Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxidative stress is induced under diabetic conditions through various pathways, including the electron transport chain in mitochondria and the nonenzymatic glycosylation reaction, and is likely involved in progression of pancreatic beta-cell dysfunction developing in diabetes. beta-Cells are vulnerable to oxidative stress, possibly due to low levels of antioxidant enzyme expression. When oxidative stress was induced in vitro in beta cells, the insulin gene promoter activity and mRNA levels were suppressed, accompanied by the reduced activity of pancreatic and duodenal homeobox factor-1 (PDX-1) (also known as IDX-1/STF-1/IPF1), an important transcription factor for the insulin gene. The suppression of oxidative stress by a potent antioxidant, N-acetyl-l-cysteine or probucol, led to the recovery of insulin biosynthesis and PDX-1 expression in nuclei and improved glucose tolerance in animal models for type 2 diabetes. As a possible cause of this, we recently found that PDX-1 was translocated from the nucleus to the cytoplasm in response to oxidative stress. Furthermore, the addition of a dominant-negative form of c-Jun N-terminal kinase (JNK) inhibited the oxidative stress-induced PDX-1 translocation, suggesting an essential role of JNK in mediating the phenomenon. Taken together, the oxidative stress-mediated activation of the JNK pathway leads to nucleocytoplasmic translocation of PDX-1 and thus is likely involved in the progression of beta-cell dysfunction found in diabetes.
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PMID:Oxidative stress and pancreatic beta-cell dysfunction. 1628 Jun 46

Recent studies in normal mice have suggested that transplanted bone marrow cells can transdifferentiate into pancreatic beta-cells at relatively high efficiency. Herein, adopting the same and alternative approaches to deliver and fate map-transplanted bone marrow cells in the pancreas of normal as well as diabetic mice, we further investigated the potential of bone marrow transplantation as an alternative approach for beta-cell replacement. In contrast to previous studies, transplanted bone marrow cells expressing green fluorescence protein (GFP) under the control of the mouse insulin promoter failed to express GFP in the pancreas of normal as well as diabetic mice. Although bone marrow cells expressing GFP under the ubiquitously expressed beta-actin promoter efficiently engrafted the pancreas of normal and hyperglycemic mice, virtually all expressed CD45 and Mac-1/Gr-1, demonstrating that they adopt a hematopoietic rather than beta-cell fate, a finding further substantiated by the complete absence of GFP(+) cells expressing insulin and the beta-cell transcription factors pancreatic duodenal homeobox factor-1 and homeodomain protein. Thus, transplanted bone marrow cells demonstrated little, if any, capacity to adopt a beta-cell fate.
Diabetes 2006 Feb
PMID:Failure of transplanted bone marrow cells to adopt a pancreatic beta-cell fate. 1644 59

Nicotinamide has been reported to induce differentiation of precursor/stem cells toward a beta-cell phenotype, increase islet regeneration, and enhance insulin biosynthesis. Exposure of INS-1 beta-cells to elevated glucose leads to reduced insulin gene transcription, and this is associated with diminished binding of pancreatic duodenal homeobox factor 1 (PDX-1) and mammalian homologue of avian MafA/l-Maf (MafA). Nicotinamide and other low-potency poly(ADP-ribose) polymerase (PARP) inhibitors were thus tested for their ability to restore insulin promoter activity. The low-potency PARP inhibitors nicotinamide, 3-aminobenzamide, or PD128763 increased expression of a human insulin reporter gene suppressed by elevated glucose. In contrast, the potent PARP-1 inhibitors PJ34 or INO-1001 had no effect on promoter activity. Antioxidants, including N-acetylcysteine, lipoic acid, or quercetin, only minimally induced the insulin promoter. Site-directed mutations of the human insulin promoter mapped the low-potency PARP inhibitor response to the C1 element, which serves as a MafA binding site. INS-1 cells exposed to elevated glucose had markedly reduced MafA protein and mRNA levels. Low-potency PARP inhibitors restored MafA mRNA and protein levels, but they had no affect on PDX-1 protein levels or binding activity. Increased MafA expression by low-potency PARP inhibitors was independent of increased MafA protein or mRNA stability. These data suggest that low-potency PARP inhibitors increase insulin biosynthesis, in part, through a mechanism involving increased MafA gene transcription.
Diabetes 2006 Mar
PMID:MafA expression and insulin promoter activity are induced by nicotinamide and related compounds in INS-1 pancreatic beta-cells. 1650 38

It is widely proposed that reactive oxygen species (ROS) contribute to beta-cell death in type 1 diabetes. We tested this in nonobese diabetic (NOD) mice using beta-cell-specific overexpression of three antioxidant proteins: metallothionein (MT), catalase (Cat), or manganese superoxide dismutase (MnSOD). Unexpectedly, the cytoplasmic antioxidants, MT and catalase, greatly accelerated diabetes after cyclophosphamide and accelerated spontaneous diabetes in male NOD mice. This occurred despite the fact that they reduced cytokine-induced ROS production and MT reduced streptozotocin diabetes in NOD mice. Accelerated diabetes onset coincided with increased beta-cell death but not with increased immune attack. Islets from MTNOD mice were more sensitive to cytokine injury. In vivo and in vitro studies indicated reduced activation of the Akt/pancreatic duodenal homeobox-1 survival pathway in MTNOD and CatNOD islets. Our study indicates that cytoplasmic ROS may have an important role for protecting the beta-cell from autoimmune destruction.
Diabetes 2006 Jun
PMID:Metallothionein and catalase sensitize to diabetes in nonobese diabetic mice: reactive oxygen species may have a protective role in pancreatic beta-cells. 1673 21

The ATP-sensitive K(+) channel (K(ATP) channel) in pancreatic beta-cells is a critical regulator in insulin secretion. We previously reported that transgenic mice expressing a dominant-negative form (Kir6.2G132S) of Kir6.2, a subunit of the K(ATP) channel, specifically in beta-cells develop severe hyperglycemia in adults (8 weeks of age). In this study, we conducted a long-term investigation of the phenotype of these transgenic mice. Surprisingly, hyperglycemia was spontaneously improved with concomitant improvement of pancreatic insulin content in the transgenic mice at >25 weeks of age. Insulin-positive cells and pancreatic duodenal homeobox 1 (PDX1)-positive cells both were clearly increased in the older compared with the younger transgenic mice. Interestingly, cells labeled with the lectin Dolichos biflorus agglutinin (DBA), a potential indicator of uncommitted pancreatic epithelial/ductal cells, were detected in the islets of the transgenic mice but not in those of wild-type mice. In addition, a subset of the DBA-labeled cells was positive for PDX1, insulin, glucagon, somatostatin, or pancreatic polypeptide. Moreover, some of the DBA-labeled cells were also positive for a proliferating cell marker. These results show that the Kir6.2G132S transgenic mouse is a useful model for studying beta-cell regeneration and that DBA-labeled cells participate in the process.
Diabetes 2006 Jul
PMID:Spontaneous recovery from hyperglycemia by regeneration of pancreatic beta-cells in Kir6.2G132S transgenic mice. 1680 60

Mutations in the gene encoding hepatocyte nuclear factor (HNF)1beta result in maturity-onset diabetes of the young-(MODY)5, by impairing insulin secretory responses and, possibly, by reducing beta-cell mass. The functional role of HNF1beta in normal beta-cells is poorly understood; therefore, in the present study, wild-type (WT) HNF1beta, or one of two naturally occurring MODY5 mutations (an activating mutation, P328L329del, or a dominant-negative form, A263insGG) were conditionally expressed in the pancreatic beta-cell line, insulin-1 (INS-1), and the functional consequences examined. Surprisingly, overexpression of the dominant-negative mutant did not modify any of the functional properties of the cells studied (including insulin secretion, cell growth and viability). By contrast, expression of WT HNF1beta was associated with a time- and dose-dependent inhibition of INS-1 cell proliferation and a marked increase in apoptosis. Induction of WT HNF1beta also inhibited the insulin secretory response to nutrient stimuli, membrane depolarisation or activation of protein kinases A and C and this correlated with a significant decrease in pancrease-duodenum homeobox-1 protein levels. The attenuation of insulin secretion was, however, dissociated from the inhibition of proliferation and loss of viability, since expression of the P328L329del mutant led to a reduced rate of cell proliferation, but failed to induce apoptosis or to alter insulin secretion. Taken together, the present results suggest that mature rodent beta-cells are sensitive to increased expression of WT HNF1beta and they imply that the levels of this protein are tightly regulated to maintain secretory competence and cell viability.
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PMID:Conditional expression of hepatocyte nuclear factor-1beta, the maturity-onset diabetes of the young-5 gene product, influences the viability and functional competence of pancreatic beta-cells. 1683 21

Successful islet transplantation depends on the infusion of sufficiently large quantities of islets, but only a fraction of transplanted islets can survive and become engrafted, and yet the underlying mechanism remains unclear. In this study, we examined the effect of sirolimus, a key component of the immunosuppressive regimen in clinical islet transplantation, on islet engraftment and function. To distinguish the effect of sirolimus on immune rejection from its effect on islet engraftment, we used a syngeneic model. Diabetic mice were transplanted with 250 islets under the renal capsule, followed by treatment with sirolimus or vehicle for 14 days. Thirty days posttransplantation, islet grafts were retrieved for the determination of insulin content and vascular density. Compared with mock-treated controls, diabetic recipient mice receiving sirolimus exhibited impaired blood glucose profiles and reduced glucose-stimulated insulin secretion, correlating with reduced intragraft insulin content and decreased vascular density. Islets exposed to sirolimus for 24 h in culture displayed significantly diminished glucose-stimulated insulin release, coinciding with decreased pancreas duodenum homeobox-1 and GLUT2 expression in cultured islets. Furthermore, sirolimus-treated diabetic recipient mice, as opposed to mock-treated controls, were associated with dyslipidemia. These data suggest that sirolimus, administered in the early posttransplantation phase, is a confounding factor for reduced islet engraftment and impaired beta-cell function in transplants.
Diabetes 2006 Sep
PMID:Sirolimus is associated with reduced islet engraftment and impaired beta-cell function. 1693 90

Type 2 diabetes is characterized by a deficit in beta-cell mass, and its incidence increases with age. Here, we analyzed beta-cell turnover in islets from 2- to 3- compared with 7- to 8-month-old rats and in human islets from 53 organ donors with ages ranging from 17 to 74 years. In cultured islets from 2- to 3-month-old rats, the age at which rats are usually investigated, increasing glucose from 5.5 to 11.1 mmol/l decreased beta-cell apoptosis, which was augmented when glucose was further increased to 33.3 mmol/l. In parallel, beta-cell proliferation was increased by both 11.1 and 33.3 mmol/l glucose compared with 5.5 mmol/l. In contrast, in islets from 7- to 8-month-old rats and from adult humans, increasing glucose concentrations from 5.5 to 33.3 mmol/l induced a linear increase in beta-cell death and a decrease in proliferation. Additionally, in cultivated human islets, age correlated positively with the sensitivity to glucose-induced beta-cell apoptosis and negatively to baseline proliferation. In rat islets, constitutive expression of Fas ligand and glucose-induced Fas receptor expression were observed only in 7- to 8-month-old but not in 2- to 3-month-old islets, whereas no age-dependent changes in the Fas/Fas ligand system could be detected in human islets. However, pancreatic duodenal homeobox (PDX)-1 expression decreased with age in pancreatic tissue sections of rats and humans. Furthermore, older rat islets were more sensitive to the high-glucose-mediated decrease in PDX-1 expression than younger islets. Therefore, differences in glucose sensitivity between human and 2- to 3-month-old rat islets may be due to both differences in age and in the genetic background. These data provide a possible explanation for the increased incidence of type 2 diabetes at an older age and support the use of islets from older rats as a more appropriate model to study glucose-induced beta-cell apoptosis.
Diabetes 2006 Sep
PMID:Aging correlates with decreased beta-cell proliferative capacity and enhanced sensitivity to apoptosis: a potential role for Fas and pancreatic duodenal homeobox-1. 3193 99

Type 1 diabetes is caused by the destruction of pancreatic beta-cells by T cells of the immune system. Islet transplantation is a promising therapy for diabetes mellitus. Bone marrow stem cells (BMSC) have the capacity to differentiate into various cell lineages including endocrine cells of the pancreas. To investigate the conditions that allow BMSC to differentiate into insulin-producing cells, a novel in vitro method was developed by using the histone deacetylase inhibitor, trichostatin A (TSA). BMSC, cultured in presence of TSA, differentiated into islet-like clusters under appropriate culture conditions. These islet-like clusters were similar to the cells of the islets of the pancreas. The islet-like clusters showed endocrine gene expression typical for pancreatic beta-cell development and function, such as insulin (I and II), glucagon, somatostatin, GLUT-2, pancreatic duodenal homeobox-1 (PDX-1), and Pax 4. Immunocytochemistry confirmed islet-like clusters contained pancreatic hormones. The colocalization of insulin and C-peptide was also observed. Enzyme-linked immunosorbent assay analysis demonstrated that insulin secretion was regulated by glucose. Western blot analysis demonstrated the presence of stored insulin. Electron microscopy of the islet-like cells revealed an ultrastructure similar to that of pancreatic beta-cells, which contain insulin granules within secretory vesicles. These findings suggest that histone-deacetylating agents could allow the differentiation of BMSC into insulin-producing beta-cells.
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PMID:Chromatin-remodeling factors allow differentiation of bone marrow cells into insulin-producing cells. 1699 May 88

High glucose concentrations have a dual effect on beta-cell turnover, inducing proliferation in the short-term and apoptosis in the long-term. Hyperglycemia leads to beta-cell production of interleuking (IL)-1beta in human pancreatic islets. Fas, a death receptor regulated by IL-1beta, is involved in glucose-induced beta-cell apoptosis. Fas engagement can be switched from death signal to induction of proliferation when the caspase 8 inhibitor, FLICE-inhibitory protein (FLIP), is active. Here, we show that IL-1beta at low concentrations may participate in the mitogenic actions of glucose through the Fas-FLIP pathway. Thus, exposure of human islets to low IL-1beta concentrations (0.01-0.02 ng/ml) stimulated proliferation and decreased apoptosis, whereas increasing amounts of IL-1beta (2-5 ng/ml) had the reverse effects. A similarly bimodal induction of FLIP, pancreatic duodenal homeobox (PDX)-1, and Pax4 mRNA expression, as well as glucose-stimulated insulin secretion, was observed. In contrast, Fas induction by IL-1beta was monophasic. Low IL-1beta also induced the IL-1 receptor antagonist (IL-1Ra), suppression of which by RNA interference abrogated the beneficial effects of low IL-1beta. The Fas antagonistic antibody ZB4 and small interfering RNA to FLIP prevented low IL-1beta-stimulated beta-cell proliferation. Consistent with our in vitro results, IL-1beta knockout mice displayed glucose intolerance along with a decrease in islet Fas, FLIP, Pax4, and PDX-1 transcripts. These findings indicate that low IL-1beta levels positively influence beta-cell function and turnover through the Fas-FLIP pathway and that IL-1Ra production prevents harmful effects of high IL-1beta concentrations.
Diabetes 2006 Oct
PMID:Low concentration of interleukin-1beta induces FLICE-inhibitory protein-mediated beta-cell proliferation in human pancreatic islets. 3193


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