Islet inflammation impairs the pancreatic beta-cell in type 2 diabetes

Onset of Type 2 diabetes occurs when the pancreatic beta-cell fails to adapt to the increased insulin demand caused by insulin resistance. Morphological and therapeutic intervention studies have uncovered an inflammatory process in islets of patients with Type 2 diabetes characterized by the presence of cytokines, immune cells, beta-cell apoptosis, amyloid deposits, and fibrosis. This insulitis is due to a pathological activation of the innate immune system by metabolic stress and governed by IL-1 signaling. We propose that this insulitis contributes to the decrease in beta-cell mass and the impaired insulin secretion observed in patients with Type 2 diabetes. DOI: https://doi.org/10.1152/physiol.00032. 2009 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-26504 Journal Article Originally published at: Donath, M Y; Böni-Schnetzler, M; Ellingsgaard, H; Ehses, J A (2009). Islet inflammation impairs the pancreatic beta-cell in type 2 diabetes. Physiology, 24:325-331. DOI: https://doi.org/10.1152/physiol.00032. 2009 Major progress has been achieved in our understanding of the pathogenesis of Type 2 diabetes (3, 13, 34, 52). Over-nutrition and inactivity promote insulin resistance. To cope with this increased demand of insulin secretion, the pancreatic islet needs to enhance its secretory activity. In most individuals, such an adaptation does occur during early stages of increased metabolic stress (characterized by over-nutrition). Although successful adaptation of the -cell permits maintenance of normal metabolism throughout life in most subjects, this adaptation eventually fails in some individuals, depending on the genetically determined ability of the -cell to adapt and the severity of the resistance to insulin. The reasons for this failure to maintain sufficient insulin secretion are a combined decrease in -cell mass and defective insulin secretion. Several mechanisms have been proposed to explain this failure, including ER stress, oxidative stress, amyloid deposition, lipotoxicity, and glucotoxicity (28, 33, 51, 54, 65). Interestingly, all these factors may induce an inflammatory response, whereas some may be the result of the inflammation (16, 17, 19, 31). Initially, an inflammatory response is probably deployed to promote -cell repair and regeneration. However, as it becomes chronic, the situation gets complicated by, e.g., the activation of auto-inflammatory processes that may then become deleterious. Interestingly, similar auto-inflammatory processes occur in insulin-sensitive tissues. Therefore, Type 2 diabetes can be considered an auto-inflammatory disease. Consequently, it can be treated by agents blocking this vicious cycle such as IL-1 antagonists, or more downstream by NFB modulation via salsalate or similar compounds (15, 59). In this article, we will review the evidence for insulitis in Type 2 diabetes, the mechanisms inducing this inflammatory process, its physiological and pathological role, and the therapeutic consequences. Evidence for an Islet Inflammatory Process in -Cell Failure During Type 2 Diabetes In 1967 it was first proposed that Type 2 diabetes is not solely due to insulin resistance but also to a failure of the insulin producing -cell to secrete an adequate amount of insulin (5). Based on numerous investigations, it is now evident that impaired insulin secretion is not only an important etiological factor in the pathogenesis of the disease but also the driving force dictating the dynamics of the disease. Indeed, although insulin resistance is present in all stages from pre-diabetes to overt diabetes, it remains constant in a single individual as long as his or her body weight remains unchanged. In contrast, the onset of diabetes and its progression is largely determined by the progressive failure of the pancreatic islet. At a pre-diabetic stage, insulin production will increase to adapt to the enhanced demand. When this adaptation fails, diabetes occurs. This failure then continues to progress, and affected individuals will require increasing antidiabetic treatment, until eventually all Type 2 diabetics require exogenous insulin to control their glycemia. In an attempt to understand the underlying cause of this progressive failure, several mechanisms have been described. It appears that in all instances they constitute various components of an inflammatory process. The first evidence for an inflammatory process in the pancreatic islet arose from the observation that hyperglycemia induces -cell apoptosis (14). By unravelling the underlying mechanism, it turned out that high glucose concentrations induce the Fas receptor, which in turn is upregulated via glucoseinduced IL-1 production (41, 43, 44). Similarly, recent evidence shows that fatty acids also promote an inflammatory response (Refs. 1, 21; and see below). More downstream, ER stress and oxidative stress also appear linked to inflammatory events. In support of