title: Fatty diabetic lung: functional impairment in a model of metabolic syndrome.
abstract: The Zucker diabetic fatty (ZDF fa/fa) rat with genetic leptin insensitivity develops obesity and Type 2 diabetes mellitus (T2DM) with age accompanied by hyperplastic changes in the distal lung (Am J Physiol Lung Cell Mol Physiol 298: L392-L403, 2010). To determine the functional consequences of structural changes, we developed a rebreathing (RB) technique to simultaneously measure lung volume, pulmonary blood flow, lung diffusing capacity (Dl(CO)), membrane diffusing capacity (Dm(CO)), pulmonary capillary blood volume (Vc), and septal tissue volume in anesthetized tracheostomized male ZDF fa/fa and matched lean (+/+) control animals at 4, 8, and 12 mo of age. Results obtained by RB technique were compared with that measured by a single-breath (SB) technique and to that expected in a wide range of species. In fa/fa animals compared with +/+, lung volumes and compliance were 13-35% lower at different ages, and the normal age-related increase in lung compliance was no longer evident. Mean pulmonary blood flow declined with age in fa/fa but not in +/+ animals. Dl(CO) measured at a given pulmonary blood flow was 20-43% lower at different ages due to reductions in both Dm(CO) and Vc. Septal tissue volume was also reduced in older fa/fa rats. We conclude that obese rats with T2DM develop significant restrictive pulmonary defects with diffusion impairment in a pattern similar to that previously reported in obese human subjects with T2DM. Functional impairment became exaggerated with age and duration of T2DM. In both fa/fa and +/+ animals, Dl(CO) measured by RB was systematically higher than by SB technique whereas lung volume was similar, a finding consistent with heterogeneous distribution of ventilation in the rat lung.
authors.affiliation: Department of Internal Medicine, Pulmonary and Critical Care Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9034, USA.
authors.forename: Cuneyt
authors.initials: C
authors.lastname: Yilmaz
authors.forename: Priya
authors.initials: P
authors.lastname: Ravikumar
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Bellotto
authors.forename: Roger H
authors.initials: RH
authors.lastname: Unger
authors.forename: Connie C W
authors.initials: CC
authors.lastname: Hsia
mesh_terms: D000367:Age Factors; D000375:Aging; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology* / Q000235:genetics; D004195:Disease Models, Animal; D006965:Hyperplasia; D008168:Lung / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology*; D008171:Lung Diseases / Q000209:etiology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008176:Lung Volume Measurements; D008297:Male; D024821:Metabolic Syndrome / Q000209:etiology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008833:Microcirculation; D009765:Obesity / Q000150:complications* / Q000235:genetics; D011652:Pulmonary Circulation; D011653:Pulmonary Diffusing Capacity; D051381:Rats; D011924:Rats, Zucker; D012039:Regional Blood Flow; D012121:Respiration, Artificial; D013997:Time Factors; D014139:Tracheostomy
references.citation: ASAIO J. 1999 Jan-Feb;45(1):32-6
references.pmid: 9952003
references.citation: J Clin Invest. 1966 Apr;45(4):493-500
references.pmid: 5937024
references.citation: Am Rev Respir Dis. 1987 Jan;135(1):223-9
references.pmid: 3492160
references.citation: Am J Cardiol. 2002 Jan 15;89(2):191-7
references.pmid: 11792341
references.citation: Am Rev Respir Dis. 1982 Apr;125(4):432-5
references.pmid: 6918202
references.citation: Am Rev Respir Dis. 1988 Jan;137(1):162-6
references.pmid: 3337458
references.citation: Vet Anaesth Analg. 2005 Jul;32(4):201-11
references.pmid: 16008717
references.citation: Mamm Genome. 2002 Aug;13(8):429-37
references.pmid: 12226708
references.citation: Am Rev Respir Dis. 1981 Mar;123(3):305-12
references.pmid: 6164318
references.citation: Exp Lung Res. 1985;9(3-4):255-75
references.pmid: 4076053
references.citation: J Appl Physiol. 1964 Jan;19:97-104
references.pmid: 14104296
references.citation: Diabet Med. 2001 Sep;18(9):749-55
references.pmid: 11606174
references.citation: J Appl Physiol (1985). 2008 Jan;104(1):218-23
references.pmid: 18006871
references.citation: Respir Physiol. 1969 Jun;7(1):43-63
references.pmid: 5809094
references.citation: Annu Rev Med. 2002;53:319-36
references.pmid: 11818477
references.citation: J Appl Physiol. 1957 Sep;11(2):290-302
references.pmid: 13475180
references.citation: Am Rev Respir Dis. 1983 Jul;128(1):125-31
references.pmid: 6688163
references.citation: Diabetes Care. 2005 Sep;28(9):2141-4
references.pmid: 16123480
references.citation: Am J Respir Crit Care Med. 1995 Aug;152(2):658-65
references.pmid: 7633723
references.citation: Am Rev Respir Dis. 1987 Mar;135(3):613-6
references.pmid: 3826889
references.citation: J Appl Physiol (1985). 1985 Dec;59(6):1773-82
references.pmid: 4077786
references.citation: Respir Physiol. 1983 Feb;51(2):183-94
references.pmid: 6844754
references.citation: J Appl Physiol (1985). 2007 Jun;102(6):2179-85
references.pmid: 17363625
references.citation: Am J Physiol Lung Cell Mol Physiol. 2010 Mar;298(3):L392-403
references.pmid: 20061442
references.citation: Diabetes. 2001 Feb;50 Suppl 1:S118-21
references.pmid: 11272168
references.citation: Bull Eur Physiopathol Respir. 1976 Nov-Dec;12(6):747-56
references.pmid: 1016802
references.citation: Pflugers Arch. 1973;340(1):11-8
references.pmid: 4735961
references.citation: Respir Physiol. 1983 Nov;54(2):173-88
references.pmid: 6665333
references.citation: Clin Physiol. 1997 Mar;17(2):171-82
references.pmid: 9156963
references.citation: Diabetes Care. 2008 Aug;31(8):1596-601
references.pmid: 18492945
references.citation: Lab Anim Sci. 1991 Jan;41(1):63-5
references.pmid: 1849591
references.citation: J Appl Physiol (1985). 1994 Aug;77(2):998-1005
references.pmid: 8002557
references.citation: J Appl Physiol (1985). 1991 Feb;70(2):561-6
references.pmid: 1902454
references.citation: Am J Physiol. 1993 Dec;265(6 Pt 2):H1946-52
references.pmid: 8285233
references.citation: Am Rev Respir Dis. 1986 Feb;133(2):286-91
references.pmid: 3946923
references.citation: J Clin Invest. 1973 Nov;52(11):2921-7
references.pmid: 4748515
references.citation: Lung. 1992;170(5):267-79
references.pmid: 1355574
references.citation: J Appl Physiol Respir Environ Exerc Physiol. 1979 Jul;47(1):32-6
references.pmid: 468670
references.citation: Diabet Med. 2005 May;22(5):563-8
references.pmid: 15842510
references.citation: Respiration. 1999;66(1):14-9
references.pmid: 9973685
references.citation: J Nucl Med. 2002 Aug;43(8):1063-71
references.pmid: 12163633
references.citation: Aviat Space Environ Med. 1977 Mar;48(3):203-9
references.pmid: 857797
references.citation: J Appl Physiol (1985). 1988 Nov;65(5):2291-6
references.pmid: 3209574
references.citation: Toxicology. 2001 Mar 28;161(3):153-63
references.pmid: 11297804
references.citation: Am J Vet Res. 1993 Oct;54(10):1752-7
references.pmid: 8250403
references.citation: Diabetes Care. 2002 Feb;25(2):370-5
references.pmid: 11815512
references.citation: Chest. 2004 Aug;126(2):559-65
references.pmid: 15302745
references.citation: Am Rev Respir Dis. 1988 Aug;138(2):284-9
references.pmid: 3057960
references.citation: J Appl Physiol (1985). 1995 Apr;78(4):1612-6
references.pmid: 7615476
references.citation: Clin Exp Pharmacol Physiol. 2005 Oct;32(10):825-31
references.pmid: 16173943
references.citation: Am Rev Respir Dis. 1979 Nov;120(5):973-83
references.pmid: 507532
references.citation: Diabetes Care. 2007 Mar;30(3):579-85
references.pmid: 17327324
references.citation: Inhal Toxicol. 2000 Jul;12(7):591-604
references.pmid: 10880146
references.citation: Comp Biochem Physiol A Comp Physiol. 1982;72(1):157-60
references.pmid: 6124354
references.citation: Respiration. 1994;61(1):32-6
references.pmid: 8177970
references.citation: J Appl Physiol Respir Environ Exerc Physiol. 1980 Jun;48(6):1052-9
references.pmid: 7380702
references.citation: Diabetes. 1975 Oct;24(10):902-4
references.pmid: 170154
references.citation: Respir Physiol Neurobiol. 2005 Apr 15;146(2-3):215-23
references.pmid: 15766909
references.citation: Am J Med. 1997 Dec;103(6):504-13
references.pmid: 9428834
references.citation: Am J Med. 2005 Mar;118(3):205-11
references.pmid: 15745714
references.citation: J Cyst Fibros. 2004 Dec;3(4):209-22
references.pmid: 15698938
references.citation: J Appl Physiol (1985). 2003 May;94(5):1926-32
references.pmid: 12562671
references.citation: Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2498-502
references.pmid: 9482914
references.citation: Am Rev Respir Dis. 1976 Jan;113(1):37-41
references.pmid: 1247213
references.citation: Endocr J. 2003 Dec;50(6):663-7
references.pmid: 14709835
references.citation: Bull Eur Physiopathol Respir. 1982 Nov-Dec;18(6):893-9
references.pmid: 6927541
references.citation: J Appl Physiol (1985). 1993 Feb;74(2):849-52
references.pmid: 8458805
references.citation: J Appl Physiol (1985). 1990 Jun;68(6):2344-57
references.pmid: 2384415
references.citation: Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4637-41
references.pmid: 9114043
references.citation: Am J Med Sci. 1999 Nov;318(5):293-7
references.pmid: 10555090
references.citation: Toxicology. 1980;18(2):111-23
references.pmid: 7256779
references.citation: Anesthesiology. 2001 Mar;94(3):489-95
references.pmid: 11374611
references.citation: J Appl Physiol (1985). 2006 Jul;101(1):289-97
references.pmid: 16601302
references.citation: Am J Respir Crit Care Med. 2004 May 1;169(9):1034-40
references.pmid: 14977623
references.citation: Eur Respir J. 1997 Aug;10(8):1850-8
references.pmid: 9272930
references.citation: J Appl Physiol Respir Environ Exerc Physiol. 1980 Nov;49(5):910-5
references.pmid: 7429915