Type 2 diabetes mellitus is affecting more than 382 million people worldwide. Although much progress has been made, a comprehensive understanding of the underlying disease mechanism is still lacking. Here we report a role for the β-cell primary cilium in type 2 diabetes susceptibility. We find impaired glucose handling in young Bbs4^−/− mice before the onset of obesity. Basal body/ciliary perturbation in murine pancreatic islets leads to impaired first phase insulin release ex and in vivo. Insulin receptor is recruited to the cilium of stimulated β-cells and ciliary/basal body integrity is required for activation of downstream targets of insulin signalling. We also observe a reduction in the number of ciliated β-cells along with misregulated ciliary/basal body gene expression in pancreatic islets in a diabetic rat model. We suggest that ciliary function is implicated in insulin secretion and insulin signalling in the β-cell and that ciliary dysfunction could contribute to type 2 diabetes susceptibility.

The islet of Langerhans is a complex endocrine micro-organ consisting of a multitude of endocrine and non-endocrine cell types. The two most abundant and prominent endocrine cell types, the beta and the alpha cells, are essential for the maintenance of blood glucose homeostasis. While the beta cell produces insulin, the only blood glucose-lowering hormone of the body, the alpha cell releases glucagon, which elevates blood glucose. Under physiological conditions, these two cell types affect each other in a paracrine manner. While the release products of the beta cell inhibit alpha cell function, the alpha cell releases factors that are stimulatory for beta cell function and increase glucose-stimulated insulin secretion. The aim of this review is to provide a comprehensive overview of recent research into the regulation of beta cell function by alpha cells, focusing on the effect of alpha cell-secreted factors, such as glucagon and acetylcholine. The consequences of differences in islet architecture between species on the interplay between alpha and beta cells is also discussed. Finally, we give a perspective on the possibility of using an in vivo imaging approach to study the interactions between human alpha and beta cells under in vivo conditions.

Phosphatidylinositide 3‐kinases (PI3Ks) play central roles in insulin signal transduction. While the contribution of class Ia PI3K members has been extensively studied, the role of class II members remains poorly understood. The diverse actions of class II PI3K‐C2α have been attributed to its lipid product PI(3) P . By applying pharmacological inhibitors, transient overexpression and small‐interfering RNA‐based knockdown of PI3K and PKB/Akt isoforms, together with PI‐lipid profiling and live‐cell confocal and total internal reflection fluorescence microscopy, we now demonstrate that in response to insulin, PI3K‐C2α generates PI(3, 4) P ₂ , which allows the selective activation of PKBα/Akt1. Knockdown of PI3K‐C2α expression and subsequent reduction of PKBα/Akt1 activity in the pancreatic β‐cell impaired glucose‐stimulated insulin release, at least in part, due to reduced glucokinase expression and increased AS160 activity. Hence, our results identify signal transduction via PI3K‐C2α as a novel pathway whereby insulin activates PKB/Akt and thus discloses PI3K‐C2α as a potential drugable target in type 2 diabetes. The high degree of codistribution of PI3K‐C2α and PKBα/Akt1 with insulin receptor B type, but not A type, in the same plasma membrane microdomains lends further support to the concept that selectivity in insulin signaling is achieved by the spatial segregation of signaling events.—Leibiger, B., Moede, T., Uhles, S., Barker, C. J., Creveaux, M., Domin, J., Berggren, P.‐O., Leibiger, I. B. Insulin‐feedback via PI3K‐C2α activated PKBα/Akt1 is required for glucose‐stimulated insulin secretion. FASEB J. 24, 1824–1837 (2010). www.fasebj.org