Role of Glucose in IRS Signaling in Rat Pancreatic Islets: Specific Effects and Interplay with Insulin

We investigated the possible interplay between insulinand glucose signaling pathways in rat pancreatic β-cellwith a special focus on the role of glucose in IRS signalingin vivo. Three groups of rats were constituted by combiningsimultaneous infusion during 48 h either of glucoseand/or insulin, or glucose+diazoxide: Hyperglycemic-Hyperinsulinemic (HGHI), euglycemic-Hyperinsulinemic(eGHI), Hyperglycemic-euinsulinemic (HGeI). Control ratswere infused with 0,9% NaCl. In HGHI and HGeI ratsplasma glucose levels were maintained at 20-22 mmol/l. IneGHI rats, plasma glucose was not different from that ofcontrols, whereas plasma insulin was much higher thanin controls. In HGHI rats, IRS-2 mRNA expression, totalprotein and phosphorylated protein amounts were increasedcompared to controls. In HGeI rats, only IRS-2mRNA expression was increased. No change was observedin eGHI rats whatever the parameter considered. In allgroups, mRNA concentration of IRS-1 was similar to thatof controls. The quantity of total and phosphorylated IRS-1 protein was dramatically increased in HGHI rats andto a lesser extent in eGHI rats. Neither mRNA nor IRS-1protein expression were modified in HGeI rats. The datasuggest that glucose and insulin play at once a specificand a complementary role in islet IRSs signaling. Especially,glucose stimulates IRS-2 mRNA expression whateverthe insulin status and independently of the secretoryprocess. The differential regulation of IRS-1 andIRS-2 expressions is in agreement with their supposed different involvement in the control of β-cell growth andfunction.