Insulin Micro-secretionin Patients with Long Duration Type 1 Diabetes: Implications of Interferon-γ?

Abstract

Type 1 diabetes (T1D) is a T-cell mediated autoimmune disease characterized by the destruction of pancreatic β-cells leading to absolute insulin deficiency [1]. Exogenous insulin represents the core of therapy for T1D that is fatal unless treated[2]. Several years of progressive autoimmune β-cells damage generally precede the clinical onset of diabetes [2]. Moreover, it has been found that the decline in insulin production in patients with T1D is variable [2]. The majority of patients with long-duration T1D has been demonstrated to be insulin microsecretors and to have residual functioning β-cells [2,3]. On this regard, it has been speculated that the small still functional β-cells could have escaped immune attack or have undergone a regeneration process known to be so far extremely limited in human adult [2,4]. Multiple immunological mechanisms have been proposed to contribute to β-cell destruction[5]. Although cytotoxic T lymphocytes directly attack β-cell in T1D, cytokines produced by immune system cells infiltrating pancreatic islets are candidate mediators of islet β-cell dysfunction and death [2-7]. Apoptosis represents the main form of cytokine-induced pancreatic β-cell death [5]. Different proinflammatory cytokines, such as Tumor necrosis factor-α (TNF-α), Interleukin-1 (IL-1) and Interferon-γ (IFN-γ), have been involved in T1D pathogenesis [1]. Among these cytokines, IFN-γ has been conventionally described as responsible for driving pancreatic islets autoimmune damage, leading to β-cell apoptosis and the initial destruction of pancreatic β-cells in the onset of diabetes [1,2,4-8]. IFNγ has been reported to influence immune and autoimmune responses by supporting the homing of diabetogenic activated T cells [8]. The development of diabetes has been linked to the accumulation of IFN-γ producing T-cells in the islets [6]. Furthermore, an association between IFN-γ polymorphism and T1D onset has been corroborated [7]. On the contrary, it has been provided evidence that IFN-γ receptor deficiency prevents diabetes [9]. What is more, reduced diabetes incidence was observed by neutralizing endogenous IFN-γ with anti IFN-γ antibodies [9,10]. Interestingly, IFN-γ has also been shown to play a major role in β-cell dysfunction associated with chronic pancreatitis [11]. The different biological effects of IFN-γ have been connected with its action in regulating gene transcription [5,7,12].