Glucose intolerance and reduced islet blood flow in transgenic mice expressing the FRK tyrosine kinase under the control of the rat insulin promoter

Abstract

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.

Understanding the cellular roles of Fyn-related kinase (FRK): implications in cancer biology

“…Although these studies as a whole demonstrate a positive role for GTK in β cell proliferation, a concomitant increase in sensitivity to cytokines that leads to β cell loss also indicates a role of the tyrosine kinase in type-I diabetes that results from the autoimmune destruction of β cells [47,73,74]. Consolidating results were also presented in a subsequent study, wherein such transgenic mice expressing a constitutively active variant of IYK, IYK-Y504F demonstrated reduced islet blood flow per islet volume, a condition that accompanied a physiological reduction in the pancreatic capillary lumen diameter as well as a type-II diabetic condition as evidenced from reduced in vivo insulin secretion [75].…”

“…The approach hold potential since GTK was shown to enhance cytokineinduced β cell death in the murine pancreas [73,75]. Thus, inhibiting GTK/FRK activity may potentially be harnessed for therapeutic intervention in diabetes.…”

Insulin Receptor Substrate-2 (Irs2) in Endothelial Cells Plays a Crucial Role in Insulin Secretion

“…These mice exhibited a decreased density of the microvasculature, and the capillaries exhibited an abnormal morphological appearance. Moreover, b-cell-specific Fyn-related kinase tyrosine kinase transgenic mice exhibited an impaired glucose-stimulated insulin secretion in vivo (25). Insulin secretion in isolated islets from these mice was similar to that of control mice; however, the islet blood flow and capillary lumen diameter in the islets were decreased.…”

Mid-life blood pressure levels and the 8-year incidence of type 2 diabetes mellitus: the Rancho Bernardo Study

“…However, a previous cross-sectional report from the Rancho Bernardo Study did not show that insulin was independently associated with hypertension 13. Another potential explanation is that high BP levels cause microvascular dysfunction that precede islet cell failure as shown in animal models 14; in epidemiological studies, biomarkers of endothelial dysfunction independently predict T2DM 15,16. Alternatively BP and T2DM could share a common gene polymorphism; for example, the renin-angiotensin system gene polymorphism associated with essential hypertension 17 has also been associated with increased risk for T2DM 18,19, although these results were not replicated in other studies20,21.…”