Researchers discover new enzyme able to fight toxic effects of sugar

The enzyme glycerol 3-phosphate phosphatase (G3PP) can stop the toxic effects of sugar in a number of the body’s organs and may lead to new treatments for obesity and type 2 diabetes.

The study was published today in the journal Proceedings of the National Academy of Sciences (PNAS).

We spoke with research team leaders S.R. Murthy Madiraju and Marc Prentki, Departments of Nutrition and Biochemistry and Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montréal.

ResearchGate: How would this new enzyme treat obesity, type 2 diabetes and metabolic syndrome?

S.R. Murthy Madiraju & Marc Prentki: When glucose is used inside the cells of our body, some of it is burned completely to produce energy. The rest is converted to glycerol-3-phosphate, which is the backbone for fat formation. Excessive glucose oxidation (burning) causes free radical formation and this can be dangerous. But excessive fat build-up is no good either. This newly discovered enzyme can regulate both these processes by preventing the increase of glycerol-3-phosphate in the cell by breaking it down. This process also diverts glucose from the oxidation process towards glycerol production. Glycerol derived from excess glucose is mostly thrown out of cells. Consequently, this new enzyme G3PP has the potential to prevent toxicity from the excess intake of sugar and fats. Its activation should help in conditions like type 2 diabetes and obesity.

Furthermore, because cancer cells like to use lot of glucose for their survival and growth, if we increase the activity of this enzyme in cancer cells it could potentially take their nutrients away causing their growth to slow down or for them to die.

RG: How did you discover G3PP?

MM & MP: Our lab has been interested in understanding the importance of excessive nutrient fuel (like glucose and fatty acids) induced stress on the function and survival of pancreatic beta cells, which produce insulin. Our previous studies indicated that production and removal of glycerol is one way that beta cells protect themselves from toxicity caused by excess fuel. They do so by producing large amounts of glycerol when presented with high levels of glucose with or without fatty acids. The source of this glycerol was initially thought to be from fat breakdown.

However, when the inhibition of fat breakdown did not prevent the formation and release of glycerol we suspected an unknown enzyme was at work. Something that generates glycerol directly by breaking down a molecule called glycerol-3-phosphate, which is produced from glucose in the cells. After further examination this turned out to be the case, which was previously unknown to occur in mammalian cells.

RG: How did you demonstrate that G3PP can treat conditions like obesity and type 2 diabetes?

MM & MP: We used adenoviral delivery of the gene coding for G3PP to rats and found that these rats gain less weight, have less blood lipids like triglycerides, low levels of low density lipoprotein, increased level of high density lipoprotein and they make less glucose from glycerol, as compared to control virus receiving rats. This is a preliminary experiment, but it gives us the proof of principle for embarking on the next major set of experiments in animal models.

RG: Would this enable us to just indulge in sugar, with no repercussions?

MM & MP: The idea is not that one can indulge without discrimination. The point of our work is that our body is equipped with an enzyme system that can help in fighting against the toxic effects of glucose. Its activation by pharmacological means is likely to be helpful in individuals with type 2 diabetes or obesity, where glucose control is lost and body tissues are exposed to excess sugar.

RG: Why is it so rare to discover novel enzymes, like G3PP?

MM & MP: Most of the enzymes related to nutrient metabolic pathways were discovered and studied in 1950s to 1970s. After this period there was a shift in research towards understanding genome function and a revolution in molecular biology followed. At that time studies related to metabolism and metabolic enzyme were not of major interest. However, once researchers realized the importance of metabolism in metabolic diseases and also cancer, their interest was re-ignited.

RG: Can you offer an estimate on how long it will take before this is available as a treatment option?

MM & MP: At this point it is premature for us to predict this. This is the first report on the existence of this type of enzyme in mammalian cells. We need to conduct more research to better understand its role under physiological and pathological conditions. And it can be potentially challenging to find drug like compounds that would increase the functionality of this enzyme. But we do have few leads on this now and we are following up on them.

Image courtesy of Michael Stern.