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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in the glucokinase (GK) gene cause two different diseases of blood glucose regulation: maturity onset diabetes of the young, type 2 (MODY-2) and persistent hyperinsulinemic hypoglycemia of infancy (PHHI). To gain further understanding of the pathophysiology of these disorders, we have used both transgenic and gene-targeting strategies to explore the relationship between GK gene expression in specific tissues and the blood glucose concentration. These studies, which have included the use of aCre/loxP gene-targeting strategy to perform both pancreatic beta-cell- and hepatocyte-specific knockouts of GK, clearly demonstrate multiple, cell-specific roles for this hexokinase that, together, contribute to the maintainance of euglycemia. In the pancreatic beta cell, GK functions as the glucose sensor, determining the threshold for insulin secretion. Mice lacking GK in the pancreatic beta cell die within 3 days of birth of profound hyperglycemia. In the liver, GK facilitates hepatic glucose uptake during hyperglycemia and is essential for the appropriate regulation of a network of glucose-responsive genes. While mice lacking hepatic GK are viable, and are only mildly hyperglycemic when fasted, they also have impaired insulin secretion in response to hyperglycemia. The mechanisms that enable hepatic GK to affect beta-cell function are not yet understood. Thus, the hyperglycemia that occurs in MODY-2 is due to impaired GK function in both the liver and pancreatic beta cell, although the defect in beta-cell function is clearly more dominant. Whether defects in GK gene expression also impair glucose sensing by neurons in the brain or enteroendocrine cells in gut, two other sites known to express GK, remains to be determined. Moreover, whether the pathophysiology of PHHI also involves multitissue dysfunction remains to be explored.
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PMID:Cell-specific roles of glucokinase in glucose homeostasis. 1123 13

Nuclear magnetic resonance (NMR) spectroscopy has made noninvasive and repetitive measurements of human hepatic glycogen concentrations possible. Monitoring of liver glycogen in real-time mode has demonstrated that glycogen concentrations decrease linearly and that net hepatic glycogenolysis contributes only about 50 percent to glucose production during the early period of a fast. Following a mixed meal, hepatic glycogen represents approximately 20 percent of the ingested carbohydrates, while only about 10 percent of an intravenous glucose load is retained by the liver as glycogen. During mixed-meal ingestion, poorly controlled type 1 diabetic patients synthesize only about 30 percent of the glycogen stored in livers of nondiabetic humans studied under similar conditions. Reduced net glycogen synthesis can be improved but not normalized by short-term, intensified insulin treatment. A decreased increment in liver glycogen content following meals was also found in patients with maturity-onset diabetes of the young due to glucokinase mutations (MODY-2). In patients with poorly controlled type 2 diabetes, fasting hyperglycemia can be attributed mainly to increased rates of endogenous glucose production, which was found by 13C NMR to be due to increased rates of gluconeogenesis. Metformin treatment improved fasting hyperglycemia in these patients through a reduction in hepatic glucose production, which could be attributed to a decrease in gluconeogenesis. In conclusion, NMR spectroscopy has provided new insights into the pathogenesis of hyperglycemia in type 1, type 2, and MODY diabetes and offers the potential of providing new insights into the mechanism of action of novel antidabetic therapies.
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PMID:Nuclear magnetic resonance studies of hepatic glucose metabolism in humans. 1123 14

Type 2 diabetes is a complex disease and genetic as well as environmental factors play a role in its pathogenesis. Six different genes have been identified so far to be responsible for rare forms of autosomal dominant, early onset type 2 diabetes mellitus. All but one are transcription factors which influence expression of the other genes through the regulation of mRNA synthesis. These are hepatocyte nuclear factor (HNF)-4 alpha, HNF-1 alpha, insulin promoter factor (IPF)-1 and HNF-1 beta, which are associated with MODY1, 3, 4, 5 respectively. MODY1 is a relatively rare and usually severe form of diabetes. It is associated with progressive hyperglycemia and frequent chronic complications. The HNF-4 alpha gene is localized on chromosome 20q. Similar clinical characteristics apply to the MODY3 form, however the latter is much more frequent among early onset, autosomal dominant type 2 diabetes (20-40%). HNF-1 alpha gene is localized on chromosome 12q. HNF-1 beta (MODY5 locus on chromosome 17q) is a protein which forms heterodimers with HNF-1 alpha. This rare form of diabetes has a clinical picture similar to MODY1 and MODY3. It is sometimes accompanied by symptoms of early kidney damage which are independent from diabetes. The other two transcription factors responsible for the development of autosomal dominant type 2 diabetes are proteins which bind directly to the insulin promoter. MODY4 (IPF-1, chromosome 13q) is a rare form and of a typical middle and late onset type 2 diabetes. BETA 2/Neurod1 has been recently associated with MODY by Dr Krolewski's group from Joslin Diabetes Center, Boston, MA, USA. BETA 2 is responsible for about 2% of autosomal dominant type 2 diabetes. The clinical characteristics depend on the localization of the mutations in the specific functional domains of the protein. Mutations identified in the glucokinase gene are associated with the MODY2 form. Glucokinase is an enzyme involved in the first level of glucose metabolism in b-cells-enzymatic phosphorylation. MODY2 is a modest form of diabetes. It is characterized by mild hyper-glycemia, mainly fasting, and the chronic complications are very rare. Glucokinase gene is localized on chromosome 7p. It is expected that in the nearest future more type 2 susceptibility genes will be identified.
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PMID:[Molecular background and clinical characteristics of autosomal dominant type 2 diabetes mellitus]. 1129 29

The role of genetic investigations in diabetes one can describe in aspect of their role in the pathogenesis of type 1 and type 2 as well as in pathogenesis of chronic complications and gene therapy of diabetes. There is not only one gene responsible for type 1 diabetes. Similarly there are many gene-candidates in type 2 diabetes. Only in 6 types of MODY the genes responsible for beta-cell dysfunction were described. In diabetic complications some role e.g. in retinopathy may be played by genes of growth factors, heparan sulfate synthesis as well as genes of adrenergic receptor beta 3. In diabetic nephropathy the genes of renin synthesis, converting enzyme, aldose reductase or angiotensin receptor can be of importance. It should be emphasized that identification of human genome and genes responsible for diabetes can contribute to introduction of gene therapy in diabetes.
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PMID:[The role of genetic studies in finding the etiopathogenesis of diabetes mellitus]. 1129 31

Type 2 diabetes is a multifactorial disease composed of subtypes strongly associated with environmental factors at one end of the spectrum and highly genetic forms at the other hand. The former forms have been largely elucidated in the last years by the identification of the 5 genes responsible for the autosomal dominant MODY subtype: glucokinase, and 4 transcription factors which play a key role in the development of the endocrine pancreas or in the expression of glucose metabolism genes. Apart from the monogenic forms of type 2 diabetes little is known about the nature of the genetic factors involved. Minor contributors include insulin, sulfamide receptor and some others. Genome scans of diabetic families have revealed susceptibility loci on chromosome 1q, 2p, 2q (where the gene calpain 10 was recently cloned), 3q, 12q and 20. The identification of diabetes susceptibility gene is the first step to define targets of new drugs against diabetes.
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PMID:[Genetics of type II diabetes]. 1129 66

Practically all types of diabetes mellitus (DM) result from complex interactions of genetic and environmental factors. Multifactorial and polygenic Type 1 DM is strongly influenced by genes controlling the immune system, mainly HLA-DQ and DR. In addition to this, many other predisposition loci, interacting with each other, have some influence on susceptibility to DM. Heterogeneous Type 2 DM, accounting for about 85% of all diabetic patients, is supposed to be induced by multiple genes defects involved in insulin action and/or insulin secretion. Other genetically influenced traits like obesity and hyperlipidemia are strongly associated with the Type 2. The group called Other specific types of DM include monogenic forms MODY 1-5 and many various subtypes of the disease, where the specific gene mutations have been identified. Both genetic and intrauterine environmental influences are likely to contribute to the abnormalities defined as Gestational DM.
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PMID:Genetic aspects of diabetes mellitus. 1136 89

Maturity-onset diabetes of the young is a heterogeneous group of autosomal dominantly inherited, young-onset beta-cell disorders. At least two consecutive generations are affected with a family member diagnosed before 25 years of age. Diabetes is caused either by mutations in the glucokinase gene (glucokinase MODY) or by mutations in transcription factors (transcription factor MODY). Glucokinase maturity-onset diabetes of the young is a mild, non-progressive hyperglycaemia caused by a resetting of the pancreatic glucose sensor. It is treated with diet, and complications are rare. Pregnancies affected by glucokinase mutations have specific management strategies and prognosis. Transcription factor maturity-onset diabetes of the young, caused by mutations in the hepatocyte nuclear factor genes HNF-1alpha, HNF-4alpha and HNF-1beta, and in insulin promoter factor-1 results in a progressive beta-cell defect with increasing treatment requirements and diabetic complications. Cystic renal disease is a prominent feature of HNF-1beta mutations. Further maturity-onset diabetes of the young genes remain to be identified. MODY is part of the differential diagnosis of diabetes presenting in the first to third decades of life. Diagnostic molecular genetic testing is available for the more common genes involved.
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PMID:Maturity-onset diabetes of the young: from clinical description to molecular genetic characterization. 1155 73

Mutations in the homeodomain-containing transcription factor hepatocyte nuclear factor-1beta (HNF-1beta) are known to cause a rare subtype of maturity-onset diabetes of the young (MODY5), which is associated with early-onset progressive non-diabetic renal dysfunction. To investigate whether mutations in HNF-1 are implicated in the pathogenesis of MODY or late-onset diabetes with and without nephropathy in Danish Caucasians we examined the HNF-1beta (TCF2) and the dimerization cofactor of HNF-1 (DCoH, PCBD) genes for mutations in 11 MODY probands, 28 type 2 diabetic patients with nephropathy, and 46 type 2 diabetic patients with an impaired beta-cell function by combined single-strand conformation polymorphism (SSCP) and heteroduplex analysis. Analysis of the promoter and nine exons including intron-exon boundaries of the HNF-1beta gene revealed one novel silent polymorphism and three previously reported intronic variants. The silent polymorphism (I91I) was found in one patient with late-onset type 2 diabetes. One of the intronic variant (IVS6+26T-->C) was examined further. Among 584 type 2 diabetic patients the allelic frequency was 13.1% (11.2-15.0%) compared to 11.6% (8.6-14.5%) in 229 glucose tolerant control subjects (NS). No difference in insulin secretion during an OGTT was seen between carriers of the different IVS6+26T-->C genotypes among the 229 middle-aged control subjects, nor among 302 glucose tolerant 60-year-old Danish Caucasians. Mutation analysis of the four exons comprising the DCoH gene revealed a previously described A-->G polymorphism located in the 3' untranslated region, which was not investigated further. In conclusion, mutations in HNF-1beta and DCoH are not a major cause of MODY or late onset type 2 diabetes in Danish Caucasian subjects.
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PMID:Studies of the variability of the hepatocyte nuclear factor-1beta (HNF-1beta / TCF2) and the dimerization cofactor of HNF-1 (DcoH / PCBD) genes in relation to type 2 diabetes mellitus and beta-cell function. 1166 23

Recently, several genes associated with early-onset, autosomal dominant Type 2 diabetes (MODY) have been identified. Mutations in the hepatocyte nuclear factor (HNF)-1alpha gene seem to account for a substantial proportion of this type of diabetes in several populations. However, it is still of interest to estimate the frequency of HNF-1alpha mutations in various ethnic groups. The aim of our study was to determine the contribution of the HNF-1alpha gene to the development of MODY in a Polish population. We selected 15 families with MODY for this project. The 10 exons and promoter region of the gene were screened for sequence differences by direct sequencing of probands DNA. We detected 7 previously described polymorphisms that were not associated with diabetes. However, one sequence difference, a deletion of a cytosine in codon 225 in exon 3 (designated S225fdelC), was a new mutation resulting in a frame shift and synthesis of a nonsense peptide from amino acid 225 to 232 followed by the stop codon. Thus, the S225fdelC mutation effectively caused the loss of a part of the DNA binding domain and the entire transactivation domain. This mutation was present in 4 affected members of the family. They developed diabetes at an early age (mean age at diagnosis 23 yr) and were characterized by severely impaired insulin secretion. In addition, one family member who was not a carrier of the S225fdelC mutation was diagnosed with diabetes. Thus, he represents an example of phenocopy. In conclusion, we have identified a new HNF-1alpha variant that represents the first MODY mutation described in a Polish population. MODY3 mutations, including those in the exon 4 "hot spot", do not appear to be a very common cause of MODY in the Polish population.
Diabetes Nutr Metab 2001 Oct
PMID:Identification of a new mutation in the hepatocyte nuclear factor-1alpha gene in a Polish family with early-onset type 2 diabetes mellitus. 1180 70

Maturity Onset Diabetes of the Young is a particular form of type 2 diabetes, classically defined by an autosomal dominant inheritance, a young age at diagnosis (before 25 years) and an insulin secretion defect. At this time, six MODY genes have been described. Beyond the apparent simplicity, the study of such monogenic model of disease may help us to approach a complex disease such as type 2 diabetes, where is involved to conserve a genetic and environmental factors network. This different approach may help us to better understand type 2 diabetes physiopathology.
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PMID:["MODY" diabetes. Beyond a monogenic disease]. 1182 Jan 67


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