According to researchers at Washington University School of Medicine in St. Louis, results from inclusive assessments of diabetes’ effects on cell metabolism may perhaps assist efforts in decreasing diabetic injury to nerves, blood vessels and other tissues.
The researchers found that by blocking the sorbitol pathway, they could possibly stop diabetic damage to nerves and blood vessels in a rat model. Sorbitol pathway is known to be one of numerous pathways in which cells employ to use the sugar glucose. Previous clinical tests of blockers for this pathway are believed to have been unsatisfactory. However, the researchers and others currently think 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. 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,” says senior author Joe Williamson, M.D., retired professor of pathology and immunology.
Usually, cells make use of glucose typically to make energy via a process called glycolysis. However, as glucose levels rise, the cells seem to begin to use glucose in a process called the sorbitol pathway. The high glucose levels associated with diabetes may perhaps increase cells’ use of glucose through glycolysis and the sorbitol pathway.
Supposedly, both processes alter a molecule known as nicotinamide adenine dinucleotide (NAD) thereby changing it to NADH, or NAD in addition to a hydrogen atom. In order to keep glycolysis achievable, cells may have to convert NADH back to NAD. If NADH levels increase relative to NAD, a metabolic imbalance could possibly occur that could limit energy production crucial for normal cell function and survival.
Pyruvate is known to be an antioxidant produced by glycolysis which usually assists in facilitating conversion of NADH into NAD. However, the sorbitol pathway seems to be unable to produce pyruvate.
Williamson along with his colleagues put forward that when diabetes increases sorbitol pathway use, it could perhaps place an increased burden on the cell thereby creating more NADH. However, the cells seem to leave relatively less pyruvate in order to help change it back into NAD.
They discovered that a cell faced with excess of NADH and too little pyruvate could turn to other enzymes in order to attain the conversion. Moreover, these enzymes seem to produce superoxide as a product in that way making them a chief source of diabetic tissue damage.
For the new research, they were believed to have tested the foremost component of this theory in a rat model of diabetes. Among other findings, they found inhibiting either of two specific steps in the sorbitol pathway seemed to have improved vascular function in the rats. Further, it appears to have reversed impaired motor nerve conduction velocity, or the speed at which nerves transmit electrical signals to arouse muscles.
Williamson further stated that, “It’s already been established in other studies that pyruvate supplementation normalizes vascular dysfunction caused by high glucose levels and slows cataract formation in diabetic animals. These results support our theories of why this happens, and others may be able to build upon this to create new and improved treatments for diabetes.”
Sorbitol pathway inhibitors similar to those used by the researchers are noted to have been earlier tested with unsatisfactory results in clinical trials. However, Williamson claims that earlier researches in animals suggest those inhibitors may not have blocked the sorbitol pathway adequately.
“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. More effective inhibitors of the sorbitol pathway are still being explored and may be able to prevent diabetic complications in the future,” elucidates Williamson.
For the moment, though, Williamson seems to emphasize that the best way for diabetics to prevent complications is to keep glucose levels as close to normal as possible. He also suggested that pyruvate, as a treatment for patients with weakly controlled diabetes may possibly merit further research, but cautions that the body metabolizes pyruvate very rapidly.
Williamson was of the opinion that pyruvate may be most instantly useful in preventing diabetic damage to the eye, where it could be applied directly as eye drops thereby quickly achieving its targets, namely the retina and lens.
The research findings have been published online in the journal, Antioxidants and Redox Signaling.