Glucose induces intracisternal type A retroviral gene transcription and translation in pancreatic beta cells.
C57BL/KsJ (BKs) and CBA/J, but not C57BL/6J (B6) mice are susceptible to the diabetogenic action of the obesity gene, "diabetes" (db). BKs and CBA/J, but not B6 mice, constitutively express intracisternal type A particles (IAP), an endogenous class of retrovirus, in beta cells and in cortical thymocytes. IAP genetic expression in these cell types included production of the group-specific antigen, p73, as well as higher-molecular mass p73-related antigens (p114-120). We used islet culture techniques to show that both transcription and translation of IAP genomes in beta cells in enhanced by glucose. Maintenance of CBA/J islets for 48 h in 16.5 mM glucose-containing medium effected a fivefold induction of IAP protein synthesis in comparison to islets cultured in low- (5.5 mM) glucose medium. Analysis of RNA from 16.5 mM glucose-cultured islets revealed induction of 7.2 and 5.4 kbp transcripts known to code for p73 and the p114-120 polypeptides, respectively. This induction in CBA/J islets was 10-15-fold on a tissue basis, and 5-7-fold on an RNA basis. Glucose induction of preproinsulin mRNA levels was also analyzed in the same samples. Islets cultured in 16.5 mM glucose showed an eightfold higher level on a tissue basis, and a fourfold increase in terms of total recovered RNA. Comparison of these glucose-inducible parameters in islets isolated from the diabetes-susceptible BKs strain vs. the resistant B6 strain revealed that expression of the group-specific retroviral p73 antigen was limited to BKs beta cells. This inbred strain control of p73 expression was also found in cortical thymocytes, with B6 thymocytes producing a 117 kD component to the exclusion of p73, while both components were expressed in thymocytes from normal BKs mice. In comparison to normal BKs males, thymocytes from four week-old genetically diabetic (db/db) BKs males showed no change in labeling of p117, but showed a sharply diminished incorporation into p73. This suggested that accelerated thymic involution characteristic of db/db mice may entail selective elimination of p73-producing cells. The possibility that glucose-stressed BKs pancreatic beta cells are marked for autoimmune elimination by the elaboration of p73 or other IAP-related proteins is discussed.
Leiter
E H
EH
Fewell
J W
JW
Kuff
E L
EL
D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D002478:Cells, Cultured; D007426:Genes, Intracisternal A-Particle; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000096:biosynthesis / Q000235:genetics; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D014176:Protein Biosynthesis / Q000187:drug effects*; D011519:Proto-Oncogenes; D012190:Retroviridae / Q000235:genetics*; D012191:Retroviridae Proteins / Q000096:biosynthesis / Q000235:genetics; D013045:Species Specificity; D013601:T-Lymphocytes / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*
D001323:Autoantibodies; D007328:Insulin; D012191:Retroviridae Proteins; D005947:Glucose