• <tr id="yyy80"></tr>
  • <sup id="yyy80"></sup>
  • <tfoot id="yyy80"><noscript id="yyy80"></noscript></tfoot>
  • 99热精品在线国产_美女午夜性视频免费_国产精品国产高清国产av_av欧美777_自拍偷自拍亚洲精品老妇_亚洲熟女精品中文字幕_www日本黄色视频网_国产精品野战在线观看 ?

    HLA class II alleles and risk for peripheral neuropathy in type 2 diabetes patients

    2016-02-09 05:17:22AhmadMarzbanJavadKianiMehrdadHajilooiHamzehRezaeiZohrehKahramfarGhasemSolgiDivisionofEndocrinologyDepartmentofInternalMedicineSchoolofMedicineHamadanUniversityofMedicalSciencesHamadanIranDepartmentofImmunologySchoolofMedi

    Ahmad Marzban, Javad Kiani, Mehrdad Hajilooi, Hamzeh Rezaei, Zohreh Kahramfar, Ghasem Solgi, Division of Endocrinology, Department of Internal Medicine, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran Department of Immunology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran3 Psoriasis Research Center, Department of Dermatology, Farshchian Hospital, Hamadan University of Medical Sciences, Hamadan, Iran

    HLA class II alleles and risk for peripheral neuropathy in type 2 diabetes patients

    Ahmad Marzban1, Javad Kiani1, Mehrdad Hajilooi2, Hamzeh Rezaei2, Zohreh Kahramfar1, Ghasem Solgi2,3,*
    1 Division of Endocrinology, Department of Internal Medicine, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
    2 Department of Immunology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
    3 Psoriasis Research Center, Department of Dermatology, Farshchian Hospital, Hamadan University of Medical Sciences, Hamadan, Iran

    How to cite this article:Marzban A, Kiani J, Hajilooi M, Rezaei H, Kahramfar Z, Solgi G (2016) HLA class II alleles and risk for peripheral neuropathy in type 2 diabetes patients. Neural Regen Res 11(11):1839-1844.

    Open access statement:This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

    Funding:This study was funded by Vice-chancellor for Research and Technology, Hamadan University of Medical Sciences of Iran, No. 9208072467.

    The potential impact of human leukocyte antigen (HLA) genotype variations on development of diabetic peripheral neuropathy (DPN) is not well determined. This study aimed to identify the association of HLA class II alleles with DPN in type 2 diabetes (T2D) patients. Totally 106 T2D patients, 49 with DPN and 57 without DPN, and 100 ethnic-matched healthy controls were analyzed. Both groups of the patients were matched based on sex, age, body mass index (BMI) and duration of T2D. Polyneuropathy was diagnosed using electrodiagnostic methods. HLA-DRB1 and DQB1 genotyping was performed in all subjects by the polymerase chain reaction with sequence-specific primers (PCR-SSP) method. T2D patients with DPN showed higher frequencies of HLA-DRB1*10 and DRB1*12 alleles compared to control group (P= 0.04). HLA-DQB1*02 allele and HLA-DRB1*07-DQB1*02 haplotype were associated with a decreased risk for developing DPN in T2D patients (P= 0.02 andP= 0.05 respectively). Also, patients with severe neuropathy showed higher frequencies of DRB1*07 (P= 0.003) and DQB1*02 (P= 0.02) alleles than those with mild-to-moderate form of neuropathy. The distribution of DRB1 and DQB1 alleles and haplotypes were not statistically different between all patients and healthy controls. Our findings implicate a possible protective role of HLA-DQB1*02 allele and HLA-DRB1*07-DQB1*02 haplotype against development of peripheral neuropathy in T2D patients. Therefore, variations in HLA genotypes might be used as genetic markers for prediction and potentially management of neuropathy in T2D patients.

    nerve regeneration; HLA-DRB1; HLA-DQB1; alleles; genotypes; haplotypes; peripheral neuropathy; type 2 diabetes; neural regeneration

    Introduction

    Neuropathy is one of the most common devastating complications of diabetes and is associated with significant morbidity, mortality and diminished quality of life (Boulton et al., 2005; Tesfaye, 2011). Pathogenesis of diabetic neuropathy has not been understood completely, and several hypotheses have been proposed for this microvascular complication in diabetic patients (Greene et al., 1992; AI, 2004). Poor glycemic control plays an important role in the development of peripheral nerve damage (Boulton et al., 1984) and molecular studies have implicated the sequential events for progression of neuropathy and recognized several key players including protein kinase C, advanced glycation end products, aldose reductase, polyol and hexosamine pathways (Balakumar et al., 2009; Wellen et al., 2010).

    The pattern and presentation of clinical diabetic neuropathy depend on various factors like duration of hyperglycemia, dyslipidemia, hypertension, smoking, increased height and exposure to other neurotoxic agents such as ethanol (Feldman et al., 1997). But, the role of genetic predisposition for this diabetic microvascular complication is uncertain and it is unclear whether the genetic factors increase the susceptibility of diabetic patients to develop neuropathy (Boulton et al., 1984). While the role of human leukocyte antigens (HLA) in pathogenesis of type 1 diabetes has been clearly established (Kiani et al., 2015), its exact role in type 2 diabetes (T2D) is less clear.

    The prevalence of HLA class II alleles and haplotypes among T2D patients have been reported in few studies but with inconsistent results (Tuomi et al., 1993; Turner et al., 1997; Motala et al., 2005; Almawi et al., 2006). Although, other aspects of T2D in relation to HLA class II genes, such as autoimmune markers (anti-GAD antibody), latent autoimmune diabetes in adults, genetic interaction between type 1 and type 2 diabetes and somewhat microvascular complications have been investigated partially (Tuomi et al., 1993; Turner et al., 1997). Nevertheless, the contribution of HLA genes in development of post diabetic complications particularly peripheral neuropathy in T2D patients remains unclear. Because of the lack of consistent data in this regard,the present study was conducted to explore whether the HLA-DRB1 and DQB1 alleles and DR-DQ haplotypes are associated with diabetic peripheral neuropathy (DPN) in patients with T2D.

    Subjects and Methods

    Subjects

    This case-control study was carried out on 106 unrelated patients with T2D (49 with DPN and 57 without DPN) who referred to outpatient diabetes clinic of Hamadan University of Medical Sciences, Iran between March 2011 and September 2013. Type 2 diabetes was defined according to the American Diabetes Association Diagnostic Criteria (American Diabetes, 2016). Patients with any of the following conditions were excluded from the study: age < 30 and over 70 years, other causes of peripheral neuropathy, use of any neurotoxic drugs like chemotherapeutic agents, history of renal or hepatic dysfunction, and alcohol abuse. All subjects completed a questionnaire consisting of general information, duration of diabetes, type of medication and history of foot ulcer and smoking status. Then, the height, weight and blood pressure for all of the study subjects were recorded. Also, 100 ethnic- and gender-matched healthy subjects with no clinical evidence or family history of T2D were enrolled among blood donors who referred to Blood Transfusion Organization as control group. The mean ages of T2D patients and control groups were 55.8 ± 6.7 years and 45.3 ± 10.6 years respectively. Also, the female-to-male ratios were 44/62 in the patients and 41/59 in the controls. The written informed consents were obtained from all study subjects, and the study protocol was approved by ethics committee, Vice-Chancellor for Research and Technology, Hamadan University of Medical Sciences, Iran, No. 16.35.9.121.

    Screening and diagnosis of DPN

    Neuropathy Symptom Score (NSS) and Neuropathy Disability Score (NDS) criteria were used for the screening of diabetic neuropathy (Young et al., 1986; Meijer et al., 2003). NSS questionnaire included questions regarding the type of sensation, time of symptoms, location of symptoms, waking up from sleep and factors that relieve symptoms. NDS consisted of neurologic examination parameters such as ankle reflex and perceptions of pinprick, cold and vibration. Each parameter takes a score from 0 to 2. The criteria for the existence of DPN were an NDS score of at least 6.0 irrespective of NSS score, or an NDS score of 3–5 in combination with an NSS score of at least 5.0 (Cabezas-Cerrato, 1998) . Nerve conduction measurements (Sierra II Wedge EMG/NCV/EP Instrument from Cadwell, 909 N. Kellogg Street, Kennewick, Washington 99336, USA) including amplitude, conduction velocity, and latency were carried out on sural, peroneal, and tibial nerves in lower limbs. The obtained values were compared with normal values (GS, 2008). Diagnosis of DPN was based on the recommended protocol (GS, 2008) so that, the case definition criterion for confirmation of DPN was an abnormality (≥ 99thor ≤ 1stpercentile) of any attribute of nerve conduction in two separate nerves, one of which must be the sural nerve (England et al., 2005). The severity of DPN was assessed by a combination of neuropathy symptoms, signs and nerve conduction abnormalities as mild, moderate and severe (Tesfaye et al., 2010).

    HLA-DRB1 and DQB1 genotyping

    Genomic DNA extraction from venous peripheral blood samples was performed by using a modified salting out method (Kiani et al., 2015). Thereafter, HLA genotyping was done by PCR with sequence specific primers using commercial low resolution HLA DR-DQ SSP kits (Olerup SSP?DQDR SSP Combi Tray, Stockholm, Sweden) based on the manufacture’s instructions. Following PCR amplification, the whole volume (10 μL) of PCR products was runned on a 2.0% agarose gel electrophoresis, stained with ethidium bromide and specific bands were visualized by UV transilluminator. Detection of specific HLA-DRB1 and HLA-DQB1 alleles were executed by SCORE software (Olerup SSP?DQ-DR SSP Combi Tray, Stockholm, Sweden). In addition, different DRB1-DQB1 haplotypes were assigned based on known HLA-DRB1 and DQB1 linkage disequilibrium in Caucasians as well as European populations using an Expectation-Maximization (EM) Algorithm as implemented in the R statistical computing environment (http://www.R-project.org).

    Statistical analysis

    The frequencies of HLA-DRB1 and DQB1 alleles and deduced DR-DQ haplotypes were calculated by direct counting of HLA phenotypes. Then, allele and haplotype frequencies were compared between the patients and controls using chisquare analysis with Yates’ correction or two-tailed Fisher’s exact test where appropriate. The risks contributed by alleles and deduced haplotypes were assessed by calculation of relative risk (RR) with 95% confidence intervals (CIs). Logistic regression analysis was implemented to determine the association between risky alleles and haplotypes and development of T2D neuropathy. Also, paired Student’st-test was performed to analyze quantitative data between the study’s groups. All of the calculations were done by using the SPSS v.16.0 for Windows and probability values less than 0.05 were considered as statistically significant.

    Results

    Forty-nine T2D patients with DPN and 57 patients without DPN as well as 100 ethnic-matched healthy controls were studied in this cohort. The demographics and clinical characteristics including sex, age, age at T2D diagnosis, treatment status, body mass index (BMI), serum creatinine and hemoglobin A1C (HbA1C) levels, hypertension and diastolic and systolic blood pressure are summarized inTable 1. The mean serum creatinine levels, HbA1C contents and BMI were significantly increased in patient groups compared to healthy controls (Table 1). Peripheral neuropathy was diagnosed by using electrodiagnostic methods.

    HLA-DRB1 and DQB1 allele and haplotype frequencies

    Distribution of HLA-DRB1 alleles were not statisticallydifferent between two groups of the patients but were comparable with healthy controls, and T2D patients with DPN showed higher significant frequencies of HLA-DRB1*10 and DRB1*12 alleles (P= 0.04;Table 2). HLA-DQB1*02 allele was more frequent in patients without DPN than in those with DPN (P= 0.04;Table 3). Haplotype analysis revealed a lower frequency of HLA-DRB1*07-DQB1*02 haplotype in patients with DPN than those without DPN (P= 0.05;Table 4). After adjusting covariates like age, age at diagnosis, duration of disease and BMI, logistic regression analysis revealedthat HLA-DQB1*02 allele and HLA-DRB1*07-DQB1*02 haplotype were significantly associated with DPN (P= 0.04 andP= 0.03, respectively;Table 5). Also, distribution of HLA alleles among T2D patients according to the severity of neuropathy revealed a higher frequencies of DRB1*07 and DQB1*02 alleles in patients with severe neuropathy than in those with mild-to-moderate neuropathy (P= 0.003 andP= 0.02, respectively;Tables 6,7). However, the HLA-DRB1 and DQB1 allele and haplotype frequencies were not statistically different between all patients and healthy controls. Although T2D patients showed higher and lower frequencies of HLA-DRB1*12 and DRB1*14 alleles respectively compared to healthy controls but, it was not statistically significant (Table 2).

    Table 1 Demographics and some of clinical characteristics of the study subjects

    Table 2 Distribution of HLA-DRB1 alleles in patients with and without diabetic peripheral neuropathy (DPN) and healthy controls

    Table 3 Distribution of HLA-DQB1 alleles in patients with and without diabetic peripheral neuropathy (DPN) and healthy controls

    Table 4 Distribution of the most frequent HLA-DRB1-DQB1 haplotypes among both groups of the patients and healthy controls

    Table 5 Logistic regression model for association between human leukocyte antigen (HLA) and diabetic peripheral neuropathy (DPN) in T2D patients

    Table 7 Distribution of HLA-DQB1 alleles among patients with diabetic peripheral neuropathy (DPN) according to severity of neuropathy

    Table 6 Distribution of HLA-DRB1 alleles among patients with diabetic peripheral neuropathy (DPN) according to severity of neuropathy

    Discussion

    Diabetic neuropathies are clinically classified to symmetrical and asymmetrical neuropathies and distal symmetrical peripheral neuropathy is the commonest form of these post-diabetes microvascular complications (Bansal et al., 2006). Nerve biopsy examinations revealed that besides the metabolic changes and ischemic injury, perivascular infiltration and immunological abnormality could be observed in these pathological conditions. Chronic inflammatory demeylinating polyneuropathy has been confirmed in twoclinical forms of diabetic neuropathies (Bansal et al., 2006). Moreover, glutamic acid decarboxylase (GAD) antibodies and latent autoimmune diabetes have been found in some of T2D patients (Tuomi et al., 1993; Turner et al., 1997). Genetic determinants particularly those involved in the affected metabolic pathway have been reported to be attributed in the pathogenesis of T2D and subsequent microvascular complications (Bansal et al., 2006; Ma et al., 2013; Brunetti et al., 2014). Disease heterogeneity in type 2 diabetes may influence the susceptibility to diabetic complications (Forsblom et al., 1998).

    The role of HLA alleles in pathogenesis of T2D and its subsequent complications is less clear and their association is still contradictory and elusive because of very limited studies on HLA-T2D relationship (Ma et al., 2013). To investigate the possible correlation between HLA class II alleles and peripheral neuropathy in a group of Iranian T2D patients, we analyzed the distribution of HLA-DRB1 and DQB1 alleles and DRB1-DQB1 haplotypes in two groups of patients (with or without DPN) as well as in ethnic -matched healthy controls.

    Our findings demonstrated a negative association between HLA-DQB1*02 allele and HLA-DRB1*07-DQB1*02 haplotype with DPN in type 2 diabetes patients. Also, we observed that HLA-DRB1*07 and DQB1*02 alleles were associated with severe form of peripheral neuropathy. Comparison of all patients and healthy controls did not show statistical differences for either HLA alleles or HLA haplotypes but, the patients with DPN separately showed higher significant frequencies of HLA-DRB1*10 and DRB1*12 alleles than controls.

    In contrast to our results, Boulton et al. (1984) and Scheinin et al. (1988) did not find any association between DPN and HLA-A, -B, -C and DR alleles among type 1 and type 2 diabetes patients, whereas, a study by Brazilay et al. (1992) depicted a direct association between HLA-DRB1*03 and DRB1*04 alleles and cardiovascular autonomic neuropathy in T1D patients. In this regard, our results showed higher and lower but insignificant frequencies of DRB1*04 and DRB1*03 alleles respectively in patients with DPN compared to those without DPN. Two studies on T2D patients showed the protective and susceptible roles of DQB1*05:01 allele for diabetic nephropathy respectively (Perez-Luque et al., 2000; Ma et al., 2013). Additionally, Ma et al (2013). demonstrated that DQA1*03:01 and 05:01 alleles are directly associated with nephropathy in T2D patients, while Perez-Luque et al. showed a positive and negative association for DRB1*15:02 and DRB1*04:07 alleles with diabetic nephropathy respectively.

    To our knowledge, the present study is the first report on potentially protective role of HLA-DQB1*02 allele and HLADRB1*07-DQB1*02 haplotype against peripheral neuropathy in T2D patients. Because of the paucity and inconsistent data regarding HLA and T2D microvascular complications particularly neuropathy, our results should be interpreted with caution and further investigations using larger cohorts and preferentially with focus on underlying mechanisms are warranted. However, the genetic factors including HLA alleles are only one of the possible contributing factors for development and progression of peripheral neuropathy and more importantly, elucidating the exact role of HLA molecules in susceptibility/protection for diabetic peripheral neuropathy remains undefined and has proved challenging.

    Comparison of the frequencies of HLA alleles and haplotypes between all patients and healthy controls in the present study did not show any significant differences. Other similar studies have revealed an association (Ghabanbasani et al., 1995; Motala et al., 2005; Ma et al., 2013) and no or weak association between HLA genes and T2D (Jaeger et al., 1997; Tipu et al., 2011). For instance, in Bahrainis, T2D was found to be positively associated with DRB1*04:01 and *07:01 alleles and negatively correlated with DRB1*11:01 and *16:01 alleles (Motala et al., 2005). Also, several DRB1-DQB1 haplotypes appeared to confer susceptibility to T2D and DRB1*16:01-DQB1*05:01 haplotype was negatively associated with T2D. Whereas, our findings revealed higher frequency of this haplotype in the patients compared to controls but it did not reach statistical significance probably due to small number of the patients in the current study. In Pakistanis, HLA-DRB1*13 alleles were found to be more frequent in T2D patients (Tipu et al., 2011) and a Chinese population showed a link between DQA1*0301 and DQA1*0501 alleles with T2D (Ma et al., 2013).

    Conclusions

    Given to complex multifactorial etiology of T2D and consequent microvascular complications, further investigations are needed to identify the predisposing genetic factors and their interaction with environmental factors in order to take preventive measures or probable better therapeutic interventions for T2D and post-diabetes complications. Taken together, we observed a plausible contribution of some HLA class-II alleles for development of DPN and even severity of this complication, but the elucidation of true association and more importantly the exact role of HLA genes in T2D and subsequent complications particularly neuropathy need replicative studies involving larger cohorts in our population as well as in different ethnic groups. Additionally, the evaluation of other immunological markers would also be worthy to identify the subjects at increased risk of this disease.

    Declaration of patient consent:The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/ have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

    Acknowledgments:The authors are grateful to all of the type 2 diabetes patients and to all staffs of Division of Endocrinology, Department of Internal Medicine, School of Medicine, Hamadan University of Medical Sciences, Iran for their participation in this study.

    Author contributions:JK, GS and MH designed the study and analyzed data. AM and HR carried out the molecular genetic tests and drafted the paper. JK and ZK conceived the study and participated in patients’ examination. All authors read and approved the final version of this paper for publication.

    Conflicts of interest:None declared.

    Plagiarism check:This paper was screened twice using CrossCheck toverify originality before publication.

    Peer review:This paper was double-blinded and stringently reviewed by international expert reviewers.

    AI V (2004) Diabetic neuropathies. In: Medical Clinics of North America.

    Almawi WY, Wakim-Ghorayeb SF, Arekat MR, Najm P, Keleshian SH, Al-Sayed N, Blanchon B, Samaha HR, Irani-Hakime N (2006) Association of selective HLA class II susceptibility-conferring and protective haplotypes with type 2 diabetes in patients from Bahrain and Lebanon. Clin Vaccine Immunol 13:1296-1298.

    American Diabetes Association (2016) 2. Classification and Diagnosis of Diabetes. Diabetes Care 39 Suppl 1:S13-22.

    Balakumar P, Arora MK, Reddy J, Anand-Srivastava MB (2009) Pathophysiology of diabetic nephropathy: involvement of multifaceted signalling mechanism. J Cardiovasc Pharmacol 54:129-138.

    Bansal V, Kalita J, Misra UK (2006) Diabetic neuropathy. Postgrad Med J 82:95-100.

    Barzilay J, Warram JH, Rand LI, Pfeifer MA, Krolewski AS (1992) Risk for cardiovascular autonomic neuropathy is associated with the HLA-DR3/4 phenotype in type I diabetes mellitus. Ann Intern Med 116:544-549.

    Boulton AJ, Vileikyte L, Ragnarson-Tennvall G, Apelqvist J (2005) The global burden of diabetic foot disease. Lancet 366:1719-1724.

    Boulton AJ, Worth RC, Drury J, Hardisty CA, Wolf E, Cudworth AG, Ward JD (1984) Genetic and metabolic studies in diabetic neuropathy. Diabetologia 26:15-19.

    Brunetti A, Chiefari E, Foti D (2014) Recent advances in the molecular genetics of type 2 diabetes mellitus. World J Diabetes 5:128-140.

    Cabezas-Cerrato J (1998) The prevalence of clinical diabetic polyneuropathy in Spain: a study in primary care and hospital clinic groups. Neuropathy Spanish Study Group of the Spanish Diabetes Society (SDS). Diabetologia 41:1263-1269.

    England JD, Gronseth GS, Franklin G, Miller RG, Asbury AK, Carter GT, Cohen JA, Fisher MA, Howard JF, Kinsella LJ, Latov N, Lewis RA, Low PA, Sumner AJ (2005) Distal symmetrical polyneuropathy: definition for clinical research. Muscle Nerve 31:113-123.

    Feldman EL, Stevens MJ, Greene DA (1997) Pathogenesis of diabetic neuropathy. Clin Neurosci 4:365-370.

    Forsblom CM, Sane T, Groop PH, Totterman KJ, Kallio M, Saloranta C, Laasonen L, Summanen P, Lepantalo M, Laatikainen L, Matikainen E, Teppo AM, Koskimies S, Groop L (1998) Risk factors for mortality in Type II (non-insulin-dependent) diabetes: evidence of a role for neuropathy and a protective effect of HLA-DR4. Diabetologia 41:1253-1262.

    Ghabanbasani MZ, Spaepen M, Buyse I, Legius E, Decorte R, Bex M, Marynen P, Bouillon R, Cassiman JJ (1995) Increased and decreased relative risk for non-insulin-dependent diabetes mellitus conferred by HLA class II and by CD4 alleles. Clin Genet 47:225-230.

    Greene DA, Sima AA, Stevens MJ, Feldman EL, Lattimer SA (1992) Complications: neuropathy, pathogenetic considerations. Diabetes Care 15:1902-1925.

    GS R (2008) Electromyography fundamentals. In.

    Jaeger C, Allendorfer J, Hatziagelaki E, Dyrberg T, Bergis KH, Federlin K, Bretzel RG (1997) Persistent GAD 65 antibodies in longstanding IDDM are not associated with residual beta-cell function, neuropathy or HLA-DR status. Horm Metab Res 29:510-515.

    Kiani J, Hajilooi M, Furst D, Rezaei H, Shahryari-Hesami S, Kowsarifard S, Zamani A, Solgi G (2015) HLA class II susceptibility pattern for type 1 diabetes (T1D) in an Iranian population. Int J Immunogenet 42:279-286.

    Ma ZJ, Sun P, Guo G, Zhang R, Chen LM (2013) Association of the HLA-DQA1 and HLA-DQB1 Alleles in Type 2 Diabetes Mellitus and Diabetic Nephropathy in the Han Ethnicity of China. J Diabetes Res 2013:452537.

    Meijer JW, Bosma E, Lefrandt JD, Links TP, Smit AJ, Stewart RE, Van Der Hoeven JH, Hoogenberg K (2003) Clinical diagnosis of diabetic polyneuropathy with the diabetic neuropathy symptom and diabetic neuropathy examination scores. Diabetes Care 26:697-701.

    Motala AA, Busson M, Al-Harbi EM, Khuzam MA, Al-Omari EM, Arekat MR, Almawi WY (2005) Susceptible and protective human leukocyte antigen class II alleles and haplotypes in bahraini type 2 (non-insulin-dependent) diabetes mellitus patients. Clin Diagn Lab Immunol 12:213-217.

    Perez-Luque E, Malacara JM, Olivo-Diaz A, Alaez C, Debaz H, Vazquez-Garcia M, Garay ME, Nava LE, Burguete A, Gorodezky C (2000) Contribution of HLA class II genes to end stage renal disease in mexican patients with type 2 diabetes mellitus. Hum Immunol 61:1031-1038.

    Scheinin T, Matikainen E, Groop L, Lepantalo M, Koskimies S, Kontiainen S (1988) HLA-antigens and immunity to insulin in insulin-dependent diabetics with or without diabetic neuropathy. Scand J Clin Lab Invest 48:327-332.

    Tesfaye S (2011) Recent advances in the management of diabetic distal symmetrical polyneuropathy. J Diabetes Investig 2:33-42.

    Tesfaye S, Boulton AJ, Dyck PJ, Freeman R, Horowitz M, Kempler P, Lauria G, Malik RA, Spallone V, Vinik A, Bernardi L, Valensi P, Toronto Diabetic Neuropathy Expert G (2010) Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care 33:2285-2293.

    Tipu HN, Ahmed TA, Bashir MM (2011) Human leukocyte antigen class II susceptibility conferring alleles among non-insulin dependent diabetes mellitus patients. J Coll Physicians Surg Pak 21:26-29.

    Tuomi T, Groop LC, Zimmet PZ, Rowley MJ, Knowles W, Mackay IR (1993) Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with a non-insulin-dependent onset of disease. Diabetes 42:359-362.

    Turner R, Stratton I, Horton V, Manley S, Zimmet P, Mackay IR, Shattock M, Bottazzo GF, Holman R (1997) UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. UK Prospective Diabetes Study Group. Lancet 350:1288-1293.

    Wellen KE, Lu C, Mancuso A, Lemons JM, Ryczko M, Dennis JW, Rabinowitz JD, Coller HA, Thompson CB (2010) The hexosamine biosynthetic pathway couples growth factor-induced glutamine uptake to glucose metabolism. Genes Dev 24:2784-2799.

    Young RJ, Zhou YQ, Rodriguez E, Prescott RJ, Ewing DJ, Clarke BF (1986) Variable relationship between peripheral somatic and autonomic neuropathy in patients with different syndromes of diabetic polyneuropathy. Diabetes 35:192-197.

    Copyedited by Li CH, Song LP, Zhao M

    *Correspondence to: Ghasem Solgi, Ph.D., gh.solgi@umsha.ac.ir.

    orcid: 0000-0001-8929-5658 (Ghasem Solgi)

    10.4103/1673-5374.194756

    Accepted: 2016-10-25

    日本欧美国产在线视频| 日韩欧美精品v在线| 九色成人免费人妻av| 午夜福利在线观看吧| 欧美中文日本在线观看视频| 97超碰精品成人国产| 99久久久亚洲精品蜜臀av| 国产精品久久久久久精品电影| 我要搜黄色片| 成年女人毛片免费观看观看9| 国产在线男女| 亚洲精品在线观看二区| 日韩强制内射视频| 成年免费大片在线观看| 18+在线观看网站| 日韩欧美 国产精品| 一进一出好大好爽视频| 男插女下体视频免费在线播放| 亚洲美女搞黄在线观看 | 亚洲av免费在线观看| 欧美日韩乱码在线| 成人鲁丝片一二三区免费| 亚洲人成网站高清观看| 亚洲中文字幕一区二区三区有码在线看| 精品一区二区免费观看| 久久午夜福利片| 亚洲人成网站在线播| 搞女人的毛片| 2021天堂中文幕一二区在线观| 亚洲美女视频黄频| 变态另类成人亚洲欧美熟女| 欧美极品一区二区三区四区| 最近2019中文字幕mv第一页| 免费在线观看成人毛片| 桃色一区二区三区在线观看| 97超级碰碰碰精品色视频在线观看| 欧美xxxx性猛交bbbb| 国产美女午夜福利| 国内精品宾馆在线| 日本一二三区视频观看| 男人和女人高潮做爰伦理| 春色校园在线视频观看| 最后的刺客免费高清国语| 春色校园在线视频观看| 亚洲成a人片在线一区二区| 中文字幕免费在线视频6| 亚洲av电影不卡..在线观看| 亚洲久久久久久中文字幕| 久久99热6这里只有精品| 桃色一区二区三区在线观看| 97超级碰碰碰精品色视频在线观看| 亚洲成a人片在线一区二区| 在线看三级毛片| 简卡轻食公司| 一级黄片播放器| 热99re8久久精品国产| 少妇熟女欧美另类| 干丝袜人妻中文字幕| 久久精品国产亚洲av天美| 欧美国产日韩亚洲一区| 免费人成在线观看视频色| 欧美潮喷喷水| 成人欧美大片| 久久久欧美国产精品| 美女被艹到高潮喷水动态| 久久亚洲国产成人精品v| 精品国内亚洲2022精品成人| 天天一区二区日本电影三级| 色哟哟哟哟哟哟| 我的老师免费观看完整版| 欧美日韩综合久久久久久| 精品午夜福利视频在线观看一区| 九九爱精品视频在线观看| 欧美潮喷喷水| 国产成人精品久久久久久| 日韩中字成人| 久久久久久大精品| 午夜福利在线观看吧| 99久国产av精品| 国内精品久久久久精免费| 小蜜桃在线观看免费完整版高清| 欧美绝顶高潮抽搐喷水| 99视频精品全部免费 在线| 久久热精品热| 成人毛片a级毛片在线播放| 永久网站在线| 国产精品综合久久久久久久免费| 亚洲av中文av极速乱| 亚洲乱码一区二区免费版| 国产一区二区在线观看日韩| 精品国产三级普通话版| 久久人人爽人人爽人人片va| 欧美性感艳星| 亚洲av免费高清在线观看| 亚洲av成人精品一区久久| 永久网站在线| 在线观看美女被高潮喷水网站| 亚洲精品456在线播放app| 又黄又爽又免费观看的视频| 五月玫瑰六月丁香| 国产日本99.免费观看| 欧美日韩国产亚洲二区| 男人的好看免费观看在线视频| 丝袜喷水一区| 亚洲精品一区av在线观看| 校园人妻丝袜中文字幕| 国产色爽女视频免费观看| 国产免费一级a男人的天堂| 国产精品三级大全| 晚上一个人看的免费电影| 看十八女毛片水多多多| 哪里可以看免费的av片| 国产美女午夜福利| 国产成人freesex在线 | 如何舔出高潮| 免费av不卡在线播放| 丰满人妻一区二区三区视频av| 99久久精品国产国产毛片| 免费人成在线观看视频色| 99国产极品粉嫩在线观看| 日本爱情动作片www.在线观看 | 国产高清视频在线观看网站| 国产精品一二三区在线看| 国产探花极品一区二区| 久久精品国产亚洲av香蕉五月| 午夜老司机福利剧场| 黄色欧美视频在线观看| 少妇人妻一区二区三区视频| 男人的好看免费观看在线视频| 亚洲丝袜综合中文字幕| 人人妻人人澡欧美一区二区| 俺也久久电影网| 啦啦啦观看免费观看视频高清| 久久欧美精品欧美久久欧美| 精品久久久久久久末码| 欧美一级a爱片免费观看看| 午夜福利高清视频| 男女视频在线观看网站免费| 成人精品一区二区免费| 国产真实伦视频高清在线观看| 欧美在线一区亚洲| 欧美潮喷喷水| 亚洲美女视频黄频| 久久久国产成人免费| 亚洲欧美成人精品一区二区| av免费在线看不卡| 少妇人妻精品综合一区二区 | 在线观看免费视频日本深夜| 国产精品精品国产色婷婷| 校园春色视频在线观看| 色哟哟哟哟哟哟| 国产精品精品国产色婷婷| 欧美另类亚洲清纯唯美| 男女啪啪激烈高潮av片| 最后的刺客免费高清国语| 美女被艹到高潮喷水动态| 欧美日韩在线观看h| 男女视频在线观看网站免费| 在线国产一区二区在线| 国产成人91sexporn| 最近在线观看免费完整版| 久久久久免费精品人妻一区二区| 亚洲一级一片aⅴ在线观看| 热99re8久久精品国产| 日韩精品中文字幕看吧| 久久久久久国产a免费观看| 干丝袜人妻中文字幕| 亚洲专区国产一区二区| 一级毛片久久久久久久久女| 午夜久久久久精精品| 日韩av不卡免费在线播放| 男女之事视频高清在线观看| 啦啦啦韩国在线观看视频| 村上凉子中文字幕在线| 99久国产av精品国产电影| 国产亚洲精品综合一区在线观看| 我的女老师完整版在线观看| 男人狂女人下面高潮的视频| 欧美一区二区精品小视频在线| 免费观看人在逋| 级片在线观看| 精华霜和精华液先用哪个| 日本一二三区视频观看| 色综合色国产| 激情 狠狠 欧美| 成年av动漫网址| 国内精品美女久久久久久| 偷拍熟女少妇极品色| 在线播放国产精品三级| 中文字幕av成人在线电影| av在线播放精品| 又黄又爽又刺激的免费视频.| 亚洲精品日韩在线中文字幕 | 亚洲久久久久久中文字幕| 国产免费一级a男人的天堂| 亚洲av第一区精品v没综合| 丝袜喷水一区| 精品国产三级普通话版| 精品人妻熟女av久视频| 日韩精品中文字幕看吧| 欧美性猛交╳xxx乱大交人| 蜜桃久久精品国产亚洲av| 悠悠久久av| 看非洲黑人一级黄片| 中国美女看黄片| 成人精品一区二区免费| 99热网站在线观看| 亚洲精品456在线播放app| 亚洲中文字幕一区二区三区有码在线看| 色综合站精品国产| 一级黄片播放器| 国产亚洲精品综合一区在线观看| 欧美+亚洲+日韩+国产| 亚洲国产欧洲综合997久久,| 99久久精品国产国产毛片| 国产在视频线在精品| 在线天堂最新版资源| 亚洲av成人av| 一进一出抽搐动态| 真人做人爱边吃奶动态| 免费看a级黄色片| 色哟哟·www| 1024手机看黄色片| 久久亚洲国产成人精品v| 国产精品一及| 中文字幕免费在线视频6| 久久热精品热| 午夜精品在线福利| .国产精品久久| a级毛片免费高清观看在线播放| 亚洲人成网站在线播| 欧美+亚洲+日韩+国产| 欧美成人一区二区免费高清观看| 免费看光身美女| 床上黄色一级片| 成熟少妇高潮喷水视频| 人人妻人人澡欧美一区二区| 国产美女午夜福利| 不卡一级毛片| 日日摸夜夜添夜夜爱| 免费一级毛片在线播放高清视频| 美女黄网站色视频| 别揉我奶头 嗯啊视频| 亚洲精品在线观看二区| 能在线免费观看的黄片| 日本-黄色视频高清免费观看| 最近视频中文字幕2019在线8| 国产在视频线在精品| 国产午夜精品久久久久久一区二区三区 | 一级黄片播放器| 在线天堂最新版资源| 校园人妻丝袜中文字幕| 人人妻人人看人人澡| 香蕉av资源在线| 欧美中文日本在线观看视频| 婷婷精品国产亚洲av在线| 春色校园在线视频观看| 亚洲专区国产一区二区| 91久久精品国产一区二区成人| 天堂av国产一区二区熟女人妻| 少妇丰满av| 久久精品国产亚洲网站| 91久久精品电影网| 久久九九热精品免费| 日韩,欧美,国产一区二区三区 | av免费在线看不卡| 亚洲精品乱码久久久v下载方式| 欧美又色又爽又黄视频| 日韩 亚洲 欧美在线| 插逼视频在线观看| 欧美xxxx黑人xx丫x性爽| 熟妇人妻久久中文字幕3abv| 嫩草影院精品99| 亚洲三级黄色毛片| 国产高清视频在线观看网站| 国产aⅴ精品一区二区三区波| 国产真实伦视频高清在线观看| 国产精品一区www在线观看| 亚洲成人av在线免费| 观看美女的网站| 日日摸夜夜添夜夜添小说| 免费电影在线观看免费观看| 久久久久久久久久久丰满| 色在线成人网| 免费在线观看成人毛片| 此物有八面人人有两片| 熟女人妻精品中文字幕| 国产高潮美女av| 插阴视频在线观看视频| 精品不卡国产一区二区三区| 欧美成人a在线观看| 亚洲无线观看免费| 亚洲性夜色夜夜综合| 人妻丰满熟妇av一区二区三区| 国产伦精品一区二区三区视频9| 99热这里只有是精品在线观看| 国产成人精品久久久久久| av卡一久久| 亚洲无线观看免费| 成人漫画全彩无遮挡| 美女被艹到高潮喷水动态| 免费不卡的大黄色大毛片视频在线观看 | 伦理电影大哥的女人| 成人三级黄色视频| 97超碰精品成人国产| av天堂中文字幕网| 国产精品一及| 欧美色视频一区免费| 色5月婷婷丁香| 三级国产精品欧美在线观看| av国产免费在线观看| 美女内射精品一级片tv| 国产激情偷乱视频一区二区| 久久人人精品亚洲av| 色播亚洲综合网| 亚洲人成网站高清观看| av中文乱码字幕在线| 亚洲欧美日韩卡通动漫| 国产色爽女视频免费观看| 国产精品久久久久久久电影| 天堂动漫精品| 少妇熟女欧美另类| 成人高潮视频无遮挡免费网站| 亚洲欧美成人综合另类久久久 | 你懂的网址亚洲精品在线观看 | 欧美激情久久久久久爽电影| 国产精品,欧美在线| 精品无人区乱码1区二区| 欧美不卡视频在线免费观看| 国产男人的电影天堂91| 蜜桃久久精品国产亚洲av| 国产乱人视频| 97在线视频观看| 97超视频在线观看视频| 久久午夜亚洲精品久久| 国产精品人妻久久久久久| 久久这里只有精品中国| 在线免费十八禁| 国产精品国产高清国产av| 久久久精品94久久精品| 晚上一个人看的免费电影| 全区人妻精品视频| 日韩欧美免费精品| 亚洲三级黄色毛片| 日韩制服骚丝袜av| 亚洲国产精品成人久久小说 | 九九爱精品视频在线观看| 欧美一区二区精品小视频在线| 久久韩国三级中文字幕| 啦啦啦韩国在线观看视频| 最好的美女福利视频网| 亚洲国产精品成人综合色| 老熟妇乱子伦视频在线观看| 国产精品一及| 麻豆av噜噜一区二区三区| 日本成人三级电影网站| 床上黄色一级片| 欧美成人精品欧美一级黄| 一个人看的www免费观看视频| 九色成人免费人妻av| 成年女人毛片免费观看观看9| 精品熟女少妇av免费看| 美女xxoo啪啪120秒动态图| 国产乱人偷精品视频| 国产三级中文精品| 最后的刺客免费高清国语| 18+在线观看网站| 久久久久久久久大av| 最新在线观看一区二区三区| av.在线天堂| 免费观看人在逋| 日韩欧美精品免费久久| 秋霞在线观看毛片| 夜夜看夜夜爽夜夜摸| 日本爱情动作片www.在线观看 | 国产午夜精品久久久久久一区二区三区 | 在线a可以看的网站| 亚洲成人精品中文字幕电影| 99久国产av精品国产电影| 精品久久久久久久人妻蜜臀av| 深夜a级毛片| 精品一区二区三区视频在线| 亚洲国产精品合色在线| 九色成人免费人妻av| 午夜精品国产一区二区电影 | 国产黄色视频一区二区在线观看 | 色视频www国产| 亚洲成人av在线免费| 听说在线观看完整版免费高清| 老女人水多毛片| 村上凉子中文字幕在线| 女的被弄到高潮叫床怎么办| 国产高清激情床上av| 别揉我奶头 嗯啊视频| 久久久成人免费电影| 日韩欧美国产在线观看| 十八禁网站免费在线| 国产精品野战在线观看| 听说在线观看完整版免费高清| 亚洲性久久影院| 男女之事视频高清在线观看| 黄色日韩在线| 毛片女人毛片| 国产三级中文精品| 性欧美人与动物交配| 一级a爱片免费观看的视频| 亚洲一区高清亚洲精品| 男人舔女人下体高潮全视频| 天堂影院成人在线观看| 亚洲熟妇熟女久久| 亚洲精华国产精华液的使用体验 | 性欧美人与动物交配| eeuss影院久久| 别揉我奶头 嗯啊视频| 免费电影在线观看免费观看| 美女被艹到高潮喷水动态| 日韩强制内射视频| 天天一区二区日本电影三级| 国模一区二区三区四区视频| 免费在线观看影片大全网站| 免费在线观看成人毛片| 国产不卡一卡二| 国产av一区在线观看免费| 国产精品免费一区二区三区在线| 国产伦精品一区二区三区四那| 舔av片在线| 国产精品99久久久久久久久| 精品久久久久久久末码| 悠悠久久av| 在线看三级毛片| 亚洲成人中文字幕在线播放| 精品久久久久久久久久久久久| 黑人高潮一二区| 免费人成在线观看视频色| 激情 狠狠 欧美| 天天一区二区日本电影三级| 插阴视频在线观看视频| 日韩av不卡免费在线播放| 美女高潮的动态| 最新中文字幕久久久久| 又黄又爽又刺激的免费视频.| 有码 亚洲区| 亚洲无线观看免费| 亚洲五月天丁香| 国产极品精品免费视频能看的| 亚洲成人久久爱视频| 午夜福利18| 国产久久久一区二区三区| 国产一区亚洲一区在线观看| 在线国产一区二区在线| 91久久精品国产一区二区成人| 插逼视频在线观看| 热99re8久久精品国产| 亚洲精品日韩av片在线观看| 老师上课跳d突然被开到最大视频| 久久人人爽人人爽人人片va| 国产伦在线观看视频一区| 国产女主播在线喷水免费视频网站 | 久久久久国产精品人妻aⅴ院| videossex国产| 三级国产精品欧美在线观看| 色视频www国产| 最新中文字幕久久久久| 国内精品久久久久精免费| 舔av片在线| 老熟妇乱子伦视频在线观看| 一本一本综合久久| 村上凉子中文字幕在线| 中文字幕人妻熟人妻熟丝袜美| 长腿黑丝高跟| 内射极品少妇av片p| 91在线精品国自产拍蜜月| 久久精品国产亚洲av涩爱 | 日本a在线网址| 亚洲久久久久久中文字幕| 少妇人妻一区二区三区视频| 少妇熟女欧美另类| 久久久久久九九精品二区国产| 国产亚洲精品久久久com| 全区人妻精品视频| 久久久久国内视频| 在线a可以看的网站| 亚洲婷婷狠狠爱综合网| 网址你懂的国产日韩在线| 亚洲欧美日韩卡通动漫| 久久久久国产网址| 午夜亚洲福利在线播放| 美女被艹到高潮喷水动态| 色综合亚洲欧美另类图片| 中文字幕免费在线视频6| 亚洲成人中文字幕在线播放| 性欧美人与动物交配| 午夜福利18| 欧美丝袜亚洲另类| 此物有八面人人有两片| 非洲黑人性xxxx精品又粗又长| 男女啪啪激烈高潮av片| 午夜爱爱视频在线播放| 成人特级黄色片久久久久久久| 亚洲精品久久国产高清桃花| 国产老妇女一区| 成人无遮挡网站| 婷婷精品国产亚洲av| 美女内射精品一级片tv| 看十八女毛片水多多多| 卡戴珊不雅视频在线播放| 国产成人freesex在线 | 日韩在线高清观看一区二区三区| 欧美性猛交黑人性爽| 中文字幕av在线有码专区| 18禁在线播放成人免费| 亚洲经典国产精华液单| 久99久视频精品免费| 黄片wwwwww| 啦啦啦观看免费观看视频高清| 观看美女的网站| 日本黄色视频三级网站网址| 久久99热6这里只有精品| 丰满的人妻完整版| 亚洲人成网站在线观看播放| 久久6这里有精品| 两个人的视频大全免费| 老司机福利观看| 久久精品影院6| 亚洲aⅴ乱码一区二区在线播放| 欧美日韩综合久久久久久| 国产中年淑女户外野战色| 99久久精品热视频| 亚洲精华国产精华液的使用体验 | 午夜久久久久精精品| 中文字幕熟女人妻在线| 女同久久另类99精品国产91| 久久99热6这里只有精品| 久久精品国产清高在天天线| 尾随美女入室| 99久久精品国产国产毛片| 国产午夜精品久久久久久一区二区三区 | 国语自产精品视频在线第100页| 亚洲va在线va天堂va国产| 伊人久久精品亚洲午夜| 久久久精品94久久精品| 欧美中文日本在线观看视频| 蜜桃亚洲精品一区二区三区| 男人舔奶头视频| 免费大片18禁| 精品福利观看| 日韩高清综合在线| 午夜福利在线观看免费完整高清在 | 亚洲国产精品sss在线观看| 内地一区二区视频在线| 菩萨蛮人人尽说江南好唐韦庄 | 亚洲国产欧洲综合997久久,| 成人精品一区二区免费| 日韩欧美免费精品| 婷婷精品国产亚洲av| 亚洲av免费高清在线观看| 91午夜精品亚洲一区二区三区| 亚洲一区高清亚洲精品| 久久精品国产自在天天线| 精品午夜福利视频在线观看一区| 久久婷婷人人爽人人干人人爱| 天堂影院成人在线观看| 国产av不卡久久| 久久久久久久久中文| 欧美一区二区国产精品久久精品| 久久久久久久久中文| 最近中文字幕高清免费大全6| 一级黄色大片毛片| 亚洲欧美日韩高清专用| 日韩精品青青久久久久久| 国产精品一二三区在线看| 少妇丰满av| 亚洲在线自拍视频| 国产精品国产三级国产av玫瑰| 亚洲丝袜综合中文字幕| 欧美一区二区亚洲| 国语自产精品视频在线第100页| 亚洲欧美清纯卡通| 日韩av不卡免费在线播放| 亚洲精品456在线播放app| 国内揄拍国产精品人妻在线| 一本精品99久久精品77| 亚洲av免费在线观看| 国产在线男女| 日本a在线网址| 夜夜看夜夜爽夜夜摸| 在线免费观看不下载黄p国产| 日韩精品青青久久久久久| 欧美成人免费av一区二区三区| 久久精品国产清高在天天线| 99精品在免费线老司机午夜| 听说在线观看完整版免费高清| 色综合色国产| 一本一本综合久久| 最好的美女福利视频网| 亚洲不卡免费看| 亚洲18禁久久av| 中文资源天堂在线| 亚洲精品影视一区二区三区av| 麻豆久久精品国产亚洲av| 国产视频内射| 国产蜜桃级精品一区二区三区| 成人一区二区视频在线观看| 日韩成人av中文字幕在线观看 | 日本一二三区视频观看| 此物有八面人人有两片| 精品日产1卡2卡| 国产成年人精品一区二区| 在线播放无遮挡| 六月丁香七月| 一进一出抽搐gif免费好疼| 又爽又黄无遮挡网站| 99热网站在线观看| 波多野结衣巨乳人妻| 日韩av在线大香蕉|