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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

As a result of advances in technology, genome searches have been carried out for susceptibility genes for type 1 diabetes in humans and in the NOD mouse. These have shown that, in the NOD mouse, diabetes susceptibility is under the control of at least ten separate chromosomal loci. In the human, in addition to HLA and INS, two new susceptibility genes have been localized, IDDM4 on chromosome 11q and IDDM5 on 6q, demonstrating the polygenic nature of type 1 diabetes and the role of HLA as the major locus. Candidate genes at these loci are the subject of current investigation. Genetic and immunological markers of disease may be of value in screening the general population for individuals at risk of developing type 1 diabetes. The predictive power of different screening strategies should be tested in order to work out the potential value to the general population of preventive therapies that are now undergoing clinical trials in high risk 'pre-diabetics'. Type 2 diabetes is genetically heterogeneous, and, since 1992, two distinct genetic subtypes have been identified. The first is defined by mutations in the GCK gene, which cause up to 60% of cases of MODY. The second, designated MIDD (maternally inherited diabetes and deafness), is defined by mutation in the mitochondrial gene for tRNA(Leu(UUR)). MIDD patients are less obese than is usual for typical type 2 diabetes, may present in early adult life or occasionally in childhood and may have been diagnosed as having autoimmune type 1 diabetes, type 2 diabetes or MODY. Typically, patients with MIDD require insulin earlier than do type 2 diabetics without mitochondrial mutations. Genetically complex diseases, such as diabetes, hypertension, cancer and coronary heart disease, are common in most populations. The approaches to the genetic analysis of diabetes outlined in this review are likely to be useful to the genetic analysis of many of these disorders. Progress in this area will have important implications for public health strategies in the next decade and beyond.
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PMID:Molecular genetics of diabetes mellitus. 757 35

Japanese diabetic patients whose mothers were also diabetic were screened, using peripheral leukocytes, for an A to G transition at nucleotide pair 3243 of the mitochondrial gene, a tRNA(Leu)(UUR) mutation. This mutation was identified in four pedigrees from among 300 unrelated patients. Diabetes mellitus cosegretated with the mutation, except in 1 young subject, and was maternally inherited. Long-term follow-up revealed that the underlying disorder in affected members is a progressive impairment of insulin secretion. In accord with this finding, this mutation was found to be highly prevalent in a subset of diabetes mellitus called slowly progressive IDDM; the mutation was identified in 3 of 27 Japanese patients enrolled in the prospective study of islet cell antibody (ICA)-positive, initially non-insulin-dependent diabetic patients, who are very likely to become insulin dependent in several years. The histologic characteristics of slowly progressive IDDM include loss, though incomplete, of pancreatic beta-cells. Mitochondrial gene defects in beta-cells could therefore cause glucose-induced signaling defects as well as beta-cell loss, which explains the wide range of diabetic phenotypes, from NIDDM phenotype to IDDM, in patients with this mitochondrial gene mutation.
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PMID:Mitochondrial diabetes mellitus--glucose-induced signaling defects and beta-cell loss. 760 14

Several studies have shown a consistent maternal effect in the transmission of Type 2 diabetes (NIDDM). The mitochondrial encephalomyopathies are a group of diseases characterized by maternal inheritance and a variety of mitochondrial DNA defects. Diabetes is a feature of some of these disorders and therefore the hypothesis arose that mitochondrial DNA mutations might play a role in patients with diabetes but no other features of neurological disease. Recent studies have confirmed that a specific point mutation in the gene encoding the mitochondrial tRNA for leucine segregates with diabetes and nerve deafness in families from the UK, Holland, France and Japan. Mitochondrial gene deletions have also been reported. Affected subjects present with progressive insulin deficiency and may fall into the broad classifications of either Type 1 (IDDM) or Type 2 diabetes (NIDDM). Future studies are aimed at searching for other mitochondrial gene defects in diabetes and attempting to explain the mechanism of hyperglycaemia by the development of phenotypic expression systems. Although an exciting development in the genetics of diabetes, currently described mitochondrial mutations do not fully explain the maternal effect in the transmission of Type 2 diabetes.
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PMID:Maternally inherited diabetes mellitus: the role of mitochondrial DNA defects. 774 54

Candidate genes for NIDDM have been screened in Japanese. Mutations in the glucokinase gene were found in apparent late-onset NIDDM patients as well as in MODY patients. Clinical characteristics in the subjects with glucokinase gene mutations are similar to those in Caucasian subjects; diabetes mellitus is generally mild and some patients actually remain as having impaired glucose tolerance. Of great interest is that all affected subjects show blunted insulin secretion response to the glucose challenge, which is most commonly observed in Japanese NIDDM patients. Thus, it is possible that impairment in the regulation of glucokinase gene expression or its enzyme activity is associated with at least some Japanese NIDDM patients, though the prevalence of the mutations in the coding region is relatively low. In contrast, a mitochondrial tRNA(Leu(UUR)) gene mutation at np 3243 appears to be much more common, and diabetes due to this mutation has a progressive nature. Insulin secretory capacity progressively decreases, eventually reaching an insulin-dependent state in most patients. A surprising result is that this gene mutation is often observed in ICA-positive IDDM patients who were initially non-insulin-dependent, so called slowly progressive IDDM patients. These results suggest that the mitochondrial gene mutation may cause beta cell loss in addition to defects in glucose-induced signaling in pancreatic beta cells, which explains that the mitochondrial gene mutation manifests a wide range of diabetic phenotypes, from NIDDM to IDDM.
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PMID:NIDDM--genetic marker; glucose transporter, glucokinase, and mitochondria gene. 785 92

Mutations in the mitochondrial gene were recently identified in a large pedigree of diabetes mellitus and deafness. As the mitochondrial gene is materially inherited, Japanese diabetic patients whose mothers were also diabetic were screened, using peripheral leucocytes, for an A to G transition at nucleotide pair 3243 of the mitochondrial gene, a tRNA(Leu(UUR)) mutation. This mutation was identified in four pedigrees from among 300 unrelated patients who were screened. Diabetes co-segregated with the mutation, except in one young subject, and was maternally inherited. The apparent onset of disease occurred between 11 and 68 years of age. Some of the affected members developed hearing impairment and congestive heart failure due to cardiomyopathy, though generally long after the onset of diabetes, and these patients had therefore not been diagnosed as having a specific form of diabetes. The duration of sulphonyl-urea treatment was not more than 8 years in these pedigrees and affected members were prone to progression to insulin-requiring diabetes. Thus, these patients were secondary sulphonylurea failures. Long-term follow-up revealed that the underlying disorder in affected members is a progressive impairment of insulin secretion. Some were initially diagnosed as having IDDM based on an apparent acute onset in youth and the clinical severity of their diabetes. Others were regarded as having MODY with an aggressive course. The mitochondrial gene mutation or diabetes is not transmitted to all offspring of the affected mothers.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mitochondrial diabetes mellitus: prevalence and clinical characterization of diabetes due to mitochondrial tRNA(Leu(UUR)) gene mutation in Japanese patients. 805 89

A family with maternally-transmitted deafness and diabetes mellitus is described. Although the proband clinically exhibited MELAS-like symptoms such as sudden-onset cerebellar ataxia and weakness of the proximal portion of the limbs in addition to deafness and diabetes mellitus, the other three members of the family had only deafness and diabetes mellitus and no neurological manifestations. The analysis of mitochondrial DNA of the two members revealed an A-->G mutation of tRNA(leu(UUR)), a mutation commonly seen in patients with MELAS. According to the clinical histories and endocrinological investigations, the type of the diabetes mellitus in this family was considered to be IDDM, which may be attributed to the dysfunction of mitochondrial of the pancreas islet cells, resulting from the mutation of the mitochondrial DNA.
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PMID:[A family with MELAS whose main manifestations are maternally-transmitted deafness and diabetes mellitus]. 840 88

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

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.
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PMID:Maternally inherited diabetes and deafness: prevalence in a hospital diabetic population. 921 10

The mitochondrial DNA tRNA[Leu(UUR)] A to G 3243 mutation is associated with maternally inherited diabetes in Caucasians and Japanese. In a Hong Kong Chinese population we have detected the 3243 mutation in 2 of 74 unrelated subjects with well characterized insulin-dependent (Type 1) diabetes mellitus (IDDM) and 2 of 75 unrelated subjects with young onset (<35 years) non-insulin-dependent diabetes (NIDDM). The 3243 mutation has only previously been associated with IDDM in Japanese. Racial differences in association of the mitochondrial 3243 mutation with IDDM suggest the influence of other genes that may increase its diabetogenic pathogenicity in Oriental races. We also found a significant excess of maternal inheritance of diabetes in the young onset NIDDM cohort, with a ratio of diabetic mothers to fathers of 2.4:1, p < 0.005. The 3243 mutation, however, only accounts for a small proportion of the observed excess maternal inheritance, and further study is needed to search for other diabetes associated mitochondrial DNA mutations.
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PMID:The mitochondrial tRNA[Leu(UUR)] A to G 3243 mutation is associated with insulin-dependent and non-insulin-dependent diabetes in a Chinese population. 945 29

A 34-year-old female IDDM patient complained of chest oppression in hypoglycemic episodes and electrocardiograms revealed reversible ischemic changes occurring concomitantly with hypoglycemia. The ECG changes improved and the chest oppression disappeared following increasing blood glucose level by glucose intake. Master's double load test and treadmill load test were positive for ischemic changes. Radioisotopic myocardial scintigraphy by thallium and BMIPP did not show any filling defects and coronary angiography revealed no remarked stenosis in the coronary arteries. She had no mitochondrial tRNA(Leu) (A-->G) gene mutation at nucleotide position 3243, but both the patient and her mother had a G-to-A transition within the replication origin of the light strand at nucleotide position 5744 of the mitochondrial gene. As the patient's maternal family had no history of ischemic heart disease, it is not clear whether mitochondrial gene mutation at nucleotide position 5744 reflects the occurrence of cardiac ischemia. Some disorders of microcirculation in capillary vessels in cardiac muscles may occur in such patients.
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PMID:An IDDM patient who complained of chest oppression with ischemic changes on ECG in insulin-induced hypoglycemia. 959 72


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