Ciliary dysfunction impairs beta-cell insulin secretion and promotes development of type 2 diabetes in rodents

Abstract

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 b-cell primary cilium in type 2 diabetes susceptibility. We find impaired glucose handling in young Bbs4 À / À 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 b-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 b-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 b-cell and that ciliary dysfunction could contribute to type 2 diabetes susceptibility.

Cell polarity defines three distinct domains in pancreatic beta cells

“…Recent work has highlighted the importance of primary cilia in β-cell function (Gerdes et al, 2014). Primary cilia are often located in the apical region within a spatial domain defined by tight junctions.…”

“…4). Given the sensory function of primary cilia (Singla and Reiter, 2006), and recent work suggesting that they are the site of enrichment of insulin receptors (Gerdes et al, 2014), this definition of a new domain within the islets has widespread implications for autocrine and paracrine signalling.…”

Bardet–Biedl syndrome: Is it only cilia dysfunction?

“…Importantly, since adipocytes secrete leptin in response to insulin and glucose, the increased glucose absorption and the overall increased adipogenesis are likely to contribute to the hyperleptinemia that characterize BBS [21,138]. In contrast, Gerdes et al have uncovered a critical role for cilia and BBS4 in pancreatic b-cell function whereby the insulin receptor is found on cilia upon stimulation, and Bbs4 À/À mice show impaired insulin secretion and signaling [139]. Altogether, these data is showing that obesity in BBS likely has multiple contributing factors where a CNS defect leading to hyperphagia, a peripheral tissue defect leading to altered adipogenesis and impaired b-cell function are likely to be contributing factors.…”

Primary Cilia and Coordination of Receptor Tyrosine Kinase (RTK) and Transforming Growth Factor β (TGF-β) Signaling

“…2A), because a recent proteomics analysis indicated that IGF-1R accumulates dramatically in photoreceptor outer segments from Bbs17/Lztfl1 mutant mice (Datta et al 2015), in which association of the BBSome with the retrograde IFT machinery is impaired (Seo et al 2011;Lechtreck 2015). Furthermore, studies using additional Bbs mutant animal models as well as BBS patient cells have confirmed a role for BBS proteins in regulating trafficking and function IGF-1/insulin signaling components, specifically the IR-B isoform (Gerdes et al 2014;Starks et al 2015), which in turn is important for controlling whole body insulin action and glucose metabolism. However, the precise mechanisms by which BBS proteins control insulin signaling and metabolism are likely to be complex, and may involve cilium-dependent as well as cilium-independent functions of BBS proteins (Marion et al 2012a;Gerdes et al 2014;Starks et al 2015).…”

“…Furthermore, studies using additional Bbs mutant animal models as well as BBS patient cells have confirmed a role for BBS proteins in regulating trafficking and function IGF-1/insulin signaling components, specifically the IR-B isoform (Gerdes et al 2014;Starks et al 2015), which in turn is important for controlling whole body insulin action and glucose metabolism. However, the precise mechanisms by which BBS proteins control insulin signaling and metabolism are likely to be complex, and may involve cilium-dependent as well as cilium-independent functions of BBS proteins (Marion et al 2012a;Gerdes et al 2014;Starks et al 2015). Finally, in addition to regulating cilia/BBSdependent adipocyte differentiation and metabolism, IGF-1/insulin signaling components have also been implicated in ciliary disassembly and cell cycle progression.…”