Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Out of 90 Portuguese patients with mitochondrial cytopathy, six harbored the A3243G mutation in the mtDNA tRNA(Leu(UUR)) gene ('MELAS mutation'). They had heterogeneous clinical features, including myopathy with stroke-like episodes, progressive external ophthalmoparesis, diabetes mellitus, and subacute encephalopathy. Histochemical and biochemical analyses of muscle biopsies showed abundant ragged-red fibers reacting positively with the cytochrome oxidase stain, and decreased respiratory chain enzyme activities. On average, the proportion of mutated mtDNA was 67% (20-88%) in tissues from patients and 21% (0-49%) in blood from 20 maternal relatives. The proportion of mutated mitochondrial genomes in muscle did not correlate with clinical presentation or duration of disease. This study, the first in Portuguese patients, confirms the frequent occurrence of the A3243G mutation in patients with mitochondrial diseases, and emphasises the usefulness of genetic testing in reaching a correct diagnosis.
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PMID:The mitochondrial DNA A3243G mutation in Portugal: clinical and molecular studies in 5 families. 1037 Oct 79

To identify abnormally expressed genes contributing to muscle insulin resistance in type 2 diabetes, we screened the mRNA populations from normal and diabetic human skeletal muscle using cDNA differential display and isolated abnormally expressed cDNA clones of mitochondrial-encoded NADH dehydrogenase 1 (ND1), cytochrome oxidase 1, tRNA(leu), and displacement loop. We then measured mRNA expression of these mitochondrial genes using a relative quantitative polymerase chain reaction method in biopsies taken before and after an insulin clamp in 12 monozygotic twin pairs discordant for type 2 diabetes and 12 matched control subjects and in muscle biopsies taken after an insulin clamp from 13 subjects with type 2 diabetes, 15 subjects with impaired glucose tolerance, and 14 subjects with normal glucose tolerance. Insulin infusion increased mRNA expression of ND1 from 1.02 +/- 0.04 to 2.55 +/- 0.30 relative units (P < 0.001) and of cytochrome oxidase 1 from 0.80 +/- 0.01 to 1.24 +/- 0.10 relative units (P < 0.001). The ND1 response to insulin correlated with glucose uptake (r = 0.46, P = 0.002). Although the rate of insulin-mediated glucose uptake was decreased in the diabetic versus the nondiabetic twins (5.2 +/- 0.7 vs. 8.5 +/- 0.8 mg x kg(-1) fat-free mass x min(-1), P < 0.01), insulin-stimulated ND1 expression was not significantly different between them (2.4 +/- 0.5 vs. 2.7 +/- 0.5 relative units). Neither was there any significant intrapair correlation of ND1 expression between the monozygotic twins (r = -0.15, NS). We conclude that insulin upregulates mitochondrial-encoded gene expression in skeletal muscle. Given the positive correlation between ND1 expression and glucose uptake and the lack of intrapair correlation between monozygotic twins, mitochondrial gene expression may represent an adaptation to intracellular glucose flux rather than an inherited trait.
Diabetes 1999 Aug
PMID:Insulin-regulated mitochondrial gene expression is associated with glucose flux in human skeletal muscle. 1042 66

The substitution of guanine for adenine at position 3243 of the leucine tRNA gene of mitochondrial DNA was originally described in association with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes). Diabetes mellitus associated with the mutation (mitochondrial diabetes) is a different phenotype from MELAS. We identified 11 patients with the mutation among 385 Japanese diabetic patients: two had MELAS and nine had mitochondrial diabetes. We present data on a male patient with mitochondrial diabetes who developed the nephrotic syndrome at the age of 23. Light microscopy revealed mesangial expansion, PAS-positive deposits and segmental sclerosis in the glomeruli. Scattered mesangial electron-dense deposits and thickening of the basement membrane were found on electron microscopy, suggesting that diabetic glomerulosclerosis accompanied by focal glomerulosclerosis (FGS). Mitochondrial diabetes may pre-dispose patients to renal complications, including forms of glomerulonephritis, such as FGS.
Diabetes Res Clin Pract 1999 Jun
PMID:Renal complications in patients with diabetes mellitus associated with an A to G mutation of mitochondrial DNA at the 3243 position of leucine tRNA. 1046 41

Cells harboring patient-derived mitochondria with an A-to-G transition at nucleotide position 3243 of their mitochondrial DNA display severe loss of respiration when compared with cells containing the wild-type adenine but otherwise identical mitochondrial DNA sequence. The amount and degree of leucylation of tRNA(Leu(UUR)) were both found to be highly reduced in mutant cells. Despite the low level of leucyl-tRNA(Leu(UUR)), the rate of mitochondrial translation was not seriously affected by this mutation. Therefore, decrease of mitochondrial protein synthesis as such does not appear to be a necessary prerequisite for loss of respiration. Rather, the mitochondrially encoded proteins seem subject to elevated degradation, leading to a severe reduction in their steady state levels. Our results favor a scheme in which the 3243 mutation causes loss of respiration through accelerated protein degradation, leading to a disequilibrium between the levels of mitochondrial and nuclear encoded respiratory chain subunits and thereby a reduction of functional respiratory chain complexes. The possible mechanisms underlying the pathogenesis of mitochondrial diabetes is discussed.
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PMID:The diabetes-associated 3243 mutation in the mitochondrial tRNA(Leu(UUR)) gene causes severe mitochondrial dysfunction without a strong decrease in protein synthesis rate. 1051 49

An A-to-G transition at position 3243 of the mitochondrial DNA is known to be a pathogenic factor for mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), diabetes and cardiomyopathy. This mutation causes dysfunction of the central nervous system in MELAS. Because the heart, as well as the brain and nervous system, is highly dependent on the energy produced by mitochondrial oxidation, these tissues are more vulnerable to mitochondrial defects. Cardiac abnormalities were assessed in 10 diabetic patients associated with this mutation using echocardiography and 123I-metaiodobenzylguanidine (MIBG) scintigraphy, and compared with 19 diabetic patients without the mutation. Duration of diabetes, therapy, control of blood glucose and diabetic complications, such as diabetic retinopathy and nephropathy, were not different between the 2 groups. Diabetic patients with the mutation had a significantly thicker interventricular septum (16.8+/-3.7 vs 11.0+/-1.6mm, p<0.001) than those without the mutation. Fractional shortening was lower in diabetic patients with the mutation than those without it (30.7+/-7.0 vs 42.5+/-6.6, p<0.001). MIBG uptake on the delayed MIBG image was significantly lower in diabetic patients with the mutation than in those without the mutation (mean value of the heart to mediastinum ratio: 1.6+/-0.2 vs 2.0+/-0.4, p>0.05). In conclusion, left ventricular hypertrophy with or without abnormal wall motion and severely reduced MIBG uptake may be characteristic in diabetic patients with a mutation in the mitochondrial tRNA(Leu(UUR)) gene.
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PMID:Cardiac abnormalities in diabetic patients with mutation in the mitochondrial tRNA(Leu(UUR)) gene. 1059 94

The A3243G mutation of mitochondrial DNA (mtDNA) has been shown to be responsible for or associated with mitochondrial myopathy, encephalopathy, lactic acidosis, strokelike episodes (MELAS) syndrome, diabetes mellitus (DM) and several other neuromuscular diseases. We used polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) to identify the A3243G mtDNA mutation and an electron microscope to examine mitochondrial derangement in the muscle biopsies of a 38-year-old man suspected to have MELAS syndrome with DM. We found great variability in the clinical presentation and in the proportion of mtDNA with the A3243G mutation in the matrilineal family members of the patient. The proband had atypical MELAS syndrome, recurrent vascular headache, and DM (MELASDM), and his mother manifested chronic progressive ptosis and DM (CPPDM). Brain magnetic resonance imaging of the proband showed high signal intensity in the left temporoparieto-occipital area on T2 weighted images (T2WI). The blood lactate level ranged from 2.32 to 4.70 mmol/l, and two-hour postprandial glucose ranged from 124 mg/dl to 148 mg/dl. The blood lactate and postprandial glucose of the proband's mother were 3.15 mmol/l and 192 mg/dl, respectively. Electron microscopic examination of a muscle biopsy of the patient showed abnormal mitochondria with decreased density of cristae and membrane degeneration. No ragged-red fibers were detected in muscle upon staining with modified Gomori trichrome. The hair follicles and blood cells of the patient and his mother showed the A3243G mutation in the tRNA(Leu)(UUR) gene. The proportions of the mutant DNA in the hair follicles and blood cells of the proband were 36.8% and 35.2%, respectively, and those of the patient's mother were 28.8% and 13.9%, respectively. We conclude that the A3243G mtDNA mutation may manifest with MELASDM or CPPDM in different matrilineal members of the same family as a result of differences in random segregation of the heteroplasmic A3243G mutant mtDNA in the affected tissues of patients.
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PMID:Phenotypic heterogeneity in a Chinese family with mitochondrial disease and A3243G mutation of mitochondrial DNA. 1064 55

The mitochondrial tRNA(Leu)(UUR) (R = A or G) gene possesses several hot spots for pathogenic mutations. A point mutation at nucleotide position 3243 or 3271 is associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes and maternally inherited diabetes with deafness. Detailed studies on two tRNAs(Leu)(UUR) with the 3243 or 3271 mutation revealed some common characteristics in cybrid cells: (i) a decreased life span, resulting in a 70% decrease in the amounts of the tRNAs in the steady state, (ii) a slight decrease in the ratios of aminoacyl-tRNAs(Leu)(UUR) versus uncharged tRNAs(Leu)(UUR), and (iii) accurate aminoacylation with leucine without any misacylation. As a marked result, both of the mutant tRNA molecules were deficient in a modification of uridine that occurs in the normal tRNA(Leu)(UUR) at the first position of the anticodon. The lack of this modification may lead to the mistranslation of leucine into non-cognate phenylalanine codons by mutant tRNAs(Leu)(UUR), according to the mitochondrial wobble rule, and/or a decrease in the rate of mitochondrial protein synthesis. This finding could explain why two different mutations (3243 and 3271) manifest indistinguishable clinical features.
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PMID:Modification defect at anticodon wobble nucleotide of mitochondrial tRNAs(Leu)(UUR) with pathogenic mutations of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. 1066 May 92

Mitochondrial DNA (mtDNA) gene defects may play a role in the development of maternally inherited diabetes mellitus and deafness (MIDD). A family from Southern Italy who showed maternal transmission of type 2 diabetes mellitus with three individuals affected is described. A 10.4 kb deletion and mutations at nucleotide positions (np) 3243, 7445 and 11778 in the mtDNA of six relatives were sought. The mitochondrial np 3243 mutation of the tRNA Leu (UUR) gene was identified in a boy affected by optic atrophy and mental retardation, as well as in his diabetic mother. No other mutations or deletions were found. Our study points out the variable phenotypic expression of the np 3243 mtDNA mutation. This may suggest the presence of other mitochondrial or nuclear mutations required to modulate the phenotype. A clinical and metabolic follow-up of all family members was necessary to understand the role of the np 3243 mutation, especially in one child affected by optic atrophy and mental retardation. Further studies will be aimed at investigating the prevalence of mutations and deletions of mtDNA in type 2 diabetes mellitus.
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PMID:Mitochondrial DNA mutation at np 3243 in a family with maternally inherited diabetes mellitus. 1066 22

Mitochondrial DNA mutations have been implicated in many diseases including diabetes mellitus. Although gestational diabetes mellitus (GDM) has been suggested to have genetic determinant and to be etiologically indistinct with non-insulin-dependent diabetes mellitus (NIDDM), its association with mitochondrial gene mutations is still unknown. In this study, 137 patients with GDM and 292 non-diabetic pregnant controls were examined for mitochondrial DNA mutations from the nucleotide 3130-4260 encompassing tRNA-Leu gene and adjacent NADH dehydrogenase 1 gene by polymerase chain reaction, single-stranded conformation polymorphism, restriction fragment length polymorphism and DNA sequencing. One heteroplasmic mutation at the position of 3398 (T-C), which changed a highly conserved methionine to threonine in NADH dehydrogenase subunit 1, was identified in 2.9% GDM patients but not in the controls, indicating its association with GDM (P = 0.01). Two novel mutations, a heteroplasmic C3254A and a homoplasmic A3399T, were also found in GDM subjects, the functional meaning of which merits further investigation. G3316A and T3394C mutations implicated in NIDDM, were seen at higher frequencies in patients with GDM than the controls. Our results suggest that mitochondrial DNA mutations may contribute to the development of GDM in some patients.
Diabetes Res Clin Pract 2000 Apr
PMID:Mitochondrial gene mutations in gestational diabetes mellitus. 1070 97

We describe an 8-day-old baby girl presenting a fatal infantile form of hypertrophic obstructive cardiomyopathy, associated with an A8296G mutation in the mitochondrial tRNA(Lys) gene. She was born from a healthy unrelated couple, and was the first infant of dizygotic twins. Soon after birth, she was noted to have tachypnea and generalized hypotonia. She had high levels of lactate and pyruvate, and was diagnosed as having hypertrophic cardiomyopathy using echocardiography. She died by cardiac failure. Mitochondrial DNA analysis was performed by sequencing after PCR-subcloning methods, and the percentage of mutation was measured using PCR-RFLP methods. In various tissues obtained at autopsy, analysis showed a heteroplasmic population of A8296G mutation in the mitochondrial tRNA(Lys) gene in all the tissues examined. Maternal inheritance was demonstrated in the family members. Our data demonstrated that an A8296G mutation in the mitochondrial tRNA(Lys) gene showed clinical heterogeneity from a milder form previously reported as mitochondrial diabetes mellitus, to a more severe form as hypertrophic obstructive cardiomyopathy, according to the spatial distribution of this mutation. Hum Mutat 15:382, 2000.
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PMID:Fatal hypertrophic cardiomyopathy associated with an A8296G mutation in the mitochondrial tRNA(Lys) gene. 1073 88


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