Obesity Blunts Insulin-Mediated Microvascular Recruitment in Human Forearm Muscle

Abstract

We have previously shown that skeletal muscle capillaries are rapidly recruited by physiological doses of insulin in both humans and animals. This facilitates glucose and insulin delivery to muscle, thus augmenting glucose uptake. In obese rats, both insulin-mediated microvascular recruitment and glucose uptake are diminished; however, this action of insulin has not been studied in obese humans. Here we used contrast ultrasound to measure microvascular blood volume (MBV) (an index of microvascular recruitment) in the forearm flexor muscles of lean and obese adults before and after a 120-min euglycemic-hyperinsulinemic (1 mU ⅐ min ؊1 ⅐ kg ؊1 ) clamp. We also measured brachial artery flow, fasting lipid profile, and anthropomorphic variables. Fasting plasma glucose (5.4 ؎ 0.1 vs. 5.1 ؎ 0.1 mmol/l, P ‫؍‬ 0.05), insulin (79 ؎ 11 vs. 38 ؎ 6 pmol/l, P ‫؍‬ 0.003), and percent body fat (44 ؎ 2 vs. 25 ؎ 2%, P ‫؍‬ 0.001) were higher in the obese than the lean adults. After 2 h of insulin infusion, whole-body glucose infusion rate was significantly lower in the obese versus lean group (19.3 ؎ 3.2 and 37.4 ؎ 2.6 mol ⅐ min ؊1 ⅐ kg ؊1 respectively, P < 0.001). Compared with baseline, insulin increased MBV in the lean (18.7 ؎ 3.3 to 25.0 ؎ 4.1, P ‫؍‬ 0.019) but not in the obese group (20.4 ؎ 3.6 to 18.8 ؎ 3.8, NS). Insulin increased brachial artery diameter and flow in the lean but not in the obese group. We observed a significant, negative correlation between ⌬MBV and BMI (R ‫؍‬ ؊0.482, P ‫؍‬ 0.027) in response to insulin. In conclusion, obesity eliminated the insulin-stimulated muscle microvascular recruitment and increased brachial artery blood flow seen in lean individuals.

Oral Glucosamine for 6 Weeks at Standard Doses Does Not Cause or Worsen Insulin Resistance or Endothelial Dysfunction in Lean or Obese Subjects

“…This is in contrast to a recent study by Clerk et al (51) that demonstrated insulin significantly increased skeletal muscle capillary volume without changing capillary flow velocity in lean (but not obese) individuals. This discrepancy with our study may be due to technical differences including lower sensitivity and precision of the MVI technique we used compared with the Power imaging technique used by Clerk et al (51) and inclusion of small arteries (diameter Ͻ350 m) in our analysis. The increase in microvascular flow velocity we observed may reflect flow dynamics in small arteries consistent with insulin-enhanced blood flow in the proximal brachial artery.…”

Microvascular Dysfunction

“…3,19 In obese subjects, the insulin-stimulated muscle microvascular recruitment is impaired. 23 We have shown, by directly visualizing capillaries in human skin, that systemic hyperinsulinemia is capable of increasing the number of perfused capillaries. 7,18 This insulin-dependent capillary recruitment is impaired in obese insulin-resistant subjects.…”

“…36 Thus, shared insulinsignaling pathways in metabolic and vascular target tissues with complementary functions may provide a mechanism to couple the regulation of glucose with hemodynamic homeostasis. 23 The net hemodynamic action of insulin is dependent on a balance between its vasodilator and vasoconstrictor effects.…”

Insulin's microvascular vasodilatory effects are inversely related to peripheral vascular resistance in overweight, but insulin‐sensitive subjects

“…This can lead to insulinstimulated vasoconstriction or impaired vasodilation if signaling from the insulin receptor to eNOS is inhibited pharmacologically or downregulated by insulin resistance, as seen in conditions of obesity and hypertension in animal studies (9,10). In obese human subjects, a blunted (micro-)vascular responsiveness to insulin has been demonstrated (11)(12)(13). Thus, endothelial insulin resistance may contribute to the development of hypertension in obesity and account in part for the epidemiological relationship between hypertension and insulin resistance (6,8,14).…”