Search

Loss of mature β-cell function and identity, or β-cell dedifferentiation, is seen in both type 1 and type 2 diabetes. Two competing models explain β-cell dedifferentiation in diabetes. In the first model, β-cells dedifferentiate in the reverse order of their developmental ontogeny. This model predicts that dedifferentiated β-cells resemble β-cell progenitors. In the second model, β-cell dedifferentiation depends on the type of diabetogenic stress. This model, which we call the "Anna Karenina" model, predicts that in each type of diabetes, β-cells dedifferentiate in their own way, depending on how their mature identity is disrupted by any particular diabetogenic stress. We directly tested the two models using a β-cell-specific lineage-tracing system coupled with RNA sequencing in mice. We constructed a multidimensional map of β-cell transcriptional trajectories during the normal course of β-cell postnatal development and during their dedifferentiation in models of both type 1 diabetes (NOD) and type 2 diabetes (BTBR-Lepob/ob ). Using this unbiased approach, we show here that despite some similarities between immature and dedifferentiated β-cells, β-cell dedifferentiation in the two mouse models is not a reversal of developmental ontogeny and is different between different types of diabetes. [ABSTRACT FROM AUTHOR]

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 b cells, is dispensable for islet morphogenesis. We further show that Slit functions as a repellent signal to b 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. [ABSTRACT FROM AUTHOR]

Dysfunction or death of pancreatic β cells underlies both types of diabetes. This functional decline begins with β cell stress and de-differentiation. Current drugs for type 2 diabetes (T2D) lower blood glucose levels but they do not directly alleviate β cell stress nor prevent, let alone reverse, β cell de-differentiation. We show here that Urocortin 3 (Ucn3), a marker for mature β cells, is down-regulated in the early stages of T2D in mice and when β cells are stressed in vitro. Using an insulin expression-coupled lineage tracer, with Ucn3 as a reporter for the mature β cell state, we screen for factors that reverse β cell de-differentiation. We find that a small molecule inhibitor of TGFβ receptor I (Alk5) protects cells from the loss of key β cell transcription factors and restores a mature β cell identity even after exposure to prolonged and severe diabetes. DOI: http://dx.doi.org/10.7554/eLife.02809.001

The axon guidance proteins, Roundabout (Robo) receptors play a critical role in morphogenesis of the islets of Langerhans. Mice with a β cell‐selective deletion of Robo (Robo βKO), show severely disrupted spatial architecture of their islets, without defects in β cell differentiation or maturity. We have recently shown that Robo βKO mice have reduced synchronous glucose‐stimulated β cell calcium oscillations in their islets in vivo, likely disrupting their pulsatile insulin secretion. Here, we analyze whole‐body metabolic regulation in Robo βKO mice. We show that Robo βKO mice have mild defects in glucose homeostasis, and altered glucagon and insulin secretion. However, we did not observe any severe whole‐body glucoregulatory phenotype following the disruption of islet architecture in Robo βKO. Our data suggest that islet architecture plays only a mild role in overall glucoregulation.Disrupted glucose homeostasis and glucagon and insulin secretion defects in Robo βKO mice. In Robo βKO mice, disrupted islet architecture leads to loosening of fine intra‐islet regulation, resulting in lower secretion of insulin from β cells and higher secretion of glucagon from ⍺ cells in the disorganized islet. [ABSTRACT FROM AUTHOR]

The spatial architecture of the islets of Langerhans is hypothesized to facilitate synchronized insulin secretion among b cells, yet testing this in vivo in the intact pancreas is challenging. Robo βKO mice, in which the genes Robo1 and Robo2 are deleted selectively in β cells, provide a unique model of altered islet spatial architecture without loss of β cell differentiation or islet damage from diabetes. Combining Robo βKO mice with intravital microscopy, we show here that Robo βKO islets have reduced synchronized intra-islet Ca2+ oscillations among β cells in vivo. We provide evidence that this loss is not due to a β cell-intrinsic function of Robo, mis-expression or mis-localization of Cx36 gap junctions, or changes in islet vascularization or innervation, suggesting that the islet architecture itself is required for synchronized Ca2+ oscillations. These results have implications for understanding structure-function relationships in the islets during progression to diabetes as well as engineering islets from stem cells. [ABSTRACT FROM AUTHOR]