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May 4, 2020
Children diagnosed at either age 6 or younger, or 13 or older have distinct disease types, opening the possibility of better tailored treatments.
New research indicates that children who are younger than age 7 when diagnosed with type 1 diabetes might have a different form or endotype of this disease in comparison to those diagnosed at age 13 or older. The findings could help inform use of emerging therapies for type 1 diabetes.
Children who fall between these two principal age ranges might have either endotype, study co-author Sarah Richardson, BSc, PhD, associate professor at the University of Exeter Medical School, told CLN Stat. “It will be important now to develop a simple blood test that allows us to distinguish between people having each endotype in order to ensure that the right immunotherapy is administered.”
Previous clinical studies have suggested the existence of different type 1 diabetes endotypes. Verifying this has been a challenge, as it is not easy to access the pancreas in living individuals, Richardson explained. Using material from the Exeter Archival Diabetes Biobank (EADB), a large, unique biobank of pancreas samples recovered from young people who died soon after being diagnosed with type 1 diabetes, Richardson and colleagues studied immune cells present in the insulin-producing islets of patients of different ages, and found evidence of two distinct forms of the disease.
“However, we wanted to confirm this in another way,” she added. The current study examined proinsulin processing within the beta cells, which is known to be altered in some people with type 1 diabetes. “We aimed to determine if these two different phenomena (immune and proinsulin processing differences) correlated with one another, which would suggest that there are differences in the underlying disease mechanisms and as such, may require subtly different treatments,” Richardson said.
Using immunohistological analysis, her team examined proinsulin and insulin distribution in the islets of pancreas samples recovered soon after the onset of diabetes in three age cohorts: young people diagnosed at <7 years, 7–12 years, and ≥13 years. These distributions “correlated with the insulitis profiles in the inflamed islets of the same groups of individuals,” the investigators noted. Another step was to measure C-peptide levels and proinsulin:C-peptide ratio in 171 patients with long-duration type 1 diabetes who had been diagnosed in these same age groups.
Researchers noticed distinct differences in proinsulin localization in the islets of older and younger patients. Children diagnosed when they were younger than age 7 produced endogenous insulin less effectively, whereas those diagnosed when they were at least 13 continued to produce normal insulin. C-peptide levels were “much lower” and the median proinsulin:C-peptide ratio was higher in children diagnosed when younger than age 7 versus those who were 13 or older when diagnosed.
Based on these findings, two distinct endotypes emerged: Type 1 Diabetes Endotype 1 (T1DE1) for those diagnosed at <7 years and Type 1 Diabetes Endotype 2 (T1DE2) for those diagnosed at ≥13 years.
“Because we have now gained an improved understanding of the different immune cell profiles in the islets of children with T1DE1 and T1DE2, new immunotherapies can be tailored to the correct group of patients,” said Richardson.
The fact that older children retained more beta cells than expected raises the possibility of reinvigorating these cells to increase their release of insulin. “This would then lead to better blood glucose control,” noted Richardson.
Conversely, the finding that young children seem to lose their beta cells more quickly and don’t produce much endogenous insulin means they could be followed more intensively throughout their lifetimes. “This will ensure that they maintain the best possible glucose control as a means to minimize the likelihood that they will develop complications such as kidney disease, cardiovascular problems, and deteriorating eyesight,” Richardson said.