Better Glycemic Control with Resveratrol

Resveratrol
Increases Insulin Sensitivity

It may become “a valuable new strategy for treating
insulin resistance and type 2 diabetes”
By Will Block


© iStockphoto.com/
Jason Lugo

hallmark of many thrill seekers is the incessant need to up the ante—to find something that’s newer, faster, more dangerous, etc., in order to get that adrenaline rush they crave. But is the need for more of whatever they’re getting a psychological or a physiological phenomenon? In one sense, the question answers itself, because all of psychology is rooted in physiology: every thought, feeling, emotion, etc., consists of neurochemical events in the brain, and those events can be influenced by the biochemical effects of hormones—adrenaline, for example—originating elsewhere in the body.

Could it be that a certain neurological resistance to the effects of adrenaline sets in when the thrills keep on coming, causing the daredevil to keep pushing the envelope? We don’t know. But we do know that resistance to another hormone, insulin, is very common. Insulin may seem boring by comparison with the glamorous adrenaline, but we ignore its great importance at our peril. If our cells become resistant to it and we therefore need ever more of it, we could be in for big trouble, spelled d-i-a-b-e-t-e-s, for which insulin resistance is the precursor condition.

How to Prevent Insulin Resistance

But what’s the precursor to insulin resistance? The development of this condition is a multistep process with strong genetic and environmental influences, and much is known about medical conditions—most notably obesity—that tend to produce it. How they produce it is another matter, about which little is known. From a practical perspective, though, all we need to know is how to prevent insulin resistance and how best to deal with it if we have it.

First of all, watch your weight. If you’re obese, lose the fat. Easily said, not so easily done, but think of it this way: your life in the short term may depend on it to some degree, and your longevity will almost certainly depend on it. Also, get regular exercise—not just to help you lose weight (if that’s what you need) but also to help prevent insulin resistance even if you’re of normal weight or skinny. Thin people can develop insulin resistance too, especially if they don’t exercise.

Resveratrol—Spectacular but Anticlimactic

And then there’s wine—red wine. As if you didn’t know, it contains resveratrol (rez·VEER·ah·troll), which is as close to a “miracle molecule” as can presently be imagined.* Consider, for example, that resveratrol, all by itself, can greatly increase the longevity of numerous organisms, from fungi to worms to insects to fish to mammals. Spectacular! By comparison with that, it’s actually anticlimactic that resveratrol is also believed (based on evidence from laboratory and animal studies) to boost physical strength and endurance and to offer strong protective effects against most of the major degenerative diseases of aging, notably cardiovascular disease, neurodegenerative diseases, cancer, arthritis, and diabetes.


*Note that we didn’t say it is a miracle molecule. There are no miracles, only things that are more or less amazing but not yet understood. Much of what we now know and take for granted about science, technology, and medicine would, not long ago, have been considered miraculous. Beware of the word miracle in any health-oriented literature—it’s sensationalist and almost always signals the work of hacks or quacks. Among the rare exceptions is the excellent book The Antioxidant Miracle by Lester Packer, who is probably the world’s leading authority on antioxidants, and Carol Colman, a gifted science writer.


Progress—What a Mess

To that industrial-strength list, add insulin resistance. But wait—if resveratrol is already believed to protect against diabetes, wouldn’t protection against insulin resistance be a part of that? Probably yes, but that doesn’t mean that we shouldn’t investigate the question of insulin resistance separately, especially when there are so many different factors that can be varied in any such study.

Young mice or old? Male or female? Conventional strain or genetically engineered strain? Lean or fat? Healthy or not? Normal diet or specialized diet? Controlled amounts of food or ad libitum feeding? High dose or low dose of the agent being tested? Oral administration or parenteral administration? Short-term or long-term administration? What was being studied? What was the theoretical premise? What experimental techniques were used? What kinds of data were acquired? What statistical methods were used for data analysis? Etc. . . .

Get the picture? No two studies are alike, and trying to figure out which factors affect the results, in what ways, and to what extent—and how (if at all) the results can be meaningfully compared with the results of other studies—can be a nightmare. It’s no wonder that the medical literature is awash in confusing, contradictory results and that the scientists are forever changing their minds about what’s good for you and what isn’t, and why. Progress is a very messy process.

The Importance of Glycemic Control

Insulin resistance occurs when our cells become increasingly resistant to the action of insulin, whose primary function is to regulate blood sugar (glucose) levels. It does this by facilitating the transport of glucose molecules from our blood into our cells, which need glucose as fuel for energy production. Insulin resistance is obviously a bad thing, and its converse, insulin sensitivity, is a good thing: the more sensitive our cells are to insulin’s action, the less insulin we need in our blood—and that’s beneficial for a variety of reasons.

It’s also beneficial to keep our blood glucose levels within normal bounds, not allowing them to “spike” too high after a meal, because that causes a corresponding spike in insulin levels. More importantly, chronic glucose spiking can damage our blood vessels and various organs in the long run. This is why the concept of glycemic control is so important. (As a bonus, it can also help with weight loss. See “Glycemic Control—Best for Weight Loss” in the September 2007 issue.)

SIRT1—A Protein Activated by Resveratrol

A group of researchers in Shanghai recently investigated the effects of resveratrol on insulin sensitivity, both in vitro (in cell cultures) and in vivo (in living organisms).1 They began not with resveratrol itself, however, but with an endogenous (from within the body) protein called SIRT1, which is known to be activated by resveratrol, i.e., resveratrol enhances the activity of SIRT1 via chemical interaction.

SIRT1 plays a key role in resveratrol’s biological actions, including increased longevity, in a wide variety of creatures. It’s the most important member of a family of seven mammalian proteins that are collectively called sirtuins (sir·TWO·ins). Sirtuins of one form or another are believed to exist in all organisms and to act similarly in all of them. This probably accounts for the similarity of resveratrol’s actions in all organisms in which it has been studied thus far.

SIRT1 Increases Insulin Sensitivity

The Chinese researchers measured SIRT1 levels in vitro (using human liver-cancer cell cultures) under both normal and insulin-resistant conditions; they then did the same in vivo, using normal and insulin-resistant mice. In both cases, they found that the SIRT1 levels were significantly reduced in the insulin-resistant condition, indicating that SIRT1 is somehow involved in that condition.

This prompted them to see whether they could induce insulin resistance (in vitro) by deliberately reducing SIRT1 levels; the latter can be done by using SIRT1 inhibitors or by “knocking out” (disabling) the gene, SIRT1, that codes for the production of this protein. The results were as expected: reduced SIRT1 levels induced insulin resistance, indicating that SIRT1 is necessary for proper insulin function.

Finally, they tried the opposite: they increased SIRT1 levels (not by using resveratrol but, believe it or not, by infecting the cells with herpes simplex virus) to see whether this would increase insulin sensitivity. Sure enough, it did, as evidenced by a significantly higher glucose uptake by the cells. Furthermore, they found that SIRT1 improved the cells’ response to insulin under insulin-resistant conditions.

Resveratrol Increases Insulin Sensitivity in a SIRT1-Dependent Manner

Switching to resveratrol, the researchers sought to determine whether it would improve insulin sensitivity in vitro. It did. Using different cell cultures, including fat cells from rats and liver-cancer cells from humans, they found that resveratrol significantly improved insulin function (a sign of improved insulin sensitivity in the cells) in both normal and insulin-resistant conditions.

In addition to serving as an activator of the SIRT1 protein, resveratrol upregulated (stimulated) the SIRT1 gene, causing more of the protein to be produced. The data indicated that resveratrol acted in a SIRT1-dependent manner, i.e., its effects could be correlated with those of SIRT1, in agreement with much prior research in this area.

Next the researchers tested resveratrol’s ability to improve insulin sensitivity in vivo, using mice that were fed a high-fat diet, which induces insulin resistance (and right there is your connection between obesity and insulin resistance, which often leads to diabetes). Trying to compensate for the insulin resistance, the mouse pancreases had been churning out large amounts of insulin, leading to excessive plasma insulin levels, which are harmful to mice (and to humans). Resveratrol significantly improved insulin sensitivity in these afflicted mice. As a result, they needed less insulin to control their glucose levels, and their insulin levels were significantly reduced—a win-win situation.

Splitting a Resveratrol Hair

Mice are not the only critters to benefit from resveratrol in scientific studies—rats get their fair share. In a study published recently by researchers in Turkey, resveratrol was given to young rats to see whether it could prevent type 1 diabetes, in which the pancreas fails to make insulin.1 It was not necessary to wait a long time to see whether diabetes would or would not develop—one can make rodents diabetic overnight with one injection of streptozotocin, a drug that destroys the pancreas’s beta cells, where insulin is made.

Oxidative stress—the cumulative effect of harmful reactive oxygen species (ROS), including free radicals—is believed to be a major factor in the destruction of beta cells and hence in the origin of type 1 diabetes. Because resveratrol is a potent antioxidant in laboratory experiments, it was thought that pretreating the rats with resveratrol 10 days before the streptozotocin injection might help prevent the development of diabetes.* (The control diabetic rats received streptozotocin but no resveratrol.)


*The authors stated that the amount of resveratrol given was 1.6 ml (milliliters) per kg of body weight, per day. Since they failed to state the concentration of this solution, however, it’s impossible to know the amount of resveratrol actually used.


The researchers did not evaluate this question directly (e.g., in terms of insulin function), but indirectly, in terms of a variety of measures of oxidative stress, reductions in which would presumably retard the development of diabetes. What they found confirmed the premise: in the resveratrol-pretreated rats, there were significant enhancements, compared with the controls, in several of the rats’ endogenous antioxidant defense mechanisms; this would, of course, tend to reduce oxidative stress from ROS.

Thus it appears that resveratrol, although it activated existing antioxidant systems, did not itself act as a primary antioxidant and should not, perhaps, be called an antioxidant. Isn’t that splitting hairs? At the risk of sounding Clintonesque, it depends on what your definition of hair is. Scientists care very much about these things, even if laymen don’t.

In any case, this finding jibes with the revelation, earlier this year, that, even though resveratrol and many other polyphenolic “antioxidants”—including the large class of compounds called flavonoids—show antioxidant activity in cell cultures (where most of the work on them has been done), they do not do so in living organisms, where it really counts.* The saving grace, however, is that they do have verifiable health benefits, but apparently via entirely different mechanisms—including, perhaps, stimulation of the body’s own antioxidant systems.


*See the sidebar “Antioxidants: A Story of Blueberries and Red Herrings” in the article “Should We Eat More Chocolate?” (July 2007).


Reference

  1. Aribal-Kocatürk P, Kavas GÖ, Büyükkagnici DI. Pretreatment effect of resveratrol on streptozotocin-induced diabetes in rats. Biol Trace Elem Res 2007;118:244-9.

How Much Resveratrol Is Enough?

The amount of resveratrol used in the mouse experiments was 2.5 mg per kg of body weight, per day. For a 75-kg (165-lb) human, this would be 187.5 mg of resveratrol per day, based solely on weight. That, however, is too crude a basis for the comparison. Taking into account the different ratios of body weight to body surface area (BSA) between mice and men provides a better basis and yields a simple scaling factor (0.081) that is used as a multiplier. This factor (which could be thought of as a body compactness factor) reduces the amount of resveratrol for human use to only 15 mg/day.

Worth noting, however, is that in two groundbreaking and highly publicized studies of resveratrol’s actions in mice published last year, the most effective amounts used were 22.4 and 400 mg/kg per day.2,3* Using the same BSA-related scaling factor as above yields human equivalent amounts (again for a 75-kg person) of 136 and 2430 mg/day, respectively.


*For discussions of these two studies, see “Revolutionary Antiaging Discovery with Resveratrol” (January 2007), and “Resveratrol Boosts Strength and Endurance in Mice” (February 2007). (In those articles, we neglected to use the BSA-related scaling factor—an oversight for which we apologize.) And for a recent article on resveratrol’s role in cellular energy production, see “Resveratrol Boosts Energy Metabolism” (August 2007).


This illustrates an important point made above: no two studies are alike, and trying to compare them can be an exercise in apples and oranges. Furthermore, extrapolating animal dosages to humans in a clinically meaningful way can be very difficult, even for those with sound professional judgment born of long experience in the field.

In reference to their study, the Chinese researchers stated,1

These results suggest that resveratrol may function at different concentration ranges with different mechanisms. . . . It seems that, at low concentrations, resveratrol exhibits biological functions in a SIRT1-dependent manner, whereas at high concentrations, it probably does so via a SIRT1-independent pathway. . . . the precise mechanisms for the functions of resveratrol remain to be elucidated. However, low effective concentrations of resveratrol in insulin sensitivity are of great therapeutic importance, since lower concentrations mean greater biological safety and lower pharmaceutical cost.

Inhibiting PTP1B Appears to Be the Key

The researchers marshaled a good deal of evidence showing that, in their study, the beneficial effects of SIRT1 and resveratrol were due to their inhibition of an enzyme called protein tyrosine phosphatase-1B (PTP1B), which is a negative regulator of insulin function, i.e., it tends to suppress it. Inhibiting the action of PTP1B allows insulin sensitivity, and hence glycemic control, to be improved. The authors stated,

In conclusion, by repressing PTP1B, SIRT1 improves insulin sensitivity under insulin-resistant conditions. Similarly, resveratrol, a potent activator of SIRT1, is also capable of enhancing insulin sensitivity both in vitro and in vivo by repressing PTP1B. These findings suggest that drugs, including resveratrol, that enhance SIRT1 function and/or expression might provide a valuable new strategy for treating insulin resistance and type 2 diabetes.

Too Good to Be True?

Resveratrol seems too good to be true—which is usually a red flag. Here, however, we’re dealing not with hype but with credible scientific research, all pointing to the idea that resveratrol really is that good. Much yet remains to be learned about this amazing molecule, but meanwhile, it’s probably a good idea to take advantage of what we already know about its remarkable health and longevity benefits. Surely you don’t feel any, uh, resistance to that idea?

References

  1. Sun C, Zhang F, Ge X, Yan T, Chen X, Shi X, Zhai Q. SIRT1 improves insulin sensitivity under insulin-resistant conditions by repressing PTP1B. Cell Metab 2007;6:307-19.
  2. Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG, Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, de Cabo R, Sinclair DA. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006 Nov 16;444(7117):337-42.
  3. Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P, Geny B, Laakso M, Puigserver P, Auwerx J. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell 2006 Dec 15;127(6):1109-22.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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