Leptin modulates β cell expression of IL-1 receptor antagonist and release of IL-1β in human islets

Abstract

High concentrations of glucose induce ␤ cell production of IL-1␤, leading to impaired ␤ cell function and apoptosis in human pancreatic islets. IL-1 receptor antagonist (IL-1Ra) is a naturally occurring antagonist of IL-1␤ and protects cultured human islets from glucotoxicity. Therefore, the balance of IL-1␤ and IL-1Ra may play a crucial role in the pathogenesis of diabetes. In the present study, we observed expression of IL-1Ra in human pancreatic ␤ cells of nondiabetic individuals, which was decreased in tissue sections of type 2 diabetic patients. In vitro, chronic exposure of human islets to leptin, a hormone secreted by adipocytes, decreased ␤ cell production of IL-1Ra and induced IL-1␤ release from the islet preparation, leading to impaired ␤ cell function, caspase-3 activation, and apoptosis. Exogenous addition of IL-1Ra protected cultured human islets from the deleterious effects of leptin. Antagonizing IL-1Ra by introduction of small interfering RNA to IL-1Ra into human islets led to caspase-3 activation, DNA fragmentation, and impaired ␤ cell function. Moreover, siIL-1Ra enhanced glucose-induced ␤ cell apoptosis. These findings demonstrate expression of IL-1Ra in the human ␤ cell, providing localized protection against leptin-and glucose-induced islet IL-1␤.A major factor determining the amount of insulin that can be secreted is ␤ cell mass, which increases during obesity (1, 2). In individuals who lose the ability to produce sufficient quantities of insulin to maintain normoglycemia in the face of insulin resistance, type 2 diabetes mellitus manifests (3). Increasing evidence suggests that not only ␤ cell function but also a progressive decrease in ␤ cell mass contributes to this (2). The deficit of ␤ cell mass in type 2 diabetes seems to be due in major part to increased ␤ cell apoptosis (2, 4). Possible mediators of the process of ␤ cell destruction include increased serum concentrations of cell nutrients. Indeed, increased free fatty acid (FFA) levels per se are known to be toxic for ␤ cells, leading to the concept of lipotoxicity (5-10). However, not all obese individuals or pretype 2 diabetes patients exhibit dyslipidemia. Thus, lipotoxicity may play an important role in the process of ␤ cell destruction but probably does not act alone. Elevated glucose concentrations induce ␤ cell apoptosis in cultured islets from diabetes-prone Psammomys obesus, an animal model of type 2 diabetes (4), in human islets (11)(12)(13)(14), and at higher concentrations also in rodent islets (9, 15). In human islets, glucoseinduced ␤ cell apoptosis and dysfunction are mediated by ␤ cell production and secretion of IL-1␤ (13). Probably already in the pretype 2 diabetic stage, insulin resistance diminishes glucose uptake, resulting in transient postprandial hyperglycemic excursions. However, it is unlikely that transient hyperglycemia is sufficient to cause progression from obesity to diabetes.Leptin is expressed primarily in the adipose tissue, and this peptide hormone plays a major role in interorgan signaling emanati...

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