Results from comprehensive assessments of diabetes’ effects on cell metabolism may aid efforts to reduce diabetic damage to nerves, blood vessels and other tissues, according to researchers at the School of Medicine and elsewhere.
The scientists found that by blocking the sorbitol pathway, one of several pathways cells employ to use the sugar glucose, they could prevent diabetic damage to nerves and blood vessels in rats. Prior clinical trials of blockers for this pathway have been disappointing, researchers said, but they now say that may be because the sorbitol pathway was inadequately blocked.
“What we’ve found should help fine-tune efforts to slow or prevent diabetes-associated complications such as hardening of the arteries, damage to vision and loss of nerve function,” said senior author Joe Williamson, M.D., retired professor of pathology and immunology. “Evidence suggests that such complications are caused by increased levels of superoxide, and our results point to the sorbitol pathway as the main source of this chemically reactive compound.”
The paper appeared online in the journal Antioxidants and Redox Signaling and will appear in print in the future.
Normally, cells use glucose mostly to make energy through a process called glycolysis. However, as glucose levels rise, cells begin to use glucose in a process called the sorbitol pathway. The high glucose levels associated with diabetes increase cells’ use of glucose via glycolysis and the sorbitol pathway.
Both processes alter a molecule known as NAD (nicotinamide adenine dinucleotide) by adding a hydrogen atom (NADH). To keep glycolysis possible, cells have to convert NADH back to NAD. If NADH levels increase relative to NAD, a metabolic imbalance occurs that can limit energy production essential for normal cell function and survival.
Pyruvate, an antioxidant produced by glycolysis, normally helps facilitate conversion of NADH into NAD. However, the sorbitol pathway does not produce pyruvate. Williamson and his colleagues theorized that when diabetes increases sorbitol pathway use, it places an increased burden on the cell by creating more NADH but leaving it with relatively less pyruvate to help change it back into NAD. They noted that a cell faced with too much NADH and too little pyruvate can turn to other enzymes to achieve the conversion, and that these enzymes produce super-oxide as a product, making them an important source of diabetic tissue damage.
In testing the first component of this theory in a rat model of diabetes, the researchers found that inhibiting either of two specific steps in the sorbitol pathway improved vascular function in the rats and reversed impaired motor nerve conduction velocity, or the speed at which nerves transmit electrical signals to stimulate muscles.
Sorbitol pathway inhibitors similar to those used by the researchers have been tested previously with disappointing results in clinical trials, but Williamson said recent studies in animals suggest those inhibitors may not have blocked the sorbitol pathway sufficiently.
“We’ve assembled what appears to be the most coherent explanation to date on how high glucose levels affect several different aspects of cell metabolism, and all the indicators point to the sorbitol pathway as the primary source of increased superoxide,” he said. “More effective inhibitors of the sorbitol pathway are still being explored and may be able to prevent diabetic complications in the future.”