Gene Expression Profiles Define a Key Checkpoint for Type 1 Diabetes in NOD Mice

Abstract

ShecDNA microarrays with >11,000 cDNA clones from an NOD spleen cDNA library were used to identify temporal gene expression changes in NOD mice (1-10 weeks), which spontaneously develop type 1 diabetes, and changes between NOD and NOD congenic mice (NO-D.Idd3/Idd10 and NOD.B10Sn-H2 b ), which have near zero incidence of insulitis and diabetes. The expression profiles identified two distinct groups of mice corresponding to an immature (1-4 weeks) and mature (6 -10 weeks) state. The rapid switch of gene expression occurring around 5 weeks of age defines a key immunological checkpoint. Sixty-two known genes are upregulated, and 18 are downregulated at this checkpoint in the NOD. The expression profiles are consistent with increased antibody production, antigen presentation, and cell proliferation associated with an active autoimmune response. Seven of these genes map to confirmed diabetes susceptibility regions. Of these seven, three are excellent candidate genes not previously implicated in type 1 diabetes. Ten genes are differentially expressed between the NOD and congenic NOD at the immature stage (Hspa8, Hif1a, and several involved in cellular functions), while the other 70 genes exhibit expression differences during the mature (6؊10 week) stage, suggesting that the expression differences of a small number of genes before onset of insulitis determine the disease progression. Diabetes 53: 366 -375, 2004 T ype 1 diabetes is a disease manifested when the insulin-producing pancreatic ␤-cells are destroyed by the immune system. Studies using the NOD mouse model, which spontaneously develops type 1 diabetes, have shown that both B-and T-cells are necessary for the development of the disease (1-5). Other immune cells, such as macrophages and dendritic cells, have also been implicated in the disease process (6). Despite extensive studies on this animal model, the underlying molecular mechanisms that lead to the development and progression of type 1 diabetes remain elusive.Previous studies primarily focused on one or a few molecules believed to be involved in the disease pathogenesis. The information obtained from these experiments is ideal for uncovering the role of specific genes. However, the single gene approach is not the ideal way to discover new genes or the molecular networks involved in the disease process. The conventional approaches of investigation have limited the rate of progress because of the complex nature of this disease. The recent development of microarray technology has provided a high-throughput approach to simultaneously analyze the expression of tens of thousands of genes. This genomic revolution has fundamentally changed how investigators can approach biomedical questions.Several studies have used the microarray approach to study gene expression in islet cells (7-9) and immune cells (10,11). Because of the preliminary nature of the published studies on the immune system, few definitive conclusions were reached. In this study, microarray technology was used to extensively profile splenic gene ...

Oxidoreductase, morphogenesis, extracellular matrix, and calcium ion-binding gene expression in streptozotocin-induced diabetic rat heart

“…Furthermore, 4 wk is in line with the two previous diabetic heart gene expression array studies, which examined animals 2 wk post-streptozotocin (31) or 3 days, 4 wk, and 6 wk poststreptozotocin (19). The diabetic rats were not treated with insulin, similar to the majority of previous gene array studies of diabetic animals (2,11,13,18,33,35,50,51,58). Streptozotocin can produce diabetes with either intravenous or intraperitoneal administration; the latter was used in the present study on the basis of previous success with this approach (55,56).…”

“…Examples of perturbed systems include protein degradation and ubiquitination, carbohydrate and lipid metabolism, nitrogen metabolism, transcription and translation, morphogenesis/organogenesis, extracellular matrix including collagen, and oxidative stress (2,11,13,18,34,35,50,51,58,61). However, there is considerable divergence among tissue types with regard to which of these systems are impacted by diabetes, as well as in the magnitude of the alterations for those systems that are affected, even for studies in which multiple tissues were examined simultaneously (31,50).…”

“…Alterations in enzyme levels and activity are linked most directly to cellular function and thereby contractile performance. However, development, aging, levels of exercise, and diseases such as diabetes may produce their effects on the function of the heart and other organs at many regulatory levels, and frequently an important event is modification of gene expression (2,11,13,18,19,31,34,35,50,51,58,61). Furthermore, transcriptional events are important to elucidate, as they form the foundation of ongoing and future gene-based therapeutic approaches for cardiac disease management.…”

Dynamic interaction between T cell-mediated β-cell damage and β-cell repair in the run up to autoimmune diabetes of the NOD mouse

“…However, these cell lines cannot model the complexity of in vivo interactions among islets, exocrine pancreas, and the host immune response seen in T1DM. Other approaches include the use of NOD mice spleens to define key checkpoints for T1DM (16). Our data, on the other hand, provide a more global survey of gene modulation in vivo over a 20-wk period and indicate that insulitis is not a progressively increasing process but a relapsing and remitting one.…”

Tissue-specific transcriptome responses in rats with early streptozotocin-induced diabetes

“…The DNA microarray approach has been applied to the study of diabetes. Examples of tissues examined include ␤-cells (5,36), immune cells or organs (7,38), adipose tissue (25), the retina (11), skeletal muscle (23,30,40), and the kidney or kidney cells (24,31,37). Many of these studies have provided novel insights into the pathophysiology of diabetes and identified previously unsuspected mechanisms deserving further investigation.…”