title: Pancreatic islet vasculature adapts to insulin resistance through dilation and not angiogenesis.
abstract: Pancreatic islets adapt to insulin resistance through a complex set of changes, including β-cell hyperplasia and hypertrophy. To determine if islet vascularization changes in response to insulin resistance, we investigated three independent models of insulin resistance: ob/ob, GLUT4(+/-), and mice with high-fat diet-induced obesity. Intravital blood vessel labeling and immunocytochemistry revealed a vascular plasticity in which islet vessel area was significantly increased, but intraislet vessel density was decreased as the result of insulin resistance. These vascular changes were independent of islet size and were only observed within the β-cell core but not in the islet periphery. Intraislet endothelial cell fenestration, proliferation, and islet angiogenic factor/receptor expression were unchanged in insulin-resistant compared with control mice, indicating that islet capillary expansion is mediated by dilation of preexisting vessels and not by angiogenesis. We propose that the islet capillary dilation is modulated by endothelial nitric oxide synthase via complementary signals derived from β-cells, parasympathetic nerves, and increased islet blood flow. These compensatory changes in islet vascularization may influence whether β-cells can adequately respond to insulin resistance and prevent the development of diabetes.
authors: Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors: Chunhua
authors: C
authors: Dai
authors: Marcela
authors: M
authors: Brissova
authors: Rachel B
authors: RB
authors: Reinert
authors: Lara
authors: L
authors: Nyman
authors: Eric H
authors: EH
authors: Liu
authors: Courtney
authors: C
authors: Thompson
authors: Alena
authors: A
authors: Shostak
authors: Masakazu
authors: M
authors: Shiota
authors: Takamune
authors: T
authors: Takahashi
authors: Alvin C
authors: AC
authors: Powers
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology*; D000818:Animals; D059305:Diet, High-Fat; D005260:Female; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D007515:Islets of Langerhans / Q000098:blood supply* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000503:physiopathology; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology; D014664:Vasodilation / Q000502:physiology*
chemical_list: D051275:Glucose Transporter Type 4
references: Metabolism. 1982 Feb;31(2):172-9
references: 7043168
references: Am J Physiol. 1998 Oct;275(4):E594-601
references: 9755077
references: J Cell Biol. 2001 Apr 30;153(3):543-53
references: 11331305
references: Diabetes. 2006 Nov;55(11):2965-73
references: 17065332
references: Am J Physiol. 1986 Dec;251(6 Pt 1):E644-7
references: 3538897
references: Nat Rev Cancer. 2010 Mar;10(3):165-80
references: 20179713
references: Nature. 1994 Dec 1;372(6505):425-32
references: 7984236
references: Microsc Res Tech. 1997 Jun 1-15;37(5-6):497-508
references: 9220427
references: Nat Med. 2003 Jun;9(6):653-60
references: 12778163
references: Diabetes Res Clin Pract. 1995 Nov;30(2):89-100
references: 8833629
references: Genes Dev. 2003 Aug 1;17(15):1835-40
references: 12897053
references: Development. 2004 Feb;131(4):807-17
references: 14736742
references: Diabetologia. 2000 Apr;43(4):393-410
references: 10819232
references: Breast Cancer Res Treat. 1995;36(2):169-80
references: 8534865
references: Acta Physiol (Oxf). 2011 Sep;203(1):61-86
references: 21689379
references: Dev Biol. 2012 Jul 1;367(1):40-54
references: 22546694
references: Philos Trans R Soc Lond B Biol Sci. 2006 May 29;361(1469):735-59
references: 16627292
references: Science. 2001 Oct 19;294(5542):564-7
references: 11577200
references: Diabetologia. 2012 Mar;55(3):707-18
references: 22167125
references: Islets. 2009 Sep-Oct;1(2):95-101
references: 21099255
references: Trends Endocrinol Metab. 2011 Jul;22(7):275-85
references: 21489811
references: Nat Rev Cancer. 2010 Jul;10(7):505-14
references: 20574450
references: Nat Rev Mol Cell Biol. 2009 Jan;10(1):53-62
references: 19197332
references: Am J Physiol. 1985 Jul;249(1 Pt 1):E43-8
references: 2409813
references: Dev Cell. 2006 Mar;10(3):397-405
references: 16516842
references: Development. 1999 Jun;126(14):3047-55
references: 10375497
references: Am J Pathol. 2007 May;170(5):1473-84
references: 17456755
references: Science. 1998 Sep 11;281(5383):1683-6
references: 9733517
references: J Clin Invest. 1997 Oct 1;100(7):1831-9
references: 9312184
references: Annu Rev Pharmacol Toxicol. 2009;49:1-30
references: 18834312
references: Acta Diabetol Lat. 1990 Jul-Sep;27(3):185-95
references: 2075782
references: Nat Clin Pract Cardiovasc Med. 2009 Jan;6(1):16-26
references: 19029993
references: Endocr Rev. 2010 Jun;31(3):343-63
references: 20164242
references: Am J Physiol Endocrinol Metab. 2010 Apr;298(4):E807-14
references: 20071562
references: Nat Rev Mol Cell Biol. 2009 Mar;10(3):165-77
references: 19234476
references: J Clin Invest. 2007 Mar;117(3):524-9
references: 17332879
references: Diabetes. 2006 Nov;55(11):2974-85
references: 17065333
references: Dev Biol. 2011 Apr 15;352(2):267-77
references: 21281624
references: Curr Biol. 2003 Jun 17;13(12):1070-4
references: 12814555
references: Endocrinology. 1991 Oct;129(4):2219-24
references: 1915103
references: Diabetes Obes Metab. 2009 Nov;11 Suppl 4:38-45
references: 19817787
references: Am J Physiol. 1999 Jan;276(1):R233-6
references: 9887200
references: Am J Physiol. 1992 May;262(5 Pt 1):E736-40
references: 1590384
references: Science. 1999 Dec 24;286(5449):2511-4
references: 10617467
references: Diabetes. 2012 Nov;61(11):2851-61
references: 22961079
references: Nat Med. 2003 Jun;9(6):713-25
references: 12778170
references: J Pathol. 2003 Jan;199(1):8-17
references: 12474221
references: Am J Physiol Endocrinol Metab. 2005 Apr;288(4):E707-14
references: 15562255
references: Diabetes. 2003 Jul;52(7):1716-22
references: 12829638
references: Nat Rev Mol Cell Biol. 2007 Jun;8(6):464-78
references: 17522591