Glucagon-like peptide 1 infusions overcome anabolic resistance to feeding in older human muscle.

Haitham Abdulla,Daniel J Wilkinson,Hannah Crossland,John P Williams,Jessica Cegielski,Philip J Atherton,Debbie Rankin,Bethan E Phillips,Kenneth Smith,Marie Limb,Mariwan Sayda,Joseph J Bass,Tereza Jandova,Iskandar Idris

doi:10.1111/acel.13202

Abstract

BackgroundDespite its known insulin‐independent effects, glucagon‐like peptide‐1 (GLP‐1) role in muscle protein turnover has not been explored under fed‐state conditions or in the context of older age, when declines in insulin sensitivity and protein anabolism, as well as losses of muscle mass and function, occur.MethodsEight older‐aged men (71 ± 1 year, mean ± SEM) were studied in a crossover trial. Baseline measures were taken over 3 hr, prior to a 3 hr postprandial insulin (~30 mIU ml−1) and glucose (7–7.5 mM) clamp, alongside I.V. infusions of octreotide and Vamin 14 (±infusions of GLP‐1). Four muscle biopsies were taken, and muscle protein turnover was quantified via incorporation of 13C6 phenylalanine and arteriovenous balance kinetics, using mass spectrometry. Leg macro‐ and microvascular flow was assessed via ultrasound and anabolic signalling by immunoblotting. GLP‐1 and insulin were measured by ELISA.ResultsGLP‐1 augmented muscle protein synthesis (MPS; fasted: 0.058 ± 0.004% hr−1 vs. postprandial: 0.102 ± 0.005% hr−1, p < 0.01), in comparison with non‐GLP‐1 trials. Muscle protein breakdown (MPB) was reduced throughout clamp period, while net protein balance across the leg became positive in both groups. Total femoral leg blood flow was unchanged by the clamp; however, muscle microvascular blood flow (MBF) was significantly elevated in both groups, and to a significantly greater extent in the GLP‐1 group (MBF: 5 ± 2 vs. 1.9 ± 1 fold change +GLP‐1 and −GLP‐1, respectively, p < 0.01). Activation of the Akt‐mTOR signalling was similar across both trials.ConclusionGLP‐1 infusion markedly enhanced postprandial microvascular perfusion and further stimulated muscle protein metabolism, primarily through increased MPS, during a postprandial insulin hyperaminoacidaemic clamp.

Highlights

Increases in muscle protein synthesis (MPS) and decreases in breakdown (MPB) after feeding, which recoup muscle protein losses during fasting, are crucial for muscle maintenance
In line with previous findings in older individuals, MPS was resistant to the impact of intravenous AA feeding under postprandial insulin conditions (Cuthbertson et al, 2005; Mitchell et al, 2017)
A sustained suppression of Muscle protein breakdown (MPB) during insulin clamps was observed throughout the postprandial insulin clamp, and to the same extent in both groups, indicating that glucagon-like peptide-1 (GLP-1) had no added effect upon the inhibition of MPB

Summary

| INTRODUCTION

Increases in muscle protein synthesis (MPS) and decreases in breakdown (MPB) after feeding, which recoup muscle protein losses during fasting, are crucial for muscle maintenance. Mean GLP-1 concentration over the postprandial period was 63 ± 15 pmol L−1 and 17 ± 4 pmol L−1 with and without GLP-1 infusion, respectively, and the AUC above baseline was significantly greater in the GLP-1 group (Figure 1a) (inset). During the postprandial clamp with insulin alone, levels rose to 25 ± 0.4 μIU ml−1 and to 31 ± 1.3 μIU ml−1 when GLP-1 was co-infused (p < 0.001 vs fasting for both) (Figure 1b); AUC above baseline is shown in the inset, for −GLP-1 and +GLP-1, p = 0.24. Arterial phenylalanine concentrations were similar at baseline in both groups (58.5 ± 2.7 μM −GLP-1 vs 60.8 ± 3.4 μM +GLP-1 and rose significantly over the first 90 min of the postprandial period in both groups more than doubling to 135.8 ± 6.8 μM and 130.5 ± 2.7 μM, respectively, both p < 0.0001 Figure 2a,b) and remained elevated throughout. MPS rose slightly, but non-significantly in the −GLP-1 group

10 Artery

Older Men

| DISCUSSION

Findings

| MATERIALS AND METHODS