Pilot Study of Resveratrol in Older Adults With Impaired Glucose Tolerance

The Effect of Resveratrol in Older Adults With Impaired Glucose Tolerance: a Double-Blind Crossover Study

Status

Completed

Phases

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01375959

Acronym

RSV

Enrollment

Registered

2011-06-20

Start date

2011-04-30

Completion date

2015-04-30

Last updated

2022-10-26

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Impaired Glucose Tolerance

Keywords

resveratrol, glucose intolerance, insulin resistance, endothelial function

Brief summary

Resveratrol is a substance found in many plants, including grapes and red wine, which is widely used as a nutritional supplement. Studies in cells and lower animals show that resveratrol has many potential benefits, including prolonging lifespan, preventing cancer and heart disease and normalization of glucose metabolism. Although use of this agent shows great promise in the treatment and/or prevention of diabetes, there have been no studies reported to date in humans. As an initial step, this proposal is for a 6 week pilot study of resveratrol treatment in older adults with impaired glucose tolerance (IGT) in order to explore its effects on post-meal blood glucose metabolism. Preliminary studies will also be conducted to explore how resveratrol works by studying cellular function (in muscle samples obtained from study participants) and by testing resveratrol's effect on blood vessel function.

Detailed description

A. Introduction and Specific Aims Resveratrol (RSV), a plant-derived polyphenol and potential activator of the mammalian sirtuin, Sirt1, has demonstrated promising effects on insulin secretion, insulin sensitivity and glucose tolerance and has extended the lifespan of obese mice. RSV is in common use as a nutritional supplement, but formal studies in humans are limited and-in particular-the metabolic effects of RSV in humans have yet to be carefully tested. The convergence of a worldwide epidemic of diabetes combined with a marked increase in the proportion of the elderly underscore the need to develop new approaches to improve glucose intolerance. We therefore propose a study of RSV treatment in older subjects with impaired glucose tolerance (IGT) to determine if there is improvement in glucose tolerance and markers of insulin resistance, mitochondrial biogenesis and vascular function. This proposal builds on our findings in a recently-completed NIH P01 on cardiovascular disease markers in older adults with IGT. It is our hypothesis that RSV has the potential to exert important metabolic effects that can be directly and safely tested in human subjects. The growing body of pre-clinical evidence, as well as our own preliminary data, provide strong support for formal tests of RSV effects on several important metabolic parameters. These proposed studies constitute a critical step in investigating the therapeutic potential of RSV, as well as providing insight into relevant mechanisms. Specific Aims: We propose a 6-week randomized, double-blind, placebo controlled cross-over study of RSV in older adults (age 50-80 years, n=38) with IGT, with the following aims: Specific Aim 1: To assess the effects of RSV (2g/day) on mixed meal tolerance in subjects with age-related glucose intolerance. In our previous studies, we developed a standard mixed meal protocol to evaluate postprandial changes in glucose, insulin and lipids. We will apply this protocol to study a cohort of older adults with impaired glucose tolerance in a double-blind, placebo controlled cross-over study of RSV treatment. Metabolic outcomes will include post-meal glucose area under the curve (AUC), calculated estimates of insulin sensitivity and insulin secretion and circulating levels of free fatty acids and triglycerides. This study will be the first to document RSV effects on glucose intolerance in humans and will provide critical information needed to inform future clinical and mechanistic investigations. We hypothesize that treatment with RSV will result in improvement in mixed meal tolerance, via effects on insulin secretion, insulin action or both, in subjects with age-related glucose intolerance. Specific Aim 2: To assess the effects of RSV on age-related decline in mitochondrial biogenesis. In animal models, RSV has been shown to enhance mitochondrial biogenesis, which may occur through activation of Sirt1, which is an important regulator of cellular energy metabolism via PGC-1α (peroxisome-proliferator-activated receptor-γ coactivator-1 alpha). We will assess this directly by measuring mitochondrial mRNA expression and DNA copy number in muscle obtained from participants after treatment with RSV compared with placebo. Studies of mitochondrial morphology and enzyme activity will be performed in collaboration with Dr. Sreekumaran Nair (Mayo Clinic), who is an expert in mitochondrial physiology. We hypothesize that treatment with RSV will result in improvement in mitochondrial number and function, which is a potential mechanism for improvement in insulin sensitivity that may occur with RSV treatment. Specific Aim 3: To assess the effects of RSV on fasting and post-meal endothelial function. Since treatment with RSV has also been reported to have beneficial cardiovascular effects, including improved vascular reactivity, we will study in vivo endothelial function. We will use reactive hyperemia peripheral arterial tonometry to assess endothelial dependent vasodilation in study subjects before and after treatment with RSV, in both the fasting and postprandial state. Augmentation index, a measure of arterial stiffness will also be assessed. We hypothesize that chronic treatment with RSV will result in improvement in endothelial function through direct vascular effects, which may be mediated via enhanced nitric oxide availability, reduced oxidative stress and/or as a consequence of improvement in glucose metabolism.

Interventions

DIETARY_SUPPLEMENTresveratrol

resveratrol 500 mg capsules, 3 capsules (1500 mg) orally twice a day for 6 weeks

DRUGPlacebo

3 placebo capsules orally twice a day for 6 weeks

Study design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

50 Years to 80 Years

Healthy volunteers

Inclusion criteria

* impaired glucose tolerance

Exclusion criteria

* history of estrogen-dependent neoplasm * use of certain drugs: high dose statins, warfarin, antiepileptics * current treatment with anti-diabetes medications * impaired liver or kidney function

Design outcomes

Primary

Measure	Time frame	Description
Post Meal Glucose Area Under the Curve	end of each of two 6 week treatment periods	Glucose AUC following a standard mixed meal challenge AUC, Area Under a Curve. There are no normal ranges but a higher value is worse than a lower value.

Secondary

Measure	Time frame	Description
Insulin Sensitivity Using a Modification of the Matsuda Index	end of each of two 6 week treatment periods	Insulin sensitivity was measured from insulin and glucose levels obtained following standard meal challenge using a modification of the Matsuda index. This was calculated based on data obtained from a 75 g oral glucose tolerance test, as follows: 10,000 divided by the square root of {(fasting plasma glucose X fasting plasma insulin) (mean plasma glucose X mean plasma insulin)}. This is a unitless measure. The Matsuda index is considered an early biomarker for metabolic dysregulation and is an effective clinical tool to define insulin sensitivity (i.e., the ability of tissues to respond to the signal of insulin) and secretory defects in individuals with impaired glucose homeostasis. The Matsuda index correlates strongly with the euglycemic insulin clamp which is a direct measure of insulin sensitivity. In the United States, it is recognized that participants who do not have insulin resistance have Matsuda Index values of \>=2.5.

Other

Measure	Time frame	Description
Insulin Secretion	end of each of two 6 week treatment periods	c-peptide deconvolution; HOMA-B
Peripheral Microvascular Endothelial Function Via Reactive Hyperemia-Peripheral Arterial Tonometry (RH-PAT) Index	end of each of two 6 week treatment periods	Reactive Hyperemia-Peripheral Arterial Tonometry (RH-PAT) index is 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. RH-PAT is a non-invasive and user-independent technique used to assess peripheral microvascular endothelial function by measuring changes in digital pulse volume during reactive hyperemia. Lower RH-PAT scores are associated with flow mediated dilatation (FMD) and may predict mortality in subjects with cardiovascular (CV) risk factors including obesity, total/HDL cholesterol ratio, diabetes, smoking and dyslipidemia.
Number of Differentially Expressed Transcripts	end of each of two 6 week treatment periods	Gene expression in skeletal muscle using RNASeq

Countries

United States

Participant flow

Participants by arm

Arm	Count
Resveratrol First resveratrol 500 mg capsules, 3 each day for 6 weeks resveratrol: resveratrol 500 mg capsules, 3 capsules (1500 mg) orally twice a day for 6 weeks	17
Placebo First matching placebo capsule containing lactose, 3 each day for 6 weeks Placebo: 3 placebo capsules orally twice a day for 6 weeks	21
Total	38

Withdrawals & dropouts

Period	Reason	FG000	FG001
First Intervention (6 Weeks)	Adverse Event	2	3
Second Intervention (6 Weeks)	Adverse Event	0	2
Second Intervention (6 Weeks)	Withdrawal by Subject	0	1

Baseline characteristics

Characteristic	Resveratrol First	Placebo First	Total
Age, Continuous	67 years STANDARD_DEVIATION 8	67 years STANDARD_DEVIATION 6	67 years STANDARD_DEVIATION 7
Region of Enrollment United States	17 participants	21 participants	38 participants
Sex: Female, Male Female	6 Participants	7 Participants	13 Participants
Sex: Female, Male Male	11 Participants	14 Participants	25 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 38	0 / 38
other Total, other adverse events	8 / 38	8 / 38
serious Total, serious adverse events	0 / 38	1 / 38

Outcome results

Primary

Post Meal Glucose Area Under the Curve

Glucose AUC following a standard mixed meal challenge AUC, Area Under a Curve. There are no normal ranges but a higher value is worse than a lower value.