or rosuvastatin; >40 mg simvastatin, pravastatin, or lovastatin). Individuals taking resveratrol or antioxidant vitamins (other than a standard multivitamin preparation) within the prior 3 months were also excluded. The study protocol was approved by the Albert Einstein College of Medicine Institutional Review Board, and all participants provided written informed consent. Resveratrol capsules were obtained from Biotiva, LLC, and independent verification of the resveratrol content of the capsules used in this study was performed in the laboratory of Rong-Fong Shen, PhD, Proteomics and Analytical Biochemistry Unit, National Institute on Aging at the National Institutes of Health. Subjects were randomly assigned to take open-label resveratrol for 4 weeks in one of the three doses: 1, 1.5, and 2 g/day, taken in divided doses. Subjects were instructed to maintain their usual dietary and physical activity patterns during their participation in the study.

insulin]) (20,21). Insulin secretion was estimated using the corrected insulin response at 30 minutes: insulin30min (mU/ mL)/glucose30min (mg/dL) × (glucose30min [mg/dL] − 70) (19). b-Cell function was assessed using the oral disposition index (DIO) calculated using the formula: (DI0–30/DG0–30) (1/I0) (22). Insulin and glucose area under the curve (AUC) were calculated using the trapezoidal method. Percent body fat was measured using bioimpedance analysis (RJL Systems, Clinton Township, MI). Endothelial function testing was performed fasting and 90 minutes following the standard meal, using reactive hyperemia peripheral arterial tonometry (RH-PAT) (23,24). RH-PAT employs a finger plethysmographic device to detect pulsatile arterial volume changes, which are sensed by a pressure transducer and transferred to a computer for analysis (EndoPAT; Itamar Medical). Studies are performed with the patient at rest, in a comfortable thermoneutral environment, and any antihypertensive medications were held until after completion of the 90-minute postmeal test. Fingertip probes are placed on the index finger of both hands, and 5 minutes of baseline recording is obtained. Blood flow is then occluded in one arm for 5 minutes, using a standard blood pressure cuff. Recording continues in both fingers during occlusion and for 5 minutes after release of the cuff. The reactive hyperemia index is calculated as the ratio of the average pulse amplitude in the posthyperemic phase divided by the average baseline amplitude, with normalization to the signal in the control arm to compensate for any systemic changes. Test–retest repeatability testing in our laboratory among healthy controls resulted in a coefficient of variability of 15.2% for tests performed 2 hours apart and 16.4% for tests performed 1–4 weeks apart. Assays were performed in the core laboratories of the Einstein Institute for Clinical and Translational Research: chemistry profiles, complete blood count, urinalysis, glucose, lipoproteins, insulin (radioimmunoassay), high sensitivity c-reactive protein (latex-enhanced tur­bidimetric assay), and adiponectin (radioimmunoassay; Linco). Statistical Analysis Data are presented as mean (±SD) for baseline values and mean (±SEM) for baseline versus resveratrol comparisons. Baseline and posttreatment variables (peak and AUC glucose, insulin, Matsuda index, etc.) were compared using a paired t-test. Since there were no apparent differences among the three resveratrol doses studied, the groups were combined for analysis. For RH-PAT index, the pre- and postmeal delta was also analyzed (baseline vs resveratrol) using paired t-test. Data analyses were performed using GraphPad Instat, v3. Results Ten subjects (seven female) with a mean age of 72 ± 3 years were enrolled. The subjects were overweight to obese and moderately insulin resistant, with a mean body mass

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Antihyperglycemic effects of short term resveratrol supplementation in type 2 diabetic patients  

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