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Intercellular Differences in Interleukin 1ß-Induced Suppression of Insulin Synthesis and Stimulation of Noninsulin Protein Synthesis by Rat Pancreatic ß-Cells¹

Diabetes Research Center, Faculty of Medicine, Vrije Universiteit Brussel, Brussels, Belgium B-1090

Address all correspondence and requests for reprints to: D. G. Pipeleers, Department of Metabolism and Endocrinology, Vrije Universiteit Brussel, Laarbeeklaan 103, B-1090 Brussels, Belgium.

The normal pancreatic ß-cell population exhibits intercellular differences in its responsiveness to glucose. This cellular heterogeneity allows glucose to regulate, in a dose-dependent manner, total rates of insulin synthesis and release. It may also predispose to intercellular differences in susceptibility to dysregulating agents. The present study examines whether this is the case for interleukin 1ß (IL-1ß), which is known to suppress glucose-induced insulin synthesis and release. The effects of the cytokine were compared on ß-cell subpopulations with, respectively, high and low sensitivity to glucose. These subpopulations were separated on the basis of differences in the cellular metabolic responsiveness to an intermediate glucose concentration (7.5 mmol/liter) and then cultured for 20 h at 5 or 20 mmol/liter with or without IL-1ß. The suppressive action of IL-1ß (0.1 ng/ml) occurred predominantly in glucose-activated ß cells, reducing their high rates of insulin synthesis and release by more than 80%. Glucose-unresponsive cells became subject to a similar inhibition after their activation during culture at 20 mmol/liter glucose. On the other hand, IL-1ß induced or enhanced the expression of several noninsulin proteins in both subpopulations. The IL-1ß-stimulated expression of inducible nitric oxide synthase (iNOS) and heat shock protein 70 was more marked in the glucose-responsive subpopulation; that of heme oxygenase and Mn superoxide dismutase was comparable in the two subpopulations. Exposure to IL-1ß resulted in 10-fold higher medium nitrite levels in both subpopulations; this effect was prevented by the iNOS blocker, N^G-methyl-L-arginine, which also prevented the IL-1ß-induced suppression in the glucose-responsive subpopulation. This study demonstrates that the cellular heterogeneity in glucose responsiveness predisposes to intercellular differences in the IL-1-induced suppression of insulin synthesis and release. While the cytokine induces the expression of noninsulin proteins such as iNOS in both glucose responsive and unresponsive cells, the subsequent nitric oxide production appears to predominantly affect glucose-stimulated functions in the glucose-activated cells.

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