V. Intra-islet connectivity, islet microenvironment, and organ cross talk

A. Intra-islet cell connectivity
Herbert Gaisano showed that intact islets (having functional intercellular connectivity) display distinct features from dispersed single beta cells that profoundly affect insulin secretion, including plasma membrane domain-specific molecular cues that define the functional polarity of β-cells, and coupling of adjacent beta cells into large clusters that promote synchronized exocytosis and pulsatile secretion.59 Guy Rutter proposed a model of intercellular communication across the islet between highly interconnected “hubs,” which act as a beta cell pacemaker, and subservient “followers,” which ensure efficient insulin secretion (Figure 7).32,60 Loss of connectivity is a feature of type 2 diabetes,61 and several attempts to increase this connectivity by restoring the functionality of “hub” cells (typically 1% to 10% of the total beta cells) have been made.32 High expression of glucokinase and low expression of Pdx1 and Nkx6.1 seem to be required for repurposing deficient hub cells.32,62

B. Complex and integrated pancreatic islet microenvironment
Alvin Powers discussed how beta cells exist in the context of a complex and integrated pancreatic islet microenvironment where they interact with other endocrine cells (mainly glucagon-secreting alpha cells and somatostatin-secreting delta cells), vascular endothelial cells,63 the extracellular matrix, neuronal projections (both sympathetic and parasympathetic fibers),64 and islet macrophages. Interendocrine cell interactions are critical in the pancreas for the regulation of glucose homeostasis, and include paracrine and autocrine signaling in addition to connections between endocrine cells via cell adhesion molecules (eg, neural cell adhesion molecule [N-CAM] and cadherins), gap junctions, and ephrin receptors and ligands. For example, blocking N-CAM prevents endocrine cell types from segregating properly and leads to abnormalities in both insulin and glucagon secretion..65 Historically, studies on the role of immune cells in the islet microenvironment have primarily focused on the autoimmune destruction of beta cells in type 1 diabetes. However, several recent studies have demonstrated an important role for islet macrophages in promoting beta cell regeneration..66 Interactions are also seen at the whole-body scale; for example, interrupted glucagon signaling in the liver leads to alpha cell proliferation and hyperplasia and reveals a hepatic alpha-cell axis.67,68 Another example of organ cross talk is the secreted protein angiopoietin-like 4, which originates from adipose tissue and links alpha cell proliferation with adipose tissue triglyceride metabolism.69 Romano Regazzi showed that failure in the coordination between organs can lead to the appearance of metabolic disorders, such as diabetes mellitus.

C. In vitro generation of beta cells for transplantation
Successful regeneration of functional β-cell mass in diabetic patients via cell-based therapy would restore normal insulin secretion and cure the disease. However, developing methods to differentiate human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hIPSCs) into pancreatic beta cells remains a major challenge (Ludovic Vallier lecture),20 and the in vivo transplantation is delicate. The transdifferentiation of pancreatic cells of other lineages into beta cells is also a promising approach.

D. Exosomes as new players in metabolic cross talk
Romano Regazzi presented exosomes the new players in the organs’ metabolic cross talk. Exosomes are small extracellular vesicles produced via the endosomal pathway and released from the cells upon fusion of multivesicular bodies with the plasma membrane. There is growing evidence that they are mediators of cell-to-cell communication. Exosomes transport bioactive proteins, mRNAs, and microRNAs that can be transferred in an active form to adjacent cells or distant organs (Figure 8). MicroRNAs are key regulators of β-cell physiology70 because they are involved in beta cell differentiation and play a key role in the acquisition of their secretory ability. Guay et al reported that exosomal microRNA horizontal transfer (ie, β-cell to β-cell) transduces apoptotic signals that originate from cytokines.71 As a proof of concept, they demonstrated that, if cel-miR-238, a Caenorhabditis elegans microRNA not present in mammalian cells, is expressed in MIN6B1 cells, a fraction of it is released in exosomes and transferred to the recipient beta cell.71 Furthermore, incubation of untreated MIN6B1 or mice islet cells in the presence of microRNA-containing exosomes isolated from the culture media of cytokine-treated MIN6B1 cells triggers apoptosis of the recipient cells. In contrast, exosomes originating from cells not exposed to cytokines have no impact on cell survival. Romano Regazzi presented data suggesting that exosomes could be implicated in the autoimmune destruction of beta cells and in type 1 diabetes,72 leading to the proposal that proteins essential for microRNA action represent a valuable target in the prevention of the disease.73 In particular, the inhibition of Ago2, a component of the RNA-induced silencing complex that is essential for microRNA action, prevented the proapoptotic effects of exosomes originating from cytokine-treated cells.71