母系遗传性糖尿病伴耳聋发病机制及诊治

母系遗传性糖尿病伴耳聋(MIDD)是一种线粒体疾病,在糖尿病患者中约占1％.其中tRNALeu(UUR) A3243G突变引起胰岛β细胞胰岛素分泌功能障碍是其致糖尿病的主要原因,但具体机制仍不明确.近年EndoC-βH1细胞系的建立为研究其机制提供了途径.尿道上皮细胞与线粒体疾病表型相关性最好,尿液可作为临床诊断和检测线粒体DNA异质性首选的样本,而MIDD的治疗仍以抗氧化剂和预防糖尿病并发症为主.A3243G突变的临床表型和MIDD突变的组织异质性仍是研究的热点,其研究对MIDD的诊断和治疗具有重要的指导意义.     

Maternally inherited diabetes and deafness: prevalence in a hospital diabetic population

Maternally inherited diabetes and deafness (MIDD) is a new sub-type of diabetes and results from an A to G substitution at position 3243 of the mitochondrial tRNA^Leu(UUR) gene. This mutation is also associated with a neurological syndrome (MELAS). Recent studies have screened carefully selected diabetic populations and have reported MIDD prevalence rates ranging from undetectable to 60 %. The aim of this work was to determine the importance of this sub-type in clinical practice by screening a routine hospital diabetic population. A total of 1440 patients (IDDM and NIDDM) of North European extraction attending two hospital diabetes services were initially screened by questionnaire. This identified 445 patients with one or more features of MIDD and/or MELAS and these subjects were then genotyped. Two patients were identified with the mutation giving a prevalence rate of 0.13 % for the whole study population, and 0.45 % for the sample with phenotypic features of MIDD. In conclusion, therefore, the 3243 mutation is associated with the phenotypically distinct MIDD sub-type, but this is rare in the routine hospital diabetic population. © 1997 by John Wiley & Sons, Ltd.     

The effects of coenzyme Q10 treatment on maternally inherited diabetes mellitus and deafness, and mitochondrial DNA 3243 (A to G) mutation

Summary The characteristic clinical features of diabetes mellitus with mitochondrial DNA (mtDNA) 3243(A-G) mutation are progressive insulin secretory defect, neurosensory deafness and maternal inheritance, referred to as maternally inherited diabetes mellitus and deafness (MIDD). A treatment for MIDD to improve insulin secretory defects and reduce deafness has not been established. The effects of coenzyme Q₁₀ (CoQ₁₀) treatment on insulin secretory response, hearing capacity and clinical symptoms of MIDD were investigated. 28 MIDD patients (CoQ₁₀-DM), 7 mutant subjects with impaired glucose tolerance (IGT), and 15 mutant subjects with normal glucose tolerance (NGT) were treated daily with oral administration of 150 mg of CoQ₁₀ for 3 years. Insulin secretory response, blood lactate after exercise, hearing capacity and other laboratory examinations were investigated every year. In the same way we evaluated 16 MIDD patients (control-DM), 5 mutant IGT and 5 mutant NGT subjects in yearly examinations. The insulin secretory response assessed by glucagon-induced C-peptide secretion and 24 h urinary C-peptide excretion after 3 years in the CoQ₁₀-DM group was significantly higher than that in the control-DM group. CoQ₁₀ therapy prevented progressive hearing loss and improved blood lactate after exercise in the MIDD patients. CoQ₁₀ treatment did not affect the diabetic complications or other clinical symptoms of MIDD patients. CoQ₁₀ treatment did not affect the insulin secretory capacity of the mutant IGT and NGT subjects. There were no side effects during therapy. This is the first report demonstrating the therapeutic usefulness of CoQ₁₀ on MIDD. [Diabetologia (1998) 41: 584–588] Received: 16 October 1997 and in revised form: 21 January 1998     

HLA-DQ polymorphism and degree of heteroplasmy of the A3243G mitochondrial DNA mutation in maternally inherited diabetes and deafness.

AIM: Maternally inherited diabetes and deafness (MIDD) associates with a mutation at position 3243 in mitochondrial DNA. Phenotypic expression of MIDD includes Type 1-like and Type 2-like diabetes. This study examined whether HLA-DQ phenotype and the degree of heteroplasmy in leucocyte and oral mucosa DNA influence clinical expression of the 3242 mutation. METHODS: In a group of 20 unrelated probands with MIDD, eight with Type 1- like diabetes, 12 with Type 2-like diabetes, HLA-DQ type and degree of heteroplasmy for the 3243 mutation were determined. HLA-DQA1/DQB1 phenotypes were categorized as predisposing, neutral or protective for autoimmune-mediated Type 1 diabetes. RESULTS: No differences were observed between Type 1 and Type 2-like MIDD groups with respect to the cumulative frequency of protective and predisposing HLA-DQ types. Predisposing HLA-DQ types are more prevalent in MIDD patients than in the control population (P < 0.05). Degrees of heteroplasmy for the 3243 mutation showed large variations in patients, ranging from 1 to 52% in leucocyte DNA. A strong correlation was seen between heteroplasmy in leucocyte DNA and DNA from oral mucosa cells (r = 0.89, P < 0.001). No correlation was observed between the degree of heteroplasmy and diabetic phenotype, even when group size was extended with diabetic relatives of patients with MIDD. The age of diagnosis of diabetes was not correlated with heteroplasmy, but the degree of heteroplasmy tended to decrease with age. CONCLUSIONS: The phenotype of diabetes in MIDD appears to be independent of HLA-DQ phenotype and degree of heteroplasmy in leucocyte and oral mucosa DNA indicating that other, as yet unknown, factors modulate clinical expression of the 3243 mutation.     

Clinical features,diagnosis and management of maternally inherited diabetes and deafness (MIDD) associated with the 3243A>G mitochondrial point mutation

Maternally inherited diabetes and deafness (MIDD) affects up to 1% of patients with diabetes but is often unrecognized by physicians. It is important to make an accurate genetic diagnosis, as there are implications for clinical investigation, diagnosis, management and genetic counselling. This review summarizes the range of clinical phenotypes associated with MIDD; outlines the advances in genetic diagnosis and pathogenesis of MIDD; summarizes the published prevalence data and provides guidance on the clinical management of these patients and their families.     

Functional and morphological abnormalities of mitochondria harbouring the tRNALeu(UUR) mutation in mitochondrial DNA derived from patients with maternally inherited diabetes and deafness (MIDD) and progressive kidney disease

Aims/hypothesis. An A to G transition at nucleotide position 3243 in the mitochondrial tRNA ^Leu(UUR) gene has been identified in patients with maternally inherited diabetes and deafness, as well as in patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes, chronic progressive external ophpthalmoplegia, cardiomyopathy and progressive kidney disease. Variations in the mitochondrial DNA haplotype as well as differences in the degree and distribution of heteroplasmy in a certain tissue are factors that may contribute to the variety in phenotypical expression of the 3243 tRNA ^Leu(UUR) mutation. We have done morphological and functional experiments on mitochondria carrying the 3243 mutation derived from patients with either maternally inherited diabetes and deafness or progressive kidney disease to prove the pathogenicity of the 3243 mutation and to examine whether the mtDNA haplotype modulates the pathobiochemistry of this mutation. Methods. We constructed clonal cell lines that contain predominantly mutated or exclusively wild-type mtDNA with a distinct mtDNA haplotype by the methodology of mitochondria-mediated transformation. Cells lacking mitochondrial DNA (ϱ°) were used as recipients and donor mitochondria were derived from fibroblasts of a patient with either maternally inherited diabetes and deafness or progressive kidney disease. The fibroblasts from these clinically distinct patients carry different mitochondrial DNA haplotypes with the 3243 mutation in heteroplasmic form. Results. Heteroplasmy in the clonal cybrid cells ranged from 0 to 100 %, reflecting the heterogeneity of the mitochondrial donor cell. Cybrid cells containing predominantly mutant mitochondrial DNA showed lactic acidosis, poor respiration and marked defects in mitochondrial morphology and respiratory chain complex I and IV activities. No differences were observed in the extent of the mitochondrial dysfunction between the mutant cells derived from the two donors. Conclusion/interpretation. These results provide evidence for a pathogenic effect of the tRNA ^Leu(UUR) mutation in maternally inherited diabetes and deafness and progressive kidney disease, and show no evidence of a contribution of the mitochondrial DNA haplotype as a modulating the biochemical expression of the mutation. [Diabetologia (1999) 42: 485–492] Received: 13 August 1998 and in final revised form: 7 December 1998     

线粒体DNA点突变有关的中国大家族母系遗传性高血压研究

目的 研究具有母系遗传性特点的原发性高血压中国大家系临床与遗传学特点。方法 对入选的1865例原发性高血压患者进行线粒体DNA测序分析,发现线粒体DNA点突变,对其进行家系随访,收集该家系成员临床资料进行分析,分析其遗传学特点。结果 该家系中母系成员高血压患病率高达55.6%,非母系成员高血压患病率15.6%（P＜0.01）;母系成员高血压发病年龄有提前的趋势[Ⅱ代（62.0±6.2）岁;Ⅲ代（46.3±5.8）岁;Ⅳ代（23.3±2.9）岁]母系成员血糖、总胆固醇、血钠明显高于非母系成员（P＜0.05）,而超声结果没有明显差异;遗传学分析发现母亲患病子代发病率明显高于父亲患病者（P＜0.05）,男女发病率没有差异（P＞0.05）;结论 该家系母系成员高血压发病率明显高于非母系成员,该家系符母系遗传特点,高血压发病与线粒体DNA突变有关,提示线粒体DNA突变可能与母系遗传性高血压发病有关,在高血压发病中发挥重要作用。     

A pilot study of mitochondrial DNA point mutation A3243G in a sample of Croatian patients having type 2 diabetes mellitus associated with maternal inheritance

Abstract In this work, patients having type 2 diabetes mellitus and diabetic mothers were tested for the presence of mitochondrial DNA point mutation A3243G. This mutation is associated with the MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes), diabetes and deafness. Twenty-two diabetic persons were screened. DNA was isolated from peripheral blood lymphocytes and from swabs of oral mucosa. The mitochondrial DNA point mutation A3243G was detected using PCR-RFLP test. The mutation was detected in oral mucosal DNA of two patients (but not from lymphocyte DNA). One patient was a man with hearing and visual impairments and proteinuria; the other was a woman having proteinuria but no hearing impairment. The mutation was not detectable in oral mucosal DNA from the control persons: 20 diabetic patients having diabetic fathers and 22 healthy, nondiabetic volunteers. The incidence of mitochondrial DNA point mutation A3243G in this study of Croatian diabetic patients is in line with data in the literature.     

Mutation in the mitochondrial tRNAleu at position 3243 and spontaneous abortions in Japanese women attending a clinic for diabetic pregnancies

Summary Mitochondrial DNA is exclusively maternally inherited. We recently found the prevalence of diabetic patients with an A to G transition at position 3243 of leucine tRNA (3243 base pair (bp) mutation) to be nearly 1 % in randomly selected Japanese subjects. Here, we report the higher prevalence of diabetic patients with the 3243 bp mutation in a specific Japanese population of women attending a diabetic pregnancy clinic. Of 102 patients with non-insulin-dependent diabetes mellitus 6 (5.9 %) were positive for the mutation, 1 (8.3 %) of 12 patients with gestational diabetes and 2 (5.9 %) out of 34 borderline diabetic patients. In contrast, none of 64 patients (0 %) with insulin-dependent diabetes mellitus had the 3243 bp mutation. Moreover, there was a difference in the prevalence of spontaneous abortions between patients with and without this mutation (27.3 vs 12.4 %). Among nine probands with the mutation, four had a history of one spontaneous abortion (p = 0.0518) and two had a history of two abortions (p = 0.0479). Two probands had a spontaneous abortion even while under strict diabetic metabolic control. The 3243 bp mutation thus may cause spontaneous abortion during pregnancy. [Diabetologia (1995) 38: 809–815] Received: 24 August 1994 and in revised form: 29 December 1994     

糖尿病与线粒体ND1点突变的关系

目的探讨湖北省线粒体基因的热点突变区域ND1点突变(3243,3316,3394,3593)与老年2型糖尿病的关系。方法采用聚合酶链反应-限制性片段长度多态性法对无血缘关系的134例老年糖尿病患者及152例正常对照个体的血细胞线粒体DNA进行突变分析。结果病例组中3316G→A点突变率为3·7%,3394T→C点突变发生率为3·0%,而对照组3316和3394的突变率分别为0·66%和0,3394组间差异比较均有显著性(P<0·05)。病例组中3593点突变发生率为0·75%,对照组未见该突变,两组间差异无显著性。未发现3243的突变。结论线粒体DNA3394T→C突变与老年线粒体糖尿病的发生与发展有关,并起着重要作用。     

线粒体tRNAleu(UUR)基因突变糖尿病

目的 探讨线粒体tRNA^leu(UUR)基因突变糖尿病（MDM）在沈阳地区汉族人中的检出率及其临床表现。方法 应用聚合酶链反应／ApaI酶解法检测100例母亲患有糖尿病（DM）的2型DM患者的tRNA^leu(UUR)基因。结果 100例患者中3例有此基因突变；结合家系调查除认识了本病一般临床表现外，尚发现几种少见表现类型：孪生儿MDM、未被证实为母系遗传的MDM及尚未发病的MDM致病基因携带者。结论 本病在有DM家族史、尤其母亲患有DM的2型DM患者中的检出率为3％；孪生儿MDM更体现了本病呈母系遗传的特点，另有一例未被证实为母系遗传的MDM，需对其进一步研究。     

Association between HLA and islet cell antibodies in diabetic patients with a mitochondrial DNA mutation at base pair 3243

Summary Islet cell antibodies (ICA), autoantibodies to glutamic acid decarboxylase (GAD) and HLA genotypes were examined in 31 patients with diabetes and a mitochondrial gene mutation located at base pair 3243 (mtDNA 3243 mutation). ICA was detected in 42 % (13/31) of these patients compared to 0 of 90 among healthy control subjects. The ICA showed a “non-restricted” pattern of staining in all 13 ICA-positive patients. In a sensitive radioligand assay only 2 of 31 (6 %) diabetic patients with the mutation were positive for both GAD65 autoantibodies and ICA, while the remaining 29 patients were GAD65 antibody negative. The ICA-positive patients had an increased frequency of the HLA-DQA1*0301 allele compared to control subjects (p<0.05). Of the diabetic patients with the mutation 45 % (14/31) had progressive clinical course of betacell failure. These results indicate that patients with an mtDNA 3243 mutation may develop islet autoimmunity associated with ICA and GAD autoantibodies. We hypothesize that the presence of HLA-DQA1*0301 in individuals with the mtDNA 3243 mutation increases the risk for diabetes and associated autoantibodies against islet cell antigens.     

线粒体DNA变异与老年2型糖尿病患者易感性的相关性

目的 研究湖北地区老年2型糖尿病(T2DM)患者中线粒体基因突变的发生率及其相关性.方法 采用PCR-RFLP、基因测序技术,对175例老年T2DM患者和200例糖耐量正常的健康老年对照组进行检测.结果 MIND1 3316(G→A)、MTTL1 3243(A→G)、MIND13394( T→C)、MIND14216(T→C) MIND14164(A→G)和MIND2 5178( T→C)变异率分别为3.26％、2.72％、1.71％、4％、34.9％;对照组检出3316(G→A)突变2例(0.99％)、4164 5例(0.99％)、5718(T→C)变异64例(32.3％),未检出3394、4216的点突变;两组间3394(T→C)变异率差别有统计学意义(P＜0.05);且T2DM组5178A基因型血清TC水平低于5178C基因型(P＜0.05),但TG、LDL-C、HDL-C、apoA、apoB、Lp(a)水平两组无统计学意义.结论 3394( T→C)与老年T2DM患者的易感性有一定关联,5178(T→C)变异与湖北地区老年汉族人T2DM的脂代谢相关.     

Age of onset possibly associated with the degree of heteroplasmy in two male siblings with diabetes mellitus having an A to G transition at 3243 of mitochondrial DNA.

We describe two male siblings with diabetes mellitus caused by mitochondrial 3243 mutation. The level of heteroplasmy in peripheral blood leucocytes was determined by a last-cycle hot PCR method. The younger brother, who had 39% heteroplasmy, developed diabetes at age of 25, and demonstrated a lean body habitus and blunted insulin secretion. The elder brother, who had 22% heteroplasmy, was diagnosed at the age of 42. The younger brother showed a higher increment of serum lactate after exercise. In these siblings the level of heteroplasmy in their peripheral blood leucocytes appeared to be associated with age of onset of diabetes.     

Prevalence and clinical characteristics of maternally inherited diabetes and deafness caused by the mt3243A > G mutation in young adult diabetic subjects in Sri Lanka

Aims The maternally inherited mt3243A > G mutation is associated with a variable clinical phenotype including diabetes and deafness (MIDD). We aimed to determine the prevalence and clinical characteristics of MIDD in a large South Asian cohort of young adult‐onset diabetic patients from Sri Lanka. Methods DNA was available from 994 subjects (age of diagnosis 16–40 years, age at recruitment ≤ 45 years). Mutation screening was performed using a QRT‐PCR method on an ABI 7900HT system using sequence‐specific probes. Samples with heteroplasmy ≥ 5.0% were considered positive. Results Nine (four males) mutation‐positive subjects were identified (prevalence 0.9%). They were diagnosed at a younger age (25.9 ± 4.8 years vs. 31.9 ± 5.6 years, P = 0.002) and were lean (body mass index [BMI] 18.7 ± 2.7 kg/m² vs. 24.7 ± 4.0 kg/m², P < 0.001) compared to NMCs. One mutation‐positive subject (11.1%) had metabolic syndrome, compared to 633 (64.3%) of NMCs. Insulin therapy within 6 months of diagnosis was used in four (44.0%) carriers compared to 6.9% of NMCs (P = 0.002). Combined screening criteria of any two of maternal history of diabetes, personal history of hearing impairment and family history of hearing impairment only identified five (55%) of the carriers, with a positive predictive value of 7.4%. Conclusions The prevalence of mt3243A > G mutation among young adult‐onset diabetic subjects from Sri Lanka was 0.9%. Our study demonstrates that a maternal family history of diabetes and either a personal and/or family history of deafness only distinguish half of patients with MIDD from Sri Lankan subjects with young‐onset diabetes.     

线粒体基因突变糖尿病家系一例分析与文献复习

通过分析一例伴有耳聋的糖尿病患者及其家系成员的临床特征和家系基因谱,从临床、生化、基因水平进行文献复习,以明确线粒体基因突变糖尿病及并发症的诊断.先证者体型消瘦、皮肤黝黑,活动耐量减低,胰岛功能进行性下降,血乳酸水平升高,肾小球滤过率正常,尿常规隐血持续阳性,且合并肠息肉,心律失常.该家系多人患有糖尿病,除先证者次兄体健外,先证者及其长兄患有糖尿病,并伴有听力下降;其母亲死于糖尿病并发症,其女听力轻度下降,血糖尚正常.家系中所有听力下降的患者基因测序结果均为线粒体基因（3243A→G）突变.文献复习表明线粒体基因突变糖尿病有多种表型,基因测序有助于最终诊断.     

Retinal and renal complications in patients with a mutation of mitochondrial DNA at position 3,243 (maternally inherited diabetes and deafness). A case–control study

AIMS/HYPOTHESIS: We assessed the prevalence and determinants of retinal and renal complications in patients with maternally inherited diabetes and deafness (MIDD). METHODS: This was a multicentre prospective study comparing the prevalence of retinopathy and renal disease in 74 patients with MIDD and 134 control patients matched for sex, age and clinical presentation at onset of diabetes, duration of diabetes and current treatment. Comparisons were adjusted for HbA(1c) and hypertension. RESULTS: In MIDD patients, HbA(1c) (7.6 +/- 1.6 vs 8.5 +/- 2.0%, p < 0.002), systolic blood pressure (126.6 +/- 16.2 vs 133.1 +/- 17.3 mmHg, p < 0.007) and prevalence of hypertension (33.8 vs 64.2%, p < 0.0001) were lower than in control patients. Prevalence of diabetic retinopathy was 3.7-fold lower in MIDD patients (6/74, 8 vs 40/134, 29.6%, p < 0.0001). Differences between groups remained significant after adjustment for hypertension, systolic blood pressure and HbA(1c). In MIDD, urinary albumin excretion (314.8 vs 80.1 mg/24 h, p = 0.035) and creatinine plasma levels (103.5 vs 82.2 micromol/l, p = 0.0178) were higher and GFR was lower. Impaired renal function (GFR <60 ml/min) was four- to sixfold more frequent in MIDD. Differences between MIDD and control diabetic patients further increased when adjusted for HbA(1c) and systolic blood pressure (p < 0.0001). Adjustment for treatment with an ACE inhibitor or angiotensin II receptor antagonist did not modify the results. CONCLUSIONS/INTERPRETATION: This study indicates that diabetic retinopathy is less prevalent in MIDD than in control diabetes. This suggests that retinal alterations due to mitochondrial disease may have a protective role. By contrast, nephropathy is far more frequent in MIDD, suggesting the presence of a specific renal disease independent of diabetic nephropathy.     

Maternally inherited diabetes and deafness: a new diabetes subtype

Summary Diabetes mellitus is a common disease with many forms of clinical expression. In addition, the development of diabetic complications is not only dependent on glycaemic control but also on individual factors which may be related to genetic heterogeneity. At present, multiple genetic factors are being recognized as contributing to the development of diabetes or possibly modulating its clinical expression. The purpose of this review is to give an overview of our current knowledge on a subtype of diabetes which is apparently caused by a single mutation in the mitochondrial DNA.Abbreviations WHO World Health Organization - IDDM insulin-dependent diabetes mellitus - NIDDM non-insulin-dependent diabetes mellitus - mtDNA mitochondrial DNA - MIDD maternally inherited diabetes and deafness - MODY maturity onset diabetes of the young - MELAS mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes     

A mitochondrial DNA variant at position 16189 is associated with type 2 diabetes mellitus in Asians

Aims/hypothesis This multinational study was conducted to investigate the association between a mitochondrial DNA (mtDNA) T16189C polymorphism and type 2 diabetes in Asians. The mtDNA 16189C variant has been reported to be associated with insulin resistance and type 2 diabetes. However, a recent meta-analysis concluded that it is negatively associated with type 2 diabetes in Europids. Since the phenotype of an mtDNA mutant may be influenced by environmental factors and ethnic differences in the nuclear and mitochondrial genomes, we investigated the association between the 16189C variant and type 2 diabetes in Asians. Methods The presence of the mtDNA 16189C variant was determined in 2,469 patients with type 2 diabetes and 1,205 non-diabetic individuals from Korea, Japan, Taiwan, Hong Kong and China. An additional meta-analysis including previously published Asian studies was performed. Since mtDNA nucleotide position 16189 is very close to the mtDNA origin of replication, we performed DNA-linked affinity chromatography and reverse-phase liquid chromatography/tandem mass spectrometry and chromatin immunoprecipitation to identify protein bound to the 16189 region. Results Analysis of participants from five Asian countries confirmed the association between the 16189C variant and type 2 diabetes [odds ratio (OR) 1.256, 95% CI 1.08–1.46, p = 0.003]. Inclusion of data from three previously published Asian studies (type 2 diabetes n = 3,283, controls n = 2,176) in a meta-analysis showed similar results (OR 1.335, 95% CI 1.18–1.51, p = 0.000003). Mitochondrial single-stranded DNA-binding protein (mtSSB) was identified as a candidate protein bound to the 16189 region. Chromatin immunoprecipitation in cybrid cells showed that mtSSB has a lower binding affinity for the 16189C variant than the wild-type sequence. Conclusions/interpretation The mtDNA 16189C variant is associated with an increased risk of type 2 diabetes in Asians. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

中国40岁以下发病的糖尿病患者线粒体基因tRNALeu(UUR)A3243G突变的研究

目的探讨中国40岁以下发病的糖尿病患者线粒体基因tRNALeu(UUR)3243A→G突变的发生率.方法 117例40岁以下发病且有糖尿病家族史的糖尿病以及90例40岁以下发病无糖尿病家族史的糖尿病患者和50例正常人分别测定体重指数(BMI)、臀腰比(WHR)、了解代谢控制、胰腺分泌和胰岛素抵抗等情况并用PCR-RFLP检测线粒体基因tRNALeu(UUR)3243A→G突变.结果糖尿病2亚组BMI分别为(25.1±3.1)和(24.1±3.4)kg/m2,差异无显著性;FBG、HbA1c均较高,且存在明显胰岛素抵抗(HOMA-IR 3.41～9.29).在207例患者中发现1例线粒体基因tRNALeu(UUR)3243A→G突变患者.在该患者家系中又发现5例存在线粒体基因突变,其中2例为非糖尿病患者.这些患者的共同特点是耳聋伴或不伴糖尿病,糖尿病患者消瘦较早使用胰岛素.结论中国40岁以下发病的糖尿病患者线粒体基因突变发生率约为0.48%,有家族史者约为0.85%.