1型糖尿病 z-bo 2020-10-23 459

　　We know that patients with type 1 diabetes suffer from absolute insulin deficiency due to islet β-cell damage. At present, insulin therapy is the main treatment. Restoring β-cell function and reversing the pathological state is still a big challenge.

　　However, a young patient with type 1 diabetes may be lucky. After taking a JAK inhibitor ruxolitinib, the young man has stopped insulin and maintained normal blood glucose levels for nearly two years. This particular case report was officially published in the New England Journal of Medicine (NEJM) recently, providing important insights into the application potential of JAK inhibitors in the field of type 1 diabetes.

　　Let’s take a look at the patient’s medical history and experience.

　　At the age of 15, the patient experienced chronic yeast infections, including skin, nails, oropharynx, chronic diarrhea, oral and rectal ulcers, repeated sinus and lung infections, and hypogammaglobulinemia . At the age of 17, he suffered from diabetic ketoacidosis (DKA), a marked increase in glycosylated hemoglobin level, low C-peptide (marker of insulin secretion), and glutamate decarboxylase antibody (anti-β cell antibody) Positive, and was diagnosed with type 1 diabetes.

　　Because this patient showed a variety of autoimmune diseases, 9 months after the diagnosis of type 1 diabetes, the medical team decided to perform genome sequencing for him to further analyze the cause of the disease. It was found that this patient had a pathogenic mutation of STAT1 (signal transducer and activator of transcription 1) (c.1154C→T, pT385 M). In other words, he suffers from STAT1 gain-of-function disease. Usually, patients with this syndrome do have a variety of autoimmune diseases, including type 1 diabetes and prone to infection.

　　Then, the medical team tried to prescribe a key drug for him-the JAK inhibitor rocotinib. In previous studies, Rucotinib has been shown to relieve many symptoms associated with this syndrome.

　　After taking Rucotinib for a few months, the patient's symptoms began to improve: chronic mucocutaneous candidiasis and autoimmune diseases subsided, the frequency of infections decreased, and the amount of exogenous insulin was also reduced.

　　"This drug has an incredible effect on his type 1 diabetes." said Dr. Lisa Forbes, his attending physician and professor of pediatrics, immunology, allergy and rheumatology at Baylor College of Medicine. After 12 months of treatment with Rucotinib (21 months after the diagnosis of type 1 diabetes), the medical team decided to stop insulin for him, and for the following 15 months, the patient's blood glucose level and other indicators remained normal. At this time, the patient has already passed the "honeymoon period" of type 1 diabetes (in the early stage of diabetes, the patient may last for several weeks to several months and only need a small dose of insulin to maintain normal blood sugar). In other words, Rucotinib does work. Effect.

　　How to evaluate the therapeutic effect of Rucotinib? According to Dr. Forbes, there may not be a "cure" at present, but the patient's type 1 diabetes has indeed been reversed. The medical team hopes that as long as patients continue to take rucotinib, the existing effects will be maintained. But the durability of this reversal effect still needs time to test.

　　The question that follows is whether rocotinib is also expected to be more widely used to treat other type 1 diabetes patients?

　　Because this particular patient happened to carry the genetic mutation targeted by Rucotinib, it is still unknown whether this drug is effective for other type 1 diabetes patients, but this case provides a potential for the disease and treatment mechanisms that lead to type 1 diabetes. Important information.

　　On the one hand, most type 1 diabetes is an autoimmune disease in which the immune system mistakenly attacks pancreatic β cells. The reasons are complex and diverse, which involve genetic factors and the strong influence of some HLA (human leukocyte antigen) genotypes, which suggests that T cells may be involved in the pathogenesis of type 1 diabetes.

　　On the other hand, in STAT1 gain-of-function diseases, the occurrence of autoimmune diseases is also considered to be related to abnormal lymphocyte activation and signal transduction. Studies have shown that natural killer cells and helper T cells 1 (Th1 ), follicular helper T cells (Tfh), and helper T cell 17 (Th17) are abnormal.

　　The effect of JAK inhibitors in the treatment of STAT1 gain-of-function diseases has accumulated relatively significant evidence, and it has indeed been proven to improve natural killer cell function and T cell abnormalities in patients.

　　Although more studies are still needed to advance further verification, the therapeutic potential of JAK inhibitors in type 1 diabetes has received a lot of attention. JDRF, the world's leading type 1 diabetes research funding and advocacy organization, has been funding JAK inhibitor research for many years, and is about to launch clinical trials for newly diagnosed type 1 diabetes patients in Australia.

　　At present, among the 7 JAK inhibitors that have been approved for marketing worldwide, the indications include rheumatoid arthritis, bone marrow fibrosis, psoriatic arthritis, ulcerative colitis, graft versus host disease, etc. "JAK inhibitors have been used to treat other autoimmune diseases, and we hope that JAK inhibitors will also have a real and profound impact on type 1 diabetes." said Frank Martin, research director of JDRF.

　　Mr. Frank Martin said, "In type 1 diabetes, these drugs are expected to weaken the immune system's response and improve the survival rate of beta cells." He also speculated that some patients with long-term type 1 diabetes may also be suppressed from JAK "They may still need insulin injections, but the amount will be less, depending on their beta cell storage."