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)

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

Maturity Onset Diabetes of the Young (MODY) is an autosomal dominant monogenic form of type 2 diabetes mellitus (DM) representing 5% of youth-onset DM in the Caucasian population. In young adults the disease can be present as either non-insulin dependent or insulin-dependent DM. The diagnosis of this genetic disorder in children and adolescents is rare because of the mild glucose metabolism disorder at this time. We performed a metabolic, autoimmune and genetic study in 40 offspring of young parents affected by insulin-dependent DM (Group A) and in 35 offspring of young parents affected by early-onset non-insulin-dependent DM (Group B). Two children of Group A (5%) were found to be affected by fasting hyperglycemia and carry a GCK gene mutation that in one case was present also in the diabetic father. Eighteen offspring of Group B (51%) were positive for GCK or HNF-1alpha gene mutations present in the affected parents. All but two of these young patients had impaired fasting glucose (IFG) or impaired glucose tolerance (IGT). Eleven of them were younger than 16 years. We conclude that screening for DM in youth should be extended to MODY in young families with both non-insulin-dependent and insulin-dependent DM. The sensitivity of the metabolic tests will precede the genetic diagnosis.
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PMID:Diagnosis of MODY in the offspring of parents with insulin-dependent and non-insulin-dependent diabetes mellitus. 1139 52

Maturity onset diabetes of the young (MODY) is a genetically heterogeneous form of type 2 diabetes that is characterized by autosomal dominant inheritance, onset in early adulthood and a primary defect in insulin secretion. Mutations in at least six genes have been shown to underlie MODY, including mutations in GCK (encoding glucokinase, also called MODY2) and mutations in HNF1A (encoding hepatocyte nuclear factor-1alpha, also called MODY3). We sequenced genomic DNA from probands of seven Canadian MODY families. In four probands, we detected four novel GCK mutations, namely IVS2-7G>A, G72R, T206R and S263P. In three other probands, we detected three HNF1A mutations, of which two were novel, namely 1051delCA and Q250X, and one had been previously reported, namely R131Q. The novel mutations expand the spectrum of MODY mutations. In addition, knowledge of the specific defect can be used to pre-symptomatically identify family members at risk for developing MODY.
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PMID:GCK and HNF1A mutations in Canadian families with maturity onset diabetes of the young (MODY). 1244 80

Maturity-onset diabetes of the young-type 1 (MODY1) is a form of monogenic type 2 diabetes mellitus (T2DM) with long-term complications due to mutations in the HNF-4alpha gene. The HNF-4alpha gene is involved in hepatic differentiation and expression of genes regulating glucose transport, glycolysis, and lipid metabolism. The abnormal glucose-stimulated insulin secretion in MODY1 subjects may be due to reduced glucose transport and glycolysis. To date, 14 mutations in the HNF-4alpha gene have been identified as a cause of either MODY1 or late-onset type 2 diabetes. So far, no screening has been performed in subjects from the Philippines. We recruited a Philippino family with autosomal dominant early-onset type 2 diabetes and screened the proband for mutations in the genes for HNF-1alpha, GCK, HNF-4alpha, IPF-1, HNF-6, and NGN3. We identified a new missense mutation in exon 5 (V199I) of the HNF-4alpha gene and 2 new single-nucleotide substitutions in intron 4, IVS4-nt4 (G --> A) and IVS4-nt20 (C --> T), all cosegregating with diabetes in the 3 affected available siblings. These variations were not present in 100 normal healthy subjects. Bioinformatic analysis suggests that these variations in the whole, and overall the IVS4-nt4 variation located at splicing site, may affect the splicing potential of intron 4. We have biochemically and clinically characterized the Philippine-1 family. We suggest that the V199I missense mutation located in the ligand binding/dimerization domain of HNF-4alpha contributes to type 2 diabetes in the Philippine-1 family. The intron variations may contribute susceptibility to diabetes.
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PMID:Triple genetic variation in the HNF-4alpha gene is associated with early-onset type 2 diabetes mellitus in a philippino family. 1528 Oct 1

Maturity-onset diabetes of the young is a genetically heterogeneous autosomal dominant form of diabetes mellitus, characterized by an early age at onset and a primary defect in beta-cell function. Forty families with a clinical presentation suggestive of MODY were screened for the most common MODY subtypes caused by mutations in the genes encoding glucokinase (GCK, MODY2) and hepatocyte nuclear 1-alpha (HNF1A/TCF1, MODY3). Overall, 14 mutations were found (35%) giving a relative frequency of 22.5% and 12.5% for MODY2 and MODY3, respectively. Five of the nine GCK mutations identified were novel and included two deletions, two nonsense, and one splice site mutation. The GCK splice donor mutation was shown to result in an aberrant transcript owing to the recruitment of a cryptic splice site. The translated protein is predicted to contain an in frame insertion of nine amino acids. Among the five HNF1A mutations identified, three were novel comprising one missense mutation, one deletion, and one insertion. In addition, several novel polymorphisms within GCK were identified and their allele frequencies estimated. Knowledge of the genetic cause of MODY has significant impact on therapeutic decision making and may help to identify family members at risk for diabetes.
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PMID:Identification of novel GCK and HNF1A/TCF1 mutations and polymorphisms in German families with maturity-onset diabetes of the young (MODY). 1584 81

Impaired insulin secretion is a fundamental defect in type 2 diabetes. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) in the genes regulating insulin secretion (SLC2A2 [encoding GLUT2], GCK, TCF1 [encoding HNF-1alpha], HNF4A, GIP, and GLP1R) are associated with the conversion from impaired glucose tolerance (IGT) to type 2 diabetes in participants of the Finnish Diabetes Prevention Study. With the exception of SLC2A2, other genes were not associated with the risk of type 2 diabetes. All four SNPs of SLC2A2 predicted the conversion to diabetes, and rs5393 (AA genotype) increased the risk of type 2 diabetes in the entire study population by threefold (odds ratio 3.04, 95% CI 1.34-6.88, P = 0.008). The risk for type 2 diabetes in the AA genotype carriers was increased in the control group (5.56 [1.78-17.39], P = 0.003) but not in the intervention group. We conclude that the SNPs of SLC2A2 predict the conversion to diabetes in obese subjects with IGT.
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PMID:Polymorphisms in the SLC2A2 (GLUT2) gene are associated with the conversion from impaired glucose tolerance to type 2 diabetes: the Finnish Diabetes Prevention Study. 1598 30

A graded relationship has been reported between fasting and postprandial plasma glucose levels and the subsequent risk of cardiovascular morbidity and mortality. We hypothesized that the GCK -30G>A promoter polymorphism is associated with elevated glycemia in the middle-aged general population of whites, as well as with features of the World Health Organization (WHO)-defined metabolic syndrome. The GCK -30G>A polymorphism was genotyped in the population-based Inter99 study cohort (5,965 subjects) and in 332 nondiabetic subjects and 1,063 patients with type 2 diabetes. In the Inter99 cohort, the GCK -30A allele was associated with increased fasting (P < 0.001) and post-oral glucose tolerance test (OGTT) plasma glucose levels (P < 0.001), and in the same cohort, the GCK -30A allele was more frequent among 1,325 subjects with the metabolic syndrome than among 1,679 subjects without any components of the metabolic syndrome (P = 0.002). Moreover, the GCK -30A allele frequency was higher among 2,587 subjects with impaired glucose regulation (IGR) than among 4,773 glucose-tolerant subjects (17.3% [95% CI 16.2-18.3] vs. 15.0% [14.3-15.7], P < 0.001, odds ratio GG vs. GA 1.21 [1.08-1.36], GG vs. AA 1.62 [1.17-2.24]). In conclusion, the GCK -30G>A polymorphism associates with elevated fasting and post-OGTT glycemia in the middle-aged general population of whites, as well as with IGR and other features of the WHO-defined metabolic syndrome.
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PMID:A -30G>A polymorphism of the beta-cell-specific glucokinase promoter associates with hyperglycemia in the general population of whites. 1618 9

Maturity-onset diabetes of the young (MODY) is mostly caused by mutations of the hepatocyte nuclear factor (HNF)-1alpha (MODY3) and glucokinase (MODY2) genes in Caucasians. But most Japanese and Chinese MODY patients are not linked to known MODY genes. In this study, we examined the genetic and clinical characteristics of Korean subjects with MODY and early onset type 2 diabetes who had been diagnosed before 15 years of age. The study included 23 unrelated subjects fulfilling the criteria for MODY (three consecutive generations of type 2 diabetes with at least one member diagnosed under the age of 25 year) and 17 unrelated subjects diagnosed with early onset type 2 DM under the age of 15 years. The HNF-4alpha (MODY1), glucokinase (MODY2) and HNF-1alpha (MODY3) genes were analysed by direct sequencing. Mutations in the HNF-1alpha gene were found in two patients (5%). One of these, P393fsdelC, was novel, and was found in a patient classified in the MODY group. The GCK gene mutation, R191W, was identified in one patient classified as early-onset type 2 DM (2.5%). No mutations were found in the HNF-4alpha gene, except the T130I variant, which is a known rare polymorphism. In conclusion, the mutations in the HNF-1alpha gene and GCK account for a small proportion, about 5% and 2.5%, respectively, in Korean MODY and early onset type 2 patients. The majority of MODY cases in the Korean population are due to defects in unknown genes.
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PMID:Genetic and clinical characteristics of Korean maturity-onset diabetes of the young (MODY) patients. 1663 67

Prior reports have suggested that variants in the genes for maturity-onset diabetes of the young (MODY) may confer susceptibility to type 2 diabetes, but results have been conflicting and coverage of the MODY genes has been incomplete. To complement our previous studies of HNF4A, we examined the other five known MODY genes for association with type 2 diabetes in Finnish individuals. For each of the five genes, we selected 1) nonredundant single nucleotide polymorphisms (SNPs) (r(2)< 0.8 with other SNPs) from the HapMap database or another linkage disequilibrium map, 2) SNPs with previously reported type 2 diabetes association, and 3) nonsynonymous coding SNPs. We tested 128 SNPs for association with type 2 diabetes in 786 index cases from type 2 diabetic families and 619 normal glucose-tolerant control subjects. We followed up 35 of the most significant SNPs by genotyping them on another 384 case subjects and 366 control subjects from Finland. We also supplemented our previous HNF4A results by genotyping 12 SNPs on additional Finnish samples. After correcting for testing multiple correlated SNPs within a gene, we find evidence of type 2 diabetes association with SNPs in five of the six known MODY genes: GCK, HNF1A, HNF1B, NEUROD1, and HNF4A. Our data suggest that common variants in several MODY genes play a modest role in type 2 diabetes susceptibility.
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PMID:Common variants in maturity-onset diabetes of the young genes contribute to risk of type 2 diabetes in Finns. 1693 1

About 2-5% of all pregnant women develop gestational diabetes mellitus (GDM) during their pregnancies and the prevalence has increased considerably during the last decade. GDM is a heterogeneous disorder that is defined as carbohydrate intolerance with onset or first recognition during pregnancy. It is manifested when pancreatic beta cells are no longer able to compensate for the increased insulin resistance during pregnancy, but the pathogenesis of the disease is still largely unknown. GDM is considered to result from interaction between genetic and environmental risk factors. Genetic predisposition to GDM has been suggested since GDM clusters in families. Also, women with mutations in MODY (Maturity onset diabetes of the young) genes often present with GDM. In addition, common variants in several candidate genes (e.g. potassium inwardly rectifying channel subfamily J, member 11 [KCNJ11], Glucokinase [GCK], Hepatocyte nuclear factor-1alpha [HNF1A] etc.) have been demonstrated to increase the risk of GDM. Old age, obesity and high fat diet represent some important non-genetic factors. There are several approaches to search for genes predisposing to a polygenic disease like GDM including linkage and association studies, expression profiling and animal models. A combination of several methods is usually necessary. Identification of the underlying genetic causes of GDM will eventually give a better view of the mechanisms that contribute to the pathophysiology of the disease. Furthermore, it may improve options to possibly prevent GDM and complications for the mother and her child. This review focuses on the genetics of GDM and possible implications in clinical practice.
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PMID:Genetics of gestational diabetes mellitus. 1734 48


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