Salsalate attenuates free fatty acid-induced microvascular and metabolic insulin resistance in humans

Abstract

Objective: Insulin recruits muscle microvasculature, thereby increasing endothelial exchange surface area. Free fatty acids (FFAs) cause insulin resistance by activating inhibitor of κB kinase β. Elevating plasma FFAs impairs insulin's microvascular and metabolic actions in vivo. Whether salsalate, an anti-inflammatory agent, prevents FFA-induced microvascular and/or metabolic insulin resistance in humans is unknown.

Research design and methods: Eleven healthy, young adults were studied three times in random order. After an overnight fast, on two occasions each subject received a 5-h systemic infusion of Intralipid ± salsalate pretreatment (50 mg/kg/day for 4 days). On the third occasion, saline replaced Intralipid. A 1 mU/kg/min euglycemic insulin clamp was superimposed over the last 2-h of each study. Skeletal and cardiac muscle microvascular blood volume (MBV), microvascular flow velocity (MFV), and microvascular blood flow (MBF) were determined before and after insulin infusion. Whole body glucose disposal rates were calculated from glucose infusion rates.

Results: Insulin significantly increased skeletal and cardiac muscle MBV and MBF without affecting MFV. Lipid infusion abolished insulin-mediated microvascular recruitment in both skeletal and cardiac muscle and lowered insulin-stimulated whole body glucose disposal (P<0.001). Salsalate treatment rescued insulin's actions to recruit muscle microvasculature and improved insulin-stimulated whole body glucose disposal in the presence of high plasma FFAs.

Conclusions: High plasma concentrations of FFAs cause both microvascular and metabolic insulin resistance, which can be prevented or attenuated by salsalate treatment. Our data suggest that treatments aimed at inhibition of inflammatory response might help alleviate vascular insulin resistance and improve metabolic control in patients with diabetes.

Figures

Figure 1

Study protocol (A) and GIRs during euglycemic-hyperinsulinemic clamps (B). Each subject was studied thrice randomly and CEU/MCE performed before and after 2-h euglycemic insulin clamp. Plasma glucose was measured every 5 min and GIR was adjusted to maintain euglycemia. AUC, area under the curve. *P < 0.007 vs. control.

Figure 2

Skeletal muscle MBV (A), MFV (B), and MBF (C) at baseline (open bar) and at end of 120-min insulin infusion (black bar). Compared with respective baseline, *P = 0.01, **P = 0.02.

Figure 3

Myocardial MBV (A), MFV (B), and MBF (C) at baseline (open bar) and at end of 120-min insulin infusion (black bar). Compared with baseline, *P = 0.01, **P = 0.001. Compared with control baseline, #P = 0.03.