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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Understanding the pathology of familial pancreatic carcinoma may provide important insights into pancreatic tumorigenesis. We now describe in detail the pancreatic pathology of an autosomal dominant pancreatic carcinoma kindred with distinct clinical, genetic, and pathologic manifestations differing from all other reported forms of sporadic or familial pancreatic neoplasia. Affected individuals develop a prodrome of diabetes mellitus, pancreatic exocrine insufficiency, and characteristic pancreatic imaging abnormalities. Eleven family members have undergone total pancreatectomy, revealing a unique and characteristic fibrocystic, lobulocentric pancreatic atrophy. This was patchy to diffuse in distribution and was invariably associated with a nesidioblastosis-like endocrine cell hyperplasia. All but one resected pancreas demonstrated glandular epithelial dysplasia: 10 had low-grade dysplasia (pancreatic intraductal neoplasia grade II of III or PanIN II) and seven also had high-grade dysplasia (pancreatic intraductal neoplasia grade III of III or PanIN III). Dysplasia was multifocal in small-to medium-sized duct-like structures within areas of acinar atrophy, microcystic change, and mucinous hyperplasia. Two pancreata had carcinomas of multiple and unusual histologic subtypes, including small cell undifferentiated carcinoma and giant cell anaplastic carcinoma. The findings in this kindred yield important information on a distinctive and previously unrecognized pancreatic cancer precursor. Recognition of this entity may help identify additional kindreds and perhaps the underlying genetic defect. As is the case for other familial cancers, the as yet unknown specific genetic defect may have wider implications for pancreatic cancer in general.
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PMID:Familial fibrocystic pancreatic atrophy with endocrine cell hyperplasia and pancreatic carcinoma. 1147 89

Increasing evidence indicates that individuals with type 2 diabetes (diabetes) are at elevated risk for several common human malignancies, including cancers of the colon, breast, endometrium, pancreas, and liver. In particular, the consistent positive results reported by prospective investigations make it unlikely that methodologic issues, occult tumors, or chance results could explain the findings. Since diabetes and impaired fasting glucose together affect >25% of Americans above age 50, even a moderate etiologic association (e.g., relative risk = 1.5) would explain >10% of involved malignancies. Laboratory studies have suggested biologically plausible mechanisms. Insulin, for example, is typically at high levels during the development and early stages of diabetes. Activation of the insulin receptor by its ligand, or cross-activation of the insulin-like growth factor-I receptor, has been shown to be mitogenic and promote tumorigenesis in various model systems. A "unifying concept," in fact, holds that hyperinsulinemia may underlie the cancer associations of several additional risk factors, including high waist circumference, visceral fat, waist-to-hip ratio, body mass index, sedentary lifestyle, and energy intake. In this review, we assess current evidence regarding the relation of type 2 diabetes with cancer, and evaluate the findings in terms of well-accepted criteria for establishing causality.
Diabetes Technol Ther 2001
PMID:The relation of type 2 diabetes and cancer. 1147 33

Expression of the SV40 T antigen (Tag) in pancreatic beta-cells in transgenic mice has been shown to induce beta-cell tumorigenesis. We generated transgenic mice in which Tag expression is inducible and reversible by the tet-on gene regulation system. These mice develop beta-cell tumors only when treated with the inducer doxycycline (dox). Tag expression in vivo is reversible upon dox withdrawal. As a result, beta-cell proliferation is greatly reduced, indicating that genetic changes, which may occur in the transformed cells, do not allow Tag-independent proliferation. Induction of Tag expression after immune recognition of self-antigens has been established triggers an autoimmune response against beta-cells, as evidenced by insulitis. Shut-off of Tag expression results in elimination of insulitis, suggesting that this process depends on continuous expression of the target antigen. In addition, the reversibility of autoimmunity suggests that beta-cell damage caused by the anti-Tag immune response does not elicit secondary responses to other newly exposed beta-cell antigens, which would have persisted after Tag elimination. beta-Cell proliferation in this model is accompanied by cell apoptosis. Apoptosis persisted for several weeks in the islets after dox removal. In close to 40% of the mice analyzed, this process reduced the islet size back to normal, suggesting the existence of a homeostatic mechanism that maintains beta-cell mass within the normal range.
Diabetes 2001 Oct
PMID:Inducible and reversible beta-cell autoimmunity and hyperplasia in transgenic mice expressing a conditional oncogene. 1157 7

Three different growth factor systems have been described acting via endothelial cell-specific receptor tyrosine kinases (RTKs). These are vascular endothelial growth factors (VEGFs), angiopoietins, and ephrins. Recent studies on gene targeting suggest that they play critical roles in embryonic development and contribute to the integrity and responses to environmental factors in the adult vasculature. Coagulation, inflammation, immune response regulation, vascular tone, stromal component synthesis, and angiogenesis are all dependent on the physiological and pathological events that affect endothelial cells in the heart, arteries, veins, and lymphatic vessels. Angiogenesis, the formation of new blood vessels from preexisting ones, takes place in adults only during hormonal control of female reproduction. All other activation of angiogenesis in adulthood occurs in response to injury or pathological processes such as tumorigenesis, diabetes, or inflammatory conditions. Insufficient growth of collateral vessels is a major problem in atherosclerotic cardiovascular disease. Controlled stimulation of angiogenesis would be of therapeutic value. Lymphangiogenesis, the mechanisms involved in the development of lymphatic vessels, was studied intensively nearly a century ago, although since then it has been neglected, perhaps because, unlike the disorders of blood vessels, those of the lymphatic vessels are seldom life-threatening. Interrupting this one-way system can cause severe disorders, including liver dysfunction, genetic disease (e.g., Milroys disease), and degenerative disease (e.g., primary lymphangiosclerosis). Recently, novel growth factors, receptors, cell surface proteins, and transcription factors have been found which play a role in the lymphatic endothelium. These are VEGF-C, VEGF-D, VEGFR-3, LYVE-1, podoplanin, and Prox-1. Until recently lymphatic vessels have been difficult to study due to a lack of appropriate tools. Monoclonal antibodies raised against VEGFR-3 and against its ligands, VEGF-C and VEGF-D, have offered an insight into expression studies in tissues. In this review, we summarize the recent data on VEGFs in the human vasculature.
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PMID:Lymphatic versus blood vascular endothelial growth factors and receptors in humans. 1159 56

Pancreatic islet neoplasms are rare endocrine tumours. The most common type is of beta-cell origin and is known as insulinoma, which can be either benign or malignant. The majority of insulinomas arise sporadically, but a small proportion develop as part of the hereditary multiple endocrine neoplasia type 1 (MEN1) syndrome. As for many human tumours, the genetic events that occur during the initiation and progression of insulinoma are poorly known. The men1 gene product, menin, is deficient in most hereditary cases, but is not obviously affected in the majority of sporadic tumours. Activation of the proto-oncogenes c-myc and ras has been observed during malignant progression, but their role in tumour initiation remains unproven. To address these questions, transgenic mouse models have been increasingly used to explore molecular and genetic events that might also precipitate human neoplasia. Transgenic mice expressing SV40 large T-antigen (Tag) oncogene in beta-cells develop tumours in a multi-stage progression from hyperplasia, angiogenesis, to solid encapsulated tumours. However, Tag, which inactivates the key tumour suppressors p53 and Rb, is not known to be involved in the pathogenesis of human insulinoma. The proto-oncogene, c-myc is implicated in beta-cell growth in both diabetes and tumorigenesis. Activation of Myc appears to be an early event in progression of human insulinoma. The effect of deregulated Myc expression on adult beta-cells in vivo has recently been investigated by developing transgenic mouse models in which the activity of Myc can be regulated ectopically. Although Myc activation initially promotes both proliferation and apoptosis in pancreatic beta-cells, apoptosis is the predominant outcome, giving rise to islet involution and diabetes. Importantly, inhibiting Myc-induced apoptosis (by co-expression of Bcl-x(L)) leads to significantly enlarged islets, many becoming highly vascularized, hyperplastic and invasive. These results suggest that, in the pancreatic beta-cells, early suppression of apoptosis is essential for the survival of Myc-activated beta-cells and islet neoplasia.
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PMID:Oncogenic co-operation in beta-cell tumorigenesis. 1173 27

Peroxisome proliferator-activated receptors control many cellular and metabolic processes. They are transcription factors belonging to the family of ligand-inducible nuclear receptors. Three isotypes called PPARalpha, PPARbeta/delta and PPARgamma have been identified in lower vertebrates and mammals. They display differential tissue distribution and each of the three isotypes fulfills specific functions. PPARalpha and PPARgamma control energy homoeostasis and inflammatory responses. Their activity can be modulated by drugs such as the hypolipidaemic fibrates and the insulin sensitising thiazolidinediones (pioglitazone and rosiglitazone). Thus, these receptors are involved in the control of chronic diseases such as diabetes, obesity, and atherosclerosis. Little is known about the main function of PPARbeta, but it has been implicated in embryo implantation, tumorigenesis in the colon, reverse cholesterol transport, and recently in skin wound healing. Here, we present recent developments in the PPAR field with particular emphasis on both the function of PPARs in lipid metabolism and energy homoeostasis (PPARalpha and PPARgamma), and their role in epidermal maturation and skin wound repair (PPARalpha and PPARbeta).
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PMID:Peroxisome proliferator-activated receptors (PPARs): from metabolic control to epidermal wound healing. 1197 Dec 2

In mammals, methionine metabolism occurs mainly in the liver via methionine adenosyltransferase-catalyzed conversion to S-adenosylmethionine. Of the two genes that encode methionine adenosyltransferase(MAT1Aand MAT2A), MAT1A is mainly expressed in adult liver whereas MAT2A is expressed in all extrahepatic tissues. Mice lacking MAT1A have reduced hepatic S-adenosylmethionine content and hyperplasia and spontaneously develop nonalcoholic steatohepatitis. In this study, we examined whether chronic hepatic S-adenosylmethionine deficiency generates oxidative stress and predisposes to injury and malignant transformation. Differential gene expression in MAT1A knockout mice was analyzed following the criteria of the Gene Ontology Consortium. Susceptibility of MAT1A knockout mice to CCl4-induced hepatotoxicity and malignant transformation was determined in 3- and 18-month-old mice, respectively. Analysis of gene expression profiles revealed an abnormal expression of genes involved in the metabolism of lipids and carbohydrates in MAT1A knockout mice, a situation that is reminiscent of that found in diabetes, obesity, and other conditions associated with nonalcoholic steatohepatitis. This aberrant expression of metabolic genes in the knockout mice was associated with hyperglycemia, increased hepatic CYP2E1 and UCP2 expression and triglyceride levels, and reduced hepatic glutathione content. The knockout animals have increased lipid peroxidation and enhanced sensitivity to CCl4-induced liver damage, which was largely due to increased CYP2E1 expression because diallyl sulfide, an inhibitor of CYP2E1, prevented CCl4-induced liver injury. Hepatocellular carcinoma developed in more than half of the knockout mice by 18 months of age. Taken together, our findings define a critical role for S-adenosylmethionine in maintaining normal hepatic function and tumorigenesis of the liver.
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PMID:Spontaneous oxidative stress and liver tumors in mice lacking methionine adenosyltransferase 1A. 1206 Jun 74

The insulin-like growth factors (IGFs), IGF-binding proteins (IGFBPs), and IGFBP proteases are the main regulators of somatic growth and cellular proliferation. IGFs are involved in growth pre-natally and post-natally. Dysregulation of the IGF axis can lead to growth disorders such as growth hormone deficiency and acromegaly. Pre-natally, this dysregulation can lead to IUGR or macrosomia. IGFs also have an important mitogenic action and play a role in tumorigenesis and cancer. These actions are regulated by co-interactions with IGFBPs, especially IGFBP-3. In addition to somatic growth and mitogenic activity, IGFs have hypoglycaemic and insulin sensitizing actions, and their dysregulation is involved in diabetes and its complications. In this chapter, we examine the role of IGFs and IGFBPs in growth, tumorigenesis and diabetes, and discuss treatment modalities for each disease involving the GH-IGF-IGFBP axis, including discussion of current in vitro and in vivo investigations in this field.
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PMID:IGFs and IGFBPs: role in health and disease. 1246 27

Annually, 1.25 million individuals suffer burns in the United States and 6.5 million experience chronic skin ulcers, often from diabetes, pressure or venous stasis. Growth factors are essential mediators of wound repair, but their success as therapeutics in wound treatment has, so far, been limited. Therefore, there is a need to identify new wound-response regulatory factors, but few have appeared in recent years. Progranulin (also called granulin or epithelin precursor, acrogranin or PC-derived growth factor) is a growth factor involved in tumorigenesis and development. Peptides derived from progranulin have been isolated from inflammatory cells, which led to suggestions that progranulin gene products are involved in the wound response, but this remains undemonstrated. We report that in murine transcutaneous puncture wounds, progranulin mRNA is expressed in the inflammatory infiltrate and is highly induced in dermal fibroblasts and endothelia following injury. When applied to a cutaneous wound, progranulin increased the accumulation of neutrophils, macrophages, blood vessels and fibroblasts in the wound. It acts directly on isolated dermal fibroblasts and endothelial cells to promote division, migration and the formation of capillary-like tubule structures. Progranulin is, therefore, a probable wound-related growth factor.
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PMID:Progranulin is a mediator of the wound response. 1252 33

The aim of this study was to compare mammary gland tumorigenesis in diabetic and non-diabetic rats. Streptozotocin and N-nitroso-N-methylurea were used to induce diabetes and mammary tumors, respectively. A suppression of mammary carcinogenesis in diabetic rats was shown by a longer latency period, a lower number of tumors per animal and a smaller final tumor volume. An 84% of the lesions developed in diabetic animals were benign tumors. Eighty day-old diabetic rats had significantly lower plasma levels of total-IGF-I and insulin versus non-diabetic rats. We postulate that the decrease in the total IGF-I and insulin levels during the promotion phase of carcinogenesis in this model plays an important role in retarding the tumor development in diabetic animals and in favoring the development of benign mammary lesions.
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PMID:Suppression of mammary gland tumorigenesis in diabetic rats. 1260 Apr 16


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