Abstract
Diabetes mellitus affects one in eleven adults worldwide. Most suffer from Type 2 Diabetes which features elevated blood glucose levels and an inability to adequately secrete or respond to insulin. Insulin producing β-cells have primary cilia which are implicated in the regulation of glucose metabolism, insulin signaling and secretion. To better understand how β-cell cilia affect glucose handling, we ablate cilia from mature β-cells by deleting key cilia component Ift88. Here we report that glucose homeostasis and insulin secretion deteriorate over 12 weeks post-induction. Cilia/basal body components are required to suppress spontaneous auto-activation of EphA3 and hyper-phosphorylation of EphA receptors inhibits insulin secretion. In β-cells, loss of cilia/basal body function leads to polarity defects and epithelial-to-mesenchymal transition. Defective insulin secretion from IFT88-depleted human islets and elevated pEPHA3 in islets from diabetic donors both point to a role for cilia/basal body proteins in human glucose homeostasis.
Highlights
Bardet-Biedl syndrome (BBS) is an oligogenic disease that is linked to more than 20 disease genes
Glucose handling was significantly impaired in the Tx-treated βICKO animals at 4 weeks (Supplementary Fig. 2a; area under the curve (AUC) = 778 mg dL−1 glucose ± 75 (s.e.m.); AUC (Tx) = 1091 mg dL−1 ± 105 (s.e.m.); one-way ANOVA, Holm-Sidak multiple comparison)
In parallel to glucose testing, we determined in vivo insulin secretion in response to stimulation with 2 g/kg intraperitoneal glucose at 8 and 12 weeks post induction, and observed significantly blunted acute insulin secretion in Tx-treated animals at both time points (Fig. 1b; group comparison Supplementary Fig. 2c; group comparison). These results show that β-cell cilia are required for adult glucose homeostasis and β-cell function
Summary
When testing Tiam[1] mRNA and protein levels, we found that they were significantly increased in Ift88-depleted cells and Tx-treated βICKO islets (Fig. 7a), indicating a change in cell polarization. To better quantify the change in cellular localization, we determined Pearson’s correlation coefficient and observed a significant decrease in Ift88-depleted cells This is indicative of a less strict spatial association between Tiam[1] and the CGN compared with controls. Our data suggest that increased Tiam[1] activity is involved in the insulin secretion defect observed in Tx-treated βICKO mice (in vivo and ex vivo) and that this effect is mediated by partially blocking EphA/EphrinA5 internalization. We suggest that our findings strongly support the case for a more detailed investigation of the role primary cilia and basal body genes and proteins might play in glucose homeostasis, insulin secretion, and T2DM
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