Diabetic neuropathic pain (DNP) is the most common disabling complication of diabetes. Emerging evidence has linked the pathogenesis of DNP to the aberrant sprouting of sensory axons into the epidermal area; however, the underlying molecular events remain poorly understood. Here we found that an axon guidance molecule, Netrin-3 (Ntn-3), was expressed in the sensory neurons of mouse dorsal root ganglia (DRGs), and downregulation of Ntn-3 expression was highly correlated with the severity of DNP in a diabetic mouse model. Genetic ablation of Ntn-3 increased the intra-epidermal sprouting of sensory axons and worsened the DNP in diabetic mice. In contrast, the elevation of Ntn-3 levels in DRGs significantly inhibited the intra-epidermal axon sprouting and alleviated DNP in diabetic mice. In conclusion, our studies identified Ntn-3 as an important regulator of DNP pathogenesis by gating the aberrant sprouting of sensory axons, indicating that Ntn-3 is a potential druggable target for DNP treatment.
Mice ; Animals ; Diabetes Mellitus, Experimental/metabolism* ; Axons/physiology* ; Diabetic Neuropathies ; Sensory Receptor Cells/metabolism* ; Neuralgia/metabolism*

Diabetic peripheral neuropathy (DPN) is one of the chronic complications of diabetic neuropathy, and also the main cause of chronic wounds and disability. Exosomes and exosomal-microRNAs (miRNAs) are closely related to DPN and participate in the signal transduction and protein expression of the peripheral nervous system by mediating intercellular communication. However, the specific role and mechanism of EVs and exosomal-miRNAs in the occurrence and development of DPN in high-glucose environments are not fully understood. This article reviews the promotion of EVs and exosomal-miRNAs in the occurrence and development of DPN in inhibiting axon growth, promoting inflammatory response, and inducing vascular injury in a high glucose environment.
Humans ; MicroRNAs/genetics* ; Exosomes/metabolism* ; Diabetic Neuropathies/metabolism* ; Signal Transduction ; Glucose/metabolism* ; Diabetes Mellitus

Diabetic peripheral neuropathy (DPN) is one of the chronic complications of diabetic neuropathy, and also the main cause of chronic wounds and disability. Exosomes and exosomal-microRNAs (miRNAs) are closely related to DPN and participate in the signal transduction and protein expression of the peripheral nervous system by mediating intercellular communication. However, the specific role and mechanism of EVs and exosomal-miRNAs in the occurrence and development of DPN in high-glucose environments are not fully understood. This article reviews the promotion of EVs and exosomal-miRNAs in the occurrence and development of DPN in inhibiting axon growth, promoting inflammatory response, and inducing vascular injury in a high glucose environment.
Humans ; MicroRNAs/genetics* ; Exosomes/metabolism* ; Diabetic Neuropathies/metabolism* ; Signal Transduction ; Glucose/metabolism* ; Diabetes Mellitus

Involvement of the peripheral nerveous system by diabetes is referred to as diabetic neuropathy. The frequency of diabetic neuropathy ranges from 5% to 60% and the pain management is one of the greatest problem. The patient was a 57-year-old man who has been treated with diabetes(DM type IIa) for about 12 years. The symmetrical pain, swelling and sensory loss on feet were started 3 months before admission and the burning pain was intensified at night with resultant insomnia. The systoms were aggravated 1 month ago and they were not relieved by any medication and physical therapy. We attempted lumbar epidural block to the patient and the result was good. So we performed a permanent lumbar sympathetic ganglion block with neurolytics(99.9% alcohol) for the long term relief of pain. The patient was satisfied with the result of the block and discharged.
Burns ; Diabetic Neuropathies* ; Foot ; Ganglia, Sympathetic ; Humans ; Metabolism ; Middle Aged ; Pain Management* ; Sleep Initiation and Maintenance Disorders ; Sympathetic Nervous System

OBJECTIVETo investigate the relationship between diabetes and somatostatin (SOM).

METHODSWe established a streptozocin-induced diabetic rats model and studied the changes of SOM mRNA in hippocampi of diabetic and normal rats by using in situ hybridication and computer image analysis. We studied the mechanism of chronic diabetes encephalopathy by observing the changes of somatostatin mRNA in the hippocampus of diabetic rats was studied.

RESULTThe number, light density and average area of positive cells in dentate gyrus area of hippocampus in diabetes model were reduced significantly as compared with normal rats (P < 0.01).

CONCLUSIONA decline in SOM mRNA expression may play a role in chronic diabetes encephalopathy because of SOM effect in brain.

Animals ; Brain Diseases ; etiology ; metabolism ; Dentate Gyrus ; metabolism ; Diabetes Mellitus, Experimental ; metabolism ; Diabetic Neuropathies ; metabolism ; Hippocampus ; metabolism ; Male ; RNA, Messenger ; biosynthesis ; Rats ; Rats, Sprague-Dawley ; Somatostatin ; biosynthesis ; genetics

OBJECTIVES: This study examined the effect of cilostazol, a potent phosphodiesterase inhibitor, on the progression of neuropathies associated with streptozotocin-induced diabetes mellitus in Sprague-Dawley rats. METHODS: Eight weeks after streptozotocin treatment, a pelleted diet containing 0.03% cilostazol (15 mg/kg body weight) was given for four weeks. Body weight, blood glucose level, motor nerve conduction velocity (MNCV), myelinated fiber density and size distribution of sciatic nerves were compared between age-matched normal rats (Group 1), control diabetic rats (Group 2) and cilostazol-treated diabetic rats (Group 3). RESULTS: Body weight was significantly reduced and blood glucose level was significantly increased in diabetic rats (Group 2 and 3) compared to normal rats. MNCV and cAMP content of sciatic nerves were significantly reduced in diabetic rats 12 weeks after streptozotocin treatment. Myelinated fiber size and density were also significantly reduced, and thickening of the capillary walls and duplication of the basement membranes of the endoneural vessels were observed in the diabetic rats. Whereas both body weight and blood glucose level of Group 3 did not differ significantly from those of Group 2, cilostazol treatment significantly increased MNCV and cAMP content of sciatic nerves in Group 3 but not to the levels observed in Group 1. MNCV positively correlated with cAMP content of sciatic nerves (r = 0.86; p < 0.001). Cilostazol treatment not only restored myelinated fiber density and size distribution but reversed some of the vascular abnormalities. CONCLUSION: These findings suggest that a reduced cAMP content in motor nerves may be involved in the development of diabetic neuropathy, and that cilostazol may prevent the progression of diabetic neuropathy by restoring functional impairment and morphological changes of peripheral nerves.
Animal ; Cyclic AMP/metabolism ; Diabetes Mellitus, Experimental/physiopathology ; Diabetes Mellitus, Experimental/drug therapy ; Diabetic Neuropathies/prevention & control* ; Diabetic Neuropathies/physiopathology ; Diabetic Neuropathies/pathology ; Male ; Neural Conduction/drug effects ; Phosphodiesterase Inhibitors/pharmacology* ; Rats ; Rats, Sprague-Dawley ; Sciatic Nerve/physiopathology ; Sciatic Nerve/pathology ; Sciatic Nerve/drug effects ; Tetrazoles/pharmacology*

BACKGROUNDWith economic growth and urbanization there have been significant changes in the life style and diet of urban residents in large cities of China, which is experiencing a rapid increase in the prevalence of diabetes. While high prevalence of diabetes has been reported, little is known of the long-term effects of diabetes in such a large population. The aim of this study was to estimate the morbidity rate of diabetic peripheral neuropathy (DPN) in a Chinese urban diabetic population with more than 10 years' disease duration, and evaluate the relevant risk factors. The clinical manifestation of DPN and pain status was also assessed.

METHODSFive hundred and sixty-five diabetes patients were recruited into the study. Symptoms and examination helped diagnose neuropathy. The clinical manifestation of DPN was assessed with a visual analog pain score (VAS). Diabetic complication status was determined from medical records. Serum lipids and lipoproteins, glycosylated hemoglobin (HbA1c), and the urinary albumin excretion rate were measured.

RESULTSThe morbidity rate of DPN was 46.6%. HbA1c, hyperlipidemia, and retinopathy were significantly associated with neuropathy, and these risk factors were correlated with other diabetic micro and/or macrovascular complications. The average VAS pain score of the DPN patients was 4.12 ± 2.07. Severe and moderate pain was experienced by 11.4% and 40.5% respectively of DPN patients. About 3.7% of diabetic subjects had lower limb ulcer or amputation.

CONCLUSIONSThe morbidity rate of DPN for diabetic patients with > 10 years duration is very high compared to the range reported for other populations in the world. The risk factors for DPN include HbA1c, hyperlipidemia, and retinopathy. In long-standing diabetic patients, DPN was not associated with diabetic duration, and half of the DPN patients experienced considerable daily suffering.

Aged ; China ; Diabetic Neuropathies ; epidemiology ; metabolism ; physiopathology ; Female ; Glycated Hemoglobin A ; metabolism ; Humans ; Hyperlipidemias ; epidemiology ; metabolism ; physiopathology ; Male ; Middle Aged ; Pain ; etiology ; Risk Factors ; Urban Population

PURPOSE: We previously reported that insulin resistance, low high-density lipoprotein (HDL) cholesterol, and glycaemic exposure Index are independently associated with peripheral neuropathy in Korean patients with type 2 diabetes mellitus. We followed the patients who participated in that study in 2006 for another 6 years to determine the relationship between insulin resistance and neuropathy. MATERIALS AND METHODS: This study involved 48 of the original 86 Korean patients with type 2 diabetes mellitus who were referred to the Neurology clinic for the assessment of diabetic neuropathy from January 2006 to December 2006. These 48 patients received management for glycaemic control and prevention of diabetic complications in the outpatient clinic up to 2012. We reviewed blood test results and the nerve conduction study findings of these patients, taken over a 6-year period. RESULTS: Low HDL cholesterol and high triglycerides significantly influenced the development of diabetic neuropathy. Kitt value (1/insulin resistance) in the previous study affected the occurrence of neuropathy, despite adequate glycaemic control with HbA1c <7%. Insulin resistance affected the development of diabetic neuropathy after 6 years: insulin resistance in 2006 showed a positive correlation with a change in sural sensory nerve action potential in 2012. CONCLUSION: Diabetic neuropathy can be affected by previous insulin resistance despite regular glycaemic control. Dyslipidaemia should be controlled in patients who show high insulin resistance because HDL cholesterol and triglycerides are strongly correlated with later development of diabetic neuropathy.
Adult ; Diabetes Mellitus, Type 2/*metabolism/*physiopathology ; Diabetic Neuropathies/*metabolism/*physiopathology ; Female ; Humans ; Insulin Resistance/*physiology ; Logistic Models ; Male ; Middle Aged

Nerve growth factor(NGF) is closely ralated to the occurrence and development of diabetic peripheral neuropathy (DPN). Traditional Chinese medicine has certain effects on the promotion of NGF expression. It analyzes the relationship of NGF and DPN and the effects of Traditional Chinese Medicine on them as well as the existing problems and looks into the future research in this domain.
Animals ; Diabetic Neuropathies ; drug therapy ; genetics ; metabolism ; Drugs, Chinese Herbal ; therapeutic use ; Gene Expression ; drug effects ; Humans ; Nerve Growth Factor ; genetics ; metabolism

AIMTo study the role of oxidative stress in the initiation and development of diabetic neuropathy.

METHODSThe diabetic rats were induced with streptozotocin (STZ). The malondialdehyde (MDA) level, total superoxide dismutase (SOD) and Na(+) -K(+) -ATPase activity were measured in the sciatic nerves at various stages of diabetes. The correlation of the MDA level and Na(+) -K(+) -ATPase activity was analyzed in diabetic rats. The pathological changes of sciatic nerve at diabetic various stages were examined by light microscopy.

RESULTSThe MDA level increased significantly in diabetic sciatic nerves as compared to controls at all time intervals. Total SOD activity increased significantly in diabetic sciatic nerves as compared to controls at one month of diabetes and progressively decreased at three/six months of diabetes. Na(+) -K(+) -ATPase activity progressively decreased at three/six months of diabetes. The correlation analysis indicated that the Na(+) -K(+) -ATPase activity was negative correlation with the MDA level in the diabetic rats. Histopathological study of the diabetic sciatic nerves showed that the pathological changes were observed at 3 months of diabetes, the changes were more serious as the diabetic duration was longer.

CONCLUSIONOxidative stress is found to occur during the early stages of STZ-induced diabetes (no neuropathy) and this state is maintained after initiation of neuropathy. The decreased Na(+) -K(+) -ATPase activity is associated with oxidative stress in the diabetic rats. Therefore, oxidative stress plays an important role in the initiation and development of diabetic neuropathy.

Animals ; Diabetes Mellitus, Experimental ; physiopathology ; Diabetic Neuropathies ; physiopathology ; Male ; Oxidative Stress ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Sciatic Nerve ; enzymology ; Sodium-Potassium-Exchanging ATPase ; metabolism ; Superoxide Dismutase ; metabolism