The little girl Lilly Jaffe was diagnosed with type 1 diabetes when she was only one month old. Because autoimmune attacks lead to impaired islet beta cells, patients with type 1 diabetes often need life-long insulin therapy, which requires great efforts from patients and their families. But Lilly is lucky. At the age of 6, she received medical treatment at the Clinical Research Center of The University of Chicago. Under the guidance of a doctor, she cut off the insulin pump after just 10 days and took urea drugs to control blood sugar instead.

This case made single-gene diabetes gradually known to people back to a decade ago. Single-gene diabetes is classified as a special type of diabetes other than type 1 and type 2. An astonishing fact is that in the past, a large number of patients with single-gene diabetes were misdiagnosed with type 1 or type 2 diabetes.

A new study from the Harvard Medical School's Joslin Diabetes Center shows that in patients diagnosed with type 1 diabetes for more than 50 years, most of the patient's residual islet beta cells are still able to secrete insulin, and a significant number of people may actually be monogenic diabetes patients. The findings were recently published in the Journal of Clinical Investigation.

The Medalist Study was initiated by the Joslin Diabetes Center in 2003. They awarded medals to patients who had been diagnosed with type 1 diabetes for more than 50 years and recruited them to join the study. The initial goal was to study the prevention of serious complications of diabetes. On this basis, various projects such as disease progression, beta cell function, and cognitive function were also carried out.

In this new analysis, the researchers recruited 1019 medalists, 55% of whom were women. The median age at the start of the study was 65 years, and the duration of type 1 diabetes averaged about 53 years. All subjects underwent genetic screening to understand whether to carry genes that cause diabetes. Other test items include human leukocyte antigen (HLA), autoantibody status, and assessment of islets by a mixed dietary tolerance test (MMTT), high glucose/arginine clamp test, and C-peptide (product of insulin synthesis) test to assess the function of beta cells.

The data showed that 43.6% of patients were positive for autoantibodies, and about one-third of patients were still able to produce detectable levels of C-peptide. Mixed dietary tolerance tests have also shown that despite long-term insulin dependence, some patients are able to respond to metabolic stimuli and changes in C-peptide levels in the body.

In addition, pathological examination of the pancreas of 68 dead patients revealed that although these patients had autoimmune attacks for more than 50 years, beta cells with insulin-secreting activity were still detected in all of them. As pointed out by the research team, in these patients, a small number of beta cells with residual function may be able to escape autoimmune damage and somehow restore the "vigor" of insulin secretion.

More importantly, some patients with type 1 diabetes may be misdiagnosed. Genetic analysis showed that 280 patients (27.5%) had single-gene variation, of which 80 (7.9%) carried mutations that may cause disease.

For this result, the research team proposed the need for genetic screening for some patients with type 1 diabetes. Patients with higher levels of C-peptide in the body are very likely to benefit from HLA risk allele assessment and single-gene diabetes screening, which will help them to develop a better treatment plan.

In an editorial published together, Dr. Fabrizio Barbetti of the Bambino Gesù Children's Hospital in Italy and Dr. Simeon I. Taylor of the University Of Maryland School Of Medicine highly commented the work of Joslin Diabetes Center. After all, long-term in-depth research is a very extraordinary achievement in itself. If genetic mutation screening is used to identify single-gene diabetics, then patients get a chance to switch to oral medication instead of continuing to receive insulin therapy.

According to a statement from the Joslin Diabetes Center, the researchers hope to conduct a clinical trial within a few months to see if patients with disease-causing genetic variants can actually switch to oral medications to control diabetes. According to the research team, this will be the first clinical study to focus on oral drug therapy for elderly patients with monogenic diabetes.

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Reference
[1] Marc Gregory Yu, et al., (2019). Residual β cell function and monogenic variants in long-duration type 1 diabetes patients. J Clin Invest, 10.1172/JCI127397.
[2] Some With Type 1 Diabetes Misdiagnosed; Call for Genetic Screening. Retrieved July 8, 2019, from https://www.medscape.com/viewarticle/915270
[3] Joslin 50 - Year Medalist Study. Retrieved July 8, 2019, from https://joslin.org/50-year-medalist-study.html
[4] Molecular medicine comes to the rescue: Targeted therapy turns life around for child with neonatal diabetes. Retrieved July 8, 2019, from http://www-news.uchicago.edu/releases/06/060911.diabetes.shtml

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