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

Maturity onset diabetes of the young (MODY) is characterized by youth-onset diabetes that is inherited in an autosomal dominant (monogenic) pattern. Classic MODY accounts for less than 5% of cases of childhood diabetes in Caucasians, presents prior to age 25 years, is nonketotic, and may not require insulin treatment. A variant form of MODY that lacks a clearly defined genetic basis occurs in African Americans [atypical diabetes mellitus (ADM)] clinically presents more acutely and is initially insulin requiring. To date, five molecular causes of classic MODY have been identified: hepatocyte nuclear factor-4 alpha (HNF-4 alpha; MODY1), glucokinase (MODY2), hepatocyte nuclear factor-1 alpha (HNF-1 alpha; MODY3), insulin promoter factor-1 (IPF-1, MODY4), and hepatocyte nuclear factor-1 beta (HNF-1 beta; MODY5). MODY is studied as a model of beta cell hypofunction and modest insulinopenia. Clinical recognition of ADM is important for patient management to avoid confusion with type 1 diabetes mellitus.
Pediatr Diabetes 2000 Jun
PMID:Molecular and biochemical analysis of the MODY syndromes. 1501 34

Variants in hepatocyte nuclear factor-4 alpha (HNF4 alpha), a transcription factor that influences the expression of glucose metabolic genes, have been correlated with maturity-onset diabetes of the young, a monogenic form of diabetes. Previously, in a genome scan of Ashkenazi Jewish type 2 diabetic families, we observed linkage to the chromosome 20q region encompassing HNF4 alpha. Here, haplotype-tag single nucleotide polymorphisms (htSNPs) were identified across a 78-kb region around HNF4 alpha and evaluated in an association analysis of Ashkenazi Jewish type 2 diabetic (n = 275) and control (n = 342) subjects. We found that two of nine htSNPs were associated with type 2 diabetes: a 3' intronic SNP, rs3818247 (29.2% case subjects vs. 21.7% control subjects; P = 0.0028, odds ratio [OR] 1.49) and a 5' htSNP located approximately 3.9 kb upstream of P2, rs1884614 (26.9% case subjects vs. 20.3% control subjects; P = 0.0078, OR 1.45). Testing of additional SNPs 5' of rs1884614 revealed a >10-kb haplotype block that was associated with type 2 diabetes. Conditioning on the probands' rs1884614 genotype suggested that the chromosomal region identified by the htSNP accounted for the linkage signal on chromosome 20q in families in which the proband carried at least one risk allele. Notably, the associations and the partitioned linkage profiles near P2 were independently observed in a Finnish sample, suggesting the presence of potential regulatory element(s) that may contribute to the risk for type 2 diabetes.
Diabetes 2004 Apr
PMID:A common polymorphism in the upstream promoter region of the hepatocyte nuclear factor-4 alpha gene on chromosome 20q is associated with type 2 diabetes and appears to contribute to the evidence for linkage in an ashkenazi jewish population. 1504 32

Hepatocyte nuclear factor 1alpha (HNF1alpha) and HNF1beta (or vHNF1) are closely related transcription factors expressed in liver, kidney, gut, and pancreatic beta-cells. Many HNF1 target genes are involved in carbohydrate metabolism. Human mutations in HNF1alpha or HNF1beta lead to maturity-onset diabetes of the young (MODY3 and MODY5, respectively), and patients present with impaired glucose-stimulated insulin secretion. The underlying defect in MODY5 is not known. Analysis of HNF1beta deficiency in mice has not been possible because HNF1beta null mice die in utero. To examine the role of HNF1beta in glucose homeostasis, viable mice deleted for HNF1beta selectively in beta-cells (beta/H1beta-KO mice) were generated using a Cre-LoxP strategy. beta/H1beta-KO mice had normal growth, fertility, fed or fasted plasma glucose and insulin levels, pancreatic insulin content, and insulin sensitivity. However, beta/H1beta-KO mice exhibited impaired glucose tolerance with reduced insulin secretion compared with wild-type mice but preserved a normal insulin secretory response to arginine. Moreover, beta/H1beta-KO islets had increased HNF1alpha and Pdx-1, decreased HNF4 mRNA levels, and reduced glucose-stimulated insulin release. These results indicate that HNF1beta is involved in regulating the beta-cell transcription factor network and is necessary for glucose sensing or glycolytic signaling.
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PMID:Selective deletion of the Hnf1beta (MODY5) gene in beta-cells leads to altered gene expression and defective insulin release. 1514 86

HNF4alpha (hepatocyte nuclear factor 4alpha) belongs to a complex transcription factor network that is crucial for the function of hepatocytes and pancreatic beta-cells. In these cells, it activates the expression of a very large number of genes, including genes involved in the transport and metabolism of glucose and lipids. Mutations in the HNF4alpha gene correlate with MODY1 (maturity-onset diabetes of the young 1), a form of type II diabetes characterized by an impaired glucose-induced insulin secretion. The MODY1 G115S (Gly115-->Ser) HNF4alpha mutation is located in the DNA-binding domain of this nuclear receptor. We show here that the G115S mutation failed to affect HNF4alpha-mediated transcription on apolipoprotein promoters in HepG2 cells. Conversely, in pancreatic beta-cell lines, this mutation resulted in strong impairments of HNF4alpha transcriptional activity on the promoters of LPK (liver pyruvate kinase) and HNF1alpha, with this transcription factor playing a key role in endocrine pancreas. We show as well that the G115S mutation creates a PKA (protein kinase A) phosphorylation site, and that PKA-mediated phosphorylation results in a decreased transcriptional activity of the mutant. Moreover, the G115E (Gly115-->Glu) mutation mimicking phosphorylation reduced HNF4alpha DNA-binding and transcriptional activities. Our results may account for the 100% penetrance of diabetes in human carriers of this mutation. In addition, they suggest that introduction of a phosphorylation site in the DNA-binding domain may represent a new mechanism by which a MODY1 mutation leads to loss of HNF4alpha function.
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PMID:The G115S mutation associated with maturity-onset diabetes of the young impairs hepatocyte nuclear factor 4alpha activities and introduces a PKA phosphorylation site in its DNA-binding domain. 1523 28

In Caucasians, maturity-onset diabetes of the young (MODY) is mostly caused by mutations in the hepatocyte nuclear factor (HNF)-1alpha (MODY3) and glucokinase (MODY2) genes. Most Japanese MODY patients, however, are not linked to known MODY genes. In this study, we examined the genetic and clinical characteristics of Chinese subjects with MODY. The study included 146 unrelated families fulfilling the minimum criteria for MODY: two consecutive generations of type II diabetes with at least one member diagnosed under the age of 25. We screened for mutations in the HNF-4alpha (MODY1), MODY2 and MODY3 genes by direct sequencing. Antibody to glutamic acid decarboxylase (GAD-Ab) was measured in subjects with MODY of unknown cause (MODYX). Insulin resistance index and other clinical data were compared in sex-, age- and duration-matched MODY3 and MODYX patients. In all, 13 families had MODY3 mutations and two had MODY2 mutations. No MODY1 mutation was found. Four of the 12 different MODY3 mutations were newly identified novel mutations (Q243E, A311D, P379R and P488fsdelC). In subjects with MODYX, 3% were GAD-Ab positive and 60% were overweight. Compared to MODY3 patients, MODYX patients had higher body mass index (P<0.02), higher insulin resistance index (P=0.001) and triglyceride level (P<0.02), lower HDL level (P=0.001) and more hypertension (P<0.05), but no significant difference in the prevalence of diabetic complications. In conclusion, MODY3 and MODY2 account for only 9 and 1%, respectively, of Chinese MODY. A majority of Chinese MODY patients are due to defects in unknown genes and appear to be characterized by insulin resistance.
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PMID:Genetic and clinical characteristics of maturity-onset diabetes of the young in Chinese patients. 1565 5

Throughout the last decade, molecular genetic studies of non-autoimmune diabetes mellitus have contributed significantly to our present understanding of this disease's complex aetiopathogenesis. Monogenic forms of diabetes (maturity-onset diabetes of the young, MODY) have been identified and classified into MODY1-6 according to the mutated genes that by being expressed in the pancreatic beta-cells confirm at the molecular level the clinical presentation of MODY as a predominantly insulin secretory deficient form of diabetes mellitus. Genomewide linkage studies of presumed polygenic type 2 diabetic populations indicate that loci on chromosomes 1q, 5q, 8p, 10q, 12q and 20q contain susceptibility genes. Yet, so far, the only susceptibility gene, calpain-10 (CAPN10), which has been identified using genomewide linkage studies, is located on chromosome 2q37. Mutation analyses of selected 'candidate' susceptibility genes in various populations have also identified the widespread Pro12Ala variant of the peroxisome proliferator-activated receptor-gamma and the common Glu23Lys variant of the ATP-sensitive potassium channel, Kir6.2 (KCNJ11). These variants may contribute significantly to the risk type 2 diabetes conferring insulin resistance of liver, muscle and fat (Pro12Ala) and a relative insulin secretory deficiency (Glu23Lys). It is likely that, in the near future, the recent more detailed knowledge of the human genome and insights into its haploblocks together with the developments of high-throughput and cheap genotyping will facilitate the discovery of many more type 2 diabetes gene variants in study materials, which are statistically powered and phenotypically well characterized. The results of these efforts are likely to be the platform for major progress in the development of personalized antidiabetic drugs with higher efficacy and few side effects.
Diabetes Obes Metab 2005 Mar
PMID:Genetics of type 2 diabetes mellitus: status and perspectives. 1571 85

Two recent publications reported association of common polymorphisms in the P2 promoter of hepatocyte nuclear factor 4alpha (HNF4alpha) (the MODY1 gene) with risk for type 2 diabetes. We attempted to reproduce this putative association by genotyping 11 single nucleotide polymorphism (SNPs) spanning the HNF4alpha coding region and the P2 promoter in >3,400 patients and control subjects from Sweden, Finland, and Canada. One SNP that was consistently associated in the two previous reports (rs1884613, in the P2 promoter region) also trended in the same direction in our sample, albeit with a lower estimated odds ratio (OR) of 1.11 (P = 0.05, one-tailed). We genotyped this SNP (rs1884613) in an additional 4,400 subjects from North America and Poland. In this sample, the association was not confirmed and trended in the opposite direction (OR 0.88). Meta-analysis of our combined sample of 7,883 people (three times larger than the two initial reports combined) yielded an OR of 0.97 (P = 0.27). Finally, we provide an updated analysis of haplotype structure in the region to guide any further investigation of common variation in HNF4alpha. Although our combined results fail to replicate the previously reported association of common variants in HNF4alpha with risk for type 2 diabetes, we cannot exclude an effect smaller than that originally proposed, heterogeneity among samples, variation in as-yet-unmeasured genotypic or environmental modifiers, or true association secondary to linkage disequilibrium (LD) with as-yet-undiscovered variant(s) in the region.
Diabetes 2005 Mar
PMID:Association testing of variants in the hepatocyte nuclear factor 4alpha gene with risk of type 2 diabetes in 7,883 people. 1573 69

Mutations in the hepatocyte nuclear factor (HNF) 4alpha gene cause a form of maturity-onset diabetes of the young (MODY1), which is a monogenic form of type 2 diabetes characterized by impaired insulin secretion by pancreatic beta-cells. HNF4alpha is a transcription factor expressed in the liver, kidney, intestine, and pancreatic islet. Multiple splice variants of the HNF4alpha gene have been identified and an isoform of HNF4alpha8, an N-terminal splice variant, is expressed in pancreatic beta-cells. However, expression levels of HNF4alpha protein in pancreatic beta-cells and the transcriptional activity of HNF4alpha8 are not yet understood. In the present study, we investigated the expression of HNF4alpha in beta-cells and examined its functional properties. Western blotting and immunohistochemical analysis revealed that the expression of HNF4alpha protein in pancreatic islets and INS-1 cells was much lower than in the liver. A reporter gene assay showed that the transactivation potential of HNF4alpha8 was significantly weaker than that of HNF4alpha2, which is a major isoform in the liver, suggesting that the total level of HNF4alpha activity is very weak in pancreatic beta-cells. We also showed that the N-terminal A/B region of HNF4alpha8 possessed no activation function and C-terminal F region negatively regulated the transcriptional activity of HNF4alpha8. The information presented here would be helpful for the better understanding of MODY1/HNF4alpha diabetes.
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PMID:Functional characterization of the HNF4alpha isoform (HNF4alpha8) expressed in pancreatic beta-cells. 1575 52

Mutations in the hepatocyte nuclear factor (HNF)-4alpha gene cause a form of maturity-onset diabetes of the young (MODY1) that is characterized by impairment of glucose-stimulated insulin secretion by pancreatic beta-cells. HNF-4alpha, a transcription factor belonging to the nuclear receptor superfamily, is expressed in pancreatic islets as well as in the liver, kidney, and intestine. However, the role of HNF-4alpha in pancreatic beta-cell is unclear. To clarify the role of HNF-4alpha in beta-cells, we generated beta-cell-specific HNF-4alpha knock-out (betaHNF-4alphaKO) mice using the Cre-LoxP system. The betaHNF-4alphaKO mice exhibited impairment of glucose-stimulated insulin secretion, which is a characteristic of MODY1. Pancreatic islet morphology, beta-cell mass, and insulin content were normal in the HNF-4alpha mutant mice. Insulin secretion by betaHNF-4alphaKO islets and the intracellular calcium response were impaired after stimulation by glucose or sulfonylurea but were normal after stimulation with KCl or arginine. Both NAD(P)H generation and ATP content at high glucose concentrations were normal in the betaHNF-4alphaKO mice. Expression levels of Kir6.2 and SUR1 proteins in the betaHNF-4alphaKO mice were unchanged as compared with control mice. Patch clamp experiments revealed that the current density was significantly increased in betaHNF-4alphaKO mice compared with control mice. These results are suggestive of the dysfunction of K(ATP) channel activity in the pancreatic beta-cells of HNF-4alpha-deficient mice. Because the K(ATP) channel is important for proper insulin secretion in beta-cells, altered K(ATP) channel activity could be related to the impaired insulin secretion in the betaHNF-4alphaKO mice.
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PMID:Hepatocyte nuclear factor-4alpha is essential for glucose-stimulated insulin secretion by pancreatic beta-cells. 1637

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.
Diabetes Res Clin Pract 2006 Oct
PMID:Genetic and clinical characteristics of Korean maturity-onset diabetes of the young (MODY) patients. 1663 67


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