Glucose induces intracisternal type A retroviral gene transcription and translation in pancreatic beta cells.

Leiter, Edward H.; Fewell, J W; Kuff, Edward L.

doi:10.1084/jem.163.1.87

Cited by 49 publications

(23 citation statements)

References 22 publications

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“…Moreover, male mice of the BKs strain are particularly sensitive to diabetes induced by multiple low-dose streptozotocin administration, whereas B6 mice are more resistant to this mode of treatment (25). The two strains also exhibit different expressions of endogenous retroviral genes in response to high glucose (26), and BKs mice but not B6 mice spontaneously produce islet autoantibodies (27). Previous experiments with transplanted islets have also demonstrated that islet cells have a higher regeneratory capacity in B6 mice than in BKs mice (28).…”

Section: Discussionmentioning

confidence: 99%

Hyperglycemia-induced B cell toxicity. The fate of pancreatic islets transplanted into diabetic mice is dependent on their genetic background.

Korsgren¹,

Jansson²,

Sandler³

et al. 1990

J. Clin. Invest.

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The role of pancreatic B cell dysfunction in the phase preceding clinical onset of insulin-dependent and non-insulin-dependent diabetes mellitus has been much debated. In this investigation, the impact of a prolonged diabetic environment on pancreatic islet B cells transplanted syngeneically under the kidney capsule of C57BL/6 (B6) and C57BL/Ks (BKs) mice was studied. Alloxan-diabetic mice bearing a subcapsular islet graft insufficient to normalize the blood glucose level were rendered normoglycemic by a second intrasplenic islet graft after various periods of hyperglycemia to examine the reversibility of hyperglycemia-induced B cell dysfunction. Using a perfusion technique of the graft-bearing kidney, it was found that both strains of mice exhibited a diminished glucose-induced insulin secretion after 6 wk of hyperglycemia, when compared with normoglycemic mice carrying islet grafts. When normoglycemia was restituted by the splenic graft after 4 or 12 wk, there was a normalization of glucose-stimulated insulin secretion in the renal islet grafts in B6 mice, whereas insulin secretion from the grafted BKs islets remained impaired. Morphometric measurements of the islet grafts demonstrated a 50% reduction in the graft volume in diabetic BKs mice after 12 wk, compared with normoglycemic animals, whereas no such decrease was observed in B6 mice. Islet grafts removed from hyperglycemic mice of both strains exhibited diminished insulin mRNA contents, and in the BKs mice there was also a reduced glucose oxidation rate in the islet grafts in vitro. This metabolic dysfunction can only partly be explained by a reduced graft size. The present findings emphasize the genetic constitution as a decisive factor for the survival and function during a period of sustained stress on a limited B cell mass. (J. Clin. Invest. 1990. 86:2161-2168

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Section: Discussionmentioning

confidence: 99%

Hyperglycemia-induced B cell toxicity. The fate of pancreatic islets transplanted into diabetic mice is dependent on their genetic background.

Korsgren¹,

Jansson²,

Sandler³

et al. 1990

J. Clin. Invest.

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“…Diabetes pathogenesis in BKS-Lepr db-1J mice was particularly responsive to dietary carbohydrate (19). Elevated glucose concentrations in vitro induced expression of defective endogenous retroviral genomes in ␤-cells from wild-type BKS but not B6 islets (20). Male BKS mice were further differentiated from B6 males in terms of their heightened sensitivity to diabetes induced by diabetogens, including alloxan (21) and multiple low doses of streptozotocin (22).…”

Section: C57blks/j and Nod/lt: Two Paradigm Diabetes-permissive Inbrementioning

confidence: 99%

Mouse Models and the Genetics of Diabetes

Leiter

Lee

2005

Diabetes

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In humans, both type 1 and type 2 diabetes exemplify genetically heterogeneous complex diseases in which epigenetic factors contribute to underlying genetic susceptibility. Extended human pedigrees often show inheritance of both diabetes types. A common pathophysiological denominator in both disease forms is pancreatic ␤-cell exposure to proinflammatory cytokines. Hence, it is intuitive that systemically expressed genes regulating ␤-cell ability to withstand chronic diabetogenic stress may represent a component of shared susceptibility to both major disease forms. In this review, the authors assemble evidence from genetic experiments using animal models developing clearly distinct diabetes syndromes to inquire whether some degree of overlap in genes contributing susceptibility can be demonstrated. The conclusion is that although overlap exists in the pathophysiological insults leading to ␤-cell destruction in the currently studied rodent models, the genetic bases seem quite distinct. Diabetes 54 (Suppl. 2):S151-S158, 2005 T he complex of genes in the HLA locus (IDDM1) contributing the major component of human susceptibility to autoimmune type 1 diabetes clearly provides a starting point for comparison for overlap with major susceptibility contributors to classic type 2 diabetes. Indications of humoral immunity against pancreatic ␤-cell autoantigens in 10 -30% of patients deemed clinically to have type 2 diabetes led to the concept that these patients exhibit latent autoimmune diabetes in adults (LADA), or "type 1.5" diabetes (1). Many LADA patients exhibit decreased frequency of the highest risk HLA class I and class II alleles and increased frequency of HLA alleles conferring strong protection against juvenile-onset type 1 diabetes (1). Although most type 2 diabetes cases clearly are not autoimmune in causation, and thus, specific HLA alleles are not identified as major type 2 diabetes susceptibility contributors, the LADA cases raise the possibility that a subset of non-HLA susceptibility may be shared. Under such circumstances, the absence of the high-risk HLA alleles results in a more slowly progressive disease that only presents in adulthood when pathophysiological stresses on ␤-cells, including obesity and insulin resistance shared in common with patients with classic type 2 diabetes, become prevalent.Polymorphisms in the upstream regulatory region of the insulin gene currently represent the strongest non-HLA locus linked to human type 1 diabetes susceptibility (IDDM2) (2). The pathogenic mechanism has not been associated with insulin processing, secretion, or action, but rather with the ability to express intrathymically and elicit T-cell tolerance to this major type 1 diabetes autoantigen (3,4). Alleles associated with resistance to type 1 diabetes, on the other hand, have been associated with polycystic ovarian syndrome (5), an insulin resistance syndrome that often leads to type 2 diabetes. Because type 2 diabetes often culminates in insulin deficiency attributed to ␤-cell failure associated with chron...

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“…During early embryogenesis, IAP transcripts can be detected in embryos from the first cleavage to blastocysts (46,56); in adult mice, IAP transcripts can be detected at significant levels in several somatic tissues (15,32; reviewed in reference 30), with highest expression in the cortical thymocytes (but still Ͻ5% of that in myeloma cells). This expression, however, varies among different mouse strains, and in several instances IAP proteins or particles could not be detected by using immunological approaches (32,34) or electron microscopy (53). The biological relevance of these transcripts, therefore, can be questioned.…”

mentioning

confidence: 99%

Germ Line-Specific Expression of Intracisternal A-Particle Retrotransposons in Transgenic Mice

Dupressoír

Heidmann

1996

Molecular and Cellular Biology

102

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Intracisternal A-particle (IAP) sequences are moderately reiterated transposable elements (approximately 1,000 copies in the mouse genome) which are closely related to retroviruses and transpose via the reverse transcription of an RNA intermediate (23, 30). They possess 5Ј and 3Ј long terminal repeats (LTRs) flanking gag-pol open reading frames (30, 42) and encode particles which are intracellular and not infectious. Several classes of IAP elements have been identified, and they differ essentially by internal deletions of various lengths and/or one specific insertion (36, 51). IAPs most probably derive from an ancient retrovirus that invaded the mouse genome and has now reached a status and life cycle compatible with, and possibly beneficial to, the host, as observed in several host-parasite associations and as extensively characterized for Drosophila species (reviewed in reference 38).These elements are not inactive, as at least some of them can still transpose. Several examples of germ line and somatic IAP transpositions (in the latter case mostly within cell lines) have been reported; they were identified as a result of either the inactivation or the activation of the genes close to which they have inserted (reviewed in references 30 and 31; see also references 13, 14, and 40 and references therein). IAP transposition can be a major source of mutations and as such contribute to the induction and/or enhancement of pathological processes (13,14,30,31,40). In fact, enhanced IAP expression and particle production is a common aberration of tumor cells, both from transplanted tumors and from established cell lines, including myelomas, neuroblastomas (32), and some cell lines treated with carcinogenic agents (26,27).IAP expression in vivo has been studied primarily by Northern (RNA) blot analysis of whole tissues. During early embryogenesis, IAP transcripts can be detected in embryos from the first cleavage to blastocysts (46, 56); in adult mice, IAP transcripts can be detected at significant levels in several somatic tissues (15, 32; reviewed in reference 30), with highest expression in the cortical thymocytes (but still Ͻ5% of that in myeloma cells). This expression, however, varies among different mouse strains, and in several instances IAP proteins or particles could not be detected by using immunological approaches (32, 34) or electron microscopy (53). The biological relevance of these transcripts, therefore, can be questioned. For instance, it is not known whether they are associated with a low level of expression from the whole population of IAP sequences or whether they correspond to a more clonal expression from a limited number of elements, possibly activated by a position effect. Previous studies tend to suggest (see also Discussion) that the second hypothesis is the most plausible, since sequencing of cDNA generated from RNA of normal tissues, including the thymus, or from tumors resulted in only a limited number of IAP subtypes (35,41). This interpretation would be consistent with the requisite for gene...

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Glucose induces intracisternal type A retroviral gene transcription and translation in pancreatic beta cells.

Cited by 49 publications

References 22 publications

Hyperglycemia-induced B cell toxicity. The fate of pancreatic islets transplanted into diabetic mice is dependent on their genetic background.

Hyperglycemia-induced B cell toxicity. The fate of pancreatic islets transplanted into diabetic mice is dependent on their genetic background.

Mouse Models and the Genetics of Diabetes

Germ Line-Specific Expression of Intracisternal A-Particle Retrotransposons in Transgenic Mice

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