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)

Phosphatidylinositol 3-kinase signaling regulates the expression of several genes involved in lipid and glucose homeostasis; deregulation of these genes may contribute to insulin resistance and progression toward type 2 diabetes. By employing RNA arbitrarily primed-PCR to search for novel phosphatidylinositol 3-kinase-regulated genes in response to insulin in isolated rat adipocytes, we identified fatty aldehyde dehydrogenase (FALDH), a key component of the detoxification pathway of aldehydes arising from lipid peroxidation events. Among these latter events are oxidative stresses associated with insulin resistance and diabetes. Upon insulin injection, FALDH mRNA expression increased in rat liver and white adipose tissue and was impaired in two models of insulin-resistant mice, db/db and high fat diet mice. FALDH mRNA levels were 4-fold decreased in streptozotocin-treated rats, suggesting that FALDH deregulation occurs both in hyperinsulinemic insulin-resistant state and hypoinsulinemic type 1 diabetes models. Moreover, insulin treatment increases FALDH activity in hepatocytes, and expression of FALDH was augmented during adipocyte differentiation. Considering the detoxifying role of FALDH, its deregulation in insulin-resistant and type 1 diabetic models may contribute to the lipid-derived oxidative stress. To assess the role of FALDH in the detoxification of oxidized lipid species, we evaluated the production of reactive oxygen species in normal versus FALDH-overexpressing adipocytes. Ectopic expression of FALDH significantly decreased reactive oxygen species production in cells treated by 4-hydroxynonenal, the major lipid peroxidation product, suggesting that FALDH protects against oxidative stress associated with lipid peroxidation. Taken together, our observations illustrate the importance of FALDH in insulin action and its deregulation in states associated with altered insulin signaling.
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PMID:Fatty aldehyde dehydrogenase: potential role in oxidative stress protection and regulation of its gene expression by insulin. 1463 78

Reactive oxygen species (ROS) is involved in autoimmune destruction of islet beta cells, which has been proven to be an important underlying pathogenesis for insulin dependent diabetes mellitus (IDDM). Calcitonin gene-related peptide (CGRP) is a widely distributed neuropeptide, which has been found to play an important role in protecting myocytes from ROS. We hypothesized that exogenous CGRP gene administration before the pathogenic stage of insulitis might suppress the production of ROS and provide a hopeful therapeutic intervention for autoimmune diabetes. We performed CGRP gene transfer by injecting naked plasmid directly into skeletal muscles of mice with electroporation enhancement to achieve a continuous expression of CGRP in skeletal muscles, and thereby its secretion into the circulation. The effect of CGRP gene transfer on the pathogenesis of diabetes was studied in autoimmune diabetic mice induced by multiple low dose streptozotocin (MLDS). The CGRP gene therapy decreased morbidity of autoimmune diabetes, and significantly ameliorated hyperglycemia in these mice. CGRP gene transfer inhibited the production of ROS and malondialdehyde (MDA). In addition, it enhanced the activity of catalase (CAT) and superoxide dismutase (SOD) significantly. The data suggest that intramuscular CGRP gene transfer ameliorates autoimmune destruction of islet beta cells, resulting in significant reduction in diabetes incidence of MLDS diabetes mice. CGRP benefits might be mediated at least in part by inhibiting the oxidative stress in islet beta cells of these mice.
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PMID:Calcitonin gene-related peptide gene therapy suppresses reactive oxygen species in the pancreas and prevents mice from autoimmune diabetes. 1469 77

Diabetes complicating pregnancy has not yet been properly evaluated in Guam and the prevalence and morbidity of infants of diabetic mothers (IDM) in Micronesian population on Guam is described. The prevalence of IDM among the Micronesian population is 5.0% vs non-Micronesian's 3.7%. 82.5% were gestational diabetic mothers (GDM) diet controlled, 10.2% were GDM insulin controlled and 6.9% had Insulin Dependent Diabetes Mellitus. LGAs were 11% of IDMs in contrast to 6.4% of total births. Ten infants (NICU) spent total of 29 days on ventilator. Cesarean delivery, LGA, oxygen and ventilatory requirements were higher in Micronesian IDMs than in the non-Micronesian IDMs. The incidence is also higher in the Micronesian population (5.0%) compared to non Micronesian population (3.7%) on Guam. Micronesian IDMs were at higher risk for cesarean delivery, recurrent hypoglycemia, oxygen and ventilatory requirements than their non-Micronesian counterparts were. There is also a higher incidence of LGA among the Micronesian population and Chuukese had the highest incidence probably because they seek late or no prenatal care. We report 5.0% prevalence of diabetes during pregnancy in Micronesian population on Guam which imposes a significant economic burden on the local government's hospital resources. Micronesian IDMs were at higher risk for cesarean delivery, LGA, recurrent hypoglycemia, oxygen and ventilatory requirements than their non-Micronesian counterparts were. Chuukese had the highest LGA incidence in the study group. About 2/3rd of the IDM stayed 1110 extra days in hospital. IDMs accounted for the majority of expensive off-island transports.
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PMID:Epidemiology of infants of diabetic mothers in indigent Micronesian population-Guam experience. 1473 4

A two-layer cold storage method (TLM) allows sufficient oxygen delivery to pancreata during preservation and resuscitates the viability of ischemically damaged pancreata in the canine pancreas transplant model. In this study, we applied a short-term preservation of the TLM to human pancreata after prolonged cold ischemia prior to islet isolation, and investigated the mechanisms of resuscitation of the ischemically damaged human pancreas by the TLM. Human pancreata were procured from cadaveric donors and preserved by the TLM for 3.2 +/- 0.5 h after 11.1 +/- 0.9 h of cold storage in UW (TLM group), or by cold UW alone for 11.0 +/- 0.3 h (UW group). Islet isolations of all pancreata were performed using the Edmonton protocol. Islet recovery and in vitro functional viability of isolated islets were significantly increased in the TLM group compared with the UW group. According to the criteria of the Edmonton protocol, 10/14 cases (71%) in the TLM group were transplanted to patients with type I diabetes mellitus compared with only 5/21 cases (24%) in the UW group. In the metabolic assessment of human pancreata, levels of energetic parameters (ATP, total adenylates, and energy charge) were significantly increased, and malondialdehyde (MDA) levels were significantly decreased after the TLM preservation. There was no observable change in the incidence or degree of mitochondrial injury after the TLM preservation. Additional short-term storage by the TLM resuscitates the ischemically damaged human pancreas by regenerating the energetic status and prevents further damage by oxidative stress, ultimately leading to improvements of islet recovery and in vitro function. Use of the TLM following prolonged storage in UW provides an excellent adjunctive protocol for treating human pancreata for the rigors of the islet isolation process.
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PMID:Short-term storage of the ischemically damaged human pancreas by the two-layer method prior to islet isolation. 1504 Jun 7

Islet transplantation offers a physiological approach for precise restoration of glucose homeostasis, thereby reversing the metabolic and neurovascular complications of diabetes. In the past, there were only a few successes with human islet transplantation and the initial results were very disappointing. However, recent reports of great successes in islet transplantation have renewed the interest in it as a possible therapeutic option for patients with type 1 diabetes. Scientists have been focusing on methods to improve the outcome of islet transplantation. The shortage of human donor pancreata has led to many efforts to expand the human donor pool, modify islet processing and preservation methods, and search for alternative islet sources. To solve the problems of islet engraftment, treating recipients during the peritransplant period with additional islets, exogenous insulin, hyperbaric oxygen, pentoxyphylline, 15-deoxyspergualin, pravastatin and nordihydroguaiaretic acid have all shown to be beneficial for the islet grafts and transplantation results. Immunomodulation and immunoisolation of donor cells have been used to overcome immunological problems, and recently, newer immunosuppressants and agents to induce tolerance have also become available. Patients with successful islet transplantations showed near normal glycemia with no hypoglycemic episode. These patients exhibited normal hepatic glucose production and improved tissue glucose disposal, despite the persistence of blunted first phase insulin peaks. The transplantation-related complications involved primarily the procedure itself and the drugs used for immunosuppression. In conclusion, islet transplantation will become a routine treatment in clinical practice once more islet sources and safer forms of immunosuppression are obtained.
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PMID:Islet transplantation: an update. 1507 84

Reactive oxygen species, such as superoxide, and nitrogen oxides, such as peroxynitrite, are thought to contribute to beta-cell destruction during the disease process that leads to type 1 diabetes. EUK-8 is a member of a new class of synthetic salen-manganese compounds with low toxicity that possess catalytic superoxide dismutase, peroxidase, and catalase activity that can inactivate superoxide and nitrogen oxides (e.g., peroxynitrite and nitrogen dioxide). We observed that EUK-8 administration inhibited the adoptive transfer of type 1 diabetes to NOD mice. In addition, administration of EUK-8 to NOD mice with established autoimmunity completely prevented the development of type 1 diabetes for up to 1 year in age, even though the treatment was discontinued after 35 weeks of age. EUK-8 treatment also prolonged the survival of islet allografts in newly diabetic NOD mice. Thus, reactive oxygen and nitrogen species contribute to the pathoetiology of both spontaneous type 1 diabetes and allograft rejection. In cultures of NIT-1 cells, EUK-8 inhibited cytotoxicity caused by superoxide as well as nitric oxide. Collectively, our findings implicate a greater role for nitrogen oxides (other than peroxynitrite) in beta-cell damage. Antioxidants designed to prevent the formation of both cytotoxic reactive oxygen and nitrogen species may effectively protect beta-cells from spontaneous autoimmunity and alloresponses.
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PMID:A salen-manganese catalytic free radical scavenger inhibits type 1 diabetes and islet allograft rejection. 1544 86

Reactive oxygen species are considered to play a role in the development of diabetes mellitus and its complications. Human MTH1 (mutT homologue 1) has 8-oxo-7,8-dihydrodeoxyguanosine triphosphatase activity, which repairs oxidized forms of dGTP. This enzyme is known to have a thermolabile Met83 variant. We examined whether Val83Met polymorphism of human MTH1 gene is associated with type 1 diabetes mellitus. We recruited 156 type 1 diabetic patients (59 males and 97 females). The polymorphism was analyzed by restriction fragment length polymorphism analysis with Nsi I. The Met/Met genotype at codon 83 was very rare in both control and patient groups. Val/Met genotype tended to be more frequent in the whole type 1 diabetic patients than in controls. When subjects were divided into subgroups according to gender, there were no differences in the genotype and allele frequencies between patients and controls in males. On the other hand, in female type 1 diabetic patients, the Val/Met genotype was more frequent than in female controls (corrected P = 0.102). The Met allele was significantly more frequent in female type 1 diabetic patients than in female controls (corrected P = 0.022). Our results suggested that the Met allele at codon 83 of MTH1 gene might be involved in the development of type 1 diabetes mellitus in the Japanese female population.
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PMID:Association study of human MTH1 gene polymorphisms with type 1 diabetes mellitus. 1551 84

The hallmark of immune-mediated type 1 diabetes is T cell-mediated destruction of the insulin-producing beta cells in the islets, which results from an imbalance between disease promoting factors and protective elements. The precise mechanisms of beta cell destruction leading to diabetes remain unclear. There are many molecules, including Fas ligand (FasL) and cytokines, such as IL-1, TNF-alpha and IFN-gamma that cause release of other cytokine-mediators that have potential to damage the beta cells. The beta cell-death appears to ultimately be caused by receptor (Fas/FasL)-mediated mechanisms and/or by secretion of cytotoxic molecules (e.g., granzymes, perforin). FasL-mediated beta cell damage might play a role in promoting insulitis and beta cell destruction in autoimmune diabetes in addition to toxic molecules, such as reactive oxygen species (superoxide, hydroxy radical, nitric oxide) or perforin. Furthermore, DNA damage in beta cells leads to poly (ADP-ribose) polymerase-activation which will increase NAD consumption and rapid depletion of NAD compromise ATP production in the cells. Nicotinamide inhibits poly (ADP-ribose) polymerase and reduces nitric oxide accumulation in the NOD pancreas and protect beta cells against radical-induced necrosis. Transgenic mice with beta cell specific overexpression of copper, zinc superoxide dismutase, or thioredoxin are resistant to autoimmune and STZ-induced diabetes. It is apparent that a number of different mechanisms of beta cell destruction are operative in type 1 diabetes. Blockage of multiple pathways, rather than a single pathway, of beta cell-death may, therefore be necessary to fully protect beta cells from destruction and thereby prevent type 1 diabetes.
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PMID:Prevention of type 1 diabetes: from the view point of beta cell damage. 1556 75

Perfluorocarbons (PFC), which store and release high levels of oxygen, have been examined as oxygen carriers. PFC was first used in organ preservation as a component of the two-layer method (TLM). The TLM is comprised of University of Wisconsin solution [UW] and oxygenated PFC for pancreas preservation. Pancreata preserved in the TLM are oxygenated through the PFC and substrates are supplied by the UW. TLM has been shown to prolong the preservation period and repair pancreatic injury caused by warm ischemia. Currently the TLM was used for pancreas preservation prior to clinical whole organ transplant. In this first clinical trial, the morphologic quality of the human pancreas graft after reperfusion was excellent compared with the pancreas stored in UW. In addition, there was no acute rejection episode of pancreata preserved by the TLM. TLM preservation of human pancreata, without initial cold UW storage, prior to islet isolation, resulted in better isolation results and improved the success rate of islet transplantation. Thus preservation of human pancreata by the TLM has become an important process for successful islet transplantation. Nowadays, PFC is routinely used for pancreas preservation prior to islet isolation, which has had a significant impact on curing type 1 diabetes.
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PMID:Clinical application of perfluorocarbons for organ preservation. 1576 67

Islet transplantation has become an accepted method to treat type 1 diabetes. To succeed and achieve normal levels of glucose in transplant recipients, the quality of the transplanted islets is of the utmost importance. Lack of oxygen during organ procurement, islet isolation, and subsequent culture triggers apoptosis or necrosis and loss of islet function, causing the yield and quality to diminish. A promising candidate for cytoprotection against oxygen deprivation is neuroglobin (Ngb). Ngb is a recently described member of globin family and is expressed in neurons, retina, and pancreatic islets. To overexpress this protein in the islets and study its ability to protect them, we utilized protein transduction. Protein transduction is achieved by fusing Ngb to the TAT/PTD transduction domain, a peptide originated from the HIV transcriptional transactivator protein. Our study proved that TAT-Ngb is an efficient fusion protein capable of protecting the human islets in culture from loss of cell mass and function, thus increasing the quality of transplantable islets. If the islets could be cultured for a longer period of time without suffering harmful effects, it would be possible to precondition the recipient and there would be more time to assess their quality and function before transplantation.
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PMID:Protection of islets in culture by delivery of oxygen binding neuroglobin via protein transduction. 1580 6


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