Amyloid and the macrophage: it's all about local production of IL-1β.

Abstract

For the past 30 years, intense effort has been directed toward understanding the molecular pathways by which cytokines, such as interleukin (IL)-1, inhibit pancreatic β-cell function and cause β-cell death. The landmark findings of the Mandrup-Poulsen and colleagues (1,2) demonstrated that IL-1, derived from conditioned media, reduces glucose-stimulated insulin secretion and causes β-cell damage. IL-1 inhibits glucose-induced insulin secretion by attenuating mitochondrial glucose oxidation to CO2 and thereby preventing the accumulation of ATP, which is necessary for ATP-sensitive K+ channel closure, β-cell depolarization, and Ca2+-dependent exocytosis of insulin granules (3−6). Nitric oxide has been identified as the molecular mediator of IL-1−induced inhibition of glucose-induced insulin secretion (5−7). The importance of IL-1−mediated β-cell damage has historically been placed in the context of autoimmune or type 1 diabetes; however, after 30 years of studies focused on the mechanisms by which IL-1 damages β-cells, the role of this cytokine in the development of type 1 diabetes remains to be fully elucidated. For example, administration of IL-1 to rodents results in an attenuation of insulin secretion, but these animals do not develop overt diabetes (8,9). Further, the administration of IL-1 to nonobese diabetic mice has been shown to attenuate disease development (10). In contrast to these studies, overexpression of the enzyme responsible for generating nitric oxide (inducible form of nitric oxide synthase) under the control of the rat insulin promoter results in the development of diabetes that occurs in a nitric oxide−dependent manner (11). These studies briefly illustrate the many complexities related to elucidating the role of IL-1 in the development of type 1 diabetes. The local generation of IL-1 in islets has also been implicated …