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Polygenic type 1 diabetes can present in neonates

12 October 2020
Appeared in BioNews 1067

A new extreme subtype of polygenic type 1 diabetes has been identified in infants under six months of age.

This research provides strong evidence that type 1 diabetes, a condition where the body's own immune system destroys insulin-producing cells, can present before the age of six months. Infants were found to present with the classic features of childhood type 1 diabetes - a high genetic risk, autoimmunity and rapid beta cell loss.

Dr Elizabeth Robertson, director of research at Diabetes UK, which co-funded the research, said: 'By revealing for the first time the existence of type 1 diabetes in the very first few months of life, these important findings rewrite our understanding of when the condition can strike and when the immune system can start to go wrong.'

Diabetes diagnosed in the first six months of life, known as neonatal diabetes, was previously thought to be solely caused by a pathogenic variant in a single gene. However, ten percent of cases diagnosed are without a monogenic cause, and were thus thought to arise from a yet unknown pathogenic variant in a gene. Now, this research has identified a new subtype of type 1 diabetes, in infants under six months of age, which is caused by pathogenic variants in multiple genes ie, polygenic.

A team of researchers, from the University of Exeter and King's College London, studied two groups of infants with diabetes onset under six months of age. The first group of infants had no detectable pathogenic variants in the 26 genetic loci known to cause neonatal diabetes. The second group of infants had monogenic neonatal diabetes with a detectable pathogenic variant.

The authors write in their paper, recently published in Diabetologia, 'To our knowledge, no polygenic autoimmune diseases (including type 1 diabetes) have been described and characterised in individuals below the age of six months.'

Interestingly, the researchers identified infants with this very early onset type 1 diabetes had a lower than average birth weight. Insulin is a potent fetal growth factor and a fetus usually begins to make insulin in the womb, aiding their growth. Hence, this result suggests that, for some infants, reduced insulin secretion occurred in utero resulting in reduced insulin-mediated growth and consequently lower birth weight.

A further characteristic of type 1 diabetes diagnosed under six months of age was rapid beta cell destruction, which was in keeping with previous data that shows an earlier age of diagnosis is associated with rapid progression to severe insulin deficiency.

Dr Matthew Johnston, first author and research fellow at the University of Exeter, said: 'This study proves that type 1 diabetes can present in the first few months of life, and in a tiny subset of infants may even begin before birth… We also found that diabetes diagnosed so young was associated with rapid progression to complete destruction of insulin producing beta cells.'

This research represents the first characterisation of polygenic autoimmunity diagnosed in the first six months of life, challenging current understanding of the early immune system. Widespread genetic testing for all neonatal diabetes genes remains vital for all infants diagnosed with diabetes under six months of age.

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