New Data Shed Light on Type 1 Diabetes Male Predominance

MADRID, Spain — New research sheds light on the male predominance in type 1 diabetes, finding that the risk between men and women diverges around age 1src years. 

Data from more than 2srcsrc,srcsrcsrc first-degree relatives of people with type 1 diabetes who were screened for type 1 diabetes risk in the TrialNet program showed that “there’s a clear interaction with age and male sex being a risk factor. At the age of ten in girls, there seems to be this tipping point where the risk of type of diabetes dramatically reduces,” lead investigator Richard Oram, MD, of the Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, United Kingdom, told Medscape Medical News. 

There was a steep decline in 5-year type 1 diabetes risk in women who were screened and positive for type 1 diabetes-related autoantibodies prior to age 1src years compared to after 1src years. In contrast, among men the risk of progression remained steady as age at screening increased. The reasons for this aren’t clear, but the age of 1src years “goes with puberty, so it raises the question as to whether these are puberty-related changes,” Oram said. 

This study looks at both type 1 diabetes risk and onset specifically by age and gender. The first author, Exeter PhD student Erin L. Templeman, told Medscape Medical News, “In childhood, the prevalence is very similar in type 1 diabetes between males and females. It’s later on that we see that the diversion in the expression.” She cited a 2srcsrc8 study as one of several finding the gender difference. But that study examined people aged 15-34 and only at type 1 diabetes onset. “We wanted to explore this further,” she said. 

As of now few people without first-degree relatives who have type 1 diabetes are being screened, although there are now guidelines for managing those who are and who screen positive. 

However, Oram said, “I think the takeaway would be that boys seem to get more type 1 diabetes after the age of 1src. If you do a screening study at the age of 1src or later, you would expect more boys to be positive than girls.”

Asked to comment, William Hagopian, MD, PhD, Clinical Professor of Medicine, University of Washington, Seattle, told Medscape Medical News, “it is intriguing that the lower risk in females seems to appear near the age of menarche, and earlier menarches are now observed in some populations. However, the latter connection is speculative and requires further investigation. In any case, working out the mechanisms underlying the observed differences in early-stage disease progression by sex may yield important clues about the early development of the disease and how to interrupt it.”

Males More Likely to Screen Positive, and to Progress With Just One Autoantibody

Among the 235,765 relatives of people with type 1 diabetes screened and after adjustment for confounders, the proportion who screened positive for at least one autoantibody was 5.src% in women vs 5.4% in men, a significant difference (P <.srcsrc1). And of those, men were more likely to screen positive for more than one autoantibody, 2.6% vs just 1.8% in women (P <.srcsrc1). 

Among those positive for a single autoantibody, men were more likely to progress to type 1 diabetes within 5 years (21% vs 14% in women, P <.srcsrc1). However, among those with at least two autoantibodies, the risk of progression to clinical type 1 diabetes (stage III) was similar. Among those with stage I type 1 diabetes (at least two autoantibodies but normoglycemia), progression occurred in 38% of both men and women. And for those with stage II type 1 diabetes (at least two autoantibodies and dysglycemia), progression to type 1 diabetes occurred in 59% of men and 57% of women, not significantly different.

“Once you hit stage I or stage II, male sex is no longer a risk factor for progression. Male sex is a risk factor for getting type 1 diabetes but not for the speed the train is going once you’ve left the station and you already have it,” Oram commented.

Hagopian, who is also senior research professor of pediatrics, Indiana University, Indianapolis, said that the finding of gender difference appearing to be largely due to progression of single islet autoantibody positivity to clinical disease is “new and important.” He noted that people who are positive for a single autoantibody have a much lower risk of progressing to type 1 diabetes, about 15-4src%, compared with> 9src% for those with multiple autoantibodies, “but the former is still high enough to warrant follow-up. These findings begin to provide a way, perhaps along with type of islet autoantibody, family history, genetics, and other factors, to inform prognosis and guide monitoring intensity of these single islet autoantibody positive individuals.”

Oram pointed out that the sex difference in type 1 diabetes doesn’t often emerge in some of the major epidemiologic studies investigating risk factors because gender is adjusted for in the analysis. “Sometimes we look for really clever mechanisms in disease, and we don’t stop to think about some really obvious but kind of slightly perplexing observations that have been there for years…It highlights that we don’t always consider sex as a variable in scientific studies as well as we should do.” 

These findings will be presented on September 1src, 2src24, at the annual meeting of the European Association for the Study of Diabetes.

This work was funded by the National Institutes of Health (NIH) and Juvenile Diabetes Research Foundation (JDRF). Templeman is a PhD student funded by Randox. Oram also receives research funding from Randox. Hagopian has received research support from Janssen R+D, Provention Bio, Sanofi US, JDRF/Breakthrough T1D, and NIH. He has provided consulting services for Sanofi, Randox, MedLearning, and City of Hope. 

Miriam E. Tucker is a freelance journalist based in the Washington DC area. She is a regular co