Glucagon-like peptide 1 recruits muscle microvasculature and improves insulin's metabolic action in the presence of insulin resistance

Abstract

Glucagon-like peptide 1 (GLP-1) acutely recruits muscle microvasculature, increases muscle delivery of insulin, and enhances muscle use of glucose, independent of its effect on insulin secretion. To examine whether GLP-1 modulates muscle microvascular and metabolic insulin responses in the setting of insulin resistance, we assessed muscle microvascular blood volume (MBV), flow velocity, and blood flow in control insulin-sensitive rats and rats made insulin-resistant acutely (systemic lipid infusion) or chronically (high-fat diet [HFD]) before and after a euglycemic-hyperinsulinemic clamp (3 mU/kg/min) with or without superimposed systemic GLP-1 infusion. Insulin significantly recruited muscle microvasculature and addition of GLP-1 further expanded muscle MBV and increased insulin-mediated glucose disposal. GLP-1 infusion potently recruited muscle microvasculature in the presence of either acute or chronic insulin resistance by increasing muscle MBV. This was associated with an increased muscle delivery of insulin and muscle interstitial oxygen saturation. Muscle insulin sensitivity was completely restored in the presence of systemic lipid infusion and significantly improved in rats fed an HFD. We conclude that GLP-1 infusion potently expands muscle microvascular surface area and improves insulin's metabolic action in the insulin-resistant states. This may contribute to improved glycemic control seen in diabetic patients receiving incretin-based therapy.

© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Figures

Figure 1

GLP-1 enhances insulin-mediated glucose disposal and muscle microvascular recruitment. Each rat received a 2-h euglycemic insulin clamp (3 mU/kg/min) for 120 min with or without GLP-1 infusion (30 pmol/kg/min) superimposed between 60 and 120 min. CEU measurements were done at 0, 60, 90, and 120 min. A: Study protocol. B: GIR during insulin clamp. C: GIR AUC between 60 and 120 min. D: MBV. E: MFV. F: MBF. G: Plasma NO levels. n = 4–15 each. Compared with 0 min, *P < 0.05; compared with insulin, #P < 0.05. VI, video intensity.

Figure 2

GLP-1 increases muscle 125I-insulin uptake. Each rat received a 90-min euglycemic insulin clamp (3 mU/kg/min) with or without simultaneous GLP-1 infusion (30 pmol/kg/min) for the last 30 min. A bolus intravenous injection of 125I-insulin (1.5 µCi) was given 5 min before the end of insulin ± GLP-1 infusions. Blood and skeletal muscle were collected for determination of intact 125I-insulin. A: Study protocol. B: Fraction of intact 125I-insulin in blood and muscle. C: Muscle insulin uptake. n = 5 each. Compared with insulin alone, *P < 0.05.

Figure 3

GLP-1 recruits muscle microvasculature in the presence of acute and chronic insulin resistance. A: Infusion protocol. Each rat received a 3-h infusion of GLP-1 (30 pmol/kg/min) or equal volume of saline. B–D: GLP-1–mediated changes in muscle microvascular parameters in the presence of acute insulin resistance induced by 4 h of lipid infusion. n = 4–5. E–G: GLP-1–mediated changes in muscle microvascular parameters in the presence of chronic insulin resistance induced by 4 weeks of HFD feeding. n = 4–7. Compared with 0 min, *P < 0.05; compared with control (Intralipid or HFD only), #P < 0.05. VI, video intensity.

Figure 4

Lipid infusion abrogates insulin-mediated but not GLP-1 + insulin–mediated muscle microvascular perfusion. A: Infusion protocol. Each rat received a systemic infusion of either saline or Intralipid + heparin for 240 min with a euglycemic insulin clamp (3 mU/kg/min) superimposed in the last 3 h and either saline or GLP-1 (30 pmol/kg/min) for the last 2 h. B: MBV. C: MFV. D: MBF; n = 10 each. E: Muscle oxygen saturation. n = 5–6. F: Plasma NO levels. n = 4–8. Compared with respective baseline (0 min), *P < 0.05; compared with Intralipid + insulin, @P < 0.05. VI, video intensity.

Figure 5

GLP-1 restores muscle metabolic insulin sensitivity during lipid infusion. Each rat received a systemic infusion of either saline or lipid for 240 min with a euglycemic insulin clamp (3 mU/kg/min) superimposed in the last 3 h and either saline or GLP-1 (30 pmol/kg/min) for the last 2 h. A: Time course of GIR (n = 10–15/group). B: GIR AUC from 60–180 min; compared with insulin alone, *P < 0.05. C: Muscle insulin uptake; n = 5–11 each. Compared with saline or Intralipid group, *P < 0.05. D: Muscle Akt phosphorylation; compared with Intralipid + insulin, *P < 0.01. E: Muscle eNOS phosphorylation. F: Muscle ERK1/2 phosphorylation. G: Aorta PKA phosphorylation; compared with Intralipid + insulin, *P < 0.01. n = 4–8/group for D–G. P, phosphorylated; T, total.

Figure 6

HFD feeding abolishes insulin-mediated but not GLP-1 + insulin–mediated muscle microvascular perfusion. Each rat was fed an LFD or HFD for 4 weeks. A: Infusion protocol. B: MBV. C: MFV. D: MBF; n = 9 to 10/group. E: Muscle oxygen saturation; n = 4–8/group. F: Plasma NO levels; n = 4–8/group. Compared with respective baseline (0 min), *P < 0.05; compared with HFD + Insulin, @P < 0.05. VI, video intensity.

Figure 7

GLP-1 infusion increases muscle insulin delivery and improves muscle metabolic response to insulin in HFD-fed rats. Each rat was fed either an LFD or HFD for 4 weeks. A: Time course of GIR. B: GIR AUC (60–180 min); n = 8–10/group. C: Muscle 125I-insulin uptake; n = 6–11/group. D: Muscle Akt phosphorylation. E: Muscle eNOS phosphorylation. F: Muscle ERK1/2 phosphorylation. G: Aorta PKA phosphorylation. n = 6–8/group for D–G. Compared with LFD + Insulin, *P < 0.05; compared with HFD + Insulin, #P < 0.05, $P < 0.01; compared with LFD or HFD, @P < 0.05. P, phosphorylated; T, total.