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)

Islet amyloid polypeptide (IAPP)('amylin') is co-produced with insulin in pancreatic beta cells and is the formative polypeptide of pancreatic amyloid in patients with type 2 (non-insulin-dependent) diabetes mellitus. Islet amyloid and type 2 diabetes occur in man, but not in rat. To study transcription regulation of IAPP gene expression in man and rat, luciferase reporter constructs containing different portions of the upstream region of both IAPP genes were expressed in transfected cells. Both the human and the rat IAPP gene constructs revealed higher promoter activity in beta cells (particularly in beta TC3 cells) than in non-beta cells. In both IAPP genes potential transcription elements, with homology to insulin gene transcription elements, were identified. beta TC3 cells provide a good model system in which to study regulation of human and rat IAPP gene expression.
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PMID:Strong promoter activity of human and rat islet amyloid polypeptide/amylin gene constructs in mouse beta cells (beta TC 3). 836 26

Glucose-induced insulin release is decreased in the spontaneously diabetic GK rat, a nonobese rodent model of type 2 diabetes. Forskolin restores the impaired insulin release in both the isolated perfused pancreas and isolated islets from these rats (Abdel-Halim et al., Diabetes 45:934-940, 1996). We demonstrate here that the insulinotropic effect of forskolin in the GK rat is due to increased generation of cAMP and that it is associated with overexpression of adenylyl cyclase (AC)-III mRNA and gene mutations. The AC-III mRNA overexpression was demonstrated by in situ hybridization using oligonucleotide probes binding to different regions of the rat AC-III mRNA. It was associated with the presence of two point mutations identified at positions -28 bp (A --> G) and -358 bp (A --> C) of the promoter region of the AC-III gene and was demonstrable in both GK rat islets and peripheral blood cells. Transfection of COS cells with a luciferase reporter gene system revealed up to 25-fold increased promoter activity of GK AC-III promoter when compared with normal rat promoter (P < 0.0001). In conclusion, forskolin restores the impaired insulin release in islets of the GK rat through enhanced cAMP generation. This is linked to overexpression of AC-III mRNA in GK islets due to two functional point mutations in the promoter region of the AC-III gene.
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PMID:Mutations in the promoter of adenylyl cyclase (AC)-III gene, overexpression of AC-III mRNA, and enhanced cAMP generation in islets from the spontaneously diabetic GK rat model of type 2 diabetes. 951 62

Conjugated linoleic acid (CLA) is a naturally occurring fatty acid which has anti-carcinogenic and anti-atherogenic properties. CLA activates PPAR alpha in liver, and shares functional similarities to ligands of PPAR gamma, the thiazolidinediones, which are potent insulin sensitizers. We provide the first evidence that CLA is able to normalize impaired glucose tolerance and improve hyperinsulinemia in the pre-diabetic ZDF rat. Additionally, dietary CLA increased steady state levels of aP2 mRNA in adipose tissue of fatty ZDF rats compared to controls, consistent with activation of PPAR gamma. The insulin sensitizing effects of CLA are due, at least in part, to activation of PPAR gamma since increasing levels of CLA induced a dose-dependent transactivation of PPAR gamma in CV-1 cells cotransfected with PPAR gamma and PPRE X 3-luciferase reporter construct. CLA effects on glucose tolerance and glucose homeostasis indicate that dietary CLA may prove to be an important therapy for the prevention and treatment of NIDDM.
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PMID:Dietary conjugated linoleic acid normalizes impaired glucose tolerance in the Zucker diabetic fatty fa/fa rat. 953 24

We determined by PCR the number of (A-C)n repeats in the 2. 1 kb upstream of the aldose reductase (AR2) gene in healthy control subjects and in patients with NIDDM in Japanese. Sixty-one patients were recruited based on the severity of retinopathy and subdivided into two groups with proliferative retinopathy and without retinopathy. Japanese exhibited 10 different alleles in this region. The most prevalent allele was designated Z ((A-C)24 repeats) allele. The Z-4 allele was significantly associated with patients with proliferative retinopathy, whereas the Z+2 allele was significantly associated with patients without retinopathy. Erythrocyte AR2 protein levels were significantly elevated in patients exhibiting the Z-4 allele compared to those exhibiting other alleles. When Z-4 allele was ligated in transfection experiments to luciferase vector containing the promoter region of the AR2 gene, the construct showed significantly higher transcription of the reporter gene compared to constructs without (A-C) repeat or with Z-2, Z or Z+2 alleles. Our results suggest that the Z-4 allele in the 2. 1 kb upstream of the AR2 gene may enhance gene transcription and may be a genetic risk factor, which determines the predisposition to retinopathy in Japanese patients with NIDDM.
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PMID:Z-4 allele upstream of the aldose reductase gene is associated with proliferative retinopathy in Japanese patients with NIDDM, and elevated luciferase gene transcription in vitro. 1057 60

Islet-1 (Isl-1) is one of the transcription factors that play an important role for the formation of the islet cells. We scanned the Isl-1 gene in 77 Japanese type 2 diabetic patients with a family history and found a heterozygous nonsense mutation (Q310X) in 1 diabetic patient. The mutation was not found in 180 nondiabetic subjects. This mutation is located in the putative transactivation domain and deletes 40 amino acids of the COOH-terminal lesion. The Q310X mutant exhibited a 50% reduction in activity compared with the wild-type when tested for stimulation of transcription of a human amylin promoter-linked luciferase reporter gene in betaTC3 cells. The patient was a 49-year-old nonobese man who was diagnosed as having type 2 diabetes at 32 years of age and has been treated with sulfonylureas. The mutation was found in his mother, who has type 2 diabetes, and in his 14-year-old daughter, who has normal glucose tolerance but a relatively low insulin response. This is the first reported finding of Isl-1 gene mutation in type 2 diabetes. Although Isl-1 is not a common predisposing gene for Japanese type 2 diabetes, the mutation in this gene may be a rare cause of diabetes in isolated families.
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PMID:Nonsense mutation of islet-1 gene (Q310X) found in a type 2 diabetic patient with a strong family history. 1096 46

Mitochondrial DNA (mtDNA) content decreased in an age-dependent manner and may be one of the causal factors in age-related type 2 diabetes. Mitochondrial transcription factor A (mtTFA), which provides the replication primer, plays a key role for the regulation of mtDNA replication and its level is proportional to mtDNA. Here, we studied on the regulatory mechanism of mtTFA expression and the factors affecting the transcriptional activity of the mtTFA promoter. The promoter of human mtTFA contains 67 CpG dinucleotides. When the plasmids bearing the mtTFA promoter (2378 bp) linked to luciferase were transiently transfected into HepG2 cells, in vitro methylation of NRF-1 site by HhaI methylase abolished the mtTFA promoter activity up to 90%, implying that the CpG methylation of NRF-1 site inactivate mtTFA promoter-driven transcriptional activity. Besides the promoter methylation, the exogenous hydrogen peroxide or glucose also modulates the promoter activity of mtTFA. The bacterially overexpressed mtTFA protein exhibits a strong binding affinity to circular DNA (perhaps to mtDNA in mitochondria in vivo) and the protection of the DNA from cleavage by a hydrogen peroxide attack. Taken all these results together, age-related alterations of oxidative stress may affect mtDNA replication via regulating mtTFA activity. Furthermore, a vicious cycle may be present between mtTFA protein level and oxidative stress in the sense of DNA damage. Further studies were necessary to prove the presence of methyl cytosine in the mtTFA promoter of either an aged or a diabetic person and the effect of oxidative stress on the mtTFA function and expression resulting in a change of the mtDNA copy number.
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PMID:Mitochondrial transcription factor A (mtTFA) and diabetes. 1173 4

Complications of diabetes have a genetic influence. Since increased inducible nitric oxide synthase (iNOS) gene ( NOS2A) expression can contribute to tissue damage, NOS2A is a worthy candidate for such a role. We therefore tested a 4-bp insertion/deletion (+/-) polymorphism 0.7 kb upstream of NOS2A for association with complications in type 2 diabetes patients, and also performed transient transfection experiments to examine the effect of this variant on promoter activity in kidney cells in culture. We investigated 379 Caucasian type 2 diabetes patients of British/European descent, 93 of whom had microalbuminuria, 26 overt nephropathy, 46 retinopathy, and 73 clinical neuropathy. Genotyping for the variant was carried out by PCR and automated Genescan analysis. Transient transfection studies involved the renal HEK 293 cell line and luciferase reporter gene constructs containing 1.1 kb of 5'-flanking DNA from '+' or '-' allele homozygotes. We found that the '+' allele frequency in patients without microalbuminuria was 12%, but was 23% in those with microalbuminuria ( P=0.0005), and was 26% in those with nephropathy ( P=0.0007), 22% in those with retinopathy ( P=0.037), and 23% in those with neuropathy ( P=0.045). The odds ratios for homozygote +/+ to have microalbuminuria or nephropathy were 2.4 (95% CI 1.4-4.2, P=0.0023) and 5.4 (95% CI 1.8-16, P=0.0009), respectively. Luciferase reporter gene constructs containing 1 kb of NOS2A promoter DNA for each allele were made and sequence analysis confirmed that the +/- variation was the only sequence difference present. Transient transfection of these into HEK 293 cells revealed 25 times higher reporter gene activity for the '+' allele compared with the '-' allele. Gel shift analysis with 30mer oligonucleotides corresponding to each allele showed specific binding to nuclear extracts, being greater for the '+' allele. Thus the '+' allele of the NOS2A promoter variant may confer higher iNOS expression, and could contribute to complications of type 2 diabetes, especially in the approximately 5% of patients homozygous for this variant.
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PMID:Association of a functional inducible nitric oxide synthase promoter variant with complications in type 2 diabetes. 1190 46

Phytanic acid, a metabolite of the chlorophyll molecule, is part of the human diet and is present in normal human serum at low micromolar concentrations. It was previously shown to be a ligand of the 9-cis-retinoic acid receptor and peroxisome proliferator-activated receptor (PPAR) a. PPAR agonists are widely used in the treatment of type 2 diabetes. Here, we report that phytanic acid is not only a transactivator of PPARa, but it also acts via PPARb and PPARg in CV-1 cells that have been cotransfected with the respective full-length receptor and an acyl-CoA oxidase-PPAR-responsive element-luciferase construct. We observed that, in contrast to other fatty acids, phytanic acid at physiological concentrations enhances uptake of 2-deoxy-D-glucose in rat primary hepatocytes. This result could be explained by the increase in mRNA expression of glucose transporters-1 and -2 and glucokinase, as determined by quantitative real-time reverse transcriptase-polymerase chain reaction. Compared with the PPARg-specific agonist ciglitazone, phytanic acid exerts only minor effects on the differentiation of C3H10T1/2 cells into mature adipocytes. These results clearly demonstrate that phytanic acid acts via different PPAR isoforms to modulate expression of genes involved in glucose metabolism, thus suggesting a potential role of phytanic acid in the management of insulin resistance.
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PMID:Phytanic acid, a natural peroxisome proliferator-activated receptor (PPAR) agonist, regulates glucose metabolism in rat primary hepatocytes. 1192 21

Previous studies have shown that renal function in type 2 diabetes correlates better with tubular changes than with glomerular pathology. Since advanced glycation end products (AGEs; AGE-albumin) and in particular carboxymethyllysine (CML) are known to play a central role in diabetic nephropathy, we studied the activation of nuclear factor kappaB (NF-kappaB) in tubular epithelial cells in vivo and in vitro by AGE-albumin and CML. Urine samples from healthy control subjects (n = 50) and type 2 diabetic patients (n = 100) were collected and tested for excretion of CML and the presence of proximal tubular epithelial cells (pTECs). CML excretion was significantly higher in diabetic patients than in healthy control subjects (P < 0.0001) and correlated with the degree of albuminuria (r = 0.7, P < 0.0001), while there was no correlation between CML excretion and HbA(1c) (r = 0.03, P = 0.76). Urine sediments from 20 of 100 patients contained pTECs, evidenced by cytokeratin 18 positivity, while healthy control subjects (n = 50) showed none (P < 0.0001). Activated NF-kappaB could be detected in the nuclear region of excreted pTECs in 8 of 20 patients with pTECs in the urine sediment (40%). Five of eight NF-kappaBp65 antigen-positive cells stained positive for interleukin-6 (IL-6) antigen (62%), while only one of the NF-kappaB-negative cells showed IL-6 positivity. pTECs in the urine sediment correlated positively with albuminuria (r = 0.57, P < 0.0001) and CML excretion (r = 0.55, P < 0.0001). Immunohistochemistry in diabetic rat kidneys and a human diabetic kidney confirmed strong expression of NF-kappaB in tubular cells. To further prove an AGE/CML-induced NF-kappaB activation in pTECs, NF-kappaB activation was studied in cultured human pTECs by electrophoretic mobility shift assays (EMSAs) and Western blot. Stimulation of NF-kappaB binding activity was dose dependent and was one-half maximal at 250 nmol/l AGE-albumin or CML and time dependent at a maximum of activation after 4 days. Functional relevance of the observed NF-kappaB activation was demonstrated in pTECs transfected with a NF-kappaB-driven luciferase reporter plasmid and was associated with an increased release of IL-6 into the supernatant. The AGE- and CML-dependent activation of NF-kappaBp65 and NF-kappaB-dependent IL-6 expression could be inhibited using the soluble form of the receptor for AGEs (RAGE) (soluble RAGE [sRAGE]), RAGE-specific antibody, or the antioxidant thioctic acid. In addition transcriptional activity and IL-6 release from transfected cells could be inhibited by overexpression of the NF-kappaB-specific inhibitor kappaBalpha. The findings that excreted pTECs demonstrate activated NF-kappaB and IL-6 antigen and that AGE-albumin and CML lead to a perpetuated activation of NF-kappaB in vitro infer that a perpetuated increase in proinflammtory gene products, such as IL-6, plays a role in damaging the renal tubule.
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PMID:Activation of tubular epithelial cells in diabetic nephropathy. 1245 11

The proglucagon gene encodes pancreatic glucagon and the glucagon-like peptides, which exert diverse effects on nutrient absorption and assimilation. The therapeutic potential of glucagon-like peptide-1 (GLP-1) has fostered interest in development of cellular engineering approaches to augment endogenous intestinal-derived GLP-1 for the treatment of type 2 diabetes. We have used adenovirus technology to examine the potential roles of the transcription factors Cdx-2/3 and Pax-6 as activators of endogenous proglucagon gene expression in enteroendocrine cell lines and in nontransformed rat intestinal cells. Adenoviral-expressed Cdx-2/3 and Pax-6 activated proglucagon promoter-luciferase activity in baby hamster kidney (BHK) fibroblasts, HEK 293 cells, and enteroendocrine cell lines. Pax-6, but not Cdx-2/3, induced expression of the endogenous proglucagon gene in enteroendocrine cell lines, but not in heterologous fibroblasts. Furthermore, transduction of primary rat intestinal cell cultures in vitro, or the rat colonic epithelium in vivo, with Ad-Pax-6 activated endogenous proglucagon gene expression. These data demonstrate that Pax-6, but not Cdx-2/3, is capable of activating the endogenous proglucagon gene in both immortalized enteroendocrine cells and the nontransformed intestinal epithelium in vivo.
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PMID:Pax-6 activates endogenous proglucagon gene expression in the rodent gastrointestinal epithelium. 1254 Jun 17


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