Is All Type 1 Diabetes the Same?

Evidence is accumulating that for patients with type 1 diabetes who have a family history of it ― defined as having at least one first-degree relative with type 1 diabetes — the disease is often substantially different from that of people with sporadic type 1 diabetes who have no family background.

The most striking difference: familial cases are associated with many more comorbidities.

Researchers hope that a better understanding how familial and sporadic diabetes differ will yield new insights into how to best tailor treatments for patients with type 1 diabetes in the future.

Results from a recent report on more than 16,000 US residents with type 1 diabetes who were enrolled in a nationwide registry showed that among the 3941 adults and children with a familial background, various comorbidities were much more prevalent compared with more than 12,000 patients who had sporadic type 1 diabetes, which was defined conservatively as not having any relative who was diagnosed with it, including those more removed than first degree.

Among those with familial disease, prevalence rates of hypertension, hyperlipidemia, atherosclerosis, retinopathy/maculopathy/vitreopathy, erectile and sexual dysfunction, gastroesophageal reflux disease, neuropathy, and nephropathy were significantly higher, as were rates of several other comorbidities.

In contrast, people with sporadic cases of type 1 diabetes were significantly more likely to have no comorbidities. Several of the comorbidities among the familial patients clustered in groups of two or three in the studied cohort. The researchers identified these prevalence patterns using a specially designed analytic, data-mining algorithm.

One example of the prevalence differences: 7.0% of the patients with familial disease and 4.4% of those with a sporadic background had both hypertension and hyperlipidemia/dyslipidemia. The relative difference between the two cohorts was greater than 50%.

7% of Type 1 Diabetes Cases Are Familial: Differences in Autoimmune Disease

The findings open a new dimension in the growing appreciation of how sporadic and familial cases differ. A 2021 report from Europe that involved assessment of a population-based registry with more than 57,000 children and teenagers with type 1 diabetes from Germany, Austria, Switzerland, and Luxembourg documented a familial prevalence of roughly 7% of the entire pediatric cohort.

The 2021 report also showed that familial disease showed up earlier. The average age of children with familial disease was 7.9 years, compared with 9.7 years among children with sporadic disease. Among the patients with familial disease, there was a higher prevalence of associated autoimmune comorbidity and indications of more aggressive autoimmunity.

The researchers found that autoimmune diseases occurred in 16.7% of those with familial type 1 diabetes compared with 13.6% of those with sporadic disease, a significant, 23% relative difference. Among the autoimmune diseases assessed, celiac disease showed the largest between-group difference, with a 6.2% prevalence among those with familial type 1 diabetes compared with a 4.2% prevalence among patients with sporadic disease.

"The higher prevalence of autoimmune and other comorbidities in people with familial type 1 diabetes might be explained by a shared genetic and environmental background in affected families," explained Beate Karges, MD, a researcher in the Division of Endocrinology and Diabetes, at RWTH Aachen University, Germany, and lead author of the European report.

The results in these two reports plus other findings suggest that the differences in risk profiles among patients with sporadic disease and those with familial type 1 diabetes are related not only to the "pathways of autoimmunity and inflammation" that help determine the "glycemic trajectory of the disease" but also influence "complications of abnormal glycemic control" in patients with familial disease, said Mark A. Clements, MD, PhD, a pediatric endocrinologist at Children's Mercy Hospital in Kansas City, Missouri, who co-authored the more recent, US report.

"If a person with familial disease has stronger autoimmunity and stronger inflammation triggered by the autoimmunity, you can hypothesize that they also have a higher prevalence of other diseases that associate with the autoimmunity and inflammation," said Clements, who is also a professor of pediatrics at the University of Missouri–Kansas City School of Medicine.

Beyond One-Size-Fits-All Type 1 Diabetes Care

While Clements stressed that his group's findings are preliminary and need confirmation and validation with other datasets, they point toward an eventual end to the current practice of "applying the same care paradigm to all patients with type 1 diabetes," he said in an interview.

A goal is to distinguish patients with familial and those with sporadic forms with distinct multivariable risk models, he added. An attraction of the artificial intelligence method he and his associates applied is that it can potentially find "important patterns [of linked comorbidities] that people cannot see."

If future studies could, for example, nail down a strong link between familial type 1 diabetes and an increased risk for developing hypertension, it could have implications for intensifying hypertension surveillance and early treatment, he suggested. "This research is getting at one way to determine a patient's lifetime risk of diabetes-related eye disease, hypertension," and other common diabetes complications.

While many of the potential implications of these findings for practice still need to be worked out, both Clements and Karges see a few immediate applications to diagnosing and managing patients with type 1 diabetes.

Stepped Up Screening

The higher prevalence of autoimmune diseases in patients with familial disease suggests the potential for personalized screening for associated autoimmune diseases, Karges suggested in an interview. "Regular screening for autoimmune thyroid and celiac disease may lead to earlier detection and treatment of comorbidities and improve patient care."

In addition, management of the index case might be aided by "enhanced psychosocial support for families coping with more than one individual with type 1 diabetes," she said.

"Once someone is diagnosed with type 1 diabetes, the risk that another [first-degree] family member also has type 1 diabetes rises fifteenfold," noted Clements.

That's why clinicians who care for patients with type 1 diabetes should be aware of and potentially act on the newly assumed risk in close relatives following an index-case diagnosis. With further research, he hopes that classifying type 1 diabetes as sporadic or familial will also inform the care received by the index patients. And he sees the potential to use detailed assessments of familial cases to work out the genetics that helps drive the comorbidity spikes in these patients.

The study run by Clements and his associates used patients selected from the T!D Exchange Clinic Registry, which enrolled more than 34,000 US residents with type 1 diabetes during 2007–2018 at any of 83 US endocrinology practices. The researchers selected for their study a disproportionately high percentage of people with familial disease, 24% of the 16,232 individuals studied. Clements noted that the roughly 7% prevalence of familial type 1 diabetes seen in the study led by Karges is a much better approximation of how often familial cases arise.

The Karges study used data compiled in the Diabetes Prospective Follow-up Registry, based at Ulm University, Germany, with patients enrolled during 1995–2018.

A key difference between the US and European studies is that the US database included a significant minority of people with adult-onset type 1 diabetes, while the Karges' study exclusively focused on type 1 diabetes in which onset occurred during childhood or adolescence.

Important differences in diet, activity, and other lifestyle and cultural factors also likely distinguish the US-based study and the one that involved patients from Central Europe, Clements noted.

Neither study received commercial funding. Clements is chief medical officer for Glooko and has received research support from Abbott Diabetes Care and Dexcom. Karges has disclosed no relevant financial relationships.

Diabetes Care. 2022;45:e56-e59. Full text

Diabetes Care. 2021;449:1116-24. Abstract

Mitchel L. Zoler is a reporter with Medscape and MDedge based in the Philadelphia region. @mitchelzoler

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