Cytokines and β-Cell Biology: from Concept to Clinical Translation

Abstract

The tale of cytokines and the ␤-cell is a long story, starting with in vitro discovery in 1984, evolving via descriptive and phenomenological studies to detailed mapping of the signalling pathways, gene-and protein expression patterns, molecular and biochemical effector mechanisms to in vivo studies in spontaneously diabetic and transgenic animal models. Only very recently have steps been taken to translate the accumulating compelling preclinical data into clinical trials. The aim of this chapter is to present an overview of early and recent key observations from our own groups as well as other laboratories that serve to illuminate the road from concept to clinical translation. (Endocrine Reviews 29: 334 -350, 2008)

The global diabetes epidemic as a consequence of lifestyle-induced low-grade inflammation

“…the phosphatidylinositol-3 kinasephosphokinase B pathway, and promotes early beta cell failure in an animal model [65]. Increased beta cell secretory activity sensitises beta cells to the pro-apoptotic action of inflammatory mediators, mainly when increasing substrate metabolism [66], but these effects are difficult to isolate from the effects of substrate-induced islet innate immunity [67]. It appears that such detrimental consequences are only clinically relevant if beta cell function and/or defences are compromised a priori, genetically, because of unfavourable conditions during organ development [68].…”

“…by inducing a chronic pro-inflammatory state in the innate immune system at a systemic level, in pancreatic islets and in obese adipose tissue. The pathways by which these factors induce activation of innate immunity are diverse and include increased production of superoxide from mitochondria and NAD(P)H oxidase, endoplasmic reticulum stress, release of LPS from the colon into the circulation, and intracellular accumulation of pro-inflammatory lipid metabolites, all of which may result in the activation of protein kinase C, mitogen-activated protein kinases or NFκB signalling, as has been reviewed elsewhere [24,35,67,94].…”

Is ARE/poly(U)-binding factor 1 (AUF1) a new player in cytokine-mediated beta cell apoptosis?

“…Production of inflammatory cytokines, such as IL-1β, IL-17, TNF and interferon-g (IFN-g), probably contribute to beta cell apoptosis in the early stages of the disease [8,9]. Peculiarly, beta cells contribute to their own destruction by activating pro-apoptotic pathways and by secreting chemokines/cytokines that participate in the build-up of islet inflammation [8].…”

“…The transcription factors nuclear factor κB (NFκB; activated by IL-1β and TNF) and signal transducer and activator of transcription-1 (STAT-1; activated by IFN-g) are important regulators of beta cell apoptosis and inflammatory responses [8,9]. Other signalling molecules activated by cytokines in beta cells are the mitogenactivated protein kinases (MAPKs) extracellular signalrelated kinase (ERK), p38 and c-jun N-terminal kinase (JNK).…”

“…The pro-apoptotic effects of NFκB in beta cells are, at least partly, due to induction of FAS and inducible nitric oxide synthase (iNOS) [8,9] (Fig. 1).…”