Distinguishing T1 from LADA—new research

Type 1 & LADA
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Found this article in Apple News:

Genetic differences help distinguish type 1 diabetes in children from ‘type 1.5’ in adults

CHOP researchers believe the discovery could lead to more effective diagnostic methods

Philadelphia, January, 2020–A multi-center team of researchers led by Children’s Hospital of Philadelphia (CHOP) has discovered a genetic signature that could help distinguish an adult-onset form of diabetes sharing many type 1 diabetes (T1D) characteristics from pediatric-onset T1D, opening the door to potentially more straightforward diagnostic tests for the adult condition and improving responses by ensuring patients receive the most appropriate treatment.

“This is our first insight into genetic differences between latent autoimmune diabetes in adults and T1D in children that may be diagnostically useful,” said study leader Struan Grant, PhD, Co-Director of the Center for Spatial and Functional Genomics at CHOP and the Daniel B. Burke Endowed Chair for Diabetes Research. “We have found a genetic means of discriminating between the two conditions without expensive and cumbersome anti-autobody screening.”

The study was published online December 16, 2019 in Diabetes Care.

Latent autoimmune diabetes in adults (LADA) is sometimes referred to as “type 1.5 diabetes” because it shares characteristics of both T1D and type 2 diabetes (T2D). Like T1D, LADA produces autoantibodies that attack the body’s insulin-producing beta cells in the pancreas. However, like those with T2D, patients with LADA are diagnosed in adulthood and do not require insulin at the time of diagnosis. For this reason, LADA is often misdiagnosed as T2D; studies have shown that up to 10% of T2D diagnoses are, in fact, LADA, and as a result patients do not respond to the commonly inappropriate treatments prescribed to them.

An earlier genome-wide association study led by CHOP found that, from a genetic perspective, LADA has more in common with T1D than with T2D. Researchers wanted to take a deeper dive and look for genetic differences that could help discriminate between LADA and T1D, meaning the diagnosis of LADA could potentially begin with a simple genotype array, rather than with a more complex and expensive autoantibody screening.

To do so, the team decided to look at the major histocompatibility complex (MHC), a highly variable region of the genome that helps drive the immune system and is implicated in T1D. Earlier studies have shown that when researchers control for T1D genetic variants in one part of the MHC, other variants associated with T1D appear in another part of the MHC.

The study team applied that methodology to both a set of T1D data as well as a cohort of LADA patients. They found that when it came to the T1D group, the results from the earlier studies held: controlling for genetic variants in one part of the MHC revealed variants in another part of the MHC.

However, researchers did not find the same effect with LADA patients. When controlling for genetic variants in the MHC in those patients, the additional association was not observed within this key region – an important genetic distinction between the two conditions. When a sensitivity test was applied to the two cohorts, researchers still saw the effect only in T1D patients, not in those with LADA.

“This suggests that these MHC class associations may be a genetic discriminator between LADA and childhood-onset T1D,” said Diana Cousminer, PhD, a geneticist at CHOP and a joint-first author of the study. “The next step is to look at this association in different ethnicities, particularly African ancestry, where the prevalence of adult-onset diabetes can be significantly higher in certain parts of the world.”

Funding for the study came from the National Institutes of Health (grants K99 HD099330 and R01 DK085212) and the Daniel B. Burke Endowed Chair for Diabetes Research.

Rajashree Mishra, Mikael Åkerlund, Diana L. Cousminer, et al. “Genetic Discrimination Between LADA and Childhood-Onset Type 1 Diabetes Within the MHC,” Diabetes Care, online December 16, 2019. https://doi.org/10.2337/dc19-0986

About Children’s Hospital of Philadelphia: Children’s Hospital of Philadelphia was founded in 1855 as the nation’s first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, Children’s Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. In addition, its unique family-centered care and public service programs have brought the 564-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://www.chop.edu

Media Contact
Dana Bate
BATED@email.chop.edu

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This is good. I hope it will lead to more research. Makes me wonder if LADA (selfishly) might end up being more “curable” than childhood onset t1… as to the extent that I understand it they’re saying that the genetic markers found in t1 were not also found in LADA? Is that correct? Maybe someone can explain it in more layman’s terms @TiaG

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This is helpful. Certainly confirms that I am definitely not LADA due to needing insulin right away?

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No not at all… many LADAs don’t need insulin for many years, some maybe even never do…

Some need insulin day 1 and are diagnosed in near death ketoacidosis and everything in between

This research just shows that there is an appearently genetic distinction between lad and childhood onset type 1… nothing beyond that

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The article did state that people with LADA “do not require insulin at the time of diagnosis.” So I wonder if the study focused only on the slow-onset form and not on adult who get “standard” rapid-onset T1D. Some adults do get truly rapid-onset T1D with symptoms for only a few weeks prior to being diagnosed in or near ketoacidosis.

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That described my onset pretty accurately… am still diagnosed as LADA.

I don’t think LADA necessarily requires a slower
onset it just is not uncommon that it occurs that way

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Likewise here…diagnosed as LADA in my late 50’s. I think “not needing insulin right away” needs more specificity. In hindsight my symptoms probably started 3 months before I had hit rock bottom and went to the doc almost in DKA. Suppose I had gone to the doc three months earlier…I could have survived those 3 months without insulin but just barely. And still would have needed insulin 3 months later. So I actually needed insulin before I was diagnosed. But survived unhealthily without starting insulin “right away” when symptoms first appeared.

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What do they consider “adult” onset? I was diagnosed T1 at age 22, but that was in 1979. I don’t know if they knew about LADA then. The way I was diagnosed, I lost so much weight that I stopped menstruation, and I went to my OB-GYN. I didn’t feel bad or unwell, but I had the classic excessive thirst and hunger symptoms. I don’t know what my BG was. They did a glucose tolerance test for my diagnosis, and then sent me to my PCP. I wasn’t admitted to the hospital, and no one said anything about DKA. I had previously had a really bad case of influenza which may have triggered it.
When I was diagnosed I had lost about 30 lbs.

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I’d lost almost 40 lbs without even realizing it… and I’m pretty lean to begin with… amazing how out of touch with my own health I was

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Me too, I’m 5’11" and when I was diagnosed I weighed 115 lbs.

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I’d lost 35-40 pounds at diagnosis (in DKA) and the doc caught that I was LADA. Yet he said maybe I’d be able manage for a while on basal insulin and metformin—not!! So no long onset for me—on to basal-bolus at about 6 weeks (at my request). Gah!

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That’s what I’m wondering as someone who was diagnosed at 22 as well. I didn’t lose a lot of weight ( but until recently, I struggled to put much weight on, spent most my childhood and early teens being underweight) but , I did have the frequent urination and thirstiness… And the general unwell feeling that a lot of people talk about like being nauseated and other stomach issues. No dka, but I was misdiagnosed as type 2 entirely because I was over 18. I didn’t start insulin immediately, but I definitely should have. Metformin did nothing, and I had like no energy to exercise after 2 months of being aware I was diabetic. Also was practically starving myself and still almost always above 200 mg/dL . With insulin I’m rarely high and almost always have a 5.5% a1c… So yeah.

I really feel like it’s off to separate adults and kids like this when some adults experience a quick onset…

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I think “quick” can be relative. Even waiting six weeks between diagnosis and insulin is “slow” compared to most kids. My experience, which I’d guess is fairly typical, was that we noticed symptoms (insanely thirsty, lack of energy, weight loss, nausea the last few days prior to diagnsois) for perhaps a couple of weeks. My mom took me to the doctor and she immediately mentioned diabetes as a potential cause and had me pee in a cup then sent me for blood work. We left and within an hour got a call from the doctor saying we needed to go to emergency immediately. So we went to the hospital and I was admitted for four days. I don’t know values, but my blood sugar and ketones were both very high and I was told if we had waited a day or two longer to see the doctor I could have gone into a coma. So I think even waiting six weeks to start insulin is a delay compared to kids, and some people are able to wait months or years (I’ve also heard of adults diagnosed one day who end up in emergency in DKA the next, so really fast onset does happen).

Either way, I think this research is only good if it helps reduce the number of adults who get misdiagnosed as Type 2. Though it seems strange to me that gene testing would be cheaper than antibody testing. I’d assume the opposite is true, but I know nothing about these things (I was diagnosed before antibody and c-peptide tests, so have never had either).

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