A new study published in the journal Diabetologia in March 2020 reports that children aged below seven years with type 1 diabetes mellitus (T1DM) have a distinct form of the condition from children aged 13 or more.
What is type 1 diabetes mellitus?
T1DM is a metabolic condition characterized by the deficiency of the hormone insulin, which is responsible for the uptake of glucose from the blood and regulation of glucose intake into muscle cells. Insulin is produced by the β-cells of the pancreas in areas called the islets of Langerhans.
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An autoimmune attack on the islet cells causes a steep reduction in the amount of insulin produced in the pancreas, causing ineffective regulation of blood sugar levels. To regain metabolic control, type 1 diabetics must take insulin injections several times a day.
Since this condition is diagnosed chiefly in children, the trauma faced by both patients and their caregivers, primarily parents, can be quite intense. This is both because of the life-threatening complications associated with the condition as well as the need for close, meticulous monitoring of blood sugar levels to prevent the death of the child as well as to ensure such patients enjoy fulfilling lives.
Previous studies by the same researchers suggested that there were two types of damage observable in pancreatic islet tissue from patients with T1DM, which correlated with the age at diagnosis. In children below seven years at diagnosis, the insulin-containing islets were proportionally reduced compared to those who were diagnosed at age 13 or above.
The current study was aimed at detecting differences in insulin processing in young patients with this condition since this is already known to be related to age at diagnosis.
The researchers looked at samples of pancreatic tissue from the Exeter pancreatic biobank, with over 130 samples, many from young people (including children) who were diagnosed to have T1DM shortly before their death. This is the largest pancreatic tissue resource of its kind worldwide. They compared the levels of proinsulin and insulin within islet cells and their correlation with the occurrence of insulitis in these samples, based upon the age categories of below seven years, 7-12 years, and above 13 years.
Secondly, they looked at differences in the circulating proinsulin: insulin ratio in people who have had T1DM, classified into the same three groups according to their date of diagnosis, in correlation with the differences seen in the pancreas. These differences include the infiltration of immune cells into the inflamed islets and the extent to which proinsulin and insulin are found at the same locations within the β-cells
In one set of samples, they found that these children failed to produce insulin, and the insulin-producing cells were breaking down rapidly. These came from children with T1DM aged less than seven years when diagnosed. However, in older children first diagnosed at age 13 or later, insulin production continued to be normal. This caused the researchers to ask whether it was possible to revive the function of these inactive β-cells to an adequate level.
To distinguish the two 'endotypes' as they term these two forms of T1DM, the investigators have assigned them new names, namely, T1DM Endotype 1 and Endotype 2 (T1DE1 and T1DE2) for the forms occurring in younger and older children, respectively. They consider that children who are first diagnosed between the ages of 7 and 12 years might have either of these endotypes.
The study shows that these two types can be distinguished by age as well as the ratio of proinsulin:C peptide, which means a simple clinical test can differentiate the two endotypes. T1DE1 is caused by a hyperactive immune response where the majority of islets are inflamed, and insulin is not processed properly, resulting in the presence of both proinsulin and C-peptide within β-cells and high proinsulin: C peptide ratio. On the other hand, T1DE2 is characterized by a less intense autoimmune attack, with proportionally more islet cells that secrete insulin and a lower ratio of proinsulin: C peptide in the peripheral blood.
The current project they are working on is to find more accurate ways of establishing the type of diabetes that each of these children has by examining the small amounts of insulin in their blood.
Researcher Noel Morgan says, "The significance of this could be enormous in helping us to understand what causes the illness, and in unlocking avenues to prevent future generations of children from getting type 1 diabetes. It might also lead to new treatments. This would be a significant step to find a cure for some people."
Speaking of new treatments, co-researcher Sarah Richardson explains, "We're seeing a lot of promise in immunotherapies which can slow disease progression, but so far that hasn't translated into effective new treatments. It could be that we need to focus on the use of different therapies in each age group, for these to be effective."
Other experts in diabetes agree, like Elizabeth Robertson of Diabetes UK, who says, "To make new treatments as effective as possible, we need to get to grips with the complexity of the condition. Today's news brings us one step closer to achieving that."
This knowledge will help to help carry out trials and develop customized treatments that could, hopefully, prevent and arrest this condition some future day.
Leete, P., Oram, R.A., McDonald, T.J. et al. Studies of insulin and proinsulin in pancreas and serum support the existence of aetiopathological endotypes of type 1 diabetes associated with age at diagnosis. Diabetologia (2020). https://doi.org/10.1007/s00125-020-05115-6