Impaired glucose homeostasis in Shb-/- mice.
Src homology 2 domain-containing protein B (SHB) is an adapter protein involved in the regulation of beta-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 beta-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 beta-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.
Akerblom
Björn
B
Department of Medical Cell Biology, Uppsala University, PO Box 571, Husargatan 3, 751 23 Uppsala, Sweden.
Barg
Sebastian
S
Calounova
Gabriela
G
Mokhtari
Dariush
D
Jansson
Leif
L
Welsh
Michael
M
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D042783:Endothelial Cells / Q000166:cytology; D005947:Glucose / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000098:blood supply / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018408:Patch-Clamp Techniques; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D001786:Blood Glucose; D018398:Homeodomain Proteins; D007328:Insulin; D011518:Proto-Oncogene Proteins; C085634:Shb protein, mouse; D015534:Trans-Activators; D042461:Vascular Endothelial Growth Factor A; C084010:pancreatic and duodenal homeobox 1 protein; C467480:vascular endothelial growth factor A, mouse; D005947:Glucose