Inflammation-induced microvascular insulin resistance is an early event in diet-induced obesity

Lina Zhao, Zhuo Fu, Jing Wu, Kevin W Aylor, Eugene J Barrett, Wenhong Cao, Zhenqi Liu, Lina Zhao, Zhuo Fu, Jing Wu, Kevin W Aylor, Eugene J Barrett, Wenhong Cao, Zhenqi Liu

Abstract

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.

Keywords: endothelial dysfunction; high-fat diet; inflammation; insulin resistance; muscle microvasculature; obesity.

© 2015 Authors; published by Portland Press Limited.

Figures

Figure 1. Effects of HFD ± sodium…
Figure 1. Effects of HFD ± sodium salicylate on insulin and NF-κB signalling in aorta
(A and B) Akt phosphorylation, (C and D) ERK1/2 phosphorylation, (E and F) eNOS phosphorylation, (G and H) IκBα phosphorylation and (I) NF-κB DNA-binding activity. (A, C, E and G) Representative Western blots; (B, D, F and H) quantitative measurements. Compared with respective control without insulin, *P<0.05. n=3–4.
Figure 2. Effects of HFD ± sodium…
Figure 2. Effects of HFD ± sodium salicylate on resistance arterial endothelial function and insulin responses
Vasodilatory responses to Ach (A–D) and insulin (E–H) were determined using distal saphenous arteries that were dissected from rats fed on either chow or an HFD for 3 days (A), 1 week (B), 2 weeks (C) and 4 weeks (D). Compared with chow, *P<0.05. Compared with HFD, #P<0.05. n=5–6.
Figure 3. Time course effect of HFD…
Figure 3. Time course effect of HFD ± sodium salicylate on insulin-mediated changes in muscle MBV
Each rat received a 2-h euglycaemic–hyperinsulinaemic clamp after an HFD for 3 days (A), 1 week (B), 2 weeks (C) and 4 weeks (D) with or without simultaneous sodium salicylate treatment. MBV was measured using CEU at baseline and 30, 60 and 120 min after the initiation of insulin infusion. Rats fed normal chow were used as a control. Compared with respective baseline (0 min), *P<0.05. n=5–6.
Figure 4. Time course effect of HFD…
Figure 4. Time course effect of HFD ± sodium salicylate on insulin-mediated changes in muscle MBF
Each rat received a 2-h euglycaemic–hyperinsulinaemic clamp after an HFD for 3 days (A), 1 week (B), 2 weeks (C) and 4 weeks (D) with or without simultaneous salicylate treatment. MBF was calculated at baseline and 30, 60 and 120 min after the initiation of insulin infusion. Rats fed normal chow were used as a control. Compared with respective baseline (0 min), *P<0.05. Compared with HFD at the same time point, #P<0.05. n=5–6.
Figure 5. Effects of HFD ± sodium…
Figure 5. Effects of HFD ± sodium salicylate on plasma NO contents
Compared with respective control without insulin, *P<0.05. n=5–6.
Figure 6. Time course effect of HFD…
Figure 6. Time course effect of HFD ± sodium salicylate on metabolic insulin sensitivity
Each rat received a 2-h euglycaemic–hyperinsulinaemic clamp after an HFD for 3 days (A), 1 week (B), 2 weeks (C) and 4 weeks (D) with or without simultaneous sodium salicylate treatment and the glucose infusion rates (GIR) were recorded. Compared with baseline, *P<0.05. Compared with HFD, #P<0.05. n=5–6.
Figure 7. Effects of HFD ± sodium…
Figure 7. Effects of HFD ± sodium salicylate on skeletal muscle insulin signalling
(A) Akt phosphorylation; (B) ERK1/2 phosphorylation. Compared with respective control without insulin, *P<0.05. n = 3.

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