| BackgroundWith the accelerated pace of life,the improvement of living standards and the increase in the pressure of life,the prevalence of diabetes(Diabetes Mellitus,DM)has increased year by year.It has become the world's recognized country with the largest increase in the number of people with diabetes.The number of diabetic patients in China accounts for about 25% of the total number of diabetes in the world.Diabetic Peripheral Neuropathy(DPN),as one of the most common ones of chronic complications of diabetes,has varied clinical manifestations and degrees of severity.DPN is characterized by numbness,cold,sensory disturbance,hypersensitivity and acupuncture-like pain of the limbs.DPN is mostly bilateral symmetry,and is often associated with diabetic angiopathy at the same time or there,severe can lead to diabetic lower extremity lesions,diabetic foot and even amputation risk.It has been the seriously threaten to the health and life safety of patients with diabetes mellitus.The DPN can promote the occurrence and development of other chronic complications of diabetes.At the same time,it is also one of the most common cause of repeated hospitalization and one of the important risk factors of diabetic foot.DPN is a serious threat to lives of patients.DPN is usually relatively insidious.When diabetic patients present the corresponding clinical symptoms,it is generally suggested that irreversible demyelination and other pathological changes have occurred in the peripheral nerve.The electrophysiological examination as the gold standard for the diagnosis of DPN,not only need to spend a lot of time and effort,but not easily carried out extensively in basic medical institutions.Its scope of application is relatively narrow.At present,the treatment of DPN is mainly based on the comprehensive treatment of internal medicine(inclding control blood glucose,antioxidant and nutritional nerve and so on).These treatments are costly and time-consuming,which results in a tremendous waste to our medical and health resources.Therefore,if the DPN can be found earlier,and was given a positive intervention measure,the risk of diabetic foot ulcers and amputations can achieve a significant reduction.It also can reduce the cost of medical expenses and improve patient's quality of life and disease.These advances have a very important significance prognosis in the comprehensive control and treatment of diabetes and DPN.The pathogenesis of DPN is not entirely clear,and now it is mainly related to the glucose metabolism,the vascular,immune,oxidative stress,neurotrophic factors and any other factors.In the long period of hyperglycemia,imbalance between oxidation system and antioxidant system(the mass production of free radical and the decreased ability of scavenging the free radical)lead to the formation of oxidative stress.Studies have shown that the administration of antioxidants to reduce the level of oxidative stress,can improve the nerve conduction velocity,and to achieve the purpose of treatment of DPN,and to reduce the oxidative stress levels.Reduced level of oxidative stress is also conducive to neuropathy repair.Nuclear transcription factor(Nuclear Factor-kappa B,NF-?B),originally is a nuclear protein factor found from B nuclear extracts,which is the pleiotropic regulator between many cell signaling pathways.It is mainly composed of five proteins,namely P50/P105(NF-?B 1),P52/ P100(NF-?B 2),P65(Rel A),Rel B and c-REL.And NF-?B exists mainly in the form of two aggregates in human cells and can specifically bind to DNA and participate in the transcription and expression of many genes such as inflammatory response,immune response,cell proliferation,differentiation and apoptosis.In the stationary state,NF-?B in the cytoplasm binds to its inhibitory protein due to the restriction of NF-?B,which is in the "no functional state".Only when it is activated by endotoxin,active oxide,cytokine,superoxide,mitogen and any other extracellular factors,the no functional NF-?B can transformedinto functional factors.The activated NF-?B enter the nucleus to regulate the gene transcription process of a large number of target genes,thus interfering with the cell growth and differentiation,apoptosis,necrosis and the occurrence of cancer.The protein encoded by target genes of NF-kappa B can mediate the body's inflammatory and immune response to regulate the proliferation,differentiation and apoptosis of immune cells,and plays an important role in this process.In recent years,there is many researches on NF-?B,and it has been found that it plays a crucial role in the development of autoimmune diseases,tumors,cardiovascular diseases and other related diseases,especially for the development of various chronic complications of diabetes.In the high glucose environment,the advanced glycation end products(Advanced Glycation End Products,AGEs)binding to its receptor RAGE,promoted phosphorylation and degradation of the NF-?B inhibitor,and activated the NF-?B.The activated NF-?B translocated into the nucleus,and then adjust the transcription process of the target gene.This process can lead to the upregulation of NF-kappa B expression,thereby contributing to the development and progression of diabetes-related complications.Studies have shown that NF-?B is not activated in the normal rat retina,but is activated in the diabetic retina,and the higher and longer of the blood sugar,the activity of NF-?B is higher.The animal experiments by Raja Sinniah showed that the activity of NF-?B increased 16-fold in diabetic rats which with large amounts of proteinuria.This result suggests that the activated NF-?B can accelerate the destruction process of renal interstitial cells.At present,the animal experiments have found that the level of peripheral blood NF-?B has been increased before the DPN.In diabetic neuropathy model of mice,by taking various modes of intervention to inhibit the NF-?B activity,the nerve conduction rate can be seen significantly improved.It concluded that NF-?B may play a certain role in the occurrence of DPN.And by inhibiting the activation of NF-?B pathway,and reducing the corresponding inflammatory response,it can antagonize the process of oxidative stress-mediated nerve,thereby slowing the progression of DPN.However,the above conclusions have not been confirmed in the clinical trials.In this study,we examined the relationship between the level of NF-?B and the development of DPN by observing the level of NF-?B in patients withdiabetic peripheral neuropathy or not,and found the new idea for the diagnosis of DPN.As the metabolic disease,the patients with diabetes often suffer from abnormal metabolism of vitamins.vitamin B1 plays an essential role in diabetes and its complications.Related animal studies have shown that vitamin B1 can prevent early diabetic nephropathy and urinary protein progression rate and also reduce the reduction of urinary protein excretion,which are both already confirmed in clinical studies.Beltramo and other scholars in the study of diabetic retinopathy found that vitamin B1 intervention can reverse the apoptosis of pericytes.Moreover,the cell apoptosis also indicates early diabetic retinopathy.Thus,there is a close relationship between vitamin B1,diabetes,and a variety of complications.Metabolic abnormalities from diabetes may be equally significant among diabetes,nephropathy and other micro-vascular lesions developments.Vitamin B1 can participate in nerve tissue repairing and signal regulation by the control of temperature hyperalgesia.This stressed the importance of vitamin B1 in the nerve activity.In the event of neurotoxicity,vitamin B1 can also reduce the concentration of reactive oxygen free radicals.In addition,since all vitamins are in the form of provitamin existing in the food or human body,because the body cannot synthesize vitamin B1 or insufficient synthesis,people must rely on everyday food supply.No studies have shown that high oral doses of vitamin B1 could cause severe adverse or toxic reactions,and we do know that excessive vitamin B1 can be metabolized by the kidneys in the form of urine and therefore eliminate the damage to the body.Based on this situation,we could say that 10 mg of oral vitamin B1 for diabetic patients is safe.Therefore,for the selected object,the supply of vitamin B1,could both ensure the normal metabolism of the body and supplement the deficiency.Although the level of NF-?B is generally high in diabetic patients,there are still very few studies related to DPN.Therefore,the purpose of this study is to analyze whether there is a difference in serum NF-?B and vitamin B1 levels between T2 DM with or without peripheral neuropathy,and then infer whether vitamin B1 and NF-?B level may be related.Next,through the supplement of exogenous vitamin B1,we plan to observe the changes in NF-?B levels and the corresponding nerve conductionvelocity,and observe the clinical effect of vitamin B1 on DPN.objective1.To explore the relationship between NF-?B and diabetes mellitus and peripheral neuropathy.2.To explore the relationship between vitamin B1 and diabetes and peripheral neuropathy.3.To explore the relationship and possible mechanisms between NF-?B and vitamin B1 in the development of diabetes and peripheral neuropathy.MethodsA total of 212 patients with type 2 diabetes mellitus who were hospitalized in the endocrine department from April 2015 to August 2016 were selected as the subjects.First,according to the clinical symptoms of peripheral neuropathy and neurological electrophysiological test results,the selected subjects were divided into diabetic peripheral neuropathy group(DPN group,that is,with clinical symptoms or neurophysiological examination results were positive,and except for previous history of lumbar spine),diabetic non-peripheral neuropathy group(DM group,that is,no clinical symptoms and nerve electrophysiological examination results were negative).A total of 100 normal healthy people(NC group,OGTT test results were negative)were randomly selected as the control group,which was comparable in the sex and age to the test group.Three groups of subjects were signed informed consent.The levels of NF-?B in peripheral blood were measured by enzyme-linked immune-sorbent assay(ELISA),and the content of vitamin B1 was determined by electro-chemi-luminescence method.The nerve conduction velocity was measured by neuro-physiological examination.The levels of NF-?B in the peripheral blood of the three groups were measured and the relationship between NF-?B and DPN was measured.The levels of serum creatinine vitamin B1,the relationship between vitamin B1 and DPN were analyzed.Then,DM group and DPN group were treated with vitamin B1,and all the selected subjects were given the same level of diet andexercise intensity.The original hypoglycemic regimen was maintained in DM group and DPN group,and the same blood glucose control level was maintained.The levels of NF-?B in peripheral blood were measured and the relationship between NF-?B level and DPN was observed before and after vitamin B1 intervention.The relationship between NF-?B and vitamin B1 was further investigated by the corresponding neurotransmission velocity.The changes of NF-?B level before and after treatment,and the therapeutic value of vitamin B1 on diabetic peripheral neuropathy,and find a more economical and effective method for the diagnosis and treatment of DPN.Results1.The difference of sex was not statistically significant in three groups(P>0.05).2.Before intervention of Vitamin B1,there were no significant differences in the indexes of age,BMI,SBP,DBP,TC,TG,LDL-C,HDL-C,MAlb / Cr among NC group,DM group and DPN group(P <0.05).But the three indicators of FPG,2hPG and HbA1 c showed the significant differences between DM group and DPN group(P<0.05).But there was no significant difference between DM group and DPN group(P> 0.05),which were analyzed by independent sample t test.It indicated the general measurement data between the two groups were comparable.3.Contrast of nerve conduction velocity before the intervention of vitamin B1Before intervention of vitamin B1,the motor nerve conduction velocity of left middle median nerve in NC group,DM group and DPN group were 50.24±6.61m/s,49.89±7.14m/s and 39.17±7.66m/s respectively before intervention of vitamin B1(P<0.01).Compared with NC group,the motor nerve conduction velocity of the left median nerve of DM group is slower,but there was no significant difference between the two groups(P> 0.05).The motor nerve conduction velocity of the left median nerve between the DM group and the DPN group was analyzed by independent sample t test.The result showed that the motor nerve conduction velocity of the left median nerve of DPN group was slower than that of DM group(P <0.05),which is consistent with the diagnostic criteria of DPN.Before intervention of Vitamin B1,the sensory nerve conduction velocity of the right sural nerve in NC group,DM group and DPN group were 49.13±6.27m/s,48.96±4.89m/s and 38.71±6.19m/s respectively(P <0.05).There was no significant difference in the sensory nerve conduction velocity of the right sural nerve between the NC group and DM group(P> 0.05).The sensory nerve conduction velocity of the right sural nerve between the DM group and the DPN group was analyzed by independent sample t test.The result showed that the sensory nerve conduction velocity of the right sural nerve of DPN group was slower than that of DM group(P<0.05),which is consistent with the diagnostic criteria of DPN.4.Contrast of the levels of NF-?B in the serum of the three groups before the intervention of vitamin B1Before the intervention of vitamin B1,the levels of serum NF-?B in NC group,DM group and DPN group were 595.18±145.74 pg/ml,641.24±139.20 pg/ml and857.47±162.09 pg/ml respectively.The levels of serum NF-?B in NC group,DM group and DPN group were significantly different(P<0.01)(analyzed by one-way ANOVA).The levels of serum NF-?B between the NC group and the DM group were analyzed by the independent sample t test.Compared with NC group,the levels of serum NF-?B in DM group is significantly higher(P<0.05).Compared with DM group,the levels of serum NF-?B in DPN group is significantly higher(P< 0.05).5.Contrast of the levels of Vitamin B1 in the serum of the three groups before the intervention of vitamin B1Before the intervention of vitamin B1,the levels of serum vitamin B1 in NC group,DM group and DPN group were 90.56±11.29nmol/L,58.72±10.98nmol/L and49.09±7.65nmol/L respectively.The levels of serum vitamin B1 in NC group,DM group and DPN group were significantly different(P <0.01)(analyzed by one-way ANOVA).The levels of serum vitamin B1 between the NC group and the DM group were analyzed by the independent sample t test.Compared with NC group,the levels of serum vitamin B1 in DM group is significantly lower(P<0.05).Compared with DM group,the levels of serum vitamin B1 in DPN group is significantly lower(P<0.05).6.Before and after the intervention of vitamin B1,The levels of FPG,2hPG,HbA1 c,NF-?B,vitamin B1 and the nerve conduction velocity in three groupsAfter the intervention of Vitamin B1,The FPG in DM group and DPN group were7.19±1.03mmol/L and 7.22±0.98mmol/L respectively,2hPG were 8.12±1.61mmol/L and 8.34±1.92mmol/L respectively,and HbA1 c were 7.08±0.79% and 7.11±1.04%respectively.Relative index of blood glucose between DM group and DPN group were no significant differences(P>0.05)which were analyzed by the independent sample t test.This result indicated that the levels of blood glucose between DM group and DPN group were good and comparable.Before and after the intervention of vitamin B1,the index of FPG,2hPG and HbA1 c were analyzed by the paired t test.There were no significant differences before and after the intervention of vitamin B1 in the index of FPG,2hPG and HbA1 c respectively(P> 0.05).After the intervention of vitamin B1,The levels of NF-?B in DM group and DPN group were 611.53±89.42 pg/ml and 769.53±62.17 pg/ml respectively.The levels of NF-?B between DM group and DPN group significantly different(P<0.05)which were analyzed by the independent sample t test.Before and after the intervention of vitamin B1,The levels of NF-?B were analyzed by the paired t test.The results showed that the level of NF-?B decreased after vitamin B1 intervention,and the difference was statistically significant(P<0.05).After the intervention of vitamin B1,The levels of vitamin B1 in DM group and DPN group were 77.02±8.71nmol/L and 67.31±5.48 nmol/L respectively.The levels of vitamin B1 between DM group and DPN group were analyzed by the independent sample t test.Compared with DM group,the level of serum vitamin B1 in DPN group is significantly lower(P< 0.05).Before and after the intervention of vitamin B1,The levels of vitamin B1 were analyzed by the paired t test.The results showed that the level of vitamin B1 increased after vitamin B1 intervention,and the difference were statistically significant(P <0.05).After the intervention of vitamin B1,the motor nerve conduction velocity of left middle median nerve between DM group and DPN group were 49.72±8.62m/s and44.78±11.46m/s respectively,and the sensory nerve conduction velocity of right sural nerve was 49.13±6.19 m/s and 43.11±10.84 m/s.The two groups of nerves were analyzed by independent sample t test.The results showed that the nerve conductionvelocity of DPN group was slower than that of DM group(P<0.05),which is consistent with the DPN diagnostic criteria.In DM group,through the left median nerve motor nerve conduction velocity and right sural nerve sensory nerve conduction velocity have become faster than after the intervention of vitamin B1,there was no statistically significant after the intervention of vitamin B1(P> 0.05).In DPN group,through the left median nerve motor nerve conduction velocity and right sural nerve sensory nerve conduction velocity have become faster than after the intervention of vitamin B1,there was no statistically significant after the intervention of vitamin B1(P> 0.05).7.Before and after the intervention of vitamin B1,the relevance between the levels of NF-?B/vitamin B1 in the peripheral blood and the nerve conduction velocityBefore the intervention of vitamin B1,the level of NF-?B in the peripheral blood was negatively correlated with the nerve conduction velocity(r=-0.579,P<0.05),and the content of vitamin B1 in peripheral blood was positively correlated with the nerve conduction velocity(r=0.812,P=0.011 <0.05).The relationship between the level of NF-?B /vitamin B1 and the nerve conduction velocity were analyzed by correlation analysis.After the intervention of vitamin B1,the level of NF-?B in peripheral blood was significantly decreased(P<0.05)under the same condition that blood glucose and other factors were not obvious changed.Therefore,we can consider that there is a certain degree of correlation between the content of vitamin B1 and the level of NF-?B.After the intervention of exogenous vitamin B1,the nerve conduction velocity improved significantly in the patients of DPN group,and the level of NF-?B decreased significantly.So,it can be inferred that vitamin B1 can affect the activity of NF-?B to a certain extent and promote the treatment of DPN.Conclusions1.The concentration of NF-?B in peripheral blood can reflect the severity of neuropathy in DPN patients,and provide a new idea for the diagnosis and treatment of DPN.2.Vitamin B1 has a certain degree of prevention and improvement on DPN.3.The content of Vitamin B1 and the level of NF-?B have a negative correlation.At a certain extent,the content of vitamin B1 can inhibit the activity of NF-?B,reduce the level of oxidative stress,improve the nerve conduction velocity,and thus achieve the purpose of the treatment of DPN. |
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