Inflammation-induced microvascular insulin resistance is an early event in diet-induced obesity.
Endothelial dysfunction and vascular insulin resistance usually coexist and chronic inflammation engenders both. In the present study, we investigate the temporal relationship between vascular insulin resistance and metabolic insulin resistance. We assessed insulin responses in all arterial segments, including aorta, distal saphenous artery and the microvasculature, as well as the metabolic insulin responses in muscle in rats fed on a high-fat diet (HFD) for various durations ranging from 3 days to 4 weeks with or without sodium salicylate treatment. Compared with controls, HFD feeding significantly blunted insulin-mediated Akt (protein kinase B) and eNOS [endothelial nitric oxide (NO) synthase] phosphorylation in aorta in 1 week, blunted vasodilatory response in small resistance vessel in 4 weeks and microvascular recruitment in as early as 3 days. Insulin-stimulated whole body glucose disposal did not begin to progressively decrease until after 1 week. Salicylate treatment fully inhibited vascular inflammation, prevented microvascular insulin resistance and significantly improved muscle metabolic responses to insulin. We conclude that microvascular insulin resistance is an early event in diet-induced obesity and insulin resistance and inflammation plays an essential role in this process. Our data suggest microvascular insulin resistance contributes to the development of metabolic insulin resistance in muscle and muscle microvasculature is a potential therapeutic target in the prevention and treatment of diabetes and its related complications.
Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22903, U.S.A.
Lina
L
Zhao
Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22903, U.S.A.
Zhuo
Z
Fu
Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22903, U.S.A. Department of Endocrinology, Central South University Xiangya Hospital, Changsha, Hunan 410008, China.
Jing
J
Wu
Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22903, U.S.A.
Kevin W
KW
Aylor
Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22903, U.S.A.
Eugene J
EJ
Barrett
Department of Nutrition, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC 27516, U.S.A.
Wenhong
W
Cao
Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22903, U.S.A. zl3e@virginia.edu).
Zhenqi
Z
Liu
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D007249:Inflammation / Q000097:blood / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009765:Obesity / Q000097:blood / Q000209:etiology* / Q000503:physiopathology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D012980:Sodium Salicylate / Q000494:pharmacology; D013997:Time Factors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015415:Biomarkers; D001786:Blood Glucose; D007328:Insulin; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D051057:Proto-Oncogene Proteins c-akt; D012980:Sodium Salicylate
endothelial dysfunction; high-fat diet; inflammation; insulin resistance; muscle microvasculature; obesity