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

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

doi:10.1111/acel.13202

Cited by 21 publications

(17 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These extrapancreatic benefits of GLP-1 require further exploration in relation to the use of existing incretin therapeutics that may be able to enhance microvascular and metabolic responses to food intake in older age. This thesis is further underlined by our recent report of GLP-1 infusions enhancing muscle protein synthetic responses to a fed-state insulin clamp in older men (48).…”

Section: Discussionmentioning

confidence: 83%

Effects of GLP-1 Infusion Upon Whole-body Glucose Uptake and Skeletal Muscle Perfusion During Fed-state in Older Men

Abdulla

Piasecki

Wilkinson

et al. 2022

The Journal of Clinical Endocrinology &Amp; Metabolism

Self Cite

View full text Add to dashboard Cite

Introduction Ageing skeletal muscles become both insulin resistant and atrophic. The hormone glucagon-like peptide 1 (GLP-1) facilitates postprandial glucose uptake as well as augmenting muscle perfusion - independent of insulin action. We thus hypothesized exogenous GLP-1 infusions would enhance muscle perfusion and positively impact glucose metabolism during fed-state clamps in older people. Methods Eight men (71 ± 1y) were studied in a randomized cross-over trial. Basal blood samples were taken prior to postprandial (fed-state) insulin and glucose clamps, accompanied by amino acid infusions, for 3 h. Reflecting this, following insertions of peripheral and femoral vessels cannulae and baseline measurements, peripheral I.V infusions of octreotide, insulin (Actrapid), 20% glucose, and mixed amino acids (AA); Vamin 14-EF) ± a femoral arterial GLP-1 infusion were started. GLP-1, insulin and C-peptide were measured by ELISA. Muscle microvascular blood flow (MBF) was assessed via contrast enhanced ultrasound (CEUS). Whole-body glucose handling was assayed by assessing glucose infusion rate (GIR) parameters. Results Skeletal muscle microvascular blood flow significantly increased in response to GLP-1 vs. feeding alone (5.0 ± 2.1 vs. 1.9 ± 0.7 fold-change from basal respectively, p = 0.008), while also increasing whole-body glucose uptake (AUC 16.9 ± 1.7 vs. 11.4 ± 1.8 mg.kg-1.180 min-1, p = 0.02 ± GLP, respectively). Conclusions The beneficial effects of GLP-1 upon whole-body glycaemic control are evident with insulin clamped at fed-state levels. GLP-1 further enhances the effects of insulin on whole-body glucose uptake in older men, underlining its role as a therapeutic target. The effects of GLP-1 in enhancing microvascular flow likely also impacts other glucose-regulatory organs, reflected by greater whole-body glucose uptake.

show abstract

Section: Discussionmentioning

confidence: 83%

Effects of GLP-1 Infusion Upon Whole-body Glucose Uptake and Skeletal Muscle Perfusion During Fed-state in Older Men

Abdulla

Piasecki

Wilkinson

et al. 2022

The Journal of Clinical Endocrinology &Amp; Metabolism

Self Cite

View full text Add to dashboard Cite

show abstract

“…Specifically, when combined with behavioral therapy, GLP-1 agonists are associated with a 5–7% weight loss after 12 months, with greater success at higher doses. GLP-1 agonists exert anabolic effects within muscle and can ameliorate muscle atrophy to preserve lean body mass in mice [ 349 ], and have recently been shown to overcome anabolic resistance to feeding in older humans [ 350 ]. The appetite suppressing effects of GLP-1 agonists would likely confer equal benefits to DS and DR patients, while the anabolic effects of GLP-1 on skeletal may prove to be helpful in those with DR obesity.…”

Section: Pharmacotherapymentioning

confidence: 99%

Targeting skeletal muscle mitochondrial health in obesity

et al. 2022

View full text Add to dashboard Cite

Metabolic demands of skeletal muscle are substantial and are characterized normally as highly flexible and with a large dynamic range. Skeletal muscle composition (e.g., fiber type and mitochondrial content) and metabolism (e.g., capacity to switch between fatty acid and glucose substrates) are altered in obesity, with some changes proceeding and some following the development of the disease. Nonetheless, there are marked interindividual differences in skeletal muscle composition and metabolism in obesity, some of which have been associated with obesity risk and weight loss capacity. In this review, we discuss related molecular mechanisms and how current and novel treatment strategies may enhance weight loss capacity, particularly in diet-resistant obesity.

show abstract

“…Therefore, endothelial dysfunction results in both impaired vasodilatory function via decreased NO bioavailability and impairments in angiogenesis, both of which are major contributors to microvascular dysfunction in ageing 76 . These aberrations may be particularly detrimental to skeletal muscle anabolism, due to the important, previously discussed link between anabolism and blood flow, 20,25 or, more specifically, microvascular perfusion and nutrient delivery 23,26 …”

Section: Connecting Age‐related Anabolic Resistance and Vascular Functionmentioning

confidence: 99%

“…76 These aberrations may be particularly detrimental to skeletal muscle anabolism, due to the important, previously discussed link between anabolism and blood flow, 20,25 or, more specifically, microvascular perfusion and nutrient delivery. 23,26 Endothelin-1 is a potent vasoconstrictor that acts as a paracrine molecule at the endothelium, playing a key role in vascular tone through binding at the ET A and ET B receptors on the endothelium and vascular smooth muscle cells. [84][85][86][87] Ageing is associated with the up-regulation of ET-1 21,88 and augmented ET-1 mediated vasoconstriction, 87,89 and ET-1 has been shown to impair glucose uptake into skeletal muscle 86 and interfere with insulin signalling in arterial smooth muscle cells.…”

Section: Endothelial Dysfunctionmentioning

confidence: 99%

The contributory role of vascular health in age‐related anabolic resistance

Banks

Rogers

Church

et al. 2021

J cachexia sarcopenia muscle

View full text Add to dashboard Cite

Sarcopenia, or the age‐related loss of skeletal muscle mass and function, is an increasingly prevalent condition that contributes to reduced quality of life, morbidity, and mortality in older adults. Older adults display blunted anabolic responses to otherwise anabolic stimuli—a phenomenon that has been termed anabolic resistance (AR)—which is likely a casual factor in sarcopenia development. AR is multifaceted, but historically much of the mechanistic focus has been on signalling impairments, and less focus has been placed on the role of the vasculature in postprandial protein kinetics. The vascular endothelium plays an indispensable role in regulating vascular tone and blood flow, and age‐related impairments in vascular health may impede nutrient‐stimulated vasodilation and subsequently the ability to deliver nutrients (e.g. amino acids) to skeletal muscle. Although the majority of data has been obtained studying younger adults, the relatively limited data on the effect of blood flow on protein kinetics in older adults suggest that vasodilatory function, especially of the microvasculature, strongly influences the muscle protein synthetic response to amino acid feedings. In this narrative review, we examine evidence of AR in older adults following amino acid and mixed meal consumption, examine the evidence linking vascular dysfunction and insulin resistance to age‐related AR, review the influence of nitric oxide and endothelin‐1 on age‐related vascular dysfunction as it relates to AR, briefly review the potential causal role of arterial stiffness in promoting skeletal muscle microvascular dysfunction and AR, and provide a brief overview and future considerations for research examining age‐related AR.

show abstract

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

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 21 publications

References 52 publications

Effects of GLP-1 Infusion Upon Whole-body Glucose Uptake and Skeletal Muscle Perfusion During Fed-state in Older Men

Effects of GLP-1 Infusion Upon Whole-body Glucose Uptake and Skeletal Muscle Perfusion During Fed-state in Older Men

Targeting skeletal muscle mitochondrial health in obesity

The contributory role of vascular health in age‐related anabolic resistance

Contact Info

Product

Resources

About