Emerging roles for β-arrestin-1 in the control of the pancreatic β-cell function and mass: New therapeutic strategies and consequences for drug screening

Abstract

Defective insulin secretion is a feature of type 2 diabetes that results from inadequate compensatory increase in β-cell mass, decreased β-cell survival and impaired glucose-dependent insulin release. Pancreatic β-cell proliferation, survival and secretion are thought to be regulated by signalling pathways linked to G-protein coupled receptors (GPCRs), such as the glucagon-like peptide-1 (GLP-1) and the pituitary adenylate cyclase-activating polypeptide (PACAP) receptors. β-arrestin-1 serves as a multifunctional adaptor protein that mediates receptor desensitization, receptor internalization, and links GPCRs to downstream pathways such as tyrosine kinase Src, ERK1/2 or Akt/PKB. Importantly, recent studies found that β-arrestin-1 mediates GLP-1 signalling to insulin secretion, GLP-1 antiapoptotic effect by phosphorylating the proapoptotic protein Bad through ERK1/2 activation, and PACAP potentiation of glucose-induced long-lasting ERK1/2 activation controlling IRS-2 expression. Together, these novel findings reveal an important functional role for β-arrestin-1 in the regulation of insulin secretion and β-cell survival by GPCRs.

Introduction

In mammals, glucose homeostasis is crucial for the survival of the organism and is controlled by a fine tuning of insulin secretion from the islets of Langerhans in the endocrine pancreas and by insulin action on its target tissues. Type 2 diabetes (T2D) is an heterogeneous disorder which is characterized by chronic hyperglycemia and its prevalence reaches epidemic proportions in occidental Europe. In spite of years of intensive researches performed in numerous international teams, the origins of T2D remain largely unknown. This relative failure is usually considered as a consequence of the complex heterogeneous nature, of polygenic origin, of the illness which combines insulin-resistance in peripheral tissues (failure of insulin action) and impaired insulin-secretion. Although the relative importance of each of these disorders in the aetiology of T2D has been largely disputed, both are necessary for the development of T2D which appears, even in the case of severe insulin-resistance, only when an impaired insulin secretion exists [1]. In addition, impaired insulin secretion may be seen very early in the natural history of T2D while insulin-resistance alone does not explain its emergence [2]. Moreover, a progressive decrease in pancreatic β-cell mass has been observed in T2D patients [3], [4]. The reduction of β-cell mass is more associated with increased β-cell death by apoptosis rather than a consequence of reduced β-cell proliferation [3]. Together, these evidences support the notion that β-cells play a central role in the etiology of T2D [1], [2], [3], [4], [5]. From a physiopathological point of view, the hypothesis may be expressed as follows: towards insulin-resistance, an healthy endocrine pancreas is able to compensate for it, by increasing the nutrient-induced insulin secretion and β-cell mass. On a particular genetic background, these compensatory mechanisms are inoperative, the pancreatic β-cell being unable to respond to the increased needs for insulin, therefore hyperglycemia appears [5].

β-cells within the islets of Langerhans biosynthesize, store and secrete insulin in response to physiological needs. Insulin secretion is primarily triggered by circulating concentrations of glucose. Glucose entry and metabolism in β-cells leads to insulin production and its exocytosis [6], [7]. Glucose-induced insulin secretory response can be radically modified by non-nutrient secretagogues such as hormones, growth factors, and neurotransmitters a majority of which acts through activation/inhibition of cellular kinases [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28]. This modulation of β-cell functions through cell kinases influences not only the insulin-secretory mechanisms, but it also affects the intrinsic biological properties of β-cells, such as β-cell mass proliferation and preservation, and the maintenance of a «competent» phenotype to physiologically respond to blood glucose level variations [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28].

The cAMP/PKA signalling pathway engaged by activation of G-protein coupled receptors (GPCRs), such as glucagon-like peptide-1 (GLP-1) or pituitary adenylate cyclase-activating polypeptide (PACAP) receptors, potentiates glucose-induced insulin secretion by regulating the dynamics of exocytosis of insulin granules, and plays a crucial role in maintaining a β-cell glucose-competent phenotype, of major importance in the pathophysiology of T2D [8], [13], [15], [27], [29], [30], [31], [32], [33], [34]. The cAMP/PKA pathway also controls the phosphorylation and activation of CREB (cAMP-Responsive Element Binding-protein), a transcription factor crucial for β-cell survival which regulates the expression of the antiapoptotic protein Bcl-2 and insulin receptor substrate-2 (IRS-2) [16], [17].

Knockout mice models, whole organism or β-cell specific using Cre-loxP approaches, to inactivate genes of the tyrosine-kinase receptors (TKRs) cascade have demonstrated that pathways linked to these receptors control insulin secretion and the normal survival/proliferative β-cell abilities in vivo. Indeed, selective insulin signalling through A and B insulin receptors in β-cells regulate via distinct PI3-kinase pathways the transcription of insulin (Insulin receptor A type and PI3-kinase class Ia), glucokinase genes (Insulin receptor B type and PI3-kinase class II-like activity), and insulin secretion [20], [22]. The lack of IGF-1 (Insulin-like growth factor-1) receptor (IGF-1R) in β-cell does not affect β-cell mass, but resulted in age-dependent impairment of glucose tolerance, associated with a decrease of insulin release. IGF-1R signalling activation induces β-cell proliferation and inhibits β-cell apoptosis [21], [35]. Down-regulation of the epidermal growth factor (EGF) receptor signalling in pancreatic islets leads to T2D due to impaired postnatal β-cell growth [25]. IRS-2 disruption impairs both peripheral insulin signalling and insulin secretion [28]. We and others showed that ERK1/2 signalling cascade plays a key role in glucose-stimulated insulin secretion [19], [24], [26]. This signalling pathway has also been shown to be involved in the functional activity of the transcription factors Beta2/NeuroD and PDX-1 (pancreatic and duodenal homeobox factor-1) resulting in a cumulative transactivation of the insulin gene promoter [36], [37], [38]. We reported that glucose-induced ERK1/2 activation also controls the functional integrity of CREB, and thus play a key role in β-cell survival [12], [39].

Defective insulin secretion is a key feature of T2D that is now thought to result from inadequate compensatory increase in β-cell mass, decreased β-cell survival and impaired glucose-dependent insulin release. β-cell proliferation, survival and secretion are regulated by signalling pathways linked to GPCRs. The exhaustive knowledge of the signalling pathways linked to activated GPCRs, such as GLP-1 and PACAP receptors, within β-cells is thus of major importance. β-arrestins serve as multifunctional adaptor proteins that link GPCRs to crucial downstream signalling pathways such as tyrosine kinase Src, ERK1/2 or Akt/PKB. Hence, the potential role of β-arrestins in GPCR signalling, controlling mass and function, was logically and recently investigated in pancreatic β-cells.