PSP/reg: a potent and enigmatic trophic factor, which is upregulated during the pathogenesis of diabetes.

Abstract

Pancreatic islet dysfunction and death, which are key characteristics of type 1 diabetes mellitus (T1DM), are now befalling also in the pathogenesis of type 2 diabetes mellitus (T2DM). Prospective studies of high-risk patients or newly diagnosed with T2DM imply that disease progression correlates with a relatively modest deterioration of insulin resistance, followed by a steep decline in residual beta cell function [1, 2], while others argue that a decrease in beta cell mass is the key contributor to the progression of T2DM [3]. It is indeed plausible to consider, that both scenarios, loss of function and loss of mass, are at work in T2DM [4]. With respect to the latter, a decrease in beta cell mass may be caused by defects in beta cell differentiation and proliferation, a decrease in beta cell size, or an increased rate of beta cell apoptosis [3, 5]. It is important to emphasize, however, that a decrease in beta cell mass does not necessarily suggest that new beta cells are not generated during disease progression. In fact, Dor and colleagues argue that beta cell mass is not static but in a constant process of cell death and renewal [6]. Conversely, Talchai et al., argue that beta cells do not undergo apoptosis, but instead cheat cell death by dedifferentiating into alpha-like cells [7]. Although it is apparent that beta cell mass regeneration does occur, it is not clear whether this happens through self-renewal of mature beta cells or through neogenesis of progenitor cells residing in the pancreas or recruited from other near-by tissues such as the liver [8]. PSP/reg (regenerating protein) belongs to the Regenerating family of proteins [9]. However, regenerating gene 1 (Reg 1) and pancreatic stone protein (PSP) have been discovered independently in the fields of diabetes and pancreatitis [10]. Sequence analysis later revealed that Reg1 and PSP are indeed identical [11], and for clarification purposes Graf and colleagues suggested that the combined terms of PSP/reg to be used in the future [10]. PSP/reg has been shown to be physiologically secreted from rat pancreatic acinar cells [12], but it’s also expressed in human non-beta islet cells [13] and in the liver [14]. Its regenerative capabilities were first identified in an unbiased screening study of genes involved in beta cell regeneration [9]. Additionally, PSP/reg has been shown to increase beta cell mass and to stimulate beta cell proliferation under physiological conditions and in rodent models of diabetes [9, 10]. A more recent study has shown that apoptotic beta cells secrete factor(s) that can stimulate PSP/reg gene induction in neighboring islet cells, which in turn are able to facilitate islet/beta cell regeneration [15]. Of note, these observations were observed in rodents, which unlike humans, have a small percentage of alpha and delta cells compared to beta (80–90 % beta) [16]. Collectively, these findings led to the conclusions that PSP/reg may be a protein involved in neogenesis and regeneration [10, 11] and may act as a growth mediator stimulating the proliferation of beta cells [9, 10]. Evidently, activation of PSP/ reg gene is thought to be an important event in islet cell regeneration and diabetogenesis. However, the mechanisms involved remain largely unknown, and more importantly, whether the ‘‘regenerating’’ neighboring islets cells are of alpha, beta, or delta origin remains an enigma. In this issue of Endocrine, Yang and colleagues describe the prognostic value of PSP/reg serum concentration in patients at different clinical stages of T2DM as well as C. Bonner (&) European Genomic Institute for Diabetes (EGID), FR 3508, 59000 Lille Cedex, France e-mail: caroline.bonner@univ-lille2.fr