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)

Maturity-onset diabetes of the young (MODY) is a monogenic subtype of diabetes mellitus characterized by a young onset of type 2 diabetes, some abnormalities of the beta-cell function and an autosomal dominant inheritance with high penetrance. MODY types represent less than 5% of all cases of type 2 diabetes. Six genetic mutations have been described, one of them affecting the glucokinase gene (MODY 2) and the others various transcription factors HNF-1alpha, HNF-4alpha, HNF-1beta, IPF-1 and NeuroD (MODY 1,3,4,5,6, respectively). These different underlying gene mutations are associated with different clinical forms of the disease. Among the two most frequent forms, MODY 2 (mutation of the glucokinase gene) has a benign clinical evolution whereas MODY 3 (mutation of HNF-1alpha gene) has a much more severe evolution. The recognition of the MODY diabetes is important in clinical practice and may lead to the discovery of new more specific molecular therapeutic targets.
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PMID:[MODY types of diabetes mellitus]. 1603 8

Because impaired insulin secretion is characteristic of type 2 diabetes in Asians, including Japanese, the genes involved in pancreatic beta-cell function are candidate susceptibility genes for type 2 diabetes. We examined the association of variants in genes encoding several transcription factors (TCF1, TCF2, HNF4A, ISL1, IPF1, NEUROG3, PAX6, NKX2-2, NKX6-1, and NEUROD1) and genes encoding the ATP-sensitive K(+) channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) with type 2 diabetes in a Japanese cohort of 2,834 subjects. The exon 16 -3c/t variant rs1799854 in ABCC8 showed a significant association (P = 0.0073), and variants in several genes showed nominally significant associations (P < 0.05) with type 2 diabetes. Although the E23K variant rs5219 in KCNJ11 showed no association with diabetes in Japanese (for the K allele, odds ratio [OR] 1.08 [95% CI 0.97-1.21], P = 0.15), 95% CI around the OR overlaps in meta-analysis of European populations, suggesting that our results are not inconsistent with the previous studies. This is the largest association study so far conducted on these genes in Japanese and provides valuable information for comparison with other ethnic groups.
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PMID:Association studies of variants in the genes involved in pancreatic beta-cell function in type 2 diabetes in Japanese subjects. 1687 4

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

More than 120 published reports have described associations between single nucleotide polymorphisms (SNPs) and type 2 diabetes. However, multiple studies of the same variant have often been discordant. From a literature search, we identified previously reported type 2 diabetes-associated SNPs. We initially genotyped 134 SNPs on 786 index case subjects from type 2 diabetes families and 617 control subjects with normal glucose tolerance from Finland and excluded from analysis 20 SNPs in strong linkage disequilibrium (r(2) > 0.8) with another typed SNP. Of the 114 SNPs examined, we followed up the 20 most significant SNPs (P < 0.10) on an additional 384 case subjects and 366 control subjects from a population-based study in Finland. In the combined data, we replicated association (P < 0.05) for 12 SNPs: PPARG Pro12Ala and His447, KCNJ11 Glu23Lys and rs5210, TNF -857, SLC2A2 Ile110Thr, HNF1A/TCF1 rs2701175 and GE117881_360, PCK1 -232, NEUROD1 Thr45Ala, IL6 -598, and ENPP1 Lys121Gln. The replication of 12 SNPs of 114 tested was significantly greater than expected by chance under the null hypothesis of no association (P = 0.012). We observed that SNPs from genes that had three or more previous reports of association were significantly more likely to be replicated in our sample (P = 0.03), although we also replicated 4 of 58 SNPs from genes that had only one previous report of association.
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PMID:Screening of 134 single nucleotide polymorphisms (SNPs) previously associated with type 2 diabetes replicates association with 12 SNPs in nine genes. 1719 90

One of the challenges in type 2 diabetes treatment is to ensure pancreas functionality with gut peptides such as glucagon-like peptide-1 (GLP-1). We have recently shown that the endogenous GLP-1 production is promoted by dietary non-digestible carbohydrates (oligofructose), the higher GLP-1 secretion could participate in the control of obesity and associated disorders. This experimental study was designed to highlight the mechanisms of endogenous increase of GLP-1 following non-digestible carbohydrate feeding. Male Wistar rats were fed a standard diet (70.4 g/100 g total carbohydrates; controls) or the same diet supplemented with oligofructose (10 g/100 g diet) for 4 weeks. GLP-1-producing L-cells of the colon were quantified by immunohistochemistry. GLP-1 was quantified by ELISA, and proglucagon, neurogenin 3 and NeuroD mRNA were measured in the colon by quantitative RT-PCR. The number of GLP-1-expressing cells was doubled in the proximal colon of oligofructose-treated rats, a phenomenon correlated with the increase in proglucagon mRNA and peptide content in the tissue. Moreover, oligofructose increased the number of enteroendocrine L-cells in the proximal colon by a mechanism involving up-regulation of two differentiation factors: neurogenin 3 and NeuroD. It is the first demonstration that nutrients fermented in the gut may promote L-cell differentiation in the proximal colon, a phenomenon contributing to a higher endogenous GLP-1 production. These results suggest a new mechanism by which dietary fibres may lower food intake and fat mass development.
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PMID:Dietary non-digestible carbohydrates promote L-cell differentiation in the proximal colon of rats. 1736 75

Inulin-type fructans have been tested for their capacity to modulate lipid and glucose metabolism in several animal models. Oligofructose (OFS) decreases food intake, fat mass development, and hepatic steatosis in normal and in obese rats; moreover, it exerts an antidiabetic effect in streptozotocin-treated rats and high-fat-fed mice. In most cases, the beneficial effects of OFS are linked to an increase of glucagon-like peptide-1 (GLP-1) level in the portal vein and of GLP-1 and proglucagon mRNA, its precursor, in the proximal colon. In this organ, OFS increases the number of GLP-1-positive L cells by promoting factors (Neurogenin 3 and NeuroD) involved in the differentiation of stem cells into L cells. The chronic administration of GLP-1 receptor antagonist exendin 9-39 totally prevents the beneficial effects of OFS (improved glucose tolerance, fasting blood glucose, glucose-stimulated insulin secretion, insulin-sensitive hepatic glucose production, and reduced body weight gain). Furthermore GLP-1 receptor knockout mice are completely insensitive to the antidiabetic actions of OFS. These findings highlight the potential interest of enhancing endogenous GLP-1 secretion by inulin-type fructans for the prevention/treatment of obesity and type 2 diabetes. Moreover, OFS is also able to modulate other gastrointestinal peptides (such as PYY and ghrelin) that could be involved in the control of food intake. Several studies in humans already support interest in OFS in the control of satiety, triglyceridemia, or steatohepatitis. The link with gut peptides production in humans remains to be proven.
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PMID:Modulation of glucagon-like peptide 1 and energy metabolism by inulin and oligofructose: experimental data. 1795

Peroxisome proliferator-activated receptor gamma-coactivator-1alpha (PGC-1alpha) is significantly elevated in the islets of animal models of diabetes. However, the molecular mechanism has not been clarified. We investigated whether the suppression of PGC-1alpha expression protects against beta-cell dysfunction in vivo and determined the mechanism of action of PGC-1alpha in beta-cells. The studies were performed in glucolipotixicity-induced primary rat islets and INS-1 cells. In vitro and in vivo approaches using adenoviruses were used to evaluate the role of PGC-1alpha in glucolipotoxicity-associated beta-cell dysfunction. The expression of PGC-1alpha in cultured beta-cells increased gradually with glucolipotoxicity. The overexpression of PGC-1alpha also suppressed the expression of the insulin and beta-cell E-box transcription factor (BETA2/NeuroD) genes, which was reversed by PGC-1alpha small interfering RNA (siRNA). BETA2/NeuroD, p300-enhanced BETA2/NeuroD, and insulin transcriptional activities were significantly suppressed by Ad-PGC-1alpha but were rescued by Ad-siPGC-1alpha. PGC-1alpha binding at the glucocorticoid receptor site on the BETA2/NeuroD promoter increased in the presence of PGC-1alpha. Ad-siPGC-1alpha injection through the celiac arteries of 90% pancreatectomized diabetic rats improved their glucose tolerance and maintained their fasting insulin levels. The suppression of PGC-1alpha expression protects the glucolipotoxicity-induced beta-cell dysfunction in vivo and in vitro. A better understanding of the functions of molecules such as PGC-1alpha, which play key roles in intracellular fuel regulation, could herald a new era of the treatment of patients with type 2 diabetes mellitus by providing protection from glucolipotoxicity, which is an important cause of the development and progression of the disease.
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PMID:Suppression of peroxisome proliferator-activated receptor gamma-coactivator-1alpha normalizes the glucolipotoxicity-induced decreased BETA2/NeuroD gene transcription and improved glucose tolerance in diabetic rats. 1952 Jul 86

The LIM-homeodomain transcription factor ISL1 (islet factor 1) is essential for pancreatic islet cell and dorsal mesenchyme development. Mutations in ISL1 are associated with maturity-onset diabetes of the young and type 2 diabetes. Whether ISL1 plays a role in the insulin gene expression has not been fully elucidated. In the present study, we show that ISL1 can synergistically activate insulin gene transcription with BETA2 in pancreatic beta cells. The protein-protein interactions of ISL1 and BETA2 are directly mediated by the LIM domains of ISL1 and the basic helix-loop-helix domain of BETA2. Deletion of the two LIM domains of ISL1 enhances the transcriptional activation of the insulin gene, indicating a key role for the homeodomain in activating the insulin promoter. Furthermore, ISL1 can bind with the A3/4 box in the rat insulin gene capital I, Ukrainian promoter through its homeodomain. ISL1 expression is up-regulated at the mRNA level in type 2 diabetes (db/db mouse model) but down-regulated by dexamethasone in rat insulinoma cells. These results suggest that ISL1 is a transcriptional activator for insulin gene expression, and the interactions of ISL1 with BETA2 are required for the transcriptional activity of the insulin gene. Reduction in Isl1 gene expression appears to be involved in the impairment of insulin expression mediated by dexamethasone.
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PMID:The LIM-homeodomain protein ISL1 activates insulin gene promoter directly through synergy with BETA2. 1961 59

Type 1 and type 2 diabetes mellitus are considered to be caused by defective control of blood glucose resulting from a reduced beta-cell mass. Thus, the restoration of a functional beta-cell mass by replacing the damaged beta-cells or stimulating beta-cell regeneration is a logical approach for the treatment of diabetes. Strategies for increasing the beta-cell mass include stimulating beta-cell replication and differentiation and inhibiting beta-cell death. Treatment with various growth factors such as GLP-1, BTC, HGF, and EGF and forced expression of beta-cell transcription factors such as Pdx-1, NeuroD, and MafA resulted in the regeneration of beta-cells in vivo. Another approach is the administration of stem/progenitor cells, which can differentiate into insulin-producing cells. However, there are no satisfactory methods yet for clinical application. Understanding the mechanisms of the regenerative process of pancreatic beta-cells will pave the way for the development of regenerative medicine for treatment of diabetes.
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PMID:In vivo regeneration of insulin-producing beta-cells. 2021 17

Maturity-onset diabetes of the young (MODY) is a clinically heterogeneous group of monogenic disorders characterized by autosomal dominant inheritance of young-onset, non-insulin-dependent diabetes. The genes involved are important in beta cell development, function and regulation and lead to disorders in glucose sensing and insulin secretion. Heterozygous GCK mutations cause impaired glucokinase activity resulting in stable, mild hyperglycaemia that rarely requires treatment. HNF1A mutations cause a progressive insulin secretory defect that is sensitive to sulphonylureas, most often resulting in improved glycaemic control compared with other diabetes treatment. MODY owing to mutations in the HNF4A gene results in a similar phenotype, including sensitivity to sulphonylurea treatment. HNF1B mutations most frequently cause developmental renal disease (particularly renal cysts) but may also cause MODY in isolation or may cause the renal cysts and diabetes syndrome (RCAD syndrome). Mutations in NEUROD1, PDX1 (IPF1), CEL and INS are rare causes of MODY. MODY is often misdiagnosed as type 1 or type 2 diabetes. However, a correct genetic diagnosis impacts treatment and identifies at-risk family members. Thus, it is important to consider a diagnosis of MODY in appropriate individuals and to pursue genetic testing to establish a molecular diagnosis.
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PMID:Who should have genetic testing for maturity-onset diabetes of the young? 2152 18


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