Altered function of insulin receptor substrate-1–deficient mouse islets and cultured β-cell lines
Rohit N. Kulkarni, … , Douglas Hanahan, C. Ronald Kahn
Rohit N. Kulkarni, … , Douglas Hanahan, C. Ronald Kahn
Published December 15, 1999
Citation Information: J Clin Invest. 1999;104(12):R69-R75. https://doi.org/10.1172/JCI8339.
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Altered function of insulin receptor substrate-1–deficient mouse islets and cultured β-cell lines

Abstract

Insulin receptor substrate–1 (IRS-1) is pivotal in mediating the actions of insulin and growth factors in most tissues of the body, but its role in insulin-producing β islet cells is unclear. Freshly isolated islets from IRS-1 knockout mice and SV40-transformed IRS-1–deficient β-cell lines exhibit marked insulin secretory defects in response to glucose and arginine. Furthermore, insulin expression is reduced by about 2-fold in the IRS-1–null islets and β-cell lines, and this defect can be partially restored by transfecting the cells with IRS-1. These data provide evidence for an important role of IRS-1 in islet function and provide a novel functional link between the insulin signaling and insulin secretion pathways.

Authors

Rohit N. Kulkarni, Jonathon N. Winnay, Molly Daniels, Jens C. Brüning, Sarah N. Flier, Douglas Hanahan, C. Ronald Kahn

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Figure 6

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Insulin content is partially restored in IRS-1 re-expressing cultured β-...
Insulin content is partially restored in IRS-1 re-expressing cultured β-cells. (a) A reduced insulin content is observed in IRS-1–/– and IRS-1+/– cells compared with WT cells. Re-expression of IRS-1 in IRS-1–/– cells (upper panel) shows a partial restoration of insulin content and is significantly higher than IRS-1–/– cells (lower panel). Values are means ± SEM (n = 6–7). *P < 0.05 versus WT; **P < 0.01 versus WT; #P < 0.05 versus IRS-1–/–. Insulin secretion is blunted in response to increasing concentrations of (b) glucose and (c) L-arginine in IRS-1–/– and IRS-1+/– β-cell lines. Results are expressed as a percent of the cellular insulin content. Values are means ± SEM (n = 6). P < 0.05 IRS-1+/– or IRS-1–/– versus WT at all concentrations; P < 0.05 IRS-1+/– versus IRS-1–/– at all concentrations except 0.01 and 0.1 mM glucose and 0.1 and 5.5 mM L-arginine.