It's Not an Apple a Day After All -- It's Strawberries: Flavonoids Could Represent Two-Fisted Assault On Diabetes and Nervous System Disorders

It's Not an Apple a Day After All -- It's Strawberries: Flavonoids Could Represent Two-Fisted Assault On Diabetes and Nervous System Disorders

  8:52:00 PM    Science Lover

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A recent study from scientists at the Salk Institute for Biological Studies suggests that a strawberry a day (or more accurately, 37 of them) could keep not just one doctor away, but an entire fleet of them, including the neurologist, the endocrinologist, and maybe even the oncologist.

Fisetin, a naturally-occurring flavonoid found most 
abundantly in strawberries, lessens complications of diabetes. 
(Credit: Courtesy of the Salk Institute for Biological Studies)

Investigations conducted in the Salk Institute's Cellular Neurobiology Laboratory (CNL) will appear in the June 27, 2011, issue of PLoS ONE. The report explains that fisetin, a naturally-occurring flavonoid found most abundantly in strawberries and to a lesser extent in other fruits and vegetables, lessens complications of diabetes. Previously, the lab showed that fisetin promoted survival of neurons grown in culture and enhanced memory in healthy mice. That fisetin can target multiple organs strongly suggests that a single drug could be used to mitigate numerous medical complications.

"This manuscript describes for the first time a drug that prevents both kidney and brain complications in a type 1 diabetes mouse model," says David Schubert, Ph.D., professor and head of the Cellular Neurobiology Laboratory and one of the manuscript's co-authors. "Moreover, it demonstrates the probable molecular basis of how the therapeutic is working."

Pam Maher, Ph.D., a senior staff scientist in the CNL, is the study's corresponding author. Maher initially identified fisetin as a neuroprotective flavonoid ten years ago. "In plants, flavonoids act as sunscreens and protect leaves and fruit from insects," she explains. "As foods they are implicated in the protective effect of the 'Mediterranean Diet.'"

Other celebrity flavonoids include polyphenolic compounds in blueberries and red wine.

Although her group's focus is neurobiology, Maher and colleagues reasoned that, like other flavonoids, fisetin might ameliorate a spectrum of disorders seen in diabetic patients. To test this, they evaluated effects of fisetin supplementation in Akita mice, a very robust model of type 1 diabetes, also called childhood onset diabetes.

Akita mice exhibit increased blood sugar typical of type 1 diabetes and display pathologies seen in serious human complications of both type 1 and 2 diabetes. Those include diabetic nephropathy or kidney disease, retinopathy, and neuropathies in which patients lose touch or heat sensations.

Mice fed a fisetin-enriched diet remained diabetic, but acute kidney enlargement-or hypertrophy-seen in untreated mice was reversed, and high urine protein levels, a sure sign of kidney disease, fell. Moreover, fisetin ingestion ameliorated anxiety-related behaviors seen in diabetic mice. "Most mice put in a large area become exploratory," says Maher. "But anxious mice tend not to move around. Akita mice showed enhanced anxiety behavior, but fisetin feeding restored their locomotion to more normal levels."



The study also defines a likely molecular mechanism underlying these effects. Researchers observed that blood and brain levels of sugars affixed to proteins known as advanced glycation end-products-or AGEs-were reduced in fisetin-treated compared to untreated Akita mice. These decreases were accompanied by increased activity of the enzyme glyoxalase 1, which promotes removal of toxic AGE precursors.

The discovery of an AGE-antagonizing enzyme upregulated by fisetin is very intriguing, because substantial evidence implicates high blood AGE levels with many if not most diabetic complications. "We know that fisetin increases activity of the glyoxalase enzyme and may increase its expression," says Maher. "But what is important is that ours is the first report that any compound can enhance glyoxalase 1 activity."

Interestingly, excessively high AGE levels also correlate with inflammatory activity thought to promote some cancers. In fact, studies published by others confirm that fisetin decreases tumorigenicity of prostate cancer cells both in culture and in animal models, which if supported would represent a major added incentive to eat your strawberries.

To ingest fisetin levels equivalent to those fed Akita mice, Maher estimates that humans would have to eat 37 strawberries a day, assuming that strawberry fisetin is as readily metabolizable by humans as fisetin-spiked lab chow is by mice. Rather than through diet, Maher envisions that fisetin-like drugs could be taken as a supplement.

Schubert notes that fisetin is also effective in mouse models of Alzheimer's disease. "We and others have shown that diabetes may be a risk factor for Alzheimer's disease, making identification of a safe prophylactic like fisetin highly significant," he says.

Maher acknowledges that the public may be suffering from flavonoid-fatigue, given media coverage of the promises of these compounds. "Polyphenolics like fisetin and those in blueberry extracts are found in fruits and vegetables and are related to each other chemically," she says. "There is increasing evidence that they all work in multiple diseases. Hopefully some combination of these compounds will eventually get to the clinic."

Schubert concurs that their findings only reinforce what common sense and our mothers told us was a healthy lifestyle. "Eat a balanced diet and as much freshly prepared organic food as possible, get some exercise, keep socially and mentally active and avoid sodas with sugar and highly processed foods since they can contain high levels of AGEs," he advises.

But he also worries that hoops that must be jumped through to bring a natural product like fisetin, as opposed to a totally synthetic drug, to clinical trials are daunting because it is difficult to protect patents on natural products. "We will never know if a compound like fisetin works in humans until someone is willing to support a clinical trial."

Also contributing to this study were Richard Dargusch and Jennifer L. Ehren, Ph.D.,of the Cellular Neurobiology Laboratory, and Kumar Sharma, M.D., and Shinichi Okada, M.D., Ph.D., of the Department of Medicine at University of California, San Diego.

Funding for the study came from the Fritz B. Burns Foundation, the Juvenile Diabetes Research Foundation, the Hewitt Foundation, and the National Institutes of Health.

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Could Diabetes Be in Your Bones?

Could Diabetes Be in Your Bones?

  8:54:00 PM    Science Lover

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Our bones have much greater influence on the rest of our bodies than they are often given credit for, according to two new studies in the July 23 issue of Cell, a Cell Press publication. Both studies offer new insights into the interplay between bone and blood sugar, based on signals sent via insulin and a bone-derived hormone known as osteocalcin.

Insulin signaling in bone favors whole-body glucose 
homeostasis by activating osteocalcin(1) Insulin signals 
osteoblasts, bone cells responsible for bone formation, 
which (2) tell osteoclasts, bone cells responsible for 
resorption, to destroy old bone. Next (3), the acidic 
(low pH) conditions created by the osteoclasts activates 
osteocalcin inside the bone. Finally (4), the active 
osteocalcin released from bone travels to the pancreas 
and stimulates the release of more insulin. (Credit: Image 
provided by Columbia University Medical Center)

Mice whose bones can't respond to insulin develop high blood sugar and insulin resistance, both hallmarks of diabetes. Those symptoms are tied to a drop in osteocalcin. The findings suggest that osteocalcin, or perhaps a drug that targets bone, might hold promise in fighting the global epidemic of type 2 diabetes, according to the researchers.

"Our study reveals a key molecular link between bone remodeling and metabolism," said Gerard Karsenty of Columbia University.

"Bone is an organ that has to pay attention to where calories are going," added Thomas Clemens of Johns Hopkins University School of Medicine. "It talks to muscle, fat, the pancreas. It's a player in energy metabolism."

And perhaps that makes a lot of sense, Karsenty said. The remodeling of bone relies on two cell types, bone-building osteoblasts and bone-resorbing osteoclasts, making bone the only organ with a cell type that is entirely focused on destroying host tissue. "On a daily basis, the formation of bone is expensive in terms of energy," he said.

In fact, the idea that the skeleton is much more than a reservoir for calcium and phosphate isn't entirely new, the researchers said. Earlier evidence by Karsenty's group had shown links between bone and the fat hormone leptin. (Obese adults are significantly less likely to develop osteoporosis.)

Scientists also had evidence that osteoblasts might respond to insulin in important ways. Osteoblasts bear insulin receptors and when treated with insulin show signs of collagen synthesis and take up more glucose, Clemens' team notes. People with type 1 diabetes due to a lack of insulin can also develop weakened bones.

Karsenty's team describes bone as a multitasker. It has mechanical, hematopoietic (blood-producing) and metabolic functions. It also acts as an endocrine organ through the release of osteocalcin hormone, which favors glucose metabolism when in its active form.

Still, Clemens said he was surprised by what they saw after developing a mouse lacking insulin receptors only in their osteoblasts. "The mice started to get fat," he said. They showed changes in their biochemistry that were consistent with insulin resistance. They also had low osteocalcin levels and fewer osteoblasts to produce less bone.

With age, the animals became even fatter and developed more marked high blood sugar accompanied by severe glucose intolerance and insulin resistance. Those symptoms improved with osteocalcin treatment.

Karsenty's group presents independent evidence for the important role of insulin in bone for keeping glucose in check through osteocalcin, in what he refers to as a "feed-forward loop." But his group goes a step further to suggest that bone-resorbing osteoclasts (not just osteoblasts) have a place in this too.

Karsenty explains that bone-building osteoblasts actually control bone resorption by osteoclasts, a process that takes place under very acidic conditions. Those conditions would also favor the chemical modification necessary to produce active osteocalcin, which can escape bone to act as a hormone.

That could be important to those who take osteoporosis drugs designed to block bone resorption, Karsenty suggests. "It's a red flag," he said. "Osteoporotic patients treated with [bone resorption inhibitors] may be at risk of glucose intolerance."

The researchers include Mathieu Ferron, Columbia University, New York, NY; Jianwen Wei, Columbia University, New York, NY; Tatsuya Yoshizawa, Columbia University, New York, NY; Andrea Del Fattore, University of L'Aquila, L'Aquila, Italy; Ronald A. DePinho, Harvard Medical School, Boston, MA; Anna Teti, University of L'Aquila, L'Aquila, Italy; Patricia Ducy, Columbia University, New York, NY; and Gerard Karsenty, Columbia University, New York, NY.

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