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)

It has been shown that combined high local hyperinsulinism and hyperglycemia after low-number islet transplantation into the livers of streptozotocin-diabetic rats lead to the development of hepatocellular neoplasms but a substantial cocarcinogenic effect of genotoxic streptozotocin could not be ruled out completely. Thus, we herein investigated this model in BB/Pfd rats (n = 805; nine experimental groups), which develop spontaneous autoimmune diabetes similar to human type 1 diabetes. After low-number islet transplantation (n = 450), the liver acini downstream of the islets show insulin-induced alterations: massive glycogen and/or fat accumulation, translocation of the insulin receptor, decrease in glucose-6-phosphatase activity, increase in expression of insulin-like growth factor (IGF)-I, IGF-II/mannose-6-phosphate receptor, insulin receptor substrate-1, Raf-1, and Mek-1, corresponding to clear cell preneoplastic foci of altered hepatocytes known from chemical hepatocarcinogenesis and identical to that in streptozotocin-diabetic Lewis rats. After 6 months, many altered liver acini progressed to other types of preneoplasias often accompanied by an overexpression of the glutathione-S transferase (placental form), IGF-I receptor, and transforming growth factor (TGF)-alpha. After 12 to 15 and 15 to 18 months, 52% and 100% of the animals showed one or multiple hepatocellular adenomas or hepatocellular carcinomas (HCCs), respectively. Conclusively, this study identifies combined hyperinsulinism and hyperglycemia as a carcinogenic mechanism for the development of HCCs in diabetic rats. Hepatocarcinogenesis is independent from additional genotoxic compounds (i.e., streptozotocin), but is primarily triggered by increased intracellular insulin signaling via pathways associated with cell growth and proliferation, such as the Ras-Raf-mitogen-activated protein kinase pathway and the IGF system, and secondarily involves other growth factors, such as TGF-alpha.
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PMID:Hepatocellular neoplasms induced by low-number pancreatic islet transplants in autoimmune diabetic BB/Pfd rats. 1645 45

Islet transplantation is increasingly used as a therapy for human type 1 diabetes mellitus. In our study, we investigated the effect of the transplantation of a low number (n = 350) of pancreatic islets into the right liver part on the neighboring portal bile ducts. Male streptozotocin- diabetic Lewis or autoimmune-diabetic BB/Pfd rats (n = 1065) were subdivided into 11 experimental groups. A few days after low-number islet transplantation, cholangiocytes adjacent to the grafts showed an increase in proliferative activity. During the next 12-24 months, many peri-insular ductules progressed via tumor-like cystic lesions to large cystic cholangiomas, accompanied by a translocation of the insulin receptor into the cytoplasm and an increase in expression of insulin-related signaling proteins (Insulin-receptor-substrate-1, Raf-1, Mek-1). After 24 months, 53% of rats with low-number transplantation exhibited at least one cholangioma >10 mm, significantly outnumbering tumor development in the transplant-free left liver part and in any control group. No cholangiocarcinomas emerged. A graft cell origin of the tumors was excluded by Y chromosome in situ hybridization in cross-gender transplantations. Conclusively, low-number intrahepatic islet transplantation, most likely acting by permanent local hyperinsulinism, leads to prolonged cholangiocellular proliferation in streptozotocin- and in autoimmune-diabetic rats, resulting in the development of benign cystic cholangiomas.
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PMID:Cystic cholangiomas after transplantation of pancreatic islets into the livers of diabetic rats. 1660 79

A relative decrease in beta-cell mass is key in the pathogenesis of type 1 diabetes, type 2 diabetes, and in the failure of transplanted islet grafts. It is now clear that beta-cell duplication plays a dominant role in the regulation of adult beta-cell mass. Therefore, knowledge of the endogenous regulators of beta-cell replication is critical for understanding the physiological control of beta-cell mass and for harnessing this process therapeutically. We have shown that concentrations of insulin known to exist in vivo act directly on beta-cells to promote survival. Whether insulin stimulates adult beta-cell proliferation remains unclear. We tested this hypothesis using dispersed primary mouse islet cells double labeled with 5-bromo-2-deoxyuridine and insulin antisera. Treating cells with 200-pm insulin significantly increased proliferation from a baseline rate of 0.15% per day. Elevating glucose from 5-15 mm did not significantly increase beta-cell replication. beta-Cell proliferation was inhibited by somatostatin as well as inhibitors of insulin signaling. Interestingly, inhibiting Raf-1 kinase blocked proliferation stimulated by low, but not high (superphysiological), insulin doses. Insulin-stimulated mouse insulinoma cell proliferation was dependent on both phosphatidylinositol 3-kinase/Akt and Raf-1/MAPK kinase pathways. Overexpression of Raf-1 was sufficient to increase proliferation in the absence of insulin, whereas a dominant-negative Raf-1 reduced proliferation in the presence of 200-pm insulin. Together, these results demonstrate for the first time that insulin, at levels that have been measured in vivo, can directly stimulate beta-cell proliferation and that Raf-1 kinase is involved in this process. These findings have significant implications for the understanding of the regulation of beta-cell mass in both the hyperinsulinemic and insulin-deficient states that occur in the various forms of diabetes.
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PMID:Insulin stimulates primary beta-cell proliferation via Raf-1 kinase. 1820 27

Diabetes results from an absolute or relative deficiency in functional pancreatic beta-cell mass. Over the past few years, there has been renewed interest in the role of insulin itself in the regulation of beta-cell fate. Numerous animal models point to a critical role for beta-cell insulin signaling in the survival and proliferation of pancreatic beta-cells. In the present article, we review new studies that elucidate the mechanism by which insulin exerts anti-apoptotic and pro-mitogenic effects on beta-cells. In particular, we highlight the emerging role for Raf-1 kinase in autocrine insulin signaling and beta-cell fate decisions. We also discuss provocative evidence that the relationship between the dose of insulin and the birth and death of beta-cells is not linear. We propose a new hypothesis based on these findings, called the 'sweet spot' hypothesis, that can explain how both upward and downward deviations from normal levels of autocrine/paracrine insulin signaling might play an important role in the pathogenesis of type 1 diabetes and type 2 diabetes. We also highlight the key experiments that are required to further test this hypothesis.
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PMID:Control of pancreatic beta-cell fate by insulin signaling: The sweet spot hypothesis. 1841 65

Pathway analyses of genome-wide association studies aggregate information over sets of related genes, such as genes in common pathways, to identify gene sets that are enriched for variants associated with disease. We develop a model-based approach to pathway analysis, and apply this approach to data from the Wellcome Trust Case Control Consortium (WTCCC) studies. Our method offers several benefits over existing approaches. First, our method not only interrogates pathways for enrichment of disease associations, but also estimates the level of enrichment, which yields a coherent way to promote variants in enriched pathways, enhancing discovery of genes underlying disease. Second, our approach allows for multiple enriched pathways, a feature that leads to novel findings in two diseases where the major histocompatibility complex (MHC) is a major determinant of disease susceptibility. Third, by modeling disease as the combined effect of multiple markers, our method automatically accounts for linkage disequilibrium among variants. Interrogation of pathways from eight pathway databases yields strong support for enriched pathways, indicating links between Crohn's disease (CD) and cytokine-driven networks that modulate immune responses; between rheumatoid arthritis (RA) and "Measles" pathway genes involved in immune responses triggered by measles infection; and between type 1 diabetes (T1D) and IL2-mediated signaling genes. Prioritizing variants in these enriched pathways yields many additional putative disease associations compared to analyses without enrichment. For CD and RA, 7 of 8 additional non-MHC associations are corroborated by other studies, providing validation for our approach. For T1D, prioritization of IL-2 signaling genes yields strong evidence for 7 additional non-MHC candidate disease loci, as well as suggestive evidence for several more. Of the 7 strongest associations, 4 are validated by other studies, and 3 (near IL-2 signaling genes RAF1, MAPK14, and FYN) constitute novel putative T1D loci for further study.
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PMID:Integrated enrichment analysis of variants and pathways in genome-wide association studies indicates central role for IL-2 signaling genes in type 1 diabetes, and cytokine signaling genes in Crohn's disease. 2409 38