Stephanie Doyle

May 16, 2008

May 16, 2008 (Orlando, Florida) — New research suggests that resveratrol, a chemical commonly found in red wine, has the ability to lower blood-sugar levels, but it might also produce certain unpleasant adverse effects.

The research was presented here at the American Association of Clinical Endocrinologists 17th Annual Meeting and Clinical Congress by Kimberly Martin, MD, a pediatric endocrinology fellow at Case Western Reserve University in Cleveland, Ohio.

Resveratrol is a naturally occurring chemical found in grapes that has been shown to have cardioprotective, anti-inflammatory, antiviral, and glucose-lowering properties. The lowering of blood glucose by resveratrol in diabetic rats has been reported by several researchers.

"All of the studies to date have focused primarily on the GLUT4 glucose transporter found inside muscle tissue and adipose tissue,'' Dr. Martin said during her presentation. "For our study, we wanted to examine how it affected the GLUT1 isoform, which is present in virtually all tissue."

For the study, researchers used Clone 9 cells, C2C12 cells, and human erythrocytes. Resveratrol and 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR) were added to the culture medium. Clone 9 cells are rat liver cells that exclusively express the GLUT1 isoform.

Researchers used Western Blot analysis to evaluate resveratrol's effect on phosphorylation of 5'AMP-activated protein kinase (AMPK). They used cytochalasin B (CB)-inhibitable 3-OMG uptake assays to measure glucose transport. They determined the effect of resveratrol on CB binding to erythrocyte ghosts in both the presence and absence of glucose.

The study concluded that resveratrol improves glycemia by stimulating glucose transport in certain tissues, including the skeletal muscle that expresses the insulin-sensitive GLUT4 isoform of glucose transporters.

More specifically, when Clone 9 cells were incubated with resveratrol (0.1 to 500 mmol/L for 1 hour), AMPK phosphorylation was slightly inhibited at low concentrations and stimulated (1.5 to 2.2 times) at concentrations above 100 mmol/L. However, the addition of resveratrol to the same cells markedly inhibited glucose transport (half maximal effective concentration [EC50] of ~25 mmol/L) — whether or not AMPK phosphorylation was augmented or suppressed.

Glucose transport was inhibited and AMPK phosphorylation was stimulated within 1 minute of cells being exposed to 100 mmol/L resveratrol. The addition of 2 mmol/L AICAR, a known stimulator of AMPK and glucose transport in these and other cells, to resveratrol-treated Clone 9 cells stimulated AMPK phosphorylation but had no effect on the suppressed rate of glucose transport.

The research, however, shows that in cells expressing the GLUT1 isoform, resveratrol blocks glucose transport by binding and inhibiting the GLUT1 transporter. This could be key because certain cells and tissues, including brain, retina, placenta, and red blood cells, express large amounts of this transporter. The presumed inhibition of the GLUT1 transporter in these tissues in vivo might therefore have undesired and negative effects on their normal function.

"This is a potential medication that could be used in multiple areas," Dr. Martin said. "The concern is that you could lower glucose in diabetics but at the same time. . . [lower] glucose levels in the brain or in other important tissues."

Rhoda Cobin, MD, a clinical professor of medicine at Mount Sinai Medical Center in New York, called resveratrol a "very hot topic."

"People think this may be the elixir,'' said Dr. Cobin, a past president of the American Association of Clinical Endocrinologists. "But there is a lot that needs to be done."

Funding was provided by a National Institutes of Health Nutrition and Metabolism Training Grant. Dr. Martin disclosed no relevant financial relationships.

American Association of Clinical Endocrinologists (AACE) 17th Annual Meeting and Clinical Congress: Abstract 229. Presented May 16, 2008.

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