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 affect glucose metabolism during fed-state clamps in older people. METHODS: Eight men (71 ± 1 years) were studied in a randomized crossover trial. Basal blood samples were taken before postprandial (fed-state) insulin and glucose clamps, accompanied by amino acid infusions, for 3 hours. Reflecting this, following insertions of peripheral and femoral vessels cannulae and baseline measurements, peripheral IV infusions of octreotide, insulin (Actrapid), 20% glucose, and mixed amino acids; Vamin 14-EF with or without a femoral arterial GLP-1 infusion were started. GLP-1, insulin, and C-peptide were measured by ELISA. Muscle microvascular blood flow was assessed via contrast enhanced ultrasound. Whole-body glucose handling was assayed by assessing glucose infusion rate 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 (area under the curve 16.9 ± 1.7 vs 11.4 ± 1.8 mg/kg-1/180 minutes-1, P = 0.02 ± GLP, respectively). CONCLUSIONS: The beneficial effects of GLP-1 on whole-body glycemic 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 affects other glucose-regulatory organs, reflected by greater whole-body glucose uptake.

Department of Anaesthesia University Hospitals Derby and Burton NHS Foundation Trust Derby DE22 3NE UK

Department of Endocrinology and Diabetes University Hospitals Derby and Burton NHS Foundation Trust Derby DE22 3NE UK

Department of Physiology and Biochemistry Faculty of Physical Education and Sport Charles University Prague 6 Czech Republic

Diabetes and Endocrinology Centre University Hospitals Birmingham NHS Foundation Trust Heartlands Hospitals Birmingham B9 5SS UK

MRC Versus Arthritis Centre for Musculoskeletal Ageing Research Centre of Metabolism Ageing and Physiology School of Medicine University of Nottingham Royal Derby Hospital Derby DE22 3DT UK

NIHR Nottingham BRC University of Nottingham Nottingham NG7 2UH UK

Zobrazit více v PubMed

Weir GC, Mojsov S, Hendrick GK, Habener JF. Glucagonlike peptide I (7-37) actions on endocrine pancreas. Diabetes. 1989;38(3):338–342. PubMed

Nathan DM, Schreiber E, Fogel H, Mojsov S, Habener JF. Insulinotropic action of glucagonlike peptide-I-(7–37) in diabetic and nondiabetic subjects. Diabetes Care. 1992;15(2):270–276. PubMed

Montrose-Rafizadeh C, Egan JM, Roth J. Incretin hormones regulate glucose-dependent insulin secretion in RIN 1046-38 cells: mechanisms of action. Endocrinology. 1994;135(2):589–594. PubMed

Elahi D, McAloon-Dyke M, Fukagawa NK, et al. . The insulinotropic actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (7-37) in normal and diabetic subjects. Regul Pept. 1994;51(1):63–74. PubMed

Larsson H, Holst JJ, Ahren B. Glucagon-like peptide-1 reduces hepatic glucose production indirectly through insulin and glucagon in humans. Acta Physiol Scand. 1997;160(4):413–422. PubMed

Todd JF, Wilding JP, Edwards CM, Khan FA, Ghatei MA, Bloom SR. Glucagon-like peptide-1 (GLP-1): a trial of treatment in non-insulin-dependent diabetes mellitus. Eur J Clin Invest. 1997;27(6):533–536. PubMed

Ryan AS, Egan JM, Habener JF, Elahi D. Insulinotropic hormone glucagon-like peptide-1-(7–37) appears not to augment insulin-mediated glucose uptake in young men during euglycemia. J Clin Endocrinol Metab. 1998;83(7):2399–2404. PubMed

Ørskov L, Holst JJ, Møller J, et al. . GLP-1 does not acutely affect insulin sensitivity in healthy man. Diabetologia. 1996;39(10):1227–1232. PubMed

Vella A, Shah P, Basu R, Basu A, Holst JJ, Rizza RA. Effect of glucagon-like peptide 1 (7-36) amide on glucose effectiveness and insulin action in people with type 2 diabetes. Diabetes. 2000;49(4):611–617. PubMed

Gutniak M, Orskov C, Holst JJ, Ahrén B, Efendic S. Antidiabetogenic effect of glucagon-like peptide-1 (7-36) amide in normal subjects and patients with diabetes mellitus. N Engl J Med. 1992;326(20):1316–1322. PubMed

D’Alessio DA, Kahn SE, Leusner CR, Ensinck JW. Glucagon-like peptide 1 enhances glucose tolerance both by stimulation of insulin release and by increasing insulin-independent glucose disposal. J Clin Invest. 1994;93(5):2263–2266. PubMed PMC

D’Alessio DA, Prigeon RL, Ensinck JW. Enteral enhancement of glucose disposition by both insulin-dependent and insulin-independent processes. A physiological role of glucagon-like peptide I. Diabetes. 1995;44(12):1433–1437. PubMed

Vella A, Shah P, Basu R, et al. . Effect of glucagon-like peptide-1(7-36)-amide on initial splanchnic glucose uptake and insulin action in humans with type 1 diabetes. Diabetes. 2001;50(3):565–572. PubMed

Chai W, Dong Z, Wang N, et al. . Glucagon-like peptide 1 recruits microvasculature and increases glucose use in muscle via a nitric oxide-dependent mechanism. Diabetes. 2012;61(4):888–896. PubMed PMC

Barrett EJ, Eggleston EM, Inyard AC, et al. . The vascular actions of insulin control its delivery to muscle and regulate the rate-limiting step in skeletal muscle insulin action. Diabetologia. 2009;52(5):752–764. PubMed PMC

Ijuin T, Hatano N, Hosooka T, Takenawa T. Regulation of insulin signaling in skeletal muscle by PIP3 phosphatase, SKIP, and endoplasmic reticulum molecular chaperone glucose-regulated protein 78. Biochim Biophys Acta. 2015;1853(12):3192–3201. PubMed

Delgado E, Luque MA, Alcantara A, et al. . Glucagon-like peptide-1 binding to rat skeletal muscle. Peptides. 1995;16(2):225–229. PubMed

Villanueva-Penacarrillo ML, Alcantara AI, Clemente F, Delgado E, Valverde I. Potent glycogenic effect of GLP-1(7-36) amide in rat skeletal muscle. Diabetologia. 1994;37(11):1163–1166. PubMed

Luque MA, Gonzalez N, Marquez L, et al. . Glucagon-like peptide-1 (GLP-1) and glucose metabolism in human myocytes. J Endocrinol. 2002;173(3):465–473. PubMed

Sjøberg KA, Holst JJ, Rattigan S, Richter EA, Kiens B. GLP-1 increases microvascular recruitment but not glucose uptake in human and rat skeletal muscle. Am J Physiol Endocrinol Metab. 2014;306(4):E355–E362. PubMed PMC

Subaran SC, Sauder MA, Chai W, et al. . GLP-1 at physiological concentrations recruits skeletal and cardiac muscle microvasculature in healthy humans. Clin Sci (Lond). 2014;127(3):163–170. PubMed PMC

Phillips BE, Atherton PJ, Varadhan K, Limb MC, Williams JP, Smith K. Acute cocoa flavanol supplementation improves muscle macro- and microvascular but not anabolic responses to amino acids in older men. Appl Physiol Nutr Metab. 2016;41(5):548–556. PubMed

Mitchell WK, Phillips BE, Williams JP, et al. . Development of a new SonovueTM contrast-enhanced ultrasound approach reveals temporal and age-related features of muscle microvascular responses to feeding. Physiol Rep. 2013;1(5):e00119. PubMed PMC

Luzi L, Giordano M, Caloni M, Castellino P. Effects of insulin and amino acids on leucine metabolism in young and middle-aged humans. Eur J Nutr. 2001;40(3):106–112. PubMed

Rasmussen BB, Fujita S, Wolfe RR, et al. . Insulin resistance of muscle protein metabolism in aging. FASEB J. 2006;20(6):768–769. PubMed PMC

Chevalier S, Goulet EDB, Burgos SA, Wykes LJ, Morais JA. Protein anabolic responses to a fed steady state in healthy aging. J Gerontol A Biol Sci Med Sci. 2011;66(6):681–688. PubMed

DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979;237(3):E214–E223. PubMed

Greenhaff PL, Karagounis LG, Peirce N, et al. . Disassociation between the effects of amino acids and insulin on signaling, ubiquitin ligases, and protein turnover in human muscle. Am J Physiol Endocrinol Metab. 2008;295(3):595–604. PubMed PMC

Phillips B, Williams J, Atherton P, et al. . Resistance exercise training improves age-related declines in leg vascular conductance and rejuvenates acute leg blood flow responses to feeding and exercise. J Appl Physiol. 2012;112(3):347–353. PubMed

Weber M-A, Krakowski-Roosen H, Delorme S, et al. . Relationship of skeletal muscle perfusion measured by contrast-enhanced ultrasonography to histologic microvascular density. J Ultrasound Med. 2006;25(5):583–591. PubMed

Wilkinson DJ, Bukhari SSI, Phillips BE, et al. . Effects of leucine-enriched essential amino acid and whey protein bolus dosing upon skeletal muscle protein synthesis at rest and after exercise in older women. Clin Nutr. 2018;37(6):2011–2021. PubMed PMC

Bukhari SSI, Phillips BE, Wilkinson DJ, et al. . Intake of low-dose leucine-rich essential amino acids stimulates muscle anabolism equivalently to bolus whey protein in older women at rest and after exercise. Am J Physiol Endocrinol Metab. 2015;308(12):E1056–E10 65. PubMed

Volpi E, Mittendorfer B, Wolf SE, Wolfe RR. Oral amino acids stimulate muscle protein anabolism in the elderly despite higher first-pass splanchnic extraction. Am J Physiol. 1999;277(3 Pt 1):E513–E520. PubMed

Flakoll PJ, Kulaylat M, Frexes-Steed M, Hill JO, Abumrad NN. Amino acids enhance insulin resistance to exogenous glucose infusion in overnight-fasted humans. JPEN J Parenter Enteral Nutr. 1991;15(2):123–127. PubMed

Skilton MR, Lai NT, Griffiths KA, et al. . Meal-related increases in vascular reactivity are impaired in older and diabetic adults: insights into roles of aging and insulin in vascular flow. Am J Physiol Heart Circ Physiol. 2005;288(3):H1404–H1410. PubMed

Bearden SE. Effect of aging on the structure and function of skeletal muscle microvascular networks. Microcirculation. 2006;13(4):279–288. PubMed

Samengo G, Avik A, Fedor B, et al. . Age-related loss of nitric oxide synthase in skeletal muscle causes reductions in calpain S-nitrosylation that increase myofibril degradation and sarcopenia. Aging Cell. 2012;11(6):1036–1045. PubMed PMC

Donato AJ, Uberoi A, Wray DW, Nishiyama S, Lawrenson L, Richardson RS. Differential effects of aging on limb blood flow in humans. Am J Physiol Heart Circ Physiol. 2006;290(1):H272–H278. PubMed

Celermajer DS, Sorensen KE, Spiegelhalter DJ, Georgakopoulos D, Robinson J, Deanfield JE. Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women. J Am Coll Cardiol. 1994;24(2):471–476. PubMed

Coggan AR, Spina RJ, King DS, et al. . Histochemical and enzymatic comparison of the gastrocnemius muscle of young and elderly men and women. J Gerontol. 1992;47(3):B71–B76. PubMed

Hamilton CA, Brosnan MJ, McIntyre M, Graham D, Dominiczak AF. Superoxide excess in hypertension and aging: a common cause of endothelial dysfunction. Hypertension. 2001;37(2 Pt 2):529–534. PubMed

Keske MA, Premilovac D, Bradley EA, Dwyer RM, Richards SM, Rattigan S. Muscle microvascular blood flow responses in insulin resistance and ageing. J Physiol. 2016;594(8):2223–2231. PubMed PMC

Wang H, Wang AX, Barrett EJ. Caveolin-1 is required for vascular endothelial insulin uptake. Am J Physiol Endocrinol Metab. 2011;300(1):E134–E1 44. PubMed PMC

Moore MC, Cherrington AD, Wasserman DH. Regulation of hepatic and peripheral glucose disposal. Best Pract Res Clin Endocrinol Metab. 2003;17(3):343–364. PubMed

Chai W, Wang W, Liu J, et al. . Angiotensin II type 1 and type 2 receptors regulate basal skeletal muscle microvascular volume and glucose use. Hypertension. 2010;55(2):523–530. PubMed PMC

Thiebaud D, Jacot E, DeFronzo RA, Maeder E, Jequier E, Felber JP. The effect of graded doses of insulin on total glucose uptake, glucose oxidation, and glucose storage in man. Diabetes. 1982;31(11):957–963. PubMed

DeFronzo RA. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes. 1988;37(6):667–687. PubMed

Abdulla H, Phillips BE, Wilkinson DJ, et al. . Glucagon-like peptide 1 infusions overcome anabolic resistance to feeding in older human muscle. Aging Cell. 2020;19(9):e13202. PubMed PMC

Zobrazit více v PubMed

ClinicalTrials.gov
NCT02370745