2型糖尿病患者胰岛β细胞功能衰竭与脂联素和抵抗素的临床相关研究

目的探讨T2DM患者胰岛β细胞功能衰竭所致APN和抵抗素的变化特点及临床意义。方法选取T2DM病程6个月者21例,6个月T2DM病程2年者20例,T2DM病程2年者18例及健康对照(NC)者21名。测量身高、体重、BP和WC,检测真胰岛素(TI)、胰岛素原(PI)、APN、抵抗素、FPG、FIns、TG、TC、HDL-C和LDL-C,计算胰岛β细胞功能指数(HOMA-β)。结果随着T2DM病程进展,胰岛β细胞功能进行性下降,TI分泌逐渐减少(P0.05)。T2DM病程较长组PI高于病程较短及NC组(P0.05)。T2DM各组TG、TC、LDL-C、APN和抵抗素与NC组比较差异有统计学意义(P0.05)。结论随着T2DM病程进展,胰岛β细胞功能逐渐衰竭,且伴随血浆APN和抵抗素水平改变,这可能是导致T2DM发病原因之一。     

不同糖代谢异常患者血浆载脂蛋白A5水平的变化及其临床意义

目的 通过比较不同糖耐量人群血浆载脂蛋白A5（ApoA5）、脂联素（APN）及TG水平,探讨其相互关系,以及ApoA5及APN降低TG的可能机制. 方法 选取新诊断T2DM患者（T2DM组）35例,IGR者（IGR组）30例及正常对照者（NGT组）35名,行静脉葡萄糖耐量试验（IVGTT）.ELISA测定空腹ApoA5及APN水平;比色法测定FFA.稳态模型评估胰岛素抵抗指数（HOMA-IR）及胰岛β细胞功能指数（HOMA-β）.探讨ApoA5与APN、血脂、FFA、HOMA-IR及HOMA-β的关系. 结果 （1）T2DM、IGR组ApoA5及APN水平低于NGT组（P＜0.05）,且T2DM组较IGR组降低更明显（P＜0.05）.（2）T2DM、IGR组TG、FFA、2 hFFA、LDL-C、FPG、2 hPG、FIns、HOMA-IR水平高于NGT组（P＜0.05）,且T2DM组较IGR组升高更明显（P＜0.05）.（3） ApoA5与TG、TC、FFA、2 hFFA、LDL-C、FPG、2 hPG、FIns、HOMA-IR、BMI及WHR呈负相关;与APN、HDL-C及HOMA-β呈正相关.（4）多元逐步回归分析显示,APN、TG、FFA、WHR及HOMA-IR是ApoA5的独立影响因素. 结论 低ApoA5及APN水平可能是IGR时期的早期敏感指标,低ApoA5及APN水平不能有效抑制血中FFA水平,可能导致高甘油三酯血症（HTG）及IR,从而共同导致IGR及T2DM的发生发展.     

2型糖尿病胰岛β细胞功能衰竭与心功能不全的临床研究

目的探讨2型糖尿病（T2DM）患者胰岛β细胞功能衰竭与心功能不全的临床表现特点及相关激素的改变,寻找针对糖尿病心功能不全的干预靶点。方法选取2008年1月至4月四川省人民医院门诊及住院部收治的T2DM患者96例（A组）、健康体检者35名（B组,健康对照）。将A组按病程和心力衰竭症状分为：新诊断及病程〈2年T2DM患者33例（A1组）、病程〉2年未出现临床显性心力衰竭症状和体征的T2DM患者32例（A2组）、病程〉2年且已出现临床显性心力衰竭症状和体征的T2DM患者31例（A3组）。入选者均测空腹血糖（FPG）、胰岛素（FINS）、真胰岛素（TI）、胰岛素原（PI）1次,注射胰岛素治疗A组患者测空腹C肽1次,以胰岛素分泌指数（Homa—Is）判定胰岛B细胞分泌功能;所有入选者均测定脑钠素（BNP）并采用心脏彩色多普勒测定左室射血分数（LVEF）、二尖瓣口舒张早期流速峰值E峰／舒张晚期流速峰值A峰（E／A）、舒张早期波e峰／舒张晚期波a峰（e／a）、峰值肺静脉血流收缩期S波／峰值肺静脉舒张早中期D波（S／D）以判定心脏功能。应用方差分析进行各组数据分析比较。结果随着T2DM病程的进展,Homa—Is进行性下降（B组为110．0±76．3、A1组为45．0±22．7、A2组为15．0±14．0、A3组为5．8±2．4,F=6．34,P〈0．05）,A3组TI及PI与其余各组比较有明显的降低。BNP随胰岛B细胞分泌功能的降低出现了显著增高[B组为（75±19）ng／L、A1组为（810±185）ng／L、A2组为（1060±264）ng／L、A3组为（2071±785）ng／L,F=8．89,P〈0．05];心脏彩超T2DM组较健康对照组E／A、e／a、S／D、LVEF均有明显下降,随着胰岛β细胞分泌功能下降差异愈明显。结论随着T2DM病程延长及胰岛β细胞功能逐渐衰竭,真胰岛素、胰岛素原分泌水平减少及心肌舒张顺应性减低和收缩力下降,使得心脏泵功能发生与供能相关的代谢障碍,从而影响和加重心力衰竭。     

2型糖尿病患者一级亲属胰岛素抵抗与胰岛B细胞功能缺陷的临床研究

目的探讨胰岛素抵抗与胰岛B细胞功能缺陷在2型糖尿病(T2DM)发生中的作用。方法收集2004年4月至2005年6月解放军总医院门诊及住院T2DM患者的既往无糖耐量异常史的一级亲属,其中糖耐量正常(NGT)组174例、空腹血糖受损(IFG)或糖耐量低减(IGT)组55例,以及12例新发T2DM与同期收集的59例新发T2DM合并为新发糖尿病(T2DM)组;以其无糖尿病家族史的配偶或无血缘关系亲友中糖耐量正常者114名作为正常对照(NC)组。酶联免疫法测定血清真胰岛素(trueinsulin,TI)、胰岛素原(proinsulin,PI)。用胰岛素抵抗指数(Homa-IR)评价胰岛素抵抗。用空腹胰岛素原与空腹胰岛素比值(PI/TI)及B细胞功能指数(Homa-B),评估胰岛B细胞功能状态,并做对比分析。结果一级亲属中NGT组与NC组相比,Homa-IR显著高于NC组,PI/TI及Homa-B显著低于NC组。而且从NC至NGT至IGT或IFG至DM组,胰岛素抵抗进行性加重。胰岛B细胞分泌缺陷进行性加重,PI/TI逐渐升高,但LnHoma-B下降直至T2DM组才具显著意义(NC组为4.40±0.60,T2DM组为3.38±0.96)。结论T2DM患者一级亲属作为糖尿病的高危人群,在发生糖代谢异常前就存在胰岛素抵抗和胰岛分泌功能缺陷,且胰岛素抵抗和胰岛分泌功能缺陷与T2DM的发病相关;胰岛素原比例增加以及胰岛素原与真胰岛素比值升高是反映胰岛分泌功能缺陷的早期标志。     

抵抗素与肥胖及2型糖尿病的关系

目的探讨抵抗素与肥胖及2型糖尿病(T2DM)的相关性。方法正常人(NC)80例、单纯肥胖(Ob)67例、T2DM77例、伴肥胖的T2DM(Ob DM)102例,测定其血清抵抗素、真胰岛素、胰岛素原、胰升糖素、空腹血糖、血脂及血压等水平,记录身高、体重等。结果四组抵抗素水平差异无统计学意义(P>0.05);抵抗素与胰岛β细胞功能、胰岛素敏感性也无相关性(P>0.05);在Ob、DM及Ob DM组抵抗素与TC呈正相关(r=0.35,0.33,0.38,P<0.05);在Ob及Ob DM组抵抗素与腰臀比呈正相关(r=0.36,0.27,P<0.05);在Ob组抵抗素与PI呈正相关(r=0.37,P<0.05)。结论抵抗素与T2DM无相关性,但可能影响肥胖及糖尿病患者的脂质代谢及胰岛素抵抗的形成。     

同型半胱氨酸和总胆红素对胰岛β细胞功能的交互作用分析

目的 探讨同型半胱氨酸（Hcy）和总胆红素（T-BIL）对胰岛β细胞功能的交互作用。方法 选取2018年5月至2021年4月于我院内分泌科就诊的T2DM患者242例（T2DM组），同期选取183名体检健康者为正常对照（NC）组，探讨T2DM的影响因素，分析高Hcy和低T-BIL对胰岛β细胞功能的交互作用。结果 T2DM组BMI、HbA1c、Hcy、FPG、FIns、TC、LDL-C及HOMA-IR高于NC组（P<0.05）,T-BIL和HOMA-β低于NC组（P<0.05）。高Hcy和低T-BIL是T2DM的影响因素。多因素Logistic回归分析显示，高Hcy、低T-BIL及二者同时存在时，胰岛β细胞功能降低的OR为1.584、1.817、7.613;OR(EF)>OR(E)+OR(F)-1，高Hcy和低T-BIL有交互作用，可进一步损伤胰岛β细胞功能。结论 高Hcy和低T-BIL对T2DM患者胰岛β细胞功能有协同交互作用，临床治疗上应重视Hcy升高及T-BIL降低，有助于保护胰岛β细胞功能。     

PPAR5基因＋294T／C多态性与2型糖尿病患者血脂和胰岛功能关系研究

目的研究2型糖尿病（T2DM）患者和糖耐量正常（NGT）者中PPARδ基因＋294T／C多态性与血脂和胰岛功能的关系。方法选取346例南京地区汉族人群，其中新诊断T2DM患者236名，NGT者110名，用Touch-down PCR检测PPAR5＋294T／C基因变异，并检测人选人群的临床指标。结果T2DM组中携带C等位基因（TC＋CC）者HOMA-β水平低于TT型（P〈0．05）；NGT人群中，携带C等位基因（TC＋CC）者LDL-C／HDL-C比值高于TT型（P〈0.05），Pearson相关分析显示NGT组携带C等位基因与LDL-C、LDL-C／HDL—C水平呈正相关（P〈0．05）。结论T2DM患者携带PPAR5＋294C等位基因者胰岛素分泌能力下降，在NGT组中PPAR5＋294T／C与脂代谢紊乱相关。     

2型糖尿病患者胰岛素抵抗和β细胞功能与代谢综合征的相关性

目的测定2型糖尿病（T2DM）合并代谢综合征（MS）患者60例、单纯T2DM患者56例和正常对照（NC）组60例的空腹血糖（FPG）、空腹胰岛素（FIns）、血压（BP）、血脂、腰围（WC）,计算HO-MA-IR和HOMA-β。结果MS组胰岛素抵抗水平明显高于T2DM组及NC组;胰岛β细胞功能明显低于T2DM组和NC组,差异均有统计学意义（P〈0.05）。MS组HOMA-IR与FPG、WC呈正相关（P〈0.05）。结论合并MS的T2DM患者的HOMA-IR最高,HOMA-β最低。T2DM患者HO-MA-IR和HOMA-β与MS密切相关。     

超重和肥胖人群血清脂联素水平与心血管多重危险因素的关系

选取32例超重和肥胖者（OW4-Ob组）和36例正常体重者（NC组），常规测量身高等，测定APN、甘油三酯（TG）、胆固醇（TC）、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）等指标。结果：（1）OW＋Ob组血清APN水平明显低于NC组（P〈0．05）；OW＋Ob组WC、SBP、DBP、FINS、FBG、TG、TC、LDL-C、IL-6、hs-CRP均高于NC组（0．000〈P〈0．05）；OW＋Ob组ISI低于NC组，HOMA-IR高于NC组。（2）APN与BMI、WC、FINS、TG、TC、LDL-C、HOMA-IR、hs-CRP呈显著负相关（0．05〉P〉0．001）；与HDL-C呈显著正相关（P〈0．05）。（3）OW＋Ob组女性血清APN水平较男性明显升高（P〈0．05），APN与T，OW＋Ob组人群中血清APN与T及T／E2均呈显著负相关（P〈0．05）。（4）HDL-C是影响血清APN水平的独立相关因素。结论：超重和肥胖者血清APN水平明显降低。低APN水平与心血管多重危险因素密切相关。     

超重和肥胖人群血清脂联素水平与心血管多重危险因素的关系

选取32例超重和肥胖者（OW4-Ob组）和36例正常体重者（NC组），常规测量身高等，测定APN、甘油三酯（TG）、胆固醇（TC）、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）等指标。结果：（1）OW＋Ob组血清APN水平明显低于NC组（P〈0．05）；OW＋Ob组WC、SBP、DBP、FINS、FBG、TG、TC、LDL-C、IL-6、hs-CRP均高于NC组（0．000〈P〈0．05）；OW＋Ob组ISI低于NC组，HOMA-IR高于NC组。（2）APN与BMI、WC、FINS、TG、TC、LDL-C、HOMA-IR、hs-CRP呈显著负相关（0．05〉P〉0．001）；与HDL-C呈显著正相关（P〈0．05）。（3）OW＋Ob组女性血清APN水平较男性明显升高（P〈0．05），APN与T，OW＋Ob组人群中血清APN与T及T／E2均呈显著负相关（P〈0．05）。（4）HDL-C是影响血清APN水平的独立相关因素。结论：超重和肥胖者血清APN水平明显降低。低APN水平与心血管多重危险因素密切相关。     

c.2425G>A mutation in the WFS1 gene associated with Wolfram syndrome: a case report

Wolfram syndrome is a rare hereditary disease characterized by clinical congenital progressive hearing impairment, diabetes mellitus, optic atrophy, and diabetes insipidus. A girl at the age of 35 months with diabetes mellitus was diagnosed as incomplete Wolfram syndrome; the patient also had optic atrophy, deafness, and diabetes mellitus. Molecular genetic examinations revealed a de novo mutation (c.2425G>A) in the WFS1 gene. No mutations were detected in the biological parents. The mutation c.2425G>A in the WFS1 gene is associated with the occurrence of Wolfram syndrome. This newly discovered mutation in the WFS1 gene may contribute to the diagnosis of Wolfram syndrome.

     

WS1 gene mutation analysis of Wolfram syndrome in a Chinese patient and a systematic review of literatures

Wolfram syndrome is a rare hereditary disease characterized by diabetes mellitus and optic atrophy. The outcome of this disease is always poor. WFS1 gene mutation is the main cause of this disease. A patient with diabetes mellitus, diabetes insipidus, renal tract disorder, psychiatric abnormality, and cataract was diagnosed with Wolfram syndrome. Mutations in open reading frame (ORF) of WFS1 gene was analyzed by sequencing. Mutations in WFS1 gene was also summarized by a systematic review in Pubmed and Chinese biological and medical database. Sequencing of WFS1 gene in this patient showed a new mutation, 1962G>A, and two other non-sense mutations, 2433A>G and 2565G>A. Systematic review included 219 patients in total and identified 172 WFS1 gene mutations, most of which were located in Exon 8. These mutations in WFS1 gene might be useful in prenatal diagnosis of Wolfram syndrome.     

Identification of a novel WFS1 mutation (AFF344-345ins) in Japanese patients with Wolfram syndrome

Wolfram syndrome (WFS) is an autosomal recessive disorder characterized by early onset diabetes mellitus, progressive optic atrophy, sensorineural deafness and diabetes insipidus. Affected individuals may also have renal tract abnormalities as well as neurogical and psychiatric syndromes. WFS1 encoding a transmembrane protein was identified as the gene responsible for WFS. We report herein a Japanese family, of which two members had this syndrome. In the WFS1 gene of these patients, we identified a novel mutation, a nine nucleotide insertion (AFF344-345ins). In addition, one of these patients had preclinical hypopituitarism, which is an unusual feature of WFS. As only the two family members homozygous for the mutation showed WFS, these data support the notion that this mutation is the cause of WFS.     

Wolfram syndrome: from definition to molecular bases

Wolfram syndrome (WS) is an autosomal recessive progressive neurodegenerative disorder characterized by diabetes mellitus and optic atrophy. Diabetes insipidus and sensorineural deafness are also noted frequently, explaining the acronym DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy and deafness) by which the syndrome is also referred. Additional manifestations such as atonic bladder, ataxia, nystagmus and predisposition for psychiatric illness may be present. The Wolfram syndrome gene, WFS1, was mapped to chromosome 4p16.1 by positional cloning. It encodes an 890-amino-acid polypeptide named wolframin. Although the wolframin function is still not completely known, its localization to the endoplasmic reticulum suggests it can play a role in calcium homeostasis, membrane trafficking and protein processing. Knowing the cellular function of wolframin is necessary for understanding the pathophysiology of Wolfram syndrome. This knowledge may lead to development of therapies to prevent or reduce the outcomes of WS.     

The novel compound heterozygous mutations, V434del and W666X, in WFS1 gene causing the Wolfram syndrome in a Chinese family

Wolfram syndrome (WFS), also known as DIDMOAD, is an infrequent cause of diabetes mellitus. WFS is an autosomal recessive neurodegenerative disease characterized by various clinical manifestations such as diabetes mellitus, optic atrophy, diabetes insipidus, deafness, neurological symptoms, renal tract abnormalities, psychiatric disorders, and gonadal disorders. The majority of patients with WFS carry the loss of function mutations in the WFS1 gene. The exons 2–8 of the WFS1 gene from one Chinese WFS patient were amplified by the polymerase chain reaction (PCR), subcloning techniques and direct sequence determination was applied to the amplified fragments. The compound heterozygous mutation of a 3-bp (GAC) deletion (V434del) and another compound heterozygous mutation (G→N)(W666X) in exon 8 of WFS1 gene was identified in the patient. Other seventeen members of her family were investigated. Four cases with heterozygotes had been found through screening for the mutation V434del and five cases for the mutation W666X in the whole family. This is the first report of WFS with the mutation V434del and W666X in the WFS1 gene. Jie Hong and Yu-wen Zhang contributed equally to this article.     

Wolfram syndrome in the Polish population: novel mutations and genotype-phenotype correlation

Objective Wolfram syndrome is a rare form of diabetes mellitus associated with optic atrophy and disorders of different organs (e.g. diabetes insipidus, hearing loss, ataxia, anaemia and many others). This syndrome is caused by recessive mutations in the wolframin gene (WFS1) localized on chromosome 4p16·1. The aim of this study was to identify the causative mutations in WFS1 in a group of Polish patients with suspected Wolfram syndrome. Design Patients and Measurements: Nine patients with clinical symptoms consistent with Wolfram syndrome (at least diabetes mellitus and optic atrophy) and 22 first‐degree relatives were examined. The molecular analysis was carried out by direct sequencing of the exons, the exon–intron junctions, and the 5′ and 3′ untranslated regions of WFS1. Results Nine different mutations in WFS1 (five of them novel) were identified in the nine patients. Six patients were homozygous for the following mutations: V412fs, S443R, W539X, V659fs. They developed diabetes at a mean age of 5·2 years. Three patients were compound‐heterozygous for the following mutations: S167fs, Q392X, Y513fs, W648X, V779G. They developed diabetes at a mean age of 6·5 years. Conclusions Mean age of diagnosis of diabetes among the Polish patients was typical for Wolfram syndrome; however, compound‐heterozygous patients were slightly older at diabetes onset.     

Molecular investigation of <Emphasis Type="Italic">WFS1</Emphasis> gene exon 8 in Iranian patients with Wolfram syndrome

Most patients with Wolfram syndrome carry mutations in WFS1, while a lower percentage present a mutation in CISD2 (also known as WFS2). The aim of this study was to investigate the presence of mutations in exon 8 of WFS1 gene in two Iranian patients with Wolfram syndrome (WFS). In this study using polymerase chain reaction (PCR) followed by direct sequencing, we screened the entire length of WSF1 gene exon 8 for presence of mutations. Patients included were two male subjects who developed diabetes mellitus earlier than the age of 8 years old, showing early-onset diabetes, followed by reduced visual acuity, deafness, and diabetes insipidus. The presence of two missense mutations G736D and R629W were confirmed. These mutations have been previously reported in patients with WFS in other populations. Identification of pathogenic mutations in patients with Wolfram syndrome will be helpful in earlier diagnosis of the disease and in understanding the frequency of mutations in various populations and their relation with clinical features of Wolfram syndrome.     

An Asian Indian woman with Wolfram syndrome on insulin pump: successful pregnancy and beyond

Wolfram syndrome (WS), or DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness), is a rare autosomal recessive neurodegenerative disorder with a median life expectancy of 30 years and occurs in one in 770,000 live births. To date only five successful pregnancies have been reported among WS subjects worldwide. Here we describe the sixth report of successful pregnancy in a WS patient and the first from India. The subject is still on an insulin pump, now 31 years old and doing well. She developed diabetes at 5 years of age, optic atrophy at 14 years, and diabetes insipidus at 25 years and had a successful delivery in 2007 while on an insulin pump. Sequencing of exonic regions of the WFS1 gene showed five changes, two of which were pathogenic (exon 8). Magnetic resonance imaging of brain showed generalized neurodegenerative changes. The benefits of continuous subcutaneous insulin infusion and that of tight metabolic control in prevention of abortions and fetal malformations in diabetes associated with pregnancy are well documented. The impression of probable pleiotropic action of insulin pumps over and above that of glycemic reduction is gaining momentum. Recent evidence supports use of insulin pumps in alleviating neuropathic pain in diabetes, probably by virtue of its action in minimizing mean amplitude of glycemic excursions not possible with conventional insulin shots. WS is a progressive neurodegenerative disorder, which will probably help us in understanding the positive impact of continuous subcutaneous insulin infusion in prolonging the life span and retarding neuronal damage in WS.     

Autosomal dominant transmission of diabetes and congenital hearing impairment secondary to a missense mutation in the WFS1 gene

Aims Mutations of the WFS1 gene have been implicated in autosomal dominant diseases, such as low‐frequency sensorineural hearing impairment (LFSNHI) and/or diabetes mellitus and/or optic atrophy. The aim was to investigate WFS1 gene sequences in a family with diabetes mellitus and hearing impairment. Methods Three members of a family with a maternally inherited combination of diabetes mellitus and hearing impairment, but no specific mutations in its mitochondrial genome, were investigated for mutations in the WFS1 gene. Results This pedigree, in which the proband had non‐insulin‐dependent diabetes mellitus and congenital hearing impairment and his mother a triple combination of diabetes mellitus, hearing impairment and optic atrophy, was found to be associated with autosomal dominant transmission of the E864K mutation of the WFS1 gene. Conclusions In the light of this confirmatory study, we recommend the systematic analysis of WFS1 gene sequences in patients with parentally inherited diabetes mellitus and deafness (± optic atrophy), in particular when diabetogenic mtDNA mutations have been excluded.