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This Article Full Text Full Text (PDF) All Versions of this Article: JOE-09-0198v1 203/2/271    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Åkerblom, B. Articles by Welsh, M. PubMed PubMed Citation Articles by Åkerblom, B. Articles by Welsh, M.

Department of Medical Cell Biology, Uppsala University, PO Box 571, Husargatan 3, 751 23 Uppsala, Sweden

(Correspondence should be addressed to M Welsh; Email: michael.welsh{at}mcb.uu.se)

^* (S Barg and G Calounova contributed equally to this work)

Src homology 2 domain-containing protein B (SHB) is an adapter protein involved in the regulation of β-cell and endothelial cell function. We have recently obtained the Shb knockout mouse, and consequently, the aim of this study was to assess the effect of Shb deletion upon β-cell function and blood glucose homeostasis. Shb–/– mice display an elevated basal blood glucose concentration, and this increase is maintained during insulin challenge in insulin sensitivity tests. To assess glucose-induced insulin secretion, pancreata were perfused, and it was observed that Shb–/– first phase insulin secretion was blunted during glucose stimulation. Gene expression of Shb–/– islets shortly after isolation was altered, with increased pancreatic and duodenal homeobox gene-1 (Pdx1) gene expression and reduced expression of Vegf-A. Islet culture normalized Pdx1 gene expression. The microvascular density of the Shb–/– islets was reduced, and islet capillary endothelial cell morphology was changed suggesting an altered microvascular function as a contributing cause to the impaired secretory activity. Capacitance measurements of depolarization-induced exocytosis indicate a direct effect on the exocytotic machinery, in particular a dramatic reduction in readily releasable granules, as responsible for the insulin-secretory defect operating in Shb–/– islets. Shb–/– mice exhibited no alteration of islet volume or β-cell area. In conclusion, loss of Shb impairs insulin secretion, alters islet microvascular morphology, and increases the basal blood glucose concentration. The impaired insulin secretory response is a plausible underlying cause of the metabolic impairment observed in this mutant mouse.