Morphogenesis of the Islets of Langerhans Is Guided by Extraendocrine Slit2 and Slit3 Signals.

The spatial architecture of the islets of Langerhans is vitally important for their correct function, and alterations in islet morphogenesis often result in diabetes mellitus. We have previously reported that Roundabout (Robo) receptors are required for proper islet morphogenesis. As part of the Slit-Robo signaling pathway, Robo receptors function in conjunction with Slit ligands to mediate axon guidance, cell migration, and cell positioning in development. However, the role of Slit ligands in islet morphogenesis has not yet been determined. Here, we report that Slit ligands are expressed in overlapping and distinct patterns in both endocrine and nonendocrine tissues in late pancreas development. We show that the function of either Slit2 or Slit3, which are predominantly expressed in the pancreatic mesenchyme, is required and sufficient for islet morphogenesis, while Slit1, which is predominantly expressed in the ß cells, is dispensable for islet morphogenesis. We further show that Slit functions as a repellent signal to ß cells. These data suggest that clustering of endocrine cells during islet morphogenesis is guided, at least in part, by repelling Slit2/3 signals from the pancreatic mesenchyme.

Endocrine cell type sorting and mature architecture in the islets of Langerhans require expression of Roundabout receptors in ß cells.

Pancreatic islets of Langerhans display characteristic spatial architecture of their endocrine cell types. This architecture is critical for cell-cell communication and coordinated hormone secretion. Islet architecture is disrupted in type-2 diabetes. Moreover, the generation of architecturally correct islets in vitro remains a challenge in regenerative approaches to type-1 diabetes. Although the characteristic islet architecture is well documented, the mechanisms controlling its formation remain obscure. Here, we report that correct endocrine cell type sorting and the formation of mature islet architecture require the expression of Roundabout (Robo) receptors in ß cells. Mice with whole-body deletion of Robo1 and conditional deletion of Robo2 either in all endocrine cells or selectively in ß cells show complete loss of endocrine cell type sorting, highlighting the importance of ß cells as the primary organizer of islet architecture. Conditional deletion of Robo in mature ß cells subsequent to islet formation results in a similar phenotype. Finally, we provide evidence to suggest that the loss of islet architecture in Robo KO mice is not due to ß cell transdifferentiation, cell death or loss of ß cell differentiation or maturation.

Synaptotagmins Tweak Functional ß Cell Maturation.

Immature ß cells secrete insulin at a lower glucose threshold compared to mature ß cells. In this issue of Developmental Cell, Huang et al. (2018) show that the increase in glucose threshold during ß cell maturation is achieved through balance between the Ca2+-sensitive synaptotagmin 7 and the Ca2+-insensitive synaptotagmin 4.

HIV-Related Cardiovascular Disease, Statins, and the REPRIEVE Trial.

HIV infection is associated with increased cardiovascular disease (CVD), and increased rates of myocardial infarction and stroke have been observed in HIV-infected individuals. After traditional risk factors that are more common among people living with HIV infection (such as smoking and diabetes) are accounted for, the excess risk for CVD persists. Recent studies suggest that increased immune activation and inflammation may contribute to excess risk for CVD in the context of HIV infection. Imaging studies in the HIV-infected population have found inflamed, noncalcified plaque that is vulnerable to rupture. Statin therapy may represent a potentially useful primary prevention strategy for CVD in HIV-infected individuals, as this class of drugs lowers lipid levels and may simultaneously reduce immune activation and inflammation. REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) is a large, multicenter study funded by the National Institutes of Health. REPRIEVE will test whether pitavastatin, a newer statin that does not have substantial interactions with antiretroviral drugs, can prevent vascular events over time among HIV-infected individuals who do not have known CVD. This study is now open to enrollment at sites throughout the United States and abroad and will hopefully provide definitive data on this important question.