Do you know if you're insulin-resistant? Insulin resistance represents the loss of sensitivity of peripheral tissues to the effects of the hormone insulin. It can predispose individuals to prediabetes (affecting more than 1 in 3 Americans) and type 2 diabetes (affecting 1 in 10 Americans). Preventing and reversing insulin resistance is essential to safeguarding cardiovascular health and wellness. The good news is that many tools can promote insulin sensitivity and glycemic control. Resveratrol has been gaining popularity since the 1990s for its anti-inflammatory, antioxidant, and protective effects on cardiometabolic and endocrine health.

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Overview of Insulin Sensitivity and Endocrine Disorders

The pancreas makes and secretes insulin, facilitating glucose uptake by cells and promoting its conversion into energy or storage as glycogen in the liver and muscles. Simultaneously, insulin inhibits the liver's production of glucose. By enhancing cellular uptake and storage of glucose while limiting its production, insulin acts as a key regulator of blood sugar, ensuring it remains within a narrow and optimal range. (19)

Insulin sensitivity refers to the body's responsiveness to insulin, with higher sensitivity ensuring efficient glucose uptake by cells. When the body becomes less responsive to insulin, a condition known as insulin resistance ensues. Data from 2021 indicates that 40% of American adults (ages 18-44) are insulin resistant. Insulin resistance impedes the effective uptake of glucose by cells, ultimately leading to elevated blood sugar levels over time. This metabolic dysfunction is often associated with obesity, physical inactivity, and a diet high in refined carbohydrates and saturated fats (11). Over time, insulin resistance can contribute to the development of various endocrine disorders, including prediabetes, type 2 diabetes mellitus, metabolic syndrome, and polycystic ovary syndrome (PCOS).

What Is Resveratrol?

Resveratrol is a naturally occurring polyphenolic compound belonging to the stilbenoid class. Its molecular structure consists of two aromatic rings connected by a styrene double bond. Natural sources of resveratrol include red grapes, red wine, peanuts, and certain berries. Plants produce resveratrol in response to environmental stressors, such as fungal infections, injury, and UV radiation. (20, 22)   

The scientific community has extensively investigated resveratrol's health effects since the 1990s. Initially linked to the "French Paradox," suggesting a potential explanation for the low coronary heart disease incidence in French populations despite high saturated fat intake, resveratrol has since been studied for its potential in preventing cancer, delaying cardiovascular and neurodegenerative diseases, improving glycemic control in type 2 diabetes, and extending lifespan in experimental models. (20, 22) 

Resveratrol exhibits antioxidant properties, acting as a scavenger of free radicals within the body to mitigate oxidative stress, which is implicated in various chronic diseases. Additionally, resveratrol has been studied for its role in activating sirtuins, a class of proteins associated with regulating cellular health and longevity. Resveratrol may contribute to cellular repair processes and impact aging by modulating these sirtuin pathways. Supplemental resveratrol has increased the lifespans of yeast, worms, fruit flies, fish, and mice. However, human studies are required to determine whether it may have similar impacts on human longevity. 

Research suggests that resveratrol may promote cardiovascular health through its ability to improve lipid profiles, reduce inflammation inflammation, and enhance endothelial function (46). Resveratrol's anti-inflammatory properties extend to its potential in mitigating neuroinflammation and modulating mitochondrial function, offering promise in preventing and treating neurological conditions. Finally, resveratrol has been found to have anti-cancer effects against human breast, prostate, stomach, colon, pancreatic, liver, skin, cervical, ovarian, and thyroid cancer cells. Animal models suggest these effects may be related to resveratrol's ability to reduce cancer cell proliferation, induce apoptosis, and inhibit angiogenesis and metastasis. (12) 

Resveratrol's Role in Insulin Sensitivity

Scientific studies have indicated that resveratrol may positively affect insulin sensitivity and glucose metabolism. Interestingly, resveratrol's insulin-sensitizing effects may be stronger in people with diabetes than those without. A meta-analysis comprising 11 studies and 338 subjects found that resveratrol consumption significantly reduced markers of fasting glucose, insulin, hemoglobin A1c, and insulin resistance in patients with diabetes. However, no significant changes were observed in nondiabetic participants' glycemic measures.

Resveratrol collectively acts on multiple points along the insulin signaling pathway to enhance insulin sensitivity. Resveratrol is known to activate SIRT1, a member of the sirtuin family of proteins associated with cellular regulation and longevity. SIRT1 modulates insulin sensitivity by deacetylating target proteins, including those involved in insulin signaling pathways. Activation of SIRT1 by resveratrol enhances insulin receptor substrate (IRS) function, facilitating efficient insulin signaling and improving cellular responsiveness to insulin. (2, 38, 44) 

Resveratrol also stimulates AMP-activated protein kinase (AMPK), an energy-sensing enzyme that regulates cellular energy balance. AMPK activation by resveratrol enhances glucose uptake and utilization by cells. AMPK activation is linked to increased mitochondrial biogenesis and improved cellular energy efficiency, contributing to enhanced insulin sensitivity. (24, 38)

GLUT4 receptors are glucose transporters responsible for facilitating the entry of glucose into cells. Resveratrol has been shown to promote the translocation of GLUT4 receptors from intracellular compartments to the cell membrane. This process increases the cell's capacity to uptake glucose, reducing blood glucose levels. The enhanced translocation of GLUT4 receptors is a key mechanism through which resveratrol improves insulin sensitivity. (14, 38) 

Integrating Resveratrol into Endocrine Health Management 

A comprehensive health plan aiming to optimize cardiometabolic health and insulin sensitivity should prioritize regular physical activity, adherence to a balanced diet, sufficient sleep, stress management practices, and weight maintenance strategies. Supplements, such as resveratrol, can play a valuable role in complementing these lifestyle habits.

Regular physical activity is a cornerstone for metabolic health, with studies consistently demonstrating its efficacy in enhancing insulin sensitivity. Engaging in aerobic exercises, such as brisk walking or cycling, has been associated with improved glucose metabolism and decreased insulin resistance. Additionally, resistance training has shown benefits in promoting muscle health and increasing insulin sensitivity. (40, 43) 

The Mediterranean diet, rich in fruits, vegetables, whole grains, and healthy fats, has been extensively studied and linked to improved cardiometabolic health. Research suggests that omega-3 fatty acids, found in fatty fish, flaxseeds, and walnuts, contribute to reduced inflammation and enhanced insulin sensitivity.

Adequate sleep is integral to overall health, and insufficient sleep has been linked to insulin resistance. Research indicates that obtaining 7-9 hours of quality sleep per night positively influences insulin sensitivity and metabolic function. Stress management techniques, such as mindfulness meditation or yoga, have also demonstrated their ability to reduce stress hormones and blood glucose.

Furthermore, maintaining a healthy body weight is crucial. Even modest weight loss has been shown to enhance insulin sensitivity and improve cardiovascular disease risk factors. Intermittent fasting has been shown to directly attenuate insulin resistance while concurrently encouraging weight loss through its impact on calorie restriction and metabolic adaptations.

Dosage and Administration of Resveratrol

Resveratrol supplements come in tablet, soft gel, capsule, and powder form. Many resveratrol supplements available in the United States contain Japanese knotweed (Polygonum cuspidatum) root extracts. Trans-resveratrol is well absorbed but is quickly metabolized and eliminated from the body. Adults have safely used resveratrol in oral doses of 250-1000 mg daily for up to three months. Meta-analyses have yielded conflicting findings regarding effective doses for improving glycemic indices in patients with type 2 diabetes. One meta-analysis showed that doses of 250-1000mg daily modestly reduce levels of blood sugar, insulin, A1c, and insulin resistance, whereas another indicated that doses of at least 1000 mg daily are needed.

Potential Interactions and Side Effects

Resveratrol generally exhibits a favorable safety profile when consumed in dietary amounts found in food sources like red grapes. Higher doses of 1000-3000 mg daily for up to six months are likely safe but may be more likely to cause gastrointestinal side effects, including nausea, abdominal pain, flatulence, and diarrhea (22, 23). 

Resveratrol may interact with certain medications. For instance, resveratrol has been shown to inhibit cytochrome P450 enzymes, which are involved in drug metabolism. This interaction could potentially affect the blood levels of medications metabolized by these enzymes, such as HMG-CoA reductase inhibitors, calcium channel antagonists, anti-arrhythmic agents, HIV protease inhibitors, immunosuppressants, antihistamines, and benzodiazepines. (22) 

Resveratrol has been found to inhibit platelet aggregation in vitro, which could potentially increase the risk of bleeding and bruising when taken with anticoagulant and blood-thinning medications like warfarin, heparin, and clopidogrel (22).

Resveratrol's impact on estrogen should also be a consideration for its use. Resveratrol's chemical structure, similar to a synthetic estrogen agonist, suggests it may also elicit estrogenic effects. While research is ongoing, it is generally recommended that individuals with estrogen-sensitive conditions, such as breast cancer, should avoid resveratrol supplements. (22)

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Resveratrol for Insulin Sensitivity: Final Thoughts

Resveratrol, a natural polyphenol, holds promise in improving insulin sensitivity and fostering better endocrine health. Its activation of SIRT1, modulation of AMPK, and promotion of GLUT4 receptor translocation contribute to enhanced glucose metabolism. With antioxidant and anti-inflammatory properties, resveratrol may provide additional benefits for individuals with cardiovascular risk factors. For the best outcomes, resveratrol should be administered alongside long-term lifestyle modifications, such as regular exercise and a balanced diet. Individuals considering resveratrol should consult with healthcare providers, especially when managing pre-existing conditions or taking medications, to ensure its safe integration into their health plan.