Beware of latent autoimmune diabetes in adults

What is latent autoimmune diabetes in adults

　　Latent autoimmune diabetes in adults (LA-DA) is an autoimmune disease characterized by slow autoimmune damage to pancreatic islet B cells, and patients with early-stage LADA are not dependent on insulin therapy. It is the most common type of autoimmune diabetes in Chinese adults. Epidemiological studies reported that the prevalence of LADA in newly diagnosed T2DM patients over 18 years old in my country was 6.1%; if the cut-off point was 30 years old, the prevalence of LADA was 5.9%; LADA accounted for about 65% of newly diagnosed TIDM patients. According to the 2018 diabetes epidemiological survey data, there are more than 10 million LADA patients in my country.
Characteristics of latent autoimmune diabetes in adults

　　LADA is characterized by positive islet autoantibodies or positive islet autoimmune T cells in adults who are independent of insulin therapy for at least six months after the diagnosis of diabetes. In 2019, the World Health Organization (WHO) classified LADA as a mixed type of diabetes, considering LADA as an independent type of diabetes; while the American Diabetes Association (ADA) classified it as a subtype of type 1 diabetes mellitus (TIDM). The main reason is that the pathogenesis of LADA is the same as that of type 1 diabetes mellitus (TIDM). The early asymptomatic stage of LADA can last for several years, and its clinical course can be divided into non-insulin-dependent and insulin-dependent stages. In the non-insulin-dependent stage, the patient’s performance is similar to that of T2DM, and the oral hypoglycemic drug treatment can control blood sugar, and there is no tendency to spontaneous ketosis. However, the decline rate of islet B cell function in LADA is faster than that in T2DM (the decrease rate of C-peptide is 3 times that of T2DM), and it is slower than that in classical TIDM. When a patient’s pancreatic islet B cell function is significantly insufficient, resulting in diabetic ketosis or acidosis, insulin treatment is necessary and the patient enters the insulin-dependent stage. The time to progression of LADA to insulin dependence was highly heterogeneous, and was related to age at onset, antibody titer, and multiple islet antibody positivity; GADA titer was the strongest predictor of islet B-cell failure in LADA patients. LADA is prone to be associated with other autoimmune diseases. The more common autoimmune diseases include autoimmune thyroid disease, celiac disease, Addison disease and autoimmune gastritis. In addition, LADA can be an important component of autoimmune polyendocrine syndrome (APS), often manifested as APS type III associated with autoimmune thyroid disease.
Complications of latent autoimmune diabetes in adults

　　Diabetic microvascular complications In the early stage of diabetes (duration < 5 years), the prevalence of retinal and nephropathy in LADA is similar to that of TIDM, but lower than that of T2DM. With prolonged disease duration (duration > 5 years), LADA has worse glycemic control, and its prevalence is close to or even higher than that of T2DM. The prevalence of neuropathy in LADA is generally higher than in T2DM.
　　Atherosclerotic cardiovascular disease (ASCVD) Although the risk factors for ASCVD in LADA, such as hypertension, dyslipidemia, and central obesity, were significantly lower than those in T2DM, most studies found that the prevalence and mortality of AS-CVD in LADA were significantly higher than those in T2DM. resemblance.
Diagnosis and testing of latent autoimmune diabetes in adults

　　The diagnostic criteria of LADA are: ① age of onset ≥ 18 years old; ② positive islet autoantibodies, or positive islet autoimmune T cells; ③ independent insulin therapy for at least six months after the diagnosis of diabetes.
　　With the above three items, LADA can be diagnosed. Therefore, GADA is the most sensitive immune indicator for diagnosing LADA, but the positive rate of CADA in LADA patients in the Chinese population is only 67%. Therefore, LADA screening in the Chinese population is often based on CADA, combined with the detection of IA-2A, ZnT8A and IAA to improve the diagnosis. Sensitivity. In addition, some patients with clinically diagnosed T2DM who are negative for antibodies have a cellular immune response to islet protein and should also be diagnosed with LADA. According to the Chinese Expert Consensus on Diagnosis and Treatment of Latent Autoimmune Diabetes in Adults (2021 Edition), GADA screening is recommended for all newly diagnosed patients with T2DM phenotype, in order to avoid missed diagnosis of LADA as early as possible. Antibody screening is recommended in diabetic patients with high risk factors for LADA if cost and testing availability are considered. Patients at high risk of LADA may be associated with the following clinical features: family history of TIDM or autoimmune disease, non-obese body type (BMI < 25 kg/m2), age of onset < 60 years. If GADA is negative, but LADA is highly suspected clinically, islet autoantibodies such as IA-2A, ZnT8A, IAA or Tspan7A should be further detected; islet antigen-specific T cell detection is still feasible if conditions permit. Treatment of latent autoimmune diabetes in adults 　　The overall goal of LADA treatment is to achieve an ideal level of glucose metabolism control; regulate islet autoimmunity, protect islet B cell function; and prevent diabetes complications and associated complications. 　　Blood sugar control target 　　The HbAlc level of LADA patients is usually recommended to be controlled below 7%; individualized control targets are established according to age, course of disease, life expectancy, complications or the severity of complications. For those whose blood sugar control reached the standard, HbAle was tested every 6 months; for those who changed the treatment plan or did not meet the blood sugar control standard, HbAle was tested every 3 months. For most LADA patients, it is recommended to control fasting blood glucose between 4.4 and 7.2 mmol/L and postprandial <10 mmol/L. The goal during pregnancy is to control the fasting blood glucose at 3.9 to 5.3 mmol/L, 1 hour postprandial blood glucose of 6.1 to 7.8 mmol/L, and 2 hours postprandial blood glucose of 5.6 to 6.7 mmol/L. 　　Hypoglycemic drugs 　　Insulin insulin therapy can protect islet β-cell function in LADA patients by promoting islet rest and inducing immune tolerance. For LADA patients with high CA-DA titers, multiple islet autoantibodies, low C-peptide levels, or poor glycemic control, insulin therapy should be initiated as soon as possible; for those with low CADA titers, C-peptide levels or better glycemic control , you can choose appropriate oral hypoglycemic drug treatment. 　　DPP-4i DPP-4i can inactivate the DPP-4 enzyme, increase the level of CLP-1, promote the secretion of insulin from islet β cells and lower blood sugar. In addition, DPP-4i can inhibit the activity of the DPP-4 enzyme of the CD26 molecule of immune cells and has an immunomodulatory effect. LADA patients treated with sitagliptin and saxagliptin alone or in combination can protect islet β-cell function. The consensus recommends that in the absence of contraindications, LADA patients can choose DPP-4i therapy. 　　TZD drugs TZD drugs activate intracellular peroxisome proliferator-activated receptors (PPARs), which can enhance insulin sensitivity and have anti-inflammatory and immunomodulatory effects. It is recommended that TZDs can be used to treat LADA in the absence of contraindications. But pay close attention to edema, cardiac function, anemia, fractures and other side effects. 　　GLP-1RA GLP-1RA acts on islet beta cells to promote insulin synthesis and secretion; acts on islet alpha cells to inhibit glucagon release; it can inhibit appetite, slow gastric emptying and lower blood sugar. GLP-1RA can play a negative immunoregulatory role by activating GLP-1R in immune cells. Although GLP-1RA has clear benefits in terms of weight loss, hypoglycemia, and cardio-renal protection in patients with T2DM, there are limited studies on the treatment of LA-DA. It is suggested that CLP-1RA can be applied to LADA patients with certain islet function. 　　SGLT2i SGLT2i can promote urinary glucose excretion and lower blood sugar. It is suggested that SGLT2i can be considered for LADA patients with high C-peptide levels and with cardio-renal complications or overweight. It should be noted that SGLT2i may increase the risk of diabetic ketoacidosis (DKA), and blood ketone levels should be monitored. 　　The biguanide drug metformin is the first-line drug for T2DM and can improve insulin sensitivity, weight loss, LDL-C levels and atherosclerosis risk in patients with TIDM. It is suggested that metformin combined with other appropriate drugs can be used to treat LADA in the absence of drug contraindications. 　　Glycosidase inhibitors For LADA patients with better islet function, glycosidase inhibitors can be considered as triple drugs according to complications and blood sugar control level. 　　Sulfonylureas Sulfonylureas make LADA islet function decline faster, which may be related to its direct action on islet beta cells, promoting insulin release and accelerating beta cell apoptosis. Patients with LADA are advised to avoid sulfonylureas. 　　Immunomodulators 　　Vitamin D Vitamin D can exert anti-inflammatory and immunomodulatory effects through the vitamin D receptor (VDR). The combination of 1α-hydroxyvitamin D 3 and insulin in the treatment of LADA patients can better improve the fasting C-peptide level than the insulin alone group. In view of the large number of vitamin D deficient people in China, and vitamin D has the effect of protecting islet function, it is recommended that LADA patients Treatment with combined vitamin D. 　　Tripterygium wilfordii polyside Tripterygium wilfordii polyside is a traditional Chinese medicine with anti-inflammatory and immunomodulatory effects. Low-dose tripterygium glycosides can be tried in combination with LADA. 　　GAD vaccine, monoclonal antibody and cell therapy 　　are still in the research stage, and the efficacy and prognosis still need to be confirmed by larger-scale clinical studies.