| 1. |
- Annerén, Cecilia, et al.
(författare)
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Glucose intolerance and reduced islet blood flow in transgenic mice expressing the FRK tyrosine kinase under the control of the rat insulin promoter
- 2007
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Ingår i: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 292:4, s. E1183-E1190
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Tidskriftsartikel (refereegranskat)abstract
- The FRK tyrosine kinase has previously been shown to transduce β-cell cytotoxic signals in response to cytokines and streptozotocin and to promote β-cell proliferation and an increased β-cell mass. We therefore aimed to further evaluate the effects of overexpression of FRK tyrosine kinase in β-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 β-cell mass is increased. The data suggest that long-term expression of active FRK in β-cells causes an in vivo insulin-secretory defect, which may be the consequence of islet vascular abnormalities that yield a decreased islet blood flow.
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| 2. |
- Lai, Enyin, et al.
(författare)
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Blood lipids affect rat islet blood flow regulation through beta(3)-adrenoceptors
- 2014
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Ingår i: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 307:8, s. E653-E663
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Tidskriftsartikel (refereegranskat)abstract
- Pancreatic islet blood perfusion varies according to the needs for insulin secretion. We examined the effects of blood lipids on pancreatic islet blood flow in anesthetized rats. Acute administration of Intralipid to anesthetized rats increased both triglycerides and free fatty acids, associated with a simultaneous increase in total pancreatic and islet blood flow. A preceding abdominal vagotomy markedly potentiated this and led acutely to a 10-fold increase in islet blood flow associated with a similar increase in serum insulin concentrations. The islet blood flow and serum insulin response could be largely prevented by pretreatment with propranolol and the selective beta(3)-adrenergic inhibitor SR-59230A. The nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester prevented the blood flow increase but was less effective in reducing serum insulin. Increased islet blood flow after Intralipid administration was also seen in islet and whole pancreas transplanted rats, i.e., models with different degrees of chronic islet denervation, but the effect was not as pronounced. In isolated vascularly perfused single islets Intralipid dilated islet arterioles, but this was not affected by SR-59230A. Both the sympathetic and parasympathetic nervous system are important for the coordination of islet blood flow and insulin release during hyperlipidemia, with a previously unknown role for beta(3)-adrenoceptors.
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| 3. |
- Lai, En Yin, et al.
(författare)
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Endothelin-1 and pancreatic islet vasculature : studies in vivo and on isolated, vascularly perfused pancreatic islets
- 2007
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Ingår i: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 292:6, s. E1616-E1623
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Tidskriftsartikel (refereegranskat)abstract
- Endothelin-1 (ET-1) is a potent endothelium-derived vasoconstrictor, which also stimulates insulin release. The aim of the present study was to evaluate whether exogenously administered ET-1 affected pancreatic islet blood flow in vivo in rats and the islet arteriolar reactivity in vitro in mice. Furthermore, we aimed to determine the ET-receptor subtype that was involved in such responses. When applying a microsphere technique for measurements of islet blood perfusion in vivo, we found that ET-1 (5 nmol/kg) consistently and markedly decreased total pancreatic and especially islet blood flow, despite having only minor effects on blood pressure. Neither endothelin A (ET(A)) receptor (BQ-123) nor endothelin-B (ET(B)) receptor (BQ-788) antagonists, alone or in combination, could prevent this reduction in blood flow. To avoid confounding interactions in vivo, we also examined the arteriolar vascular reactivity in isolated, perfused mouse islets. In the latter preparation, we demonstrated a dose-dependent constriction in response to ET-1. Administration of BQ-123 prevented this, whereas BQ-788 induced a right shift in the response. In conclusion, the pancreatic islet vasculature is highly sensitive to exogenous ET-1, which mediates its effect mainly through ET(A) receptors.
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