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)

Glibenclamide as a second-generation compound of sulfonylurea has widely been used in the treatment of type 2 diabetes patients. It has been shown that it induces apoptosis in beta cells, which is partially mediated by Ca(2+) influx. Here, we investigated the role of nitric oxide (NO) and nitric oxide synthase (NOS) isoforms on glibenclamide-induced apoptosis in rat insulinoma cells. Our results showed that glibenclamide induces NO generation (measured as nitrite) that is accompanied with decrease of cell viability in a defined concentration of glibenclamide. The effects of glibenclamide on cell viability were partially inhibited after treatment with N(G)-nitro-L-arginine methyl ester (L-NAME), inhibitor more selective for constitutive nitric oxide synthase, and in the presence of D600--a blocker of voltage-gated L-type Ca(2+) channels inhibited Ca(2+) influx into beta cells, whereas aminoguanidine (AG), a preferential inhibitor of inducible NOS, was significantly less effective. Analysis of DNA fragmentation by electrophoresis and staining with Hoechest 33342 and propidium iodide showed that L-NAME, but not AG, prevented DNA fragmentation and decreased the number of cells with condensed and fragmented nuclei. It revealed that the effects of glibenclamide on apoptosis were partially inhibited by treatment with L-NAME. In conclusion, we have shown that NO production in glibenclamide treated cells may be involved in the induction of apoptotic cell death in pure beta cell line and it may be due to Ca(2+) dependent activation of constitutive NOS isoforms.
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PMID:Nitric oxide involvement in pancreatic beta cell apoptosis by glibenclamide. 1625 81

Defective glucose-stimulated insulin secretion is the main cause of hyperglycemia in type 2 diabetes mellitus. Mutations in HNF-1alpha cause a monogenic form of type 2 diabetes, maturity-onset diabetes of the young (MODY), characterized by impaired insulin secretion. Here we report that collectrin, a recently cloned kidney-specific gene of unknown function, is a target of HNF-1alpha in pancreatic beta cells. Expression of collectrin was decreased in the islets of HNF-1alpha (-/-) mice, but was increased in obese hyperglycemic mice. Overexpression of collectrin in rat insulinoma INS-1 cells or in the beta cells of transgenic mice enhanced glucose-stimulated insulin exocytosis, without affecting Ca(2+) influx. Conversely, suppression of collectrin attenuated insulin secretion. Collectrin bound to SNARE complexes by interacting with snapin, a SNAP-25 binding protein, and facilitated SNARE complex formation. Therefore, collectrin is a regulator of SNARE complex function, which thereby controls insulin exocytosis.
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PMID:The HNF-1 target collectrin controls insulin exocytosis by SNARE complex formation. 1633 Mar 18

The physiological effects of glucose-dependent insulinotropic polypeptide (GIP) are mediated through specific receptors expressed on target cells. Because aberrant GIP receptor (GIPR) expression has been implicated in abnormal GIP responses associated with type 2 diabetes mellitus and food-induced Cushing's syndrome, we sought to identify factors that regulate the GIPR. We previously demonstrated that sequences between -1 and -100 of the GIPR gene were sufficient to direct transcription in a rat insulinoma cell line (RIN38). In the present study, we compared the 5'-flanking regions of the rat and human GIPR gene and demonstrated 88% identity within the first 92 bp. Subsequent serial deletion analyses showed that the region between -85 and -40 is essential for maximal promoter activity. Within this region, we identified three putative Sp1 binding motifs, located at positions -77, -60, and -50, that can specifically bind both Sp1 and Sp3. Whereas mutation of the Sp1 sites at -50 and -60 led to 36 and 40% reduction in promoter activity, respectively, mutation of the Sp1 motif at -70 did not affect promoter activity. Cotransfection of S2 Schneider cells with GIPR-luciferase chimeric constructs and either Sp1 or Sp3 expression vectors indicated that both Sp1 and the long form of Sp3 activate transcription through binding to the Sp1 sites located between -100 and -40. Lastly, chromatin immunoprecipitation analyses revealed that both Sp1 and Sp3 bind to the GIPR promoter region in RIN38 cells. These results indicate that cell-specific expression of GIPR is associated with the binding of the transcription factors Sp1 and Sp3 to the GIPR promoter.
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PMID:Sp1/Sp3 binding is associated with cell-specific expression of the glucose-dependent insulinotropic polypeptide receptor gene. 1640 75

ATP sensitive potassium (K(ATP)) channels have important functions in neuroendocrine tissue, in smooth and skeletal muscle and in the heart. In pancreatic beta cells the K(ATP) channels, which are formed by 4 ion channels (Kir6.2) and 4 regulatory sulfonylurea receptors (SUR1), control the glucose stimulated release of insulin. The Kir6.2/SUR1 K(ATP) channels are also present in the brain and in other neuroendocrine tissues. Blockers of Kir6.2/SUR1 channels, e.g. glibenclamide and repaglinide stimulate release of insulin and are used for treatment of type 2 diabetes. Openers of Kir6.2/SUR1 channels, e.g. diazoxide, have in contrast only found limited clinical use in treatment of hypersecretion of insulin associated with certain tumours (insulinoma) and genetic disorders (persistent hyperinsulinemia and hypoglycemia of infancy, PHHI). Recent studies have however, indicated that openers of Kir6.2/SUR1 channels could be useful in treatment of e.g. metabolic disorders and diseases of the CNS. The clinical use of diazoxide has been hampered by its lack of potency and selectivity giving rise to side effects, such as oedema and hirsutism and new selective openers of Kir6.2/SUR1 channels have been pursued. This has provided several structurally diverse series, which include 1,2,4-thiadiazine 1,1-dioxide derivatives, like BPDZ 62, BPDZ 73, NNC 55-0462, NNC 55-0118 and NN414, cyanoguanidines, nitropyrazoles and 4-sulfamoylphenylbenzamides. NN414 has been shown to be a potent and Kir6.2/SUR1 selective K(ATP) channels opener, which inhibits glucose stimulated insulin release in vitro and in vivo and which has beneficial effects on glucose homeostasis in preclinical and clinical studies.
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PMID:Towards selective Kir6.2/SUR1 potassium channel openers, medicinal chemistry and therapeutic perspectives. 1647 28

We report a case of recurrent hypoglycaemia in a long-standing type 2 diabetic patient, despite dramatic reduction in her anti-diabetic therapy. Subsequent investigations revealed an insulinoma as the cause. This patient was treated medically with diazoxide therapy, as multiple co-morbidities were felt to preclude surgical intervention. Although insulinoma is rare in the elderly and exceedingly rare in the context of type 2 diabetes, it should be given due consideration when no other exacerbating factor is found.
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PMID:A mysterious case of normalising blood sugar: insulinoma in a long-standing diabetic patient. 1663 74

Type 2 diabetes mellitus is associated with increased oxidative stress. Free radicals produced during this stress may damage various cellular components. Gliclazide, a second-generation sulfonylurea, is an oral hypoglycemic drug that possesses antioxidant properties. Therefore, gliclazide may diminish the harmful consequences of oxidative stress in diabetic patients. The aim of our study was to evaluate the action of gliclazide on DNA damage and repair in normal human peripheral blood lymphocytes and insulinoma mouse cells (beta-TC-6). DNA damage and repair were induced by hydrogen peroxide, gamma and ultraviolet radiation and MNNG (N-methyl-N'-nitro-N-nitrosoguanidine) in the presence or absence of gliclazide and were analysed by the alkaline comet assay. DNA double-strand breaks were assayed by pulsed-field gel electrophoresis. Gliclazide protected DNA of both kinds of cells from DNA damage induced by chemicals and radiations. These results suggest that gliclazide may diminish the risk of free radical-related diseases associated with type 2 diabetes mellitus and possibly cancer.
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PMID:Effect of gliclazide on DNA damage in human peripheral blood lymphocytes and insulinoma mouse cells. 1696 9

Although many studies using rodent islets and insulinoma cell lines have been performed to determine the role of insulin in the regulation of islet function, the autocrine effect of insulin on insulin gene expression is still controversial, and no consensus has yet been achieved. Because very little is known about the insulin signaling pathway in human islets, we used single-cell RT-PCR to profile the expression of genes potentially involved in the insulin signaling cascade in human beta-cells. The detection of mRNAs for insulin receptor (IR)A and IRB; insulin receptor substrate (IRS)-1 and IRS-2; phosphoinositide 3-kinase (PI3K) catalytic subunits p110alpha, p110beta, PI3KC2alpha, and PI3KC2gamma; phosphoinositide-dependent protein kinase-1; protein kinase B (PKB)alpha, PKBbeta, and PKBgamma in the beta-cell population suggests the presence of a functional insulin signaling cascade in human beta-cells. Small interfering RNA-induced reductions in IR expression in human islets completely suppressed glucose-stimulated insulin gene expression, suggesting that insulin regulates its own gene expression in human beta-cells. Defects in this regulation may accentuate the metabolic dysfunction associated with type 2 diabetes.
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PMID:Identification of insulin signaling elements in human beta-cells: autocrine regulation of insulin gene expression. 1700 50

Liver X receptor (LXR)alpha and LXRbeta play important roles in fatty acid metabolism and cholesterol homeostasis. Although the functional roles of LXR in the liver, intestine, fat, and macrophages are well established, its role in pancreatic beta-cells has not been clearly defined. In this study, we revealed that chronic activation of LXR contributes to lipotoxicity-induced beta-cell dysfunction. We observed significantly elevated expression of LXR in the islets of diabetic rodent models, including fa/fa ZDF rats, OLETF rats, and db/db mice. In primary pancreatic islets and INS-1 insulinoma cells, activation of LXR with a synthetic ligand, T0901317, stimulated expression of the lipogenic genes ADD1/SREBP1c, FAS, and ACC and resulted in increased intracellular lipid accumulation. Moreover, chronic LXR activation induced apoptosis in pancreatic islets and INS-1 cells, which was synergistically promoted by high glucose conditions. Taken together, we suggest lipid accumulation caused by chronic activation of LXR in beta-cells as a possible cause of beta-cell lipotoxicity, a key step in the development of type 2 diabetes.
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PMID:Chronic activation of liver X receptor induces beta-cell apoptosis through hyperactivation of lipogenesis: liver X receptor-mediated lipotoxicity in pancreatic beta-cells. 1736 26

Insulinoma in a patient with pre-existing diabetes is extremely rare. A 74-year-old woman with type 2 diabetes mellitus who had been treated with a sulfonylurea for 6 years began experiencing frequent episodes of hypoglycemia. Endogenous hyperinsulinism was found 9 months after the sulfonylurea was discontinued, and transabdominal ultrasonography and magnetic resonance imaging identified a pancreatic tumor. Pathology examination of the resected tumor demonstrated an insulinoma. Postoperatively, the patient had no further episodes of hypoglycemia. Thereafter, she required insulin to control her hyperglycemia. Although hypoglycemic agents are the commonest cause of hypoglycemia in type 2 diabetes, insulinomas may occur in these patients. This possibility should be considered if the hypoglycemia persists despite dose adjustment or cessation of the drugs.
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PMID:Insulinoma causing hypoglycemia in a patient with type 2 diabetes. 1756 74

The endocannabinoid, arachidonoylethanolamide (AEA), and the peroxisome proliferator-activated receptor (PPAR)-alpha ligand, oleylethanolamide (OEA) produce opposite effects on lipogenesis. The regulation of OEA and its anti-inflammatory congener, palmitoylethanolamide (PEA), in adipocytes and pancreatic beta-cells has not been investigated. We report here the results of studies on acylethanolamide regulation in these cells during obesity and hyperglycaemia, and provide an overview of acylethanolamide role in metabolic control. We analysed by liquid chromatography-mass spectrometry OEA and PEA levels in: 1) mouse 3T3F442A adipocytes during insulin-induced differentiation, 2) rat insulinoma RIN m5F beta-cells kept in 'low' or 'high' glucose, 3) adipose tissue and pancreas of mice with high fat diet-induced obesity (DIO), and 4) in visceral fat or blood of obese or type 2 diabetes (T2D) patients. In adipocytes, OEA levels remain unchanged during differentiation, whereas those of PEA decrease significantly, and are under the negative control of both leptin and PPAR-gamma. PEA is significantly downregulated in subcutaneous adipose tissue of DIO mice. In RIN m5F insulinoma beta-cells, OEA and PEA levels are inhibited by 'very high' glucose, this effect being enhanced by insulin, whereas in cells kept for 24 h in 'high' glucose, they are stimulated by both glucose and insulin. Elevated OEA and PEA levels are found in the blood of T2D patients. Reduced PEA levels in hypertrophic adipocytes might play a role in obesity-related pro-inflammatory states. In beta-cells and human blood, OEA and PEA are down- or up-regulated under conditions of transient or chronic hyperglycaemia, respectively.
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PMID:Role and regulation of acylethanolamides in energy balance: focus on adipocytes and beta-cells. 1770 23


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