Researchers have shown that fisetin, a type of flavonoid found in strawberries and to a lesser extent in other foods, reduces neurologic complications and kidney damage in a mouse model of type 1 diabetes.
The research, published online June 27 in PLoS ONE, suggests that fisetin may reduce diabetes complications by protecting nerve cells from toxic insults and by direct effects of antioxidant and anti-inflammatory activity.
Significantly, the study found that oral fisetin reduced methylglyoxal-protein glycation in the kidney, brain, and blood of diabetic mice, lending support to the hypothesis that complications of diabetes share common pathogenic mechanisms, the study authors say.
Fisetin, or a synthetic version of it, might eventually be used to treat patients with diabetes, said corresponding author, Pamela Maher, PhD, senior staff scientist at The Salk Institute for Biological Studies, Cellular Neurobiology Laboratory, La Jolla, California.
"A compound that could reduce some or all of these complications has a real potential for improving quality of life for people with diabetes," Dr. Maher said. "Such a compound could also reduce the impact on the healthcare system, because treating people with diabetes — particularly when they develop these complications — is a major contributor to increased costs of healthcare."
Akita Mouse Model
For their experiments, the researchers used Akita mice, which, because of a mutation in the insulin gene, develop the pathologic characteristics of type 1 diabetes, including diabetic nephropathy and elevated anxiety symptoms. Male Akita mice develop hyperglycemia by 4 weeks of age.
The researchers added the equivalent of about 25 to 40 mg/kg of fisetin daily to the food of the Akita mice and of wild-type control mice and tested blood glucose levels at 12 and 24 weeks. Fisetin had no effect on blood glucose in either the Akita or control mice.
At baseline, the kidneys of the Akita mice were significantly heavier than those of controls, consistent with hypertrophy associated with diabetic nephropathy. Their kidneys were significantly reduced in size by fisetin, which had no effect on the kidneys of control mice.
Urine analysis also showed significant albuminuria in the Akita mice that was almost completely eliminated by dietary fisetin. Fisetin had no effect on the albumin:creatinine ratio in control mice.
The researchers also found that oxidative markers were elevated in the kidneys of Akita mice but not in the control animals and that this was prevented by feeding the animals fisetin.
Interestingly, the study authors noted that a recent epidemiologic study found kidney disease is a marker for brain dysfunction in people with type 1 diabetes.
As for markers of inflammation associated with diabetes, the researchers found that C-reactive protein (CRP) was significantly increased in the plasma of Akita mice and that this increase, too, was attenuated by the fisetin-rich diet.
Akita mice have significantly less locomotor activity than normal mice and spend a relatively long time immobile. These, according to Dr. Maher, are signs of anxiety behavior, a central nervous system complication of diabetes. Humans with diabetes, too, tend to be anxious and may have other mood disorders, she said.
But Akita mice fed fisetin showed a significant reduction in these anxiety-related symptoms with tests of distance traveled and time spent ambulatory showing that these functions were restored to near-normal levels. Fisetin had no effect on this type of behavior in the control mice.
The study appeared to uncover a likely molecular mechanism underlying these biological effects. Dr. Maher explained that in animals, as with humans, an increase in blood glucose can lead to sugars, or products derived from sugars, being added to proteins, a process leading to advanced glycation end products (AGEs) that can change the function of these proteins.
This causes the proteins not only to function improperly themselves but also to impede the function of other proteins, creating inflammation. People with diabetes are known to be in a chronic systemic inflammatory state, with increased inflammatory markers, including CRP.
This proinflammatory state can lead to oxidative stress, causing further damage to proteins and tissues and leading ultimately to diabetes-related complications, said Dr. Maher.
In this study, AGEs were reduced in fisetin-treated mice. These decreases were accompanied by increased activity of the enzyme glyoxalase 1, which promotes removal of toxic AGE precursors. The finding that fisetin can enhance glyoxalase 1 activity is important because evidence implicates high blood AGE levels with diabetic complications, according to the study authors.
Dr. Maher and her colleagues have been studying fisetin for about a decade. They were originally interested in identifying compounds in a model of neuronal cell death with the hope of adding to current Alzheimer's disease (AD) research.
Their laboratory has already shown that fisetin promotes survival of neurons grown in culture and enhances memory in healthy mice. "Fisetin stood out as being very effective and having several properties that we thought might make it particularly beneficial for treating not only neurologic disorders but other diseases as well," said Dr. Maher.
The connection between diabetes and AD led the researchers to test fisetin in a diabetes model. "One reason for that is that the diabetes model is developed much more rapidly than the AD model, so we were able to do this study a lot faster than the AD studies, which we are still doing but are not yet finished."
Flavonoids are thought to protect the leaves and fruit of plants against the sun and insects. They're an integral part of the healthy "Mediterranean" diet that is rich in fruits and vegetables and includes red wine, which contains flavonoids called polyphenols.
The fisetin flavonoid is found in highest quantities (160 µg/g) in strawberries, but even that isn't very much. To consume the equivalent of what the mice ate in the study, an average 150-lb person would have to down 37 strawberries every day, said Dr. Maher. Fisetin is more soluble in fat than water, so consuming strawberries with something like cream might aid absorption, although "there are obviously concerns about eating too much cream," she said.
Fisetin is also found, although in 5- to 10-fold lower levels, in apples and persimmons and even smaller amounts in kiwi fruit, peaches, grapes, tomatoes, onions, and cucumbers.
Supplements containing fisetin are apparently available over the Internet but in doses substantially lower than those used in this study. Dr. Maher cautioned against buying fisetin from questionable sources because of concerns about contamination.
The researchers have identified another compound — Dr. Maher is secretive about which one — that they think may work synergistically with fisetin. They're keen to test the effects of the 2 compounds together in the Akita mouse model.
As well, they want fisetin to be tested in a human clinical trial. "We've just started talking to a drug company that has shown some interest in using this compound for complications of diabetes, but we're at the very early stages."
True Test to Come
Approached for a comment, Thomas Chelimsky, MD, director, autonomic disorders, and professor of neurology at the Neurologic Institute, Case Western Reserve University and Case Medical Center, Cleveland, Ohio, said he found the study very interesting. However, he pointed out that in the recent past other agents have initially held promise but didn't pan out in the end.
The real test, said Dr. Chelimsky, who is also a member of the American Academy of Neurology, is whether fisetin makes a difference in a large population of patients.
"I don't have any doubts about the report here, and it clearly makes a fairly large difference, but the question is, does it work in actual people who have diabetes and who don't follow instructions to the letter; animals follow instructions to the letter because they have to."
The study adds to the growing body of evidence of the health benefits of flavonoids, said Dr. Chelimsky. "Beyond just talking about diabetes, this research adds to growing information that flavonoids are good for you."