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Gene Mutation Responsible for Hypoglycemia May be Cured with Cancer Drug

Tim Boyer's picture

A gene mutation responsible for a severe type of hypoglycemia may be cured with a cancer drug that is targeted for a nearly identical gene. Researchers report in this week’s journal Science the discovery of why some patients suffer from severe hypoglycemia and how it may be cured.

Hypoglycemia is killer of patients with diabetes. Typically, hypoglycemia results when an excessive amount of insulin is circulating in the bloodstream causing rapid depletion of blood sugar needed for brain and other organ activity. This overproduction of insulin is life-threatening and can cause confusion, seizures and loss of consciousness.

However, in some cases, a severe form of hypoglycemia results that is not due to an overproduction of insulin. In approximately one out of every 100,000 births an infant presents with hypoglycemia of unknown origin. Recently, scientists at the Institute of Metabolic Science and the Wellcome Trust Sanger Institute in collaboration with medical specialists in Cambridge, London and Paris have found a genetic mutation in a shared gene with three unrelated children born with severe hypoglycemia. None of the children’s parents have hypoglycemia.

According to a statement attributed to Dr. Robert Semple, a Wellcome Trust Scientist at the Institute of Metabolic Science at the University of Cambridge, “Fear of low blood sugar has dominated the lives of these patients and their families, and for many years the lack of an obvious cause has added to their anxiety. Offering families an explanation for a rare disease is usually of great value to them in its own right, but in this case it is particularly exciting that our findings open the door for a new and specific treatment in the future.”

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In the 7 October issue of the journal Science, Dr. Semple and his colleagues report their discovery of the genetic mutation that is responsible for the severe hypoglycemia in all three children. By doing a comparative analysis of the children’s DNA, the researchers found that all three carry the same de novo mutation, p.Glu17Lys, in the serine/threonine kinase AKT2 gene. AKT2 plays an important role in insulin signal transmission of the body’s tissues.

Two of the children were heterozygotes (carrying one mutated copy and one normal copy of the AKT2 gene). The third child carried a mosaic form of the mutation which means that some cells possessed at least one copy of the mutation whereas other cells carried both normal copies of the AKT2 gene. The genetic mutations resulted in a type of continuous “on” signal that prevented or significantly decreased the insulin expression needed to transfer sugar in the blood to the body’s tissues.

As it turns out, the discovery that a mutation is in the AKT2 gene is serendipitous. The AKT2 gene for insulin signaling is very similar to the AKT1 gene involved in several types of cancers. The authors of the paper believe that the genetic similarity between the two genes may allow treatment of patients with severe hypoglycemia with AKT1-cancer blocking drugs that are currently being tested in cancer clinical trial studies.

According to Prof Stephen O’Rahilly, co-author of the paper, “I went down to Great Ormond Street to see one of these patients, then a young child, about 10 years ago. It is enormously satisfying that we have finally understood the cause of his problem and very exciting that a potential therapy immediately suggests itself for this young man and others with this, probably under-recognized, condition.”

“An Activating Mutation of AKT2 and Human Hypoglycemia Science” DOI: 10.1126/science.1210878
University of Cambridge Research News