Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We screened 214 Japanese NIDDM (non-insulin-dependent) diabetic patients with a family history of diabetes for mutations in the mitochondrial tRNA(Leu(UUR)) gene using polymerase chain reaction-restriction fragment length polymorphism and direct sequencing. Six patients were identified as having an A to G transition at position 3243 (3243 mutation), but no patients were detected with a T to C transition at position 3271, in the mitochondrial tRNA(Leu(UUR)) gene. These two mutations were not present in 85 healthy control subjects. It was disclosed that the patients' mothers were also affected by diabetes mellitus in five of the six cases. In these six affected patients, the 3243 mutation shows variable phenotypes, such as the degree of multiple organ involvement, intrafamilial and interfamilial differences in disease characteristics, and the degree of the involvement of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) phenotype. Endocrinological examinations revealed that those diabetic patients with the 3243 mutation show not only beta-cell dysfunction, but also a defect in alpha-cell function, which is considered characteristic of diabetes with the 3243 mutation. When compared with 50 selected diabetic control subjects without the 3243 mutation, whose mothers, but not fathers, were found to have diabetes, it was established statistically that those with the 3243 mutation possess the following clinical characteristics; 1) the age of diabetes onset is lower, 2) they have lean body constitutions, and 3) they are more likely to be treated with insulin than control subjects. We suggest that diabetes with the 3243 mutation possesses phenotypes distinct from those in common forms of diabetes.
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PMID:Diabetes mellitus carrying a mutation in the mitochondrial tRNA(Leu(UUR)) gene. 926 98

The molecular genetics of mitochondria relevant to NIDDM is described, because the mutations in mitochondrial DNA cause diabetes. The non-Mendelian genetics, including maternal inheritance, heteroplasmy, stochastic segregation are characteristic of mitochondrial gene. Since aging causes rapid loss of mitochondrial function, which results in the retardation of insulin secretion via ATP-sensitive K-channel. This loss is not caused by the age-dependent mutation in the mitochondrial DNA, but by a nuclear aging, perhaps accompanied by the shortening of telomere. This was shown by the cybrid experiment. The aged mitochondria in cytoplasts are transferred to immortal rho = cells (cells devoid of mitochondrial DNA) and restored its oxidative and transcriptional activities (J. Biol. Chem. 269:6878, 1994). Thus, the control mechanism of transcription in mitochondria has been analyzed. The genes for mitochondrial transcription factor (mtTF1) an MRP-RNA have been sequenced and their regulatory elements are found (BBRC 194:544, 1993 etc.) The mutations in mitochondrial DNA that cause diabetes have been found, and from the stochastic segregation of the heteroplasmic mutated mitochondrial DNA, we could explain why the MELAS mutation is concentrated in some tissue (J. Neurol. Sci. 120:174, 1993). Although there have been many reports on the mitochondrial mutations found in diabetic patients, we have to be careful on polymorphism (J. Biol. Chem. in press).
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PMID:[Molecular genetics of mitochondria and diabetes]. 798 85

Non-insulin-dependent diabetes mellitus (NIDDM) has a strong genetic component and maternal factors have recently been implicated in disease inheritance. The mitochondrial myopathies are a group of diseases which often show maternal inheritance as a result of mtDNA defects; some patients have impaired glucose tolerance. Occasional families with maternally inherited diabetes and deafness associated with a deletion or point mutation of mtDNA have been reported. To assess the importance of mitochondrial gene defects in NIDDM, 150 unrelated diabetic subjects from Wales, UK and 68 unrelated patients with diabetes and at least one affected sibling from England, UK were studied. Southern blot analysis did not show any large mtDNA deletions or duplications. One patient had a mutation in the mitochondrial tRNAleu(UUR) gene at bp 3243. This mutation is commonly associated with the syndrome of mitochondrial encephalomyopathy, lactic acidosis and stroke like episodes (MELAS). Study of this patient and his siblings showed a distinct form of late-onset diabetes associated with nerve deafness but no clinical features of the MELAS syndrome. No diabetic subject was shown to have the mtDNA mutation at position 8344 (tRNA(lys)) which has previously been described in the syndrome of mitochondrial encephalomyopathy and red-ragged fibres (MERRF). The role of other mitochondrial gene defects in diabetes and the pathophysiological basis of glucose intolerance in patients with the MELAS mutation requires further elucidation.
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PMID:Mitochondrial gene defects in patients with NIDDM. 926 98

In 79 South Indian nuclear pedigrees ascertained via probands with NIDDM and both parents living, parental diabetic status was established through previously diagnosed NIDDM (n = 97) or oral glucose tolerance testing (n = 61). There was no significant difference between diabetes prevalence in mothers and fathers (60 vs 53 (76% vs 67%), respectively, p = 0.22). 'Age at diabetes diagnosis' survival curves did differ according to parental gender (p = 0.02) but this may reflect gender differences in health provision rather than pathophysiology. No maternal excess effects of the magnitude evident in previous studies were detected, suggesting either ethnic differences or overestimation of the maternal effect when reported histories of parental diabetes have been used. The tRNA(Leu(UUR) gene region was studied for diabetes-associated variation given the role of mutations in this gene in some pedigrees displaying maternal transmission of NIDDM. None of 142 unrelated South Indian NIDDM subjects displayed the MELAS mutation at nt3243. However, sequencing identified two variants of potential importance: (a) at nt3290 in the tRNA(Leu(UUR) gene, seen in 7/142 diabetic and 1/85 control subjects (p = 0.11), (b) at nt3316 in the ND1 gene (4/142 vs 1/85 subjects, respectively (p = 0.51)). Further studies are needed to determine the relevance of these variants to the development of NIDDM.
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PMID:Evaluation of the importance of maternal history of diabetes and of mitochondrial variation in the development of NIDDM. 873 23

We describe a family with two cases of adult-onset mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome. Interestingly, the proband also had non-insulin dependent diabetes mellitus and hyperthyroidism. Endocrinological studies demonstrated a high titer of TSH receptor antibody in the proband and elevated levels in her maternal relatives. Analysis of mitochondrial DNA (mtDNA) showed an A-to-G transition at nucleotide position 3243 in the tRNA (Leu(UUR)) gene (A3243G) in the three generations of the family. Furthermore, a previously described -260 bp tandem duplication in the D-loop region of mtDNA was also found in the proband and her maternal relatives. To our knowledge, such kind of duplication has never before been reported in the MELAS syndrome. The proportions of mtDNA with the -260 bp tandem duplication and A3243G point mutation were 12.5% and 82% in the muscle, respectively, and 1.6% and 35% in the blood cells, respectively, of the proband. We conclude that the hyperthyroidism in this MELAS patient may be related to the tandem duplication in the D-loop of mtDNA. This study further substantiates the importance of searching for additional genetic mutations in mitochondrial encephalomyopathic patients with new clinical phenotypes.
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PMID:MELAS syndrome associated with a tandem duplication in the D-loop of mitochondrial DNA. 883 8

An A-to-G mutation at np3243 in tRNA(Leu) (UUR) gene of the mitochondrial DNA has been described to associate with diabetes mellitus. This exists within the sequence that is important for binding termination factor, which ends the transcription of one of the two major transcripts. We investigated the prevalence of this mutation in randomly selected 276 NIDDM+ 24 IGT, 94 IDDM, and 115 non-diabetic control subjects. The mutation was also reported to exist frequently in slowly progressive IDDM. We recruited 116 juvenile onset autoimmune Type 1 diabetes and 154 autoimmune thyroid diseases to see if this mutation is involved in autoimmunity. We identified this mutation in 3 of 300 NIDDM+IGT (1%). None from IDDM or control group, nor from autoimmune disease group had this mutation. The patients with this mutation did not have cerebro-muscular symptoms as were observed in MELAS. One patient had only slight glucose intolerance indicating diabetes with this mutation may have various phenotypes. Genetic area around tRNA(Leu) (UUR) is a hot spot for pathological mutations. We directly sequenced this area of mtDNA from diabetes and identified a new polymorphism in ND-1 gene, which is situated downstream of tRNALeu (UUR) gene. We screened 154 IDDM and 254 NIDDM+ IGT patients, and identified it in 3 NIDDM and 2 IGT subjects. Both of the NIDDM patients had bilateral hearing impairment. None from 207 non-diabetic control subjects and IDDM were positive for this mutation. Its prevalence was a little more than that of an A-G mutation at np3243.
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PMID:Mitochondrial gene mutations that affect the binding of the termination factor and their prevalence among Japanese diabetes mellitus. 884 39

Diabetes mellitus associated with mitochondrial tRNA mutation at position 3243(DM-Mt3243) is a new disease. Patients have a distinctly different picture from MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). During observations at the Saiseikai Central Hospital, the following findings were noted in DM-Mt3243 patients: DM-Mt3243 patients are diagnosed earlier with diabetes, compared to NIDDM (non-insulin dependent diabetes mellitus) controls without family history. DM-Mt3243 patients often need insulin more often than NIDDM controls without family history. Post-treatment neuropathy and insulin edema are often found in DM-Mt3243, and the two phenomena possibly have a similar pathophysiology related to mitochondrial dysfunction. Ambiguous psychiatric disorders of functional psychosis are observed frequently in DM-Mt3243. Mild headache is common in DM-Mt3243 cases. Ambiguous neuromuscular abnormalities such as sleep disturbance, paresthesia of the legs, edema of the legs, and palpitation may be symptoms associated with mitochondrial dysfunction in DM-Mt3243. Coenzyme Q may be effective in the relief of these neuromuscular symptoms.
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PMID:Diabetes mellitus associated with 3243 mitochondrial tRNA(Leu(UUR)) mutation: clinical features and coenzyme Q10 treatment. 926 20

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.
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PMID:A pilot study of mitochondrial DNA point mutation A3243G in a sample of Croatian patients having type 2 diabetes mellitus associated with maternal inheritance. 1566 Feb 1

Adipocytes play an integrative role in the regulation of energy metabolism and glucose homeostasis in the human body. Functional defects in adipocytes may cause systemic disturbance of glucose homeostasis. Recent studies revealed mitochondrial abnormalities in the adipose tissue of patients with type 2 diabetes. In addition, patients with mitochondrial diseases usually manifest systemic metabolic disorder. However, it is unclear how mitochondrial dysfunction in adipocytes affects the regulation of glucose homeostasis. In this study, we induced mitochondrial dysfunction and overproduction of reactive oxygen species (ROS) by addition of respiratory inhibitors oligomycin A and antimycin A and by knockdown of mitochondrial transcription factor A (mtTFA), respectively. We found an attenuation of the insulin response as indicated by lower glucose uptake and decreased phosphorylation of Akt upon insulin stimulation of adipocytes with mitochondrial dysfunction. Furthermore, the expression of glucose transporter 4 (Glut4) and secretion of adiponectin were decreased in adipocytes with increased ROS generated by defective mitochondria. Moreover, the severity of insulin insensitivity was correlated with the extent of mitochondrial dysfunction. These results suggest that higher intracellular ROS levels elicited by mitochondrial dysfunction resulted in impairment of the function of adipocytes in the maintenance of glucose homeostasis through attenuation of insulin signaling, downregulation of Glut4 expression, and decrease in adiponectin secretion. Our findings substantiate the important role of mitochondria in the regulation of glucose homeostasis in adipocytes and also provide a molecular basis for the explanation of the manifestation of diabetes mellitus or insulin insensitivity in a portion of patients with mitochondrial diseases such as MELAS or MERRF syndrome.
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PMID:Mitochondrial dysfunction leads to impairment of insulin sensitivity and adiponectin secretion in adipocytes. 2325 16

The 3243A>G mutation of mtDNA usually is associated with MELAS syndrome. Here we report a patient with the 3243A>G mutation presenting only recurrent muscle fatigue and elevated levels of serum creatine kinase (CK). The mother of the proband was referred to us for type 2 diabetes mellitus, muscle pain and sensorineural hearing loss. The percentage of mutation load in different tissues was similar in both subjects, except in the urinary epithelium. The mutation load in the son's urinary epithelial cells (UEC) was consistently higher (nearly 50%) than in his muscle (nearly 20%). We conclude that a correlation between the proportion of the UEC mutation load and the severity of the disease was lacking in this pedigree. The use of UEC as the tissue of choice in the noninvasive diagnosis of the 3243A>G mutation offers a very attractive alternative to muscle biopsy. Finally, our data expand the clinical spectrum of the 3243A>G mutation.
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PMID:A case of 3243A>G mutation in mtDNA presenting as apparently idiopathic hyperCKemia. 2446 40


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