The pancreatic islet as a signaling hub

Abstract

Over the last two decades we have focused on beta cell signal transduction, bringing many new insights, especially in the context of insulin signal transduction, the role of inositol polyphosphates and the regulation of cytoplasmic free Ca²⁺ concentration. However, there has been a growing awareness that the beta cell, which is mandatory for insulin secretion, has a unique context within the micro-organ of the pancreatic Islet of Langerhans. In this environment the beta cell both mediates and receives paracrine regulation, critical for the control of blood glucose homeostasis. Failure of an appropriate beta cell function leads to the development of diabetes mellitus.

In our quest to understand the molecular events maintaining beta cell function we have faced two key challenges. Firstly, whilst there are many similarities between signal transduction in pancreatic islets between the much used rodent models and humans there are some notable differences. Critical distinctions between rodent and primate can be made in the structure of the islet, including the arrangement of the islet cells, the innervation pattern and the microcirculation. This means that important signaling interactions between islets cells, mediated through for example insulin, glucagon, GABA, glutamate and ATP, will have a unique human framework. The second challenge was to be able to take the discoveries we have made using in vitro systems and examine them in an in vivo context. Advances in in vivo imaging achieved by utilizing the anterior chamber of the eye as a transplantation site for pancreatic islets make it possible for non-invasive, longitudinal studies at single cell resolution in real time of islet cell physiology and pathology. Thus it is becoming possible to study the insulin secreting pancreatic beta cell within the framework of the unique micro-organ, the Islet of Langerhans, for the first time in a physiological context, i.e. when being innervated and connected to the blood supply.

Introduction

Over the last decade our laboratory has made significant progress in developing an understanding of signal transduction in the pancreatic beta cell. Areas of particular note include the regulation of cytoplasmic free Ca²⁺ concentration, [Ca²⁺]_i, the function of inositol polyphosphates and insulin receptor signaling (Barker and Berggren, 2012; Leibiger et al., 2008; Yang and Berggren, 2005). These investigations, in turn, have lead to novel insights into important regulatory events in pancreatic beta cells including apoptosis, the secretion of insulin, and the regulation of key genes (Barker and Berggren, 2012; Leibiger et al., 2008; Yang and Berggren, 2005). The beta cell, however, does not operate in isolation, but is part of a micro-organ known as the Islet of Langerhans. Islets consist not only of beta cells but also of alpha, delta and PP cells, together with other cells like endothelial cells, that constitute the blood capillaries, or neurons that innervate the islets. This architecture immediately suggests the opportunity for paracrine interactions between the different islet cells and thus increases the complexity of the signaling processes. There are also important ramifications that have emerged from studies looking at beta cell–beta cell interactions (Jain and Lammert, 2009) and the importance of the interactions of the cells with the endothelial cells that constitute the blood vessels (Eberhard et al., 2010). Notwithstanding this complexity, we were faced with two significant further challenges.

The first challenge was the fact that ours and other studies have largely been based on rodent islets and not human islets, mostly due to lack of availability of human material. This became a serious issue when our investigations into human islets revealed radical differences between rodent and primate islet structure/function relationships (Cabrera et al., 2006, 2008; Jacques-Silva et al., 2010; Rodriguez-Diaz et al., 2011a, 2011b) and thus the possibility of fundamentally different signaling contexts. Ultimately, we and others wish to understand the context of the pancreatic beta cell and islet function and dysfunction from the perspective of an important human disease, namely diabetes. Thus information that has come purely from rodent models is likely to be at best preliminary, and at worst misleading, about how islet signal transduction may be disrupted in diabetes.

The second challenge we faced was the lack of an in vivo context. Virtually all experiments regarding islet cell signal transduction, and indeed islet cell biology in general, have been conducted in an in vitro environment. Unfortunately, it is quite likely that the in vivo environment is rather different from that found in vitro. This reflects the need to orchestrate a coordinated regulation of plasma glucose homeostasis in the whole organism. Clearly, systematic human in vivo experiments of the breadth and depth needed to resolve the expected molecular complexity of islet cell signal transduction are not possible and the in vivo context therefore needed to be in terms of an animal model.

Faced with these two challenges, we have first studied signal transduction in human islets and how it may differ from that of rodents. Secondly, we have established an in vivo system to examine both islet cell biology and ultimately, signal transduction. This novel in vivo platform is the application of the anterior chamber of the eye as non-invasive imaging platform suitable for real-time, longitudinal studies. The remainder of this review will detail how far we have progressed in addressing these two challenges and how we see this developing in the future.