The insulin receptor (IR) is expressed by insulin-secreting β-Cells, but its cellular function is unknown. We transfected βTC6-F7 β-Cells with cDNAs encoding either wild-type or mutant kinase-inactive (A/K1018) IRs, and by fluorescence-activated cell sorting generated polyclonal β-cell lines that overexpressed each receptor type at levels two- to fourfold higher than the parental cells. β-Cells overexpressing wild-type IRs had a proportional increase in insulin-stimulated tyrosine kinase activity; no change occurred in β-Cells expressing the mutant IR. We observed a threefold increase in cellular insulin content in β-Cells that overexpressed the wildtype IR, as determined by radioimmunoassay. This increase occurred despite a fivefold elevated rate of both basal and 10 mmol/l glucose-induced insulin secretion. Fractional insulin secretion (percentage of total cell insulin releasable at 10 mmol/l glucose) was unchanged in β-Cells overexpressing the wild-type IR compared with the parental β-cell line. Insulin content and insulin secretion were unaffected by overexpression of kinase-inactive IRs. Steady-state insulin mRNA levels were elevated twofold in the β-Cells overexpressing the wild-type IR and unchanged in the β-Cells expressing the kinase-inactive receptor, as determined by Northern blot analysis. The rate of insulin mRNA degradation measured in the presence of 5 μg/ml actinomycin D was not significantly affected in either cell line. In the absence of glucose, the basal level of (pro)insulin biosynthesis in the β-Cells overexpressing the wild-type IR increased significantly (61%) compared with the pcells transfected with the kinase-inactive IR. These data indicate that IR signaling can regulate insulin gene transcription and can modulate the steady-state insulin content of β-Cells.
Insulin Receptor Signaling in the β-Cell Influences Insulin Gene Expression and Insulin Content: Evidence for Autocrine β-Cell Regulation
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Gang G Xu, Paul L Rothenberg; Insulin Receptor Signaling in the β-Cell Influences Insulin Gene Expression and Insulin Content: Evidence for Autocrine β-Cell Regulation. Diabetes 1 August 1998; 47 (8): 1243–1252. https://doi.org/10.2337/diab.47.8.1243
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