1936-P: Muscle Ischemia Impairs Insulin-Mediated Microvascular Recruitment

Abstract

Diabetes predisposes patients to peripheral artery disease (PAD). Muscle microvasculature plays a critical role in maintaining muscle function and health by delivering oxygen, nutrients and hormones to myocytes. Insulin dilates precapillary arterioles to increase muscle perfusion. To define the impact of ischemia to muscle microvascular perfusion and microvascular response to insulin, adult male rats were subject to hind limb ischemic surgery. Total hind limb blood flow was determined using laser Doppler blood flowmetry and muscle microvascular blood volume (MBV) measured using contrast-enhanced ultrasound in both the ischemic (left) and control (right) hind limb. Ischemic to control limb (I/C) ratios were calculated. Hyperinsulinemic euglycemia clamps were performed to determine microvascular responses to insulin. Hind limb ischemic surgery decreased total limb blood flow by ∼70% immediately, from a pre-surgical I/C ratio of 1.10 ± 0.07 to 0.34 ± 0.06. The I/C ratios then progressively increased to 0.45 ± 0.08, 0.54 ± 0.06, 0.67 ± 0.11, and 0.74± 0.11 on postsurgical day 3, 7, 14 and 21 respectively. Similarly, ischemic surgery decreased MBV promptly from a pre-surgical I/C ratio of 1.01 ± 0.04 to 0.39 ± 0.06. MBV I/C ratios completely recovered on day 3 (1.11 ± 0.09) and remained stable afterwards. Insulin induced similar increases in muscle MBV in both legs before surgery (I/C ratio 1.14 ± 0.16) but the increase was much less in ischemic leg on day 3 (I/C ratio 0.63 ± 0.15). Microvascular insulin responses fully recovered on day 7 (I/C ratio 0.97± 0.25). We conclude that hind limb ischemia is associated with decreased total blood flow, muscle microvascular perfusion as well as microvascular responses to insulin. While the recovery in muscle microvascular perfusion precedes that of total limb blood flow, recovery in muscle microvascular response to insulin is delayed. These changes may contribute to muscle injury in patients with diabetes and the muscle microvasculature is potentially a therapeutic target for PAD. Disclosure N. Wang: None. Z. Liu: None. Funding American Diabetes Association (1-17-ICTS-059 to Z.L.); National Institutes of Health (R01DK102359)