Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The minisatellite DNA polymorphism consisting of a variable number of tandem repeats (VNTR) at the human INS (insulin gene) 5'-flanking region has demonstrated allelic effects on insulin gene transcription in vitro and has been associated with the level of insulin gene expression in vivo. We now show that this VNTR also has effects on the nearby insulin-like growth factor II gene (IGF2) in human placenta in vivo and in the HepG2 hepatoma cell line in vitro. We show that higher steady-state IGF2 mRNA levels are associated with shorter alleles (class I) than the longer class III alleles in term placentae. In vitro, reporter gene activity was greater from reporter gene constructs with IGF2 promoter 3 in the presence of class I alleles than from those with class III. Taken together with the documented transcriptional effects on the insulin gene, we propose that the VNTR may act as a long range control element affecting the expression of both INS and IGF2. The localization of a type 1 diabetes susceptibility locus (IDDM2) to the VNTR itself suggests that either or both of these genes may be involved in the biologic effects of IDDM2.
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PMID:The INS 5' variable number of tandem repeats is associated with IGF2 expression in humans. 960 16

The liver is an attractive target organ for insulin gene expression in type 1 diabetes as it contains appropriate cellular mechanisms of regulated gene expression in response to blood glucose and insulin. We hypothesize that insulin production regulated by both glucose and insulin may be achieved using the promoter of the glucose 6-phosphatase gene (G6Pase), the expression of which in the liver is induced by glucose and suppressed by insulin. Recombinant adenoviral vectors expressing the reporter gene CAT or insulin under transcriptional direction of the G6Pase promoter were constructed. Glucose-stimulated as well as self-limiting insulin production was achieved in vector-transduced hepatoma cells in which expression of the insulin gene was controlled by the G6Pase promoter. While insulin strongly inhibited the G6Pase promoter activity under low glucose conditions, its inhibitory capacity was attenuated when glucose levels were elevated. At the physiologic glucose level of 5.5 mM glucose, vector-transduced hepatoma cells produced a self-limited level of insulin at approximately 0.2-0.3 ng/ml, which is within the range of fasting levels of insulin in normal animals. These results indicate that the G6Pase promoter possesses desirable features and may be developed for regulated hepatic insulin gene expression in type 1 diabetes.
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PMID:Glucose-stimulated and self-limiting insulin production by glucose 6-phosphatase promoter driven insulin expression in hepatoma cells. 1111 Apr 11

The basis for accelerated atherosclerosis in diabetes is unclear. Diabetes is associated with loss of heparan sulfate (HS) from the liver, which may impede lipoprotein clearance and thereby worsen atherosclerosis. To study hepatic HS loss in diabetes, we examined regulation of HS N-deacetylase/N-sulfotransferase-1 (NDST), a key enzyme in hepatic HS biosynthesis. Hepatic NDST mRNA, protein, and enzymatic activity were suppressed by >50% 2 weeks after induction of type 1 diabetes in rats. Treatment of diabetic rats with enalapril, an ACE inhibitor, had no effect on hyperglycemia or hepatic NDST mRNA levels, yet increased hepatic NDST protein and enzymatic activity. Similar results were obtained in diabetic animals treated with losartan, which blocks the type 1 receptor for angiotensin II (AngII). Consistent with these findings, diabetic livers exhibited increased ACE expression, and addition of AngII to cultured hepatoma cells reduced NDST activity and protein. We conclude that diabetes substantially suppresses hepatic NDST mRNA, protein, and enzymatic activity. AngII contributes to suppression of NDST protein and enzymatic activity, whereas mRNA suppression occurs independently. Suppression of hepatic NDST may contribute to diabetic dyslipidemia, and stimulation of NDST activity by AngII inhibitors may provide cardiovascular protection.
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PMID:Loss of heparan N-sulfotransferase in diabetic liver: role of angiotensin II. 1579 51

Insulin production afforded by hepatic gene therapy (HGT) retains promise as a potential treatment for type 1 diabetes, but successful approaches have been limited. We employed a novel and previously untested promoter for this purpose, glucose transporter-2 (GLUT2) to drive insulin production via delivery by recombinant adeno-associated virus (rAAV). In vitro, the GLUT2 promoter was capable of robust glucose-responsive expression in transduced HepG2 human hepatoma cells. Therefore, rAAV constructs were designed to express the furin-cleavable human preproinsulin B10 gene, under the control of the murine GLUT2 promoter and packaged for delivery with rAAV expressing the type 5 capsid. Streptozotocin-induced diabetic mice were subjected to hepatic portal vein injection immediately followed by implantation of a sustained-release insulin pellet to allow time for transgenic expression. All mice injected with the rAAV5-GLUT2-fHPIB10 virus remained euglycemic for up to 35 days post-injection, with 50% euglycemic after 77 days post-injection. In contrast, mock-injected mice became hyperglycemic within 15 days post-injection following dissolution of the insulin pellet. Serum levels of both human insulin and C-peptide further confirmed successful transgenic delivery by the rAAV5-GLUT2-fHPIB10 virus. These findings indicate that the GLUT2 promoter may be a potential candidate for regulating transgenic insulin production for hepatic insulin gene therapy in the treatment of type I diabetes.
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PMID:Glucose transporter-2 (GLUT2) promoter mediated transgenic insulin production reduces hyperglycemia in diabetic mice. 1622 91

Since the discovery of the hepatitis C virus (HCV) in 1989, attention has been paid to the association of chronic HCV infection and the development of diabetes. The risk factors for diabetes include older age, HCV genotype 3, severe liver fibrosis, family history of diabetes, and liver/kidney transplantation. Emerging evidence in animals and humans has shown that HCV infection induces hepatic steatosis and increases tumor necrosis factor-alpha level, both resulting in the development of insulin resistance and subsequent type 2 diabetes. It is suggested that the presence of diabetes and hepatic steatosis may enhance fibrosis progression, hepatocellular carcinoma, and atherosclerosis. Interferon is reportedly associated with improved glucose tolerance. However, interferon might enhance underlying autoimmunity against beta cells, leading to overt type 1 diabetes that is genetically predisposed or give rise to hyperglycemia, resulting in the development of type 2 diabetes. In light of the national epidemic of type 2 diabetes, the link between HCV and diabetes would be a major public health problem. Further clinical researches are awaited in order to effectively detect, prevent, and treat HCV-associated type 2 diabetes, which would also slow the progression of hepatitis C itself.
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PMID:Hepatitis C infection and diabetes. 1650 40

The Reg family of proteins has been studied in the context of growth and regeneration in several organs including pancreatic islets. We previously suggested that Reg proteins act as autoantigens in type 1 diabetes, based on evidence that a member of the Reg family (hepatocellular carcinoma intestine pancreas [HIP]/pancreatitis-associated protein [PAP]) was overexpressed in the islets of a patient who died after sudden onset of type 1 diabetes, and that, in NOD mice, Reg-specific T-cells adoptively transferred diabetes. In the current study, we developed antisera to detect individual Reg members in mouse islets and found that RegIIIalpha was present in the non-beta-cell portion of the islets, while RegII was predominantly expressed in beta-cells. Vaccination of NOD mice with the separately expressed N-terminal (NtfrII) or C-terminal (CtfrII) portion of RegII revealed a dichotomy: NtfrII vaccination accelerated and CtfrII vaccination delayed type 1 diabetes. Vaccination with CtfrII was more effective when given at later stages in the pathogenesis of type 1 diabetes, a time dependency different from that seen with other antigen-dependent vaccine strategies in NOD mice, which might have therapeutic implications. In conclusion, RegII is a novel beta-cell-derived autoantigen in NOD mice. The autoimmune response against this protein may convert a regenerative into an islet-destructive process accelerating development of type 1 diabetes.
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PMID:RegII is a beta-cell protein and autoantigen in diabetes of NOD mice. 1719 62

Niacin (nicotinic acid and nicotinamide) is a vitamin used as a source of the NAD+ and NADP+ coenzymes required for many metabolic processes. Its low dietary levels induce the development of pellagra. Niacin has been used for decades in the treatment of patients with disturbed lipid and lipoprotein metabolism, this being the main cause of atherosclerotic changes in cardiovascular diseases. It is still the most efficacious drug in terms of its ability to increase HDL cholesterol content accompanied by a decrease in all atherogenic lipoproteins (VLDL, LDL, and L(a)) as well as fatty acids and triglycerides. Niacin also increases adiponectin level, which might result in additional atheroprotection. There are studies confirming the beneficial action of niacin against migraine and hyperphosphatemia associated with renal failure, ethanol-induced neurodegeneration, and loss of beta-cell function in type 1 diabetes. Moreover, it augments plasma tryptophan concentrations in HIV-infected patients and thyroid radiosensitivity to 131I. Inhibition of the invasion of hepatoma cells has also been proven. However, it is necessary to point out that the currently applied niacin preparations might exhibit such side effects as cutaneous flushing, gastrointestinal disturbances, and hepatotoxicity, particularly during treatment with sustained-release niacin preparations. The recent discovery of the G-protein-coupled receptor GPR109A, which mediates the antilipolytic effects induced by nicotinic acid in adipocytes as well as cutaneous vasodilation, allows the development of new agents interacting with this receptor. In view of these observations, niacin therapy must be accompanied by control of the choice of niacin preparation and its dose in order to eliminate or at least limit its side effects.
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PMID:[Niacin in therapy]. 1755 32

Nuclear factor-kappaB (NF-kappaB) is responsible for the expression by regulating many genes for immune response, cell adhesion, differentiation, proliferation, angiogenesis and apoptosis. The function of NF-kappaB is inhibited by binding to NF-kappaB inhibitor (IkappaB), and imbalance of NF-kappaB and IkappaB has been associated with development of many diseases, including tumours. In this review, we focus on polymorphisms of the NFKB and NFKBI genes in relation to development of common inflammatory diseases including ulcerative colitis (UC), Crohn's disease (CD), rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis, giant cell arthritis, type 1 diabetes, multiple sclerosis, celiac disease, and Parkinson's disease, as well as susceptibility of several cancers, such as oral squamous cell carcinoma, colorectal cancer (CRC), hepatocellular carcinoma, breast cancer and myeloma.
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PMID:NFKB and NFKBI polymorphisms in relation to susceptibility of tumour and other diseases. 1770 19

Numerous complications can occur in celiac disease, nutritional (growth failure in children, malnutrition, vitamin deficiencies), hematologic (anaemia), bone disease (osteoporosis, fracture), gynaecologic (hypo fertility), cardiovascular (coronaropathy, venous thrombosis), neurological (peripheral neuropathy), hepatic (cytolysis, cirrhosis). Celiac disease is associated with an increased risk of autoimmune diseases (type 1 diabetes, thyroiditis), and cancer (upper digestive tract, hepatocellular carcinoma, lymphoma). The main digestive complications are microscopic colitis and refractory sprue, which are resistant to gluten-free diet. It can be associated with a monoclonal proliferation of intraepithelial lymphocytes (type 2 refractory sprue), which may be considered as a cryptic lymphoma and can lead to invasive T lymphoma, which occurs in one celiac patient in 1000. Gluten-free diet protects from the occurrence of most complications and correct the over-mortality related to these complications.
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PMID:[Complications of celiac disease]. 2162 50

Streptozotocin (STZ) is an antibiotic often used in the treatment of different types of cancers. It is also highly cytotoxic to the pancreatic beta-cells and therefore is commonly used to induce experimental type 1 diabetes in rodents. Resistance towards STZ-induced cytotoxicity in cancer cells has also been reported. Our previous studies have reported organ-specific toxicity and metabolic alterations in STZ-induced diabetic rats. STZ induces oxidative stress and metabolic complications. The precise molecular mechanism of STZ-induced toxicity in different tissues and carcinomas is, however, unclear. We have, therefore, investigated the mechanism of cytotoxicity of STZ in HepG2 hepatoma cells in culture. Cells were treated with different doses of STZ for various time intervals and the cytotoxicity was studied by observing the alterations in oxidative stress, mitochondrial redox and metabolic functions. STZ induced ROS and RNS formation and oxidative stress as measured by an increase in the lipid peroxidation as well as alterations in the GSH-dependent antioxidant metabolism. The mitochondria appear to be a highly sensitive target for STZ toxicity. The mitochondrial membrane potential and enzyme activities were altered in STZ treated cells resulting in the inhibition of ATP synthesis. ROS-sensitive mitochondrial aconitase activity was markedly inhibited suggesting increased oxidative stress in STZ-induced mitochondrial toxicity. These results suggest that STZ-induced cytotoxicity in HepG2 cells is mediated, at least in part, by the increase in ROS/RNS production, oxidative stress and mitochondrial dysfunction. Our study may be significant for better understanding the mechanisms of STZ action in chemotherapy and drug induced toxicity.
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PMID:Streptozotocin-induced cytotoxicity, oxidative stress and mitochondrial dysfunction in human hepatoma HepG2 cells. 2275 29


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