Clinical Study on the Improvement of Diabetic Neuropathic Pain by Liraglutide

1. Diabetic neuropathic pain seriously affects the quality of life, clinical problems are difficult, and new treatment methods are urgently needed.

Diabetic neuropathy is one of the most common complications of diabetes mellitus. The study of investigators shows that the prevalence rate of diabetic neuropathy diagnosed in downtown Shanghai is as high as 61.8%. The most common type of diabetic peripheral neuropathy is distal symmetric polyneuropathy, which is the main cause of diabetic neuropathic pain (DNP). Diabetic neuropathic pain can affect about one fifth of diabetic patients, which can lead to the decrease of daily activities, even the loss of work, severe depression, and quality of life. The pathogenesis of diabetic neuropathic pain is complex and not yet fully clear, so there is a lack of available and effective treatment. At present, the first-line clinical treatment drugs include pregabalin, duloxetine, amitriptyline, gabapentin and venlafaxine, etc., and these drugs sometimes relieve the symptoms of diabetic neuropathic pain not obvious, and have more side effects, which has become a difficult problem in clinical treatment. Therefore, it is urgent to explore effective drugs for diabetic neuropathic pain.

2. The clinical observation and animal study of the investigators show that the GLP-1 receptor agonist (liraglutide) can improve diabetic neuropathic pain.

1. Diabetic neuropathic pain is related to brain microglia. In the animal model of diabetes mellitus, investigators found the phenomenon of abnormal activation of microglia. Previous studies showed that the abnormal activation of microglia at the level of spinal cord was closely related to diabetic neuropathic pain, and microglia at the level of spinal cord played an important role in the transmission of pain. As the center of pain loop, the activity of microglia in cerebral cortex and thalamus is less related to diabetic neuropathic pain.

   Therefore, investigators used STZ induced diabetic neuropathy model of SD rats. Before STZ injection (0 week), at the 2nd, 4th, 6th and 12th week after STZ induced hyperglycemia. The investigators monitored the changes of body weight, blood glucose level and pain threshold of mechanical pain and thermal pain in rats. The investigators used [18F] dpa714 specific marker transfer protein TSPO to carry out PET / CT scan of brain to reflect microglia in each brain area. After PET / CT scan, EMG was used to evaluate the degree of peripheral nerve injury. The results showed that after STZ injection, compared with the control group, the blood glucose of STZ group increased gradually, and with the increase of blood glucose, the nerve conduction velocity of diabetic rats decreased gradually. Mechanical pain decreased significantly in 4-6 weeks, thermal pain threshold decreased significantly in 4 weeks, and mechanical pain and thermal pain sensitivity disappeared in 12 weeks. The results of PET / CT showed that in cortex, hippocampus, thalamus, hypothalamus and pituitary, dpa714 standard uptake value was significantly higher than other time points in the fourth week, and significantly higher than that in the control group. The correlation analysis indicated that the pain threshold of thermal pain was significantly related to the activity of microglia in thalamus and hypothalamus. Previous studies have shown that hyperglycemia can induce neuropathic pain. Thermal hyperalgesia occurs 4 weeks after hyperglycemia, while mechanical hyperalgesia occurs 4-6 weeks. PET / CT study showed that the activity of microglia in the brain of diabetic rats increased in the fourth week, and the activity of microglia was significantly related to the occurrence of heat pain. It has not been reported that the relationship between the activity of microglia and diabetic neuropathic pain was directly observed by PET / CT.

2. Liraglutide can regulate the activation of microglia Glucagon like peptide 1 (GLP-1) acts by binding to GLP-1 receptor, which is a G protein coupled receptor. A large number of studies have shown that GLP-1 receptor agonists can improve the activation of macrophages, microglia as macrophages in the brain, and GLP-1 receptor agonists can improve the activation of macrophages. However, few studies have shown that in vitro cultured astrocytes and microglia, GLP-1 analogues can change the morphology of glial cells, reduce IL-1 β and increase cAMP level at mRNA level.

   Therefore, liraglutide, the GLP-1 agonist, was selected as the intervention drug . BV2 microglia cell line was used as the following treatment methods: liraglutide was co cultured with LPS or high glucose, and liraglutide was added after LPS and high glucose induced activation. After treatment, the levels of IL-6 and TNF - α in the supernatant of the cells were observed. The results showed that liraglutide was added in advance before induction and activation. Or the level of IL-6 and TNF - α released by BV2 could be significantly reduced by using liraglutide. Therefore, liraglutide can regulate LPS and high glucose induced microglia activation.

3. Animal experiments show that liraglutide can improve diabetic neuropathic pain. On the basis of previous work, the investigators further studied the effect of liraglutide on diabetic neuropathic pain at the animal level. SD rats were divided into three groups: normal blood glucose group, normal saline control group and 200ug / kg / dliraglutide injection group. The latencies and thresholds of thermal and mechanical pain were monitored weekly. It was observed that for diabetic neuropathic pain rats, the peripheral injection of GLP-1 receptor agonist (liraglutide 200ug / kg / D) significantly increased the thermal pain threshold at 4 weeks, the mechanical pain threshold at 8 weeks, and the pain sensitivity disappeared at 12 weeks in both the normal saline control group and the liraglutide injection group.
4. Observation of clinical cases In clinical work, the investigators observed some obese patients with neuropathic pain in type 2 diabetes mellitus. In the process of using GLP-1 receptor agonist to control blood glucose, the symptoms of pain were also significantly improved. In addition, a clinical study showed that the use of sitagliptin (DPP-IV inhibitor, which can inhibit the degradation of GLP-1 in vivo) can also improve diabetic neuropathic pain. However, these observations and studies have significant limitations, not excluding the effect of blood glucose lowering itself in the population level, nor exploring the mechanism.

3. The clinical study of liraglutide in improving diabetic neuropathic pain has better clinical value.

The investigators found that liraglutide can improve the activation of microglia, and it can significantly alleviate diabetic neuropathic pain at the animal level and clinical cases. The systematic study of liraglutide used to improve neuropathic pain in diabetic patients has not been reported, and this subject has better clinical value.

Therefore, considering the hypoglycemic effect of liraglutide on the basis of previous studies, the investigators plan to select diabetic neuropathic pain patients whose blood sugar is not up to standard in this study, and give Mecobalamin (one of the commonly used drugs recommended in the guidelines for prevention and treatment of diabetes mellitus to treat neuropathy). At the same time, on the basis of the original hypoglycemic treatment, participants were randomly divided into one group to be given liraglutide and the other group to be increased/adjusted insulin. After 3 months, the improvement of diabetic neuropathic pain in the two groups under the condition of similar blood glucose level were observed. The purpose of this study was to evaluate the safety and efficacy of liraglutide in improving diabetic neuropathic pain.