Paracrine signalling loops in adult human and mouse pancreatic islets: netrins modulate beta cell apoptosis signalling via dependence receptors

Abstract

Aims/hypothesis Adult pancreatic islets contain multiple cell types that produce and secrete well characterised hormones, including insulin, glucagon and somatostatin. Although it is increasingly apparent that islets release and respond to more secreted factors than previously thought, systematic analyses are lacking. We therefore sought to identify potential autocrine and/or paracrine islet growth factor loops, and to characterise the function of the netrin family of islet-secreted factors and their receptors, which have been previously unreported in adult islets. Methods Gene expression databases, islet-specific tag sequencing libraries and microarray datasets of FACS purified beta cells were used to compile a list of secreted factors and receptors present in mouse or human islets. Netrins and their receptors were further assessed using RT-PCR, Western blot analysis and immunofluorescence staining. The roles of netrin-1 and netrin-4 in beta cell function, apoptosis and proliferation were also examined. Results We identified 233 secreted factors and 234 secreted factor receptors in islets. The presence of netrins and their receptors was further confirmed. Downregulation of caspase-3 activation was observed when MIN6 cells were exposed to exogenous netrin-1 and netrin-4 under hyperglycaemic conditions. Reduction in caspase-3 cleavage was linked to the decrease in dependence receptors, neogenin and unc-5 homologue A, as well as the activation of Akt and extracellular signal-regulated protein kinase (ERK) signalling. Conclusions/interpretation Our results highlight the large number of potential islet growth factors and point to a context-dependent pro-survival role for netrins in adult beta cells. Since diabetes results from a deficiency in functional beta cell mass, these studies are important steps towards developing novel therapies to improve beta cell survival.

Intraislet SLIT–ROBO signaling is required for beta-cell survival and potentiates insulin secretion

“…programmed cell death | glucose metabolism | intracellular calcium signaling E merging evidence highlights the important role of locally released pancreatic islet peptide factors on beta-cell mass growth, maintenance, and survival (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). We have published a list of 233 ligands and 234 receptors expressed in islets and/or beta cells (12).…”

“…We have published a list of 233 ligands and 234 receptors expressed in islets and/or beta cells (12). Although our list is undoubtedly not comprehensive, it provides a starting point for the investigation of factors in adult islets that had previously only been reported in other cell types or in fetal pancreas (12).…”

The quest to make fully functional human pancreatic beta cells from embryonic stem cells: climbing a mountain in the clouds

“…Third, I propose the creation of an online resource from which islet biologists and stem cell biologists can leverage functional data from hundreds of human islet preparations (Fig. 2), much in the way that bioinformaticians query geneexpression data [51,52]. This could be linked to existing and emerging 'omics databases, including the islet biology components of the Human Diabetes Proteome Project (www.hdpp.…”

“…While depth and coverage remain technical hurdles, these approaches will soon shed much-needed light on the functional heterogeneity of human islet cell subtypes and states, as well as the variability observed in in vitro derived cultures. Although insulin is by far the major secreted product of primary beta cells, this cell type likely expresses hundreds of other secreted proteins [52], several of which have known physiological roles [52][53][54]. Future studies should also address the completeness of insulin processing, as it is possible that improperly processed and/or secreted insulin can provoke or accelerate beta cell directed autoimmunity [55].…”

Tuning to the right signal

“…In this issue of Diabetologia, Carol Yang, Quin Wills and Jim Johnson systematically evaluate the beta cell-protective properties of an extensive panel of over 200 factors on primary mouse beta cells [4]. These factors were selected on the basis of the expression of their cognate receptors in mouse or human islets, derived from prior work by the authors [5] among many others [6][7][8][9][10]. Recognising that beta cell stress in diabetes can occur in many different shapes and forms [3], each factor was systematically evaluated in five distinct islet cell culture conditions, reflective of different type 1 or type 2 diabetes-associated stresses.…”