Functional effects of transgenic expression of cholera toxin in pancreatic beta-cells.
Investigation of intracellular pathways of stimulus-secretion signaling in vivo is possible by transgenic expression of agents known to influence specific biochemical interactions in the cells. The objective of the present study was to establish an experimental model for analyzing signal transduction mechanisms in pancreatic beta-cells in vivo, by expressing the cholera toxin A1 subunit under control of the insulin promoter, intending a constant activation of the Gs-protein, and thereby constant generation of cAMP. Surprisingly, the transgenic mice demonstrated mild hyperglycemia and hypoinsulinemia in vivo, and diminished glucose-induced insulin release from the in vitro perfused pancreas, whereas the pancreatic insulin content was normal. These observations suggest a deficiency in either the insulin release mechanisms or glucose recognition. Although the translated cholera toxin A1 subunit was biologically active, there was no increase in the islet content of cAMP. We conclude that the observed phenotype in the cholera toxin transgenic mice may be caused by a deleterious effect of the transgene itself on beta-cell function, or that counter regulatory mechanisms may compensate for the transgene-induced changes in intracellular enzymatic pathways.
Wogensen
L
L
Department of Neuropharmacology CVN-10, Scripps Research Institute, La Jolla, CA 92037.
Ma
Y H
YH
Grodsky
G M
GM
Robertson
R P
RP
Burton
F
F
Sutcliffe
J G
JG
Sarvetnick
N
N
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D002772:Cholera Toxin / Q000096:biosynthesis* / Q000235:genetics; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology*; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics; D007328:Insulin / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction
D007328:Insulin; D011993:Recombinant Fusion Proteins; D005576:Colforsin; D002772:Cholera Toxin; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D005947:Glucose; D015056:1-Methyl-3-isobutylxanthine