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)

Most patients with type 2 diabetes mellitus will eventually require insulin therapy to achieve or maintain adequate glycaemic control. The introduction of insulin analogues, with pharmacokinetics that more closely mimic endogenous insulin secretion, has made physiologic insulin replacement easier to achieve for many patients. However, there are also concerns regarding alteration of binding affinities for the insulin receptor (IR) or insulin-like growth factor-1 receptor (IGF-1R) may increase the mitogenic potential of some analogues. Therefore, this article will review the relevant preclinical and clinical data to assess the mitogenic potential of insulin glargine, a basal insulin analogue, compared with regular human insulin (RHI). Searches of the PubMed database were performed using terms that included 'IR,' 'insulin-like growth factor-1,' 'IGF-1R,' 'type 2 diabetes mellitus,' and 'insulin glargine.' Original articles and reviews of published literature were retrieved and reviewed. Although one study reported increased binding affinity of insulin glargine for the IGF-1R and increased mitogenic potential in cells with excess IGF-1Rs (Saos/B10 osteosarcoma cells), most in vitro binding-affinity and cell-culture studies have demonstrated behaviour of insulin glargine comparable to that of RHI for both IR and IGF-1R binding, insulin signalling, and metabolic and mitogenic potential.Currently published in vivo carcinogenic studies and human clinical trial data have shown that insulin glargine is not associated with increased risk for either cancer or the development or progression of diabetic retinopathy.
Diabetes Metab Res Rev 2007 Nov
PMID:Insulin glargine and receptor-mediated signalling: clinical implications in treating type 2 diabetes. 1792 76

NOD.Idd3/5 congenic mice have insulin-dependent diabetes (Idd) regions on chromosomes 1 (Idd5) and 3 (Idd3) derived from the nondiabetic strains B10 and B6, respectively. NOD.Idd3/5 mice are almost completely protected from type 1 diabetes (T1D) but the genes within Idd3 and Idd5 responsible for the disease-altering phenotype have been only partially characterized. To test the hypothesis that candidate Idd genes can be identified by differential gene expression between activated CD4+ T cells from the diabetes-susceptible NOD strain and the diabetes-resistant NOD.Idd3/5 congenic strain, genome-wide microarray expression analysis was performed using an empirical Bayes method. Remarkably, 16 of the 20 most differentially expressed genes were located in the introgressed regions on chromosomes 1 and 3, validating our initial hypothesis. The two genes with the greatest differential RNA expression on chromosome 1 were those encoding decay-accelerating factor (DAF, also known as CD55) and acyl-coenzyme A dehydrogenase, long chain, which are located in the Idd5.4 and Idd5.3 regions, respectively. Neither gene has been implicated previously in the pathogenesis of T1D. In the case of DAF, differential expression of mRNA was extended to the protein level; NOD CD4+ T cells expressed higher levels of cell surface DAF compared with NOD.Idd3/5 CD4+ T cells following activation with anti-CD3 and -CD28. DAF up-regulation was IL-4 dependent and blocked under Th1 conditions. These results validate the approach of using congenic mice together with genome-wide analysis of tissue-specific gene expression to identify novel candidate genes in T1D.
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PMID:Genome-wide microarray expression analysis of CD4+ T Cells from nonobese diabetic congenic mice identifies Cd55 (Daf1) and Acadl as candidate genes for type 1 diabetes. 1817 47

A deficit in IL-4 production has been previously reported in both diabetic human patients and non-obese diabetic (NOD) mice. In addition, re-introducing IL-4 into NOD mice systemically, or as a transgene, led to a beneficial outcome in most studies. Here, we show that prediabetic, 12-week old female NOD mice have a deficit in IL-4 expression in the pancreatic lymph nodes (PLN) compared to age-matched diabetes-resistant NOD.B10 mice. By bioluminescence imaging, we demonstrated that the PLN was preferentially targeted by bone marrow-derived dendritic cells (DCs) following intravenous (IV) administration. Following IV injection of DCs transduced to express IL-4 (DC/IL-4) into 12-week old NOD mice, it was possible to significantly delay or prevent the onset of hyperglycemia. We then focused on the PLN to monitor, by microarray analysis, changes in gene expression induced by DC/IL-4 and observed a rapid normalization of the expression of many genes, that were otherwise under-expressed compared to NOD.B10 PLN. The protective effect of DC/IL-4 required both MHC and IL-4 expression by the DCs. Thus, adoptive cellular therapy, using DCs modified to express IL-4, offers an effective, tissue-targeted cellular therapy to prevent diabetes in NOD mice at an advanced stage of pre-diabetes, and may offer a safe approach to consider for treatment of high risk human pre-diabetic patients.
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PMID:Tissue-targeted therapy of autoimmune diabetes using dendritic cells transduced to express IL-4 in NOD mice. 1833 72

Whole genome oligo-microarrays were used to characterize age-dependent and tissue-specific changes in gene expression in pancreatic lymph nodes, spleen, and peripheral blood cells, obtained from up to 8 individual NOD mice at 6 different time points (1.5 to 20 weeks of age), compared to NOD.B10 tissue controls. "Milestone Genes" are genes whose expression was significantly changed (approximately 3 fold) as the result of splicing or changes in transcript level. Milestone Genes were identified among genes within type one diabetes (T1D) susceptibility regions (Idd). Milestone Genes showing uniform patterns of changes in expression at various time points were identified, but the patterns of distribution and kinetics of expression were unique to each tissue. Potential T1D candidate genes were identified among Milestone Genes within Idd regions and/or hierarchical clusters. These studies identified tissue- and age-specific changes in gene expression that may play an important role in the inductive or destructive events of T1D.
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PMID:Tissue- and age-specific changes in gene expression during disease induction and progression in NOD mice. 1880 20

The goal of diabetes mellitus treatment is to maintain long-term near-normoglycaemia to prevent the onset or progression of long-term complications. In order to achieve tight glycaemic control and improve the quality of life for diabetic patients, a number of novel insulin preparations, insulin analogues, have been constructed thanks to recombinant DNA technologies and advanced protein chemistry. Because structurally modified insulins may differ from human insulin not only in metabolic but also in mitogenic potencies there were concerns raised about the possibility of increased insulin analogue proliferative action or tumourigenesis. In vitro and in vivo studies on insulin analogues in comparison to endogenous insulin have been performed to closely monitor the insulin analogue action profiles. Insulin glargine was the only one presenting a significant increase in affinity to insulin-like growth factor type 1 (IGF-1) receptor. However, there was controversy regarding the safety of insulin glargine use because of its potential risk of mitogenicity but it proved to be true only for human osteosarcoma cells Saos/B10. Outcomes of the studies performed on lines other than cancer cells and on animals did not present any increased mitogenic activity nor mitogenic potency of insulin glargine in comparison to human insulin.
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PMID:Mitogenic potency of insulin glargine. 1922 3

It is not clear why the development of protective Th2 cells is poor in type 1 diabetes (T1D). c-Maf transactivates the IL-4 gene promoting Th2 cell development; therefore, abnormalities in c-Maf may contribute to reduced IL-4 production by CD4 cells from nonobese diabetic (NOD) mice. In this study we demonstrate that despite normal expression, c-Maf binds poorly to the IL-4 promoter (IL-4p) in NOD CD4 cells. Immunoblotting demonstrates that c-Maf can be modified at lysine 33 by SUMO-1 (small ubiquitin-like modifier 1). Sumoylation is facilitated by direct interaction with the E2-conjugating enzyme Ubc9 and increases following T cell stimulation. In transfected cells, sumoylation decreases c-Maf transactivation of IL-4p-driven luciferase reporter activity, reduces c-Maf binding to the IL-4p in chromatin immunoprecipitation assays, and enhances c-Maf localization into promyelocytic leukemia nuclear bodies. Sumoylation of c-Maf is increased in NOD CD4 cells as compared with CD4 cells from diabetes-resistant B10.D2 mice, suggesting that increased c-Maf sumoylation contributes to immune deviation in T1D by reducing c-Maf access to and transactivation of the IL-4 gene.
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PMID:SUMO conjugation contributes to immune deviation in nonobese diabetic mice by suppressing c-Maf transactivation of IL-4. 1955 42

Idd5.1 regulates T1D susceptibility in nonobese diabetic (NOD) mice and has two notable candidate genes, Ctla4 and Icos. Reduced expression of one of the four CTLA-4 isoforms, ligand-independent CTLA-4 (liCTLA-4), which inhibits in vitro T cell activation and cytokine production similarly to full-length CTLA-4 (flCTLA-4), has been hypothesized to increase type 1 diabetes (T1D) susceptibility. However, further support of this hypothesis is required since the Idd5.1 haplotypes of the diabetes-susceptible NOD and the resistant B10 strains differ throughout Ctla4 and Icos. Using haplotype analysis and the generation of novel Idd5.1-congenic strains that differ at the disease-associated Ctla4 exon 2 single-nucleotide polymorphism, we demonstrate that increased expression of liCTLA-4 correlates with reduced T1D susceptibility. To directly assess the ability of liCTLA-4 to modulate T1D, we generated liCTLA-4-transgenic NOD mice and compared their diabetes susceptibility to nontransgenic littermates. NOD liCTLA-4-transgenic mice were protected from T1D to the same extent as NOD.B10 Idd5.1-congenic mice, demonstrating that increased liCTLA-4 expression alone can account for disease protection. To further investigate the in vivo function of liCTLA-4, specifically whether liCTLA-4 can functionally replace flCTLA-4 in vivo, we expressed the liCTLA-4 transgene in CTLA-4(-/-) B6 mice. CTLA-4(-/-) mice expressing liCTLA-4 accumulated fewer activated effector/memory CD4(+) T cells than CTLA-4(-/-) mice and the transgenic mice were partially rescued from the multiorgan inflammation and early lethality caused by the disruption of Ctla4. These results suggest that liCTLA-4 can partially replace some functions of flCTLA-4 in vivo and that this isoform evolved to reinforce the function of flCTLA-4.
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PMID:Genetic evidence that the differential expression of the ligand-independent isoform of CTLA-4 is the molecular basis of the Idd5.1 type 1 diabetes region in nonobese diabetic mice. 1978 79

Type 1 diabetes results from the autoimmune destruction of insulin-producing beta cells by T cells specific for beta cell Ags, including insulin. In humans, the non-MHC locus conferring the strongest disease susceptibility is the insulin gene, and alleles yielding lower thymic insulin expression are predisposing. We sought to incorporate this characteristic into an HLA-transgenic model of the disease and to determine the influence of reduced thymic insulin expression on CD8+ T cell responses to preproinsulin. We examined NOD.Ins2(-/-) mice, which do not express insulin in the thymus and show accelerated disease, to determine whether they exhibit quantitative or qualitative differences in CD8+ T cell responses to preproinsulin. We also generated NOD.Ins2(-/-) mice expressing type 1 diabetes-associated HLA-A*0201 (designated NOD.beta2m(-/-).HHD.Ins2(-/-)) in an effort to obtain an improved humanized disease model. We found that CD8+ T cell reactivity to certain insulin peptides was more readily detected in NOD.Ins2(-/-) mice than in NOD mice. Furthermore, the proportion of insulin-reactive CD8+ T cells infiltrating the islets of NOD.Ins2(-/-) mice was increased. NOD.beta2m(-/-).HHD.Ins2(-/-) mice exhibited rapid onset of disease and had an increased proportion of HLA-A*0201-restricted insulin-reactive T cells, including those targeting the clinically relevant epitope Ins B10-18. Our results suggest that insulin alleles that predispose to type 1 diabetes in humans do so, at least in part, by facilitating CD8+ T cell responses to the protein. We propose the NOD.beta2m(-/-).HHD.Ins2(-/-) strain as an improved humanized disease model, in particular for studies seeking to develop therapeutic strategies targeting insulin-specific T cells.
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PMID:Ins2 deficiency augments spontaneous HLA-A*0201-restricted T cell responses to insulin. 1996 11

Regulatory T cells appear to show great potential for use in cellular therapy. In particular, CD4(-)CD8(-) (double negative (DN)) T cells, which compose 1-3% of the total number of T lymphocytes, exhibit prominent antigen-specific immune tolerance properties and confer immune tolerance in models of allografts and xenografts. We have recently shown that autoimmune-diabetes-prone mice carry fewer DN T cells and that this phenotype contributes to autoimmune-prone diabetes susceptibility, suggesting that increasing DN T-cell number in autoimmune-prone individuals may be of therapeutic interest. To achieve this goal, we must first determine whether the remaining DN T cells in autoimmune-prone mice are functional. In addition, we must identify the parameters that regulate the numbers of DN T cells. Herein, we evaluate the immunoregulatory properties of DN T cells in the autoimmune-prone non-obese diabetic (NOD) genetic background. Using 3A9 TCR transgenic mice, we show that DN T cells from both diabetes-resistant B10.Br and genetically autoimmune-prone NOD.H2(k) mice show an equivalent immunoregulatory potential on a per cell basis. However, upon stimulation, there is a 10-fold increase in the number of 3A9 TCR transgenic DN T cells that produce interleukin 10 (IL-10) from NOD.H2(k) mice in comparison with B10.Br mice. We further showed that IL-10 facilitates DN T-cell apoptosis and thus may regulate the number of DN T cells. Taken together, our results show that, although reduced in number, DN T cells from mice carrying an autoimmune-prone genetic background exhibit a potent cytotoxic potential and that DN T-cell expansion is regulated, at least in part, by IL-10.
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PMID:Interleukin-10 limits the expansion of immunoregulatory CD4-CD8- T cells in autoimmune-prone non-obese diabetic mice. 2071 38

The autoimmune disorder primary Sjogren's syndrome (SS) is associated with xerostomia and xerophthalmia. SS pathogenesis involves both genetic/epigenetic and environmental factors. A major potential contributor is oxidative stress associated with damage to cellular components, including DNA. We reported previously that the green tea polyphenol epigallocatechin-3-gallate (EGCG) normalizes the elevated levels of proliferating cell nuclear antigen (PCNA), a key component of DNA repair, in the NOD mouse model for SS and type 1 diabetes. The current study examined levels of the antioxidant enzymes peroxiredoxin 6 (PRDX6), catalase and superoxide dismutase (SOD), as well as PCNA, in NOD.B10.Sn-H2 mice, a model for primary SS, and determined the effect of EGCG on their expression. PCNA elevation was detected in the submandibular gland and pancreas by 8 weeks of age in water-fed mice, and increased through 14 weeks of age, prior to overt onset of symptoms. This early PCNA elevation was followed by a decline of peroxiredoxin 6 protein. In contrast, EGCG-fed mice exhibited normal levels of PCNA and peroxiredoxin 6, comparable to healthy untreated BALB/c mice. Similar patterns were observed in the pancreas, even though these mice do not develop diabetes. Thus, elevated PCNA is an early biomarker for exocrine glandular dysfunction associated with SS-like autoimmune disease, accompanied subsequently by decreased PRDX6 antioxidant enzyme levels that could further contribute to oxidative stress, and these changes precede inflammatory cell infiltration. Importantly, EGCG consumption normalizes the expression of these biomarkers in this model. These observations could lead to early diagnosis and intervention of autoimmune disorders.
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PMID:Epigallocatechin-3-gallate modulates antioxidant and DNA repair-related proteins in exocrine glands of a primary Sjogren's syndrome mouse model prior to disease onset. 2284 93


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