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)

We describe a family which demonstrates and expands the extreme clinical variability now known to be associated with the A-->G transition at nucleotide position 3243 of the mitochondrial DNA. The propositus presented at birth with clinical manifestations consistent with diabetic embryopathy including anal atresia, caudal dysgenesis, and multicystic dysplastic kidneys. His co-twin was normal at birth, but at 3 months of life, presented with intractable seizures later associated with developmental delay. The twins' mother developed diabetes mellitus type I at the age of 20 years and gastrointestinal problems at 22 years. Since age 19 years, the maternal aunt has had recurrent strokes, seizures, mental deterioration and deafness, later diagnosed as MELAS syndrome due to the tRNA(Leu(UUR)) A-->G mutation. A maternal uncle had diabetes mellitus type I, deafness, and normal intellect, and died at 35 years after recurrent strokes. This pedigree expands the known clinical phenotype associated with tRNA(Leu(UUR)) A-->G mutation and raises the possibility that, in some cases, diabetic embryopathy may be due to a mitochondrial cytopathy that affects both the mother's pancreas (and results in diabetes mellitus and the metabolic dysfunction associated with it) and the embryonic/fetal and placental tissues which make the embryo more vulnerable to this insult.
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PMID:The expanding clinical phenotype of the tRNA(Leu(UUR)) A-->G mutation at np 3243 of mitochondrial DNA: diabetic embryopathy associated with mitochondrial cytopathy. 872 72

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

An A3243G point mutation of the mitochondrial tRNA(Leu(UUR)) gene was detected in a Caucasian family with maternal diabetes mellitus and signs of mitochondrial dysfunction such as muscular hypotonia, encephalopathy, lactic acidosis, stroke-like episodes (MELAS), neurosensory hearing loss, cardial pre-excitation, and short stature. Low levels (10 JDF) of islet cell antibodies (ICA) in insulin-treated diabetes of the mother and impaired glucose tolerance with high levels of ICA (80 JDF) in her older son indicated that mitochondrial diabetes mellitus may involve beta cell damage. Furthermore, exocrine pancreas cell damage may also occur since the stroke-like episodes of this son were combined with pancreatitis. In all family members HLA types and plasma antioxidants were determined. Normal concentrations of hydro- and lipophilic antioxidants (including ubiquinol-10) were found.
Exp Clin Endocrinol Diabetes 1996
PMID:Islet cell antibodies in diabetes mellitus associated with a mitochondrial tRNA(Leu(UUR)) gene mutation. 881 38

A mitochondrial A 3243 G mutation in the tRNA(Leu(UUR)) gene was first described as a common cause of MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like syndrome). This same mutation is also the cause of a totally different disorder, a subtype of diabetes mellitus which is inherited maternally and often associated with sensorineural hearing loss. In this paper, we report on a Japanese boy with A 3243 G who developed a previously undescribed combination of symptoms, nephropathy and growth hormone deficiency. The patient first presented with short stature and moderate mental retardation. Growth hormone (GH) provocation tests showed deficient growth hormone secretion. During the course of follow up, he presented with progressive nephropathy followed by the development of diabetes mellitus. The results of laboratory tests and renal biopsy were against incidental association of known types of nephropathy. On PCR-RFLP analysis, the percentage of mutated mtDNA was higher in the renal biopsy specimen than 12 peripheral blood leucocytes. Our case suggests that mitochondrial diseases should be taken into account when there is nephropathy of unknown cause. In addition, the presence of growth hormone deficiency may account for part of the mechanism leading to short stature commonly seen in these patients.
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PMID:Nephropathy and growth hormone deficiency in a patient with mitochondrial tRNA(Leu(UUR)) mutation. 881 55

Mitochondrial gene mutations are found to cause certain forms of diabetes mellitus and related syndromes. To study the prevalence of mitochondrial gene mutations in subjects with non-insulin-dependent diabetes mellitus (NIDDM) in Taiwan, 23 pedigrees with multiple siblings affected with NIDDM were consecutively collected from patients living in northern Taiwan. The A-to-G mutation at position 3243 np in the tRNA Leu gene and the mutation at position 8344 were screened by PCR-RFLP methods and confirmed by direct DNA sequence analysis. Among 23 NIDDM pedigrees, one pedigree was found to carry the 3243 np mutation. There was no 8344 np mutation in this series. Clinical features of this pedigree were consistent with mitochondrial disease in terms of maternal transmission, relatively early onset, non-obesity, insulin-requirement and association with hearing impairment. There was no correlation between the degree of heteroplasmy of mitochondrial gene mutation in leukocyte DNA and clinical severity. We conclude that a mitochondrial gene defect is an important genetic factor in familial cases with NIDDM in Taiwan.
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PMID:Mitochondrial gene mutations in familial non-insulin-dependent diabetes mellitus in Taiwan. 882 3

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

In the last few years, several mitochondrial DNA mutations and deletions have been described in association with various human diseases. Mitochondrial disorders, though long regarded strictly as neuromuscular diseases, may in fact involve non-neuromuscular symptoms. Diabetes mellitus has been reported in patients presenting with large mtDNA rearrangements (deletion, deletion-duplication) or in association with mtDNA point mutations, generally in tRNA genes (tRNA(Leu(UUR)). Genetic studies have shown that these disorders occur in sporadic cases or can be maternally inherited. The main clinical feature of mitochondrial diabetes is its nearly-consistent association with other symptoms (deafness, neurologic disorders, cardiac failure, renal failure, etc.). This paper provides a review of different types of mtDNA abnormalities associated with diabetes and a study of the prevalence of mitochondrial diabetes mellitus.
Diabetes Metab 1996 Oct
PMID:Mitochondrial diabetes mellitus. 889 89

Some patients with Type 2 (non-insulin-dependent) diabetes mellitus possess a mitochondrial mutation in the tRNA(Leu(UUR)) gene at position 3243 bp. These subjects show a maternal mode of inheritance and often have hearing defects. In French and Japanese populations, this mutation may be present in 1-3% of subjects with a family history of diabetes. We assessed the prevalence of this mutation in newly diagnosed diabetic subjects in the UK white Caucasian population. The 3243 bp mutation was not detected in 500 randomly selected Type 2 diabetic subjects, 50 gestational diabetic subjects, and members of a MODY pedigree. Two of 748 (0.27%) Type 2 diabetic subjects with a family history of diabetes were found to possess the mutation. These subjects had an early age of diagnosis (M 38 years; F 36 years) and were non-obese. The male patient showed evidence of markedly impaired beta-cell function and deafness, while the female was not deaf, had approximately 50% of normal pancreatic function and responded well to diet. The mutation in the tRNA(Leu(UUR)) gene probably occurs in only approximately 0.1-0.2% of white Caucasian Type 2 diabetic patients in the UK.
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PMID:UKPDS 21: low prevalence of the mitochondrial transfer RNA gene (tRNA(Leu(UUR))) mutation at position 3243bp in UK Caucasian type 2 diabetic patients. 901 52

Altered prostanoid metabolism participates in the pathogenesis of diabetic complications. The rate-limiting enzyme in the control of prostanoid metabolism is constitutive cyclo-oxygenase (COX-1). This study examined the possibility that altered prostanoid metabolism derives from altered COX-1 expression in those tissues from diabetic rats, with characteristic changes in prostanoid production and related haemodynamics. This account also describes a procedure for estimation of minute amounts of COX-1 mRNA by reverse transcription and competitive polymerase chain reaction (RT-cPCR) amplification. In streptozotocin-diabetic rats (STZ-D, 55 mg/kg body weight), compared with age-matched controls, the level of COX-1 mRNA (in attomoles/micrograms tRNA +/- 1SD) was significantly decreased in sciatic nerve (0.50 +/- 0.26 versus 0.89 +/- 0.32 in controls; P < 0.05) and thoracic aorta (3.99 +/- 1.67 versus 8.80 +/- 2.37 in controls; P < 0.05). There were no differences in COX-1 mRNA in diabetic and control rat kidney and retina, though there was a trend towards increased expression with diabetes in the latter. Evening primrose oil (EPO) treatment increased COX-1 mRNA in nerve and retina to levels in diabetic rats that were higher than those of non-diabetic controls (1.21 +/- 0.28 for nerve and 0.065 +/- 0.017 for retina, where control retinae gave 0.031 +/- 0.020-see above for nerve). Treatment of diabetic rats with an aldose reductase inhibitor was without effect on COX-1 mRNA levels in the tissues examined. This study demonstrates that the changes in COX-1 mRNA levels in diabetic rats are organ specific and suggests that altered prostanoid metabolism can, in part, be explained by altered COX-1 expression. Apart from providing arachidonate as substrate for COX, EPO stimulates COX-1 expression in some tissues.
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PMID:Expression of constitutive cyclo-oxygenase (COX-1) in rats with streptozotocin-induced diabetes; effects of treatment with evening primrose oil or an aldose reductase inhibitor on COX-1 mRNA levels. 905 26

Diabetes mellitus associated with 3243 mitochondrial tRNA(Leu(UUR)) mutation (DM-Mt3243) is a subtype of the mitochondrial multisystem syndromes, usually lacking myopathy. Muscle biopsies were obtained from 5 patients with diabetes and one patient with impaired glucose tolerance, all possessing the 3243 mutation without hallmarks of MELAS. The specimens were subjected to histochemical, biochemical, and genetic analysis. Ragged-red fibers were seen in 4 of the 6 patients (67%), and focal cytochrome c oxidase deficiency in 3 (50%). Strongly succinate dehydrogenase-reactive blood vessels was found in 5 patients (83%). The histochemical signs were present even when the mutant percentage was very low. The percentage of mutant DNA was almost always higher in muscles than in leukocytes. The combination of allele specific PCR amplification and PCR-RFLP method was useful to evaluate the mutant proportion. The mutant percentage in muscle was under 50% in 5 (83%) patients. Mitochondrial enzyme activity was deficient only in one patient. This study presents the detailed muscle histopathology in the DM-Mt3243 group. Abnormal histopathologic findings seemed similar to those noted in MELAS. However, mutant percentage in muscles was lower than that of MELAS, and respiratory chain enzyme activity was well preserved.
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PMID:Muscle histopathology in diabetes mellitus associated with mitochondrial tRNA(Leu(UUR)) mutation at position 3243. 907 28


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