Glucose intolerance and reduced islet blood flow in transgenic mice expressing the FRK tyrosine kinase under the control of the rat insulin promoter.
The FRK tyrosine kinase has previously been shown to transduce beta-cell cytotoxic signals in response to cytokines and streptozotocin and to promote beta-cell proliferation and an increased beta-cell mass. We therefore aimed to further evaluate the effects of overexpression of FRK tyrosine kinase in beta-cells. A transgenic mouse expressing kinase-active FRK under control of the insulin promoter (RIP-FRK) was studied with regard to islet endocrine function and vascular morphology. Mild glucose intolerance develops in RIP-FRK male mice of at least 4 mo of age. This effect is accompanied by reduced glucose-stimulated insulin secretion in vivo and reduced second-phase insulin secretion in response to glucose and arginine upon pancreas perfusion. Islets isolated from the FRK transgenic mice display a glucose-induced insulin secretory response in vitro similar to that of control islets. However, islet blood flow per islet volume is decreased in the FRK transgenic mice. These mice also exhibit a reduced islet capillary lumen diameter as shown by electron microscopy. Total body weight and pancreas weight are not significantly affected, but the beta-cell mass is increased. The data suggest that long-term expression of active FRK in beta-cells causes an in vivo insulin-secretory defect, which may be the consequence of islet vascular abnormalities that yield a decreased islet blood flow.
Annerén
Cecilia
C
Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
Welsh
Michael
M
Jansson
Leif
L
D000818:Animals; D002196:Capillaries / Q000648:ultrastructure; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology*; D006706:Homeostasis; D066298:In Vitro Techniques; D007328:Insulin / Q000235:genetics* / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology; D007515:Islets of Langerhans / Q000098:blood supply* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D010179:Pancreas / Q000098:blood supply; D010477:Perfusion; D011401:Promoter Regions, Genetic; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D012039:Regional Blood Flow; D019076:Transgenes
D007328:Insulin; D011505:Protein-Tyrosine Kinases; D005947:Glucose