Voluntary wheel running selectively augments insulin-stimulated vasodilation in arterioles from white skeletal muscle of insulin-resistant rats

Abstract

Background: Exercise (RUN) prevents declines in insulin-mediated vasodilation, an important component of insulin-mediated glucose disposal, in rats prone to obesity and insulin resistance.

Objective: Determine whether RUN (1) improves insulin-stimulated vasodilation after insulin resistance has been established, and (2) differentially affects arterioles from red and white muscle.

Methods: Insulin signaling and vasoreactivity to insulin (1-1000 μIU/mL) were assessed in 2A from the Gw and Gr of SED OLETF rats at 12 and 20 weeks of age (SED12, SED20) and those undergoing RUN (RUN20) or caloric restriction (CR20; to match body weight of RUN) from 12 to 20 weeks.

Results: Glucose and insulin responses to i.p. glucose were reduced in RUN20, elevated in SED20 (p < 0.05 vs. SED12), and maintained in CR20. Insulin-stimulated vasodilation was greater in Gw but not Gr, 2As of RUN20 (p < 0.01 vs. all groups), and was improved by ET-1 receptor inhibition in Gw 2As from SED20 and CR20 (p < 0.05). There were no differences in microvascular insulin signaling among groups or muscle beds.

Conclusions: RUN selectively improved insulin-mediated vasodilation in Gw 2As, in part through attenuated ET-1 sensitivity/production, an adaptation that was independent of changes in adiposity and may contribute to enhanced insulin-stimulated glucose disposal.

Figure 1

Daily running distance (km/d) (A) and speed (m/min) (B) of the RUN20 group.

Figure 2

(A) Total, fat and lean mass (g) and percent body fat (% Fat). (B) Epididymal, omental, and retroperitoneal fat mass (g). All data are expressed as means ± SE. Different letters denote statistically significant between-group differences, such that groups not sharing the same letter are significantly different from one another(P < 0.05).

Figure 3

Glycosylated hemoglobin (HbA1c, %). All data are expressed as means ± SE. (*) indicates that CR20 and RUN20 are lower than both sedentary groups (SED12 and SED20)(P < 0.05).

Figure 4

Fasting (A) glucose and (B) insulin. (C) Glucose and (D) insulin responses to i.p. glucose tolerance test. AUC; area under the curve. All data are expressed as means ± SE. (*) denotes statistically different than all other groups(P < 0.05).

Figure 5

Vascular reactivity, to insulin alone or insulin in the presence of the non-selective ET-1 receptor tezosentan. Dose-response curves to graded doses of insulin alone (A, B) or insulin in the presence of tezosentan (C, D) in red portion of gastrocnemius (A, C) and white (B, D, F) portion of the gastrocnemius muscle are presented.. Statistical analysis revealed both a dose effect and a group effect on insulin responses but there was no group by dose interaction. Therefore we examined the group effect by pooling so that reactivity to insulin is expressed as mean percent possible dilation across all doses of insulin in second order arterioles of (E) red and (F) white portions of the gastrocnemius. All data are expressed as means ± SE. Different letters denote statistical significance, such that groups not sharing the same letter are significantly different from one another (P < 0.01). *Significantly different from no inhibitor, within group (P < 0.05).

Figure 6

Protein expression of phospho-specific (A, B) eNOS, (C, D) Akt, and (E, F) MAPK in second and third order arterioles from (A, C, E) red and (B, D, F) white portions of the gastrocnemius muscles of OLETF rats under basal (−Insulin) or insulin-stimulated conditions (+Insulin). Total and phospho-specific densities were quantified, and the ratios of phosphospecific to total density were calculated. Delta – difference between – Insulin and +Insulin; eNOS - endothelial nitric oxide synthase; MAPK – mitogen activated protein kinase. Data are expressed as means ± SE.

Figure 7

Protein expression of cytochrome c, a marker of mitochondrial content, in the heart, red, mixed, and white gastrocnemius (Gr, Gm, and Gw, respectively), and soleus. Data are expressed as means ± SE. (*) denotes significantly higher in the SED12 group compared to other groups(P < 0.05).