title: Markers of Islet Endothelial Dysfunction Occur in Male B6.BKS(D)-Leprdb/J Mice and May Contribute to Reduced Insulin Release.
abstract: Islet endothelial cells produce paracrine factors that support β-cell function and growth. Endothelial dysfunction underlies diabetic microvascular complications; thus, we hypothesized that in diabetes, islet endothelial cells become dysfunctional, which may contribute to β-cell secretory dysfunction. Islets/islet endothelial cells were isolated from diabetic B6.BKS(D)-Leprdb/J male (db/db) mice, treated with or without the glucose-lowering agent phlorizin, or from C57BL/6J mice fed a high-fat diet for 18 weeks and appropriate controls. Messenger RNA (mRNA) and/or the protein levels of the cell adhesion molecule E-selectin (Sele), proinflammatory cytokine interleukin-6 (Il6), vasoconstrictor endothelin-1 (Edn1), and endothelial nitric oxide synthase (Nos3; Nos3) were evaluated, along with advanced glycation end product immunoreactivity. Furthermore, an islet endothelial cell line (MS-1) was exposed to diabetic factors (glucose, palmitate, insulin, and tumor necrosis factor-α) for six days. Conditioned media were collected from these cells, incubated with isolated islets, and glucose-stimulated insulin secretion and insulin content were assessed. Islet endothelial cells from db/db mice exhibited increased Sele, Il6, and Edn1 mRNA levels, decreased Nos3 protein, and accumulation of advanced glycation end products. Phlorizin treatment significantly increased Nos3 protein levels but did not alter expression of the other markers. High-fat feeding in C57BL/6J mice resulted in increased islet Sele, Il6, and Edn1 but no change in Nos3. Exposure of islets to conditioned media from MS-1 cells cultured in diabetic conditions resulted in a 50% decrease in glucose-stimulated insulin secretion and 30% decrease in insulin content. These findings demonstrate that, in diabetes, islet endothelial cells show evidence of a dysfunctional phenotype, which may contribute to loss of β-cell function.
authors.affiliation: Division of Metabolism, Endocrinology and Nutrition, Veterans Affairs Puget Sound Health Care System, Seattle, Washington.|Department of Medicine, University of Washington, Seattle, Washington.
authors.forename: Meghan F
authors.initials: MF
authors.lastname: Hogan
authors.affiliation: Division of Metabolism, Endocrinology and Nutrition, Veterans Affairs Puget Sound Health Care System, Seattle, Washington.|Department of Medicine, University of Washington, Seattle, Washington.
authors.forename: Amy W
authors.initials: AW
authors.lastname: Liu
authors.affiliation: Division of Metabolism, Endocrinology and Nutrition, Veterans Affairs Puget Sound Health Care System, Seattle, Washington.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Peters
authors.affiliation: Division of Metabolism, Endocrinology and Nutrition, Veterans Affairs Puget Sound Health Care System, Seattle, Washington.
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Willard
authors.affiliation: Division of Metabolism, Endocrinology and Nutrition, Veterans Affairs Puget Sound Health Care System, Seattle, Washington.|Department of Medicine, University of Washington, Seattle, Washington.
authors.forename: Zaheen
authors.initials: Z
authors.lastname: Rabbani
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington.
authors.forename: Erik C
authors.initials: EC
authors.lastname: Bartholomew
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington.
authors.forename: Adam
authors.initials: A
authors.lastname: Ottley
authors.affiliation: Division of Metabolism, Endocrinology and Nutrition, Veterans Affairs Puget Sound Health Care System, Seattle, Washington.|Department of Medicine, University of Washington, Seattle, Washington.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Hull
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D042783:Endothelial Cells / Q000378:metabolism; D004727:Endothelium / Q000503:physiopathology*; D005947:Glucose; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010695:Phlorhizin
chemical_list: D015415:Biomarkers; D007328:Insulin; D010695:Phlorhizin; D005947:Glucose