University of Montreal Hospital Research Centre (CRCHUM) scientists have identified a new enzyme that could protect the body from toxic levels of intra-cell sugar. When there is too much sugar in the body it gets processed into glycerol-3-phosphate, a buildup of which can damage internal organs. The team behind the study proved that G3PP is able to extract excess sugar from cells.

Their discovery should lead to the development of therapeutics for obesity and type 2 diabetes.

“When glucose is abnormally elevated in the body, glucose-derived glycerol-3 phosphate reaches excessive levels in cells, and exaggerated glycerol 3 phosphate metabolism can damage various tissues,” said Marc Prentki, principal investigator at the CRCHUM and professor at the University of Montreal.

“We found that G3PP is able to breakdown a great proportion of this excess glycerol phosphate to glycerol and divert it outside the cell, thus protecting the insulin producing beta cells of pancreas and various organs from toxic effects of high glucose levels.”

Mammalian cells derive the bulk of their energy from oxidizing glucose and fatty acids. These substances govern many physiological processes, from insulin and glucose production, all the way to fat accumulation and nutrient metabolization. But a too large intake of glucose disrupts these processes and can lead to obesity, type 2 diabetes and cardiovascular diseases.

Beta cells in the pancreas respond to changes in blood sugar levels, cracking up or toning down on insulin — a hormone that controls glucose and fat utilization. Usually this keeps blood sugar levels stable and cells happy and well supplied with fuel. As glucose is being used in cells, glycerol-3-phosphate is formed, a molecule central to metabolism since it is needed for both energy production and fat formation.

But when these nutrients are found in excess, they can actually damage beta cells, inhibiting their function. Blood sugar levels remain unchecked, skyrocket, and damage the beta cells even further. This leads to a vicious circle, shutting down the body’s system of managing its fuel. G3PP however isn’t produced by beta cells, and the team hopes it can be used to regulate formation and storage of fat as well as production of glucose in the liver.

“By diverting glucose as glycerol, G3PP prevents excessive formation and storage of fat” says Dr Murthy Madiraju, a scientist at CRCHUM.

Dr Prentki added: ‘It is extremely rare since the 1960s that a novel enzyme is discovered at the heart of metabolism of nutrients in all mammalian tissues, and likely this enzyme will be incorporated in biochemistry textbooks.’

The research team is currently in the process of discovering ‘small molecule activators of G3PP’ to treat cardio-metabolic disorders. These drugs will form a new class of drugs, being unique in the way they operate inside the body.

The treatment will first have to be confirmed in several animal trials before drugs for human use can be developed.

“This is an interesting paper and to some extent unusual as new enzymes involved in metabolic control are rare,” said Professor Iain Broom, Director of the Centre for Obesity Research & Epidemiology, Robert Gordon University.

But we should take great care as we develop this class of drugs, he adds”

“Care should be taken, however, in reading too much into the possibilities for treatment of disease by focusing on such individual enzymes, especially as the evidence for this control mechanism comes from isolated cells.”

“This paper does have an important finding, however, and should not be dismissed lightly – but I would draw the line at statements of ‘guilt-free sugary treats’,” he said, referring to the media’s take on the story. ”

This is not an accurate by-line for this interesting piece of science.”

The paper can be found online in the journal Proceedings of the National Academy of Sciences.

 

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