G-protein–coupled receptors controlling pancreatic β-cell functional mass for the treatment of type 2 diabetes

Abstract

The first phase of insulin secretion is altered during the early stages of diabetes and is followed by progressive loss of the ability of glucose to stimulate insulin secretion. The primary causes of insulin secretory defects are still unknown. Better understanding of the signaling pathways linked to the activation of G-protein–coupled receptors and their mutual interactions in the β-cells remains crucial. This represents a prerequisite for any strategy to develop therapeutic tools that aim to modulate the insulin secretory function and/or mass of β-cells. This review summarizes knowledge over the last two years on G-protein–coupled receptors functionally expressed in β-cells, which present key features for the development of therapy for type 2 diabetes.

Introduction

Type 2 diabetes (T2D) is a serious health problem that affects million people worldwide [1]. The pathophysiology of T2D is characterized by insulin resistance and progressive impairment of β-cell function. The insulin resistance of T2D, although important for its pathophysiology, is not sufficient to establish the disease unless major deficiency of β-cell function coexists [2]. Reduced β-cell mass has also been proposed to be associated with T2D [3]. Therefore, innovative therapeutic strategies aiming at preserving β-cell function and survival are of great interest to slow the progression or even to prevent T2D [4,5]. β-Cell dysfunction and death are caused by multiple stressors including chronic hyperglycemia (glucotoxicity), lipotoxicity, oxidative stress, endoplasmic reticulum (ER) stress, the formation of amyloid deposits, and proinflammatory cytokines [6]. Unfortunately, none of the currently and widely prescribed antidiabetic drugs favor the maintenance of endogenous functional β-cell mass, revealing an unmet medical need.

In vivo, the insulin secretion is triggered by the circulating nutrients, mainly by the glucose [7,8]. Glucose triggers insulin secretion when it is taken up into the β-cell through the glucose transporter 2. When glucose is metabolized, the ATP/ADP ratio is increased. This results in the closure of the ATP-sensitive potassium channels and membrane depolarization which favors the opening of the voltage-gated calcium channels increasing the calcium influx within the β-cell. Elevation of the calcium concentration in the cytosol triggers insulin secretion (Figure 1) [8]. The glucose-induced insulin secretion is radically modulated in terms of amplitude by many factors such as hormones, growth factors, or neurotransmitters, most which act by activation or inhibition of intracellular signaling pathways engaged by seven membrane-spanning G-protein–coupled receptors (GPCRs) or tyrosine kinase receptors. Activation of GPCRs results in different β-cell signaling, involving the cAMP/protein kinase A (PKA)/Epac, and the inositol triphosphate (IP3)/diacylglycerol (DAG) pathways, as well as changes in protein phosphorylation and protein acylation. The cAMP/PKA and the IP3/DAG pathways engaged during the activation of GPCRs are among the most important signaling pathways for the β-cell biology (Figure 1). Gαs mediates increases in intracellular cAMP associated with increased insulin secretion, while Gαi mediates decreases in intracellular cAMP and inhibition of insulin secretion. Gαq mediates increases in IP3 and DAG production through the activation of phospholipase C (PLC) associated with increased release of calcium (Ca2+) from the ER and enhanced insulin secretion [9,10]. GPCRs control the dynamics of the exocytosis of insulin granules to maintain the state of differentiation and to regulate the β-cell survival programs [9]. Table 1 presents the GPCRs expressed in β-cells (in bold the GPCRs covered in this review).