Cadherins in islet β-cells: more than meets the eye.

In 1975, Orci et al. (1) reported that human islet cells contain specialized membrane domains that are compatible with the ultrastructural features of two types of intercellular junctions: tight junctions and gap junctions. Since then, numerous reports have demonstrated critical functions for these cell–cell junctional complexes in islet cells (2–8). Eventually, a number of proteins were identified that regulated cell aggregation, islet cell–type segregation, architectural organization within islets of Langerhans, and state of differentiation, cell growth, and hormone secretion (9–16). Hints that direct islet cell-to-islet cell interactions are required for proper insulin secretion were uncovered in the 1980s when it was observed that single (isolated) b-cells are unresponsive to glucose unless they are given the opportunity to reaggregate into small clusters (17). Even more interesting, it was observed that islet cell types harbor specific cell-to-cell recognition signatures that drive their reaggregation into organoids that have architectural organization indistinguishable from that of native islets (18). These earlier observations have inspired numerous investigations that have led to a more complete understanding of mechanisms regulating islet cell development, architectural organization, and function. In a time of considerable interest in the development of cell-based replacement therapies for diabetes, lessons learned over the past three decades on the function of cell adhesion molecules in islet cells harbor significant translational implications. Hence, promoting the function of select members of the cadherin and integrin families of adhesion receptors plays an important role in the derivation of b-cells from multipotent stem cells; in the isolation, culture, and survival of organ donor–derived islets; and in the successful engraftment and function following transplantation. This article focuses on adhesion receptors of the cadherin superfamily (19,20), which were referred to as uvomorulin in early work by Kemler et al. (21). Over the past three decades, the function of cadherins in epithelia has evolved from simple cell–cell adhesion molecules that populate subcellular domains called “adherens junctions” to biochemical transducers of signaling processes that contribute to the development, homeostasis, and function of multiple tissues (22–24). Interestingly, cadherins can also function as mechanosensors that affect cell phenotype and function in a dose-dependent manner (25,26). It appears that the transmission of forces from cellular domains occupied by E-cadherin to F-actin filaments is regulated by the intracellular recruitment and accumulation of a number of effector proteins at sites of cell–cell adhesion (27,28). As a result, cells that are in contact with each other through cadherin-mediated junctions sense tension forces that are directly proportional to the degree of actinanchored cadherin adhesions. In turn, these forces elicit mechanosensory signals from cadherin complexes that ultimately impact on cell phenotype and function in multiple cell types (29,30), including pancreatic islets (31). In this issue of Diabetes, Parnaud et al. (32) uncover direct involvement of Eand N-cadherin in the control of b-cell secretory function in response to glucose. The authors used an elegant approach in which recombinant E-, N-, or P-cadherin ectodomains fused to the Fc of immunoglobulin (E-cad/Fc, N-cad/Fc, or P-cad/Fc) were used for protein mimicry to support islet cell attachment (Fig. 1). This approach allowed them to emulate cadherin-mediated adhesions in single b-cells adherent to a substrate that presented high concentrations of recombinant E-cad/Fc, N-cad/Fc, or P-cad/Fc as if presented by another cell (Fig. 1). Insulin secretion was monitored using a powerful hemolytic plaque assay developed by Salomon and Meda in 1986 that allows probing of the secretion of single b-cells (33–35). This reductionist experimental environment showed a surprisingly close to normal insulin secretory behavior even in single-adherent b-cells. Essential findings of the new report include the demonstration that cadherin-mediated adhesion in single b-cells, but not a-cells, is positively regulated by glucose and that it is associated with increased insulin secretion.