Glucagon-like peptide-1 elicits vasodilation in adipose tissue and skeletal muscle in healthy men

Ali Asmar, Meena Asmar, Lene Simonsen, Sten Madsbad, Jens J Holst, Bolette Hartmann, Charlotte M Sorensen, Jens Bülow, Ali Asmar, Meena Asmar, Lene Simonsen, Sten Madsbad, Jens J Holst, Bolette Hartmann, Charlotte M Sorensen, Jens Bülow

Abstract

In healthy subjects, we recently demonstrated that during acute administration of GLP-1, cardiac output increased significantly, whereas renal blood flow remained constant. We therefore hypothesize that GLP-1 induces vasodilation in other organs, for example, adipose tissue, skeletal muscle, and/or splanchnic tissues. Nine healthy men were examined twice in random order during a 2-hour infusion of either GLP-1 (1.5 pmol kg-1 min-1) or saline. Cardiac output was continuously estimated noninvasively concomitantly with measurement of intra-arterial blood pressure. Subcutaneous, abdominal adipose tissue blood flow (ATBF) was measured by the 133Xenon clearance technique. Leg and splanchnic blood flow were measured by Fick's Principle, using indocyanine green as indicator. In the GLP-1 study, cardiac output increased significantly together with a significant increase in arterial pulse pressure and heart rate compared with the saline study. Subcutaneous, abdominal ATBF and leg blood flow increased significantly during the GLP-1 infusion compared with saline, whereas splanchnic blood flow response did not differ between the studies. We conclude that in healthy subjects, GLP-1 increases cardiac output acutely due to a GLP-1-induced vasodilation in adipose tissue and skeletal muscle together with an increase in cardiac work.

Keywords: Adipose tissue; GLP‐1; blood flow; skeletal muscle; splanchnic circulation; vasodilation.

© 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Figures

Figure 1
Figure 1
The experimental timeline.
Figure 2
Figure 2
Arterial (radial) and venous (femoral and hepatic) plasma concentrations of total GLP‐1 (A and D), intact GLP‐1 (B and E), and GLP‐1 9‐36amide (C and F) during the GLP‐1 or saline infusion. Data are presented as means ± SE. *indicates statistically significant extraction of GLP‐1 during the GLP‐infusion compared with saline.
Figure 3
Figure 3
Arterial plasma concentrations of insulin (A and B) and arterial blood glucose concentrations (C and D). Left panel shows the time course of the concentrations during the infusions from 0 to 120 min. Right panel shows the integrated effect during the infusions from 0 to 120 min compared with baseline. Data are presented as means ± SE.
Figure 4
Figure 4
Cardiac output (A and B) and mean arterial pressure (C and D). Left panel shows the time course of the measurements during the infusions from 0 to 120 min. Right panel shows the integrated effect during the infusions from 0 to 120 min compared with baseline. Data are presented as means ± SE.
Figure 5
Figure 5
Intra‐arterial blood pressure (A–F) and heart rate (G and H). Left panel shows the time course of the measurements during the infusions from 0 to 120 min. Right panel shows the integrated effect during the infusions from 0 to 120 min compared with baseline. Data are presented as means ± SE.
Figure 6
Figure 6
Subcutaneous, abdominal adipose tissue blood flow (adipose tissue blood flow) (A and B). A shows the time course of the measurements during the infusions from 0 to 120 min. B shows the integrated effect during the infusions from 0 to 120 min compared with baseline. Data are presented as means ± SE
Figure 7
Figure 7
Leg blood flow (A and B) and splanchnic blood flow (C and D). Left panel shows the time course of the measurements during the infusions from 0 to 120 min. Right panel shows the integrated effect during the infusions from 0 to 120 min compared with baseline. Data are presented as means ± SE.

References

    1. Asmar, M. , Simonsen L., Madsbad S., Stallknecht B., Holst J. J., and Bulow J.. 2010. Glucose‐dependent insulinotropic polypeptide may enhance fatty acid re‐esterification in subcutaneous abdominal adipose tissue in lean humans. Diabetes 59:2160–2163.
    1. Asmar, M. , Simonsen L., Arngrim N., Holst J. J., Dela F., and Bulow J.. 2014. Glucose‐dependent insulinotropic polypeptide has impaired effect on abdominal, subcutaneous adipose tissue metabolism in obese subjects. Int. J. Obes. 38:259–265.
    1. Asmar, A. , Simonsen L., Asmar M., Madsbad S., Holst J. J., Frandsen E., et al. 2015. Renal extraction and acute effects of glucagon‐like peptide‐1 on central and renal hemodynamics in healthy men. Am. J. Physiol. Endocrinol. Metabol. 308:E641–E649.
    1. Asmar, A. , Simonsen L., Asmar M., Madsbad S., Holst J. J., Frandsen E., et al. 2016a. Glucagon‐like peptide‐1 does not have acute effects on central or renal hemodynamics in patients with type 2 diabetes without nephropathy. Am. J. Physiol. Endocrinol. Metabol. 310:E744–E753.
    1. Asmar, M. , Arngrim N., Simonsen L., Asmar A., Nordby P., Holst J. J., et al. 2016b. The blunted effect of glucose‐dependent insulinotropic polypeptide in subcutaneous abdominal adipose tissue in obese subjects is partly reversed by weight loss. Nutr. Diabetes. 6:e208.
    1. Asmar, M. , Simonsen L., Asmar A., Holst J. J., Dela F., and Bulow J.. 2016c. Insulin plays a permissive role for the vasoactive effect of GIP regulating adipose tissue metabolism in human. J. Clin. Endocrinol. Metab. 101:3155–3162.
    1. Basu, A. , Charkoudian N., Schrage W., Rizza R. A., Basu R., and Joyner M. J.. 2007. Beneficial effects of GLP‐1 on endothelial function in humans: dampening by glyburide but not by glimepiride. Am. J. Physiol. Endocrinol. Metab. 293:E1289–E1295.
    1. Bertin, E. , Arner P., Bolinder J., and Hagstrom‐Toft E.. 2001. Action of glucagon and glucagon‐like peptide‐1‐(7‐36) amide on lipolysis in human subcutaneous adipose tissue and skeletal muscle in vivo. J. Clin. Endocrinol. Metab. 86:1229–1234.
    1. Bogert, L. W. , and van Lieshout J. J.. 2005. Non‐invasive pulsatile arterial pressure and stroke volume changes from the human finger. Exp. Physiol. 90:437–446.
    1. Bulow, J. , Astrup A., Christensen N. J., and Kastrup J.. 1987a. Blood flow in skin, subcutaneous adipose tissue and skeletal muscle in the forearm of normal man during an oral glucose load. Acta Physiol. Scand. 130:657–661.
    1. Bulow, J. , Jelnes R., Astrup A., Madsen J., and Vilmann P.. 1987b. Tissue/blood partition coefficients for xenon in various adipose tissue depots in man. Scand. J. Clin. Lab. Invest. 47:1–3.
    1. Bulow, J. , Simonsen L., Wiggins D., Humphreys S. M., Frayn K. N., Powell D., et al. 1999. Co‐ordination of hepatic and adipose tissue lipid metabolism after oral glucose. J. Lipid Res. 40:2034–2043.
    1. Drucker, D. J. 2006. The biology of incretin hormones. Cell Metab. 3:153–165.
    1. Drucker, D. J. 2016. The Cardiovascular Biology of Glucagon‐like Peptide‐1. Cell Metab. 24:15–30.
    1. Eipel, C. , Abshagen K., and Vollmar B.. 2010. Regulation of hepatic blood flow: the hepatic arterial buffer response revisited. World J. Gastroenterol. 16:6046–6057.
    1. Enevoldsen, L. H. , Simonsen L., Macdonald I. A., and Bulow J.. 2004. The combined effects of exercise and food intake on adipose tissue and splanchnic metabolism. J. Physiol. 561:871–882.
    1. Enevoldsen, L. H. , Simonsen L., and Bulow J.. 2005. Postprandial triacylglycerol uptake in the legs is increased during exercise and post‐exercise recovery. J. Physiol. 568:941–950.
    1. Gloerich, M. , and Bos J. L.. 2010. Epac: defining a new mechanism for cAMP action. Annu. Rev. Pharmacol. Toxicol. 50:355–375.
    1. Hilsted, J. , Bonde‐Petersen F., Madsbad S., Parving H. H., Christensen N. J., Adelhoj B., et al. 1985. Changes in plasma volume, in transcapillary escape rate of albumin and in subcutaneous blood flow during hypoglycaemia in man. Clin. Sci. (London, England: 1979) 69: 273–277.
    1. Hovind, P. , Simonsen L., and Bulow J.. 2010. Decreased leg glucose uptake during exercise contributes to the hyperglycaemic effect of octreotide. Clin. Physiol. Funct. Imaging 30:141–145.
    1. Imholz, B. P. , Wieling W., van Montfrans G. A., and Wesseling K. H.. 1998. Fifteen years experience with finger arterial pressure monitoring: assessment of the technology. Cardiovasc. Res. 38:605–616.
    1. Karpe, F. , Fielding B. A., Ardilouze J. L., Ilic V., Macdonald I. A., and Frayn K. N.. 2002a. Effects of insulin on adipose tissue blood flow in man. J. Physiol. 540:1087–1093.
    1. Karpe, F. , Fielding B. A., Ilic V., Humphreys S. M., and Frayn K. N.. 2002b. Monitoring adipose tissue blood flow in man: a comparison between the (133)xenon washout method and microdialysis. Int. J. Obes. Relat. Metab. Disord. 26:1–5.
    1. Kogire, M. , Inoue K., Sumi S., Doi R., Takaori K., Yun M., et al. 1988. Effects of synthetic human gastric inhibitory polypeptide on splanchnic circulation in dogs. Gastroenterology 95: 1636–1640.
    1. Koska, J. , Sands M., Burciu C., D'Souza K. M., Raravikar K., Liu J., et al. 2015. Exenatide Protects Against Glucose‐ and Lipid‐Induced Endothelial Dysfunction: Evidence for Direct Vasodilation Effect of GLP‐1 Receptor Agonists in Humans. Diabetes 64:2624–2635.
    1. Langewouters, G. J. , Wesseling K. H., and Goedhard W. J.. 1984. The static elastic properties of 45 human thoracic and 20 abdominal aortas in vitro and the parameters of a new model. J. Biomech. 17:425–435.
    1. Langewouters, G. J. , Goedhard W. J., and Wesseling K. H.. 1985. The effect of aging and sclerosis on the viscoelastic properties of the human thoracic aorta. Tijdschr. Gerontol. Geriatr. 16:61–70.
    1. Leech, C. A. , Chepurny O. G., and Holz G. G.. 2010. Epac2‐dependent rap1 activation and the control of islet insulin secretion by glucagon‐like peptide‐1. Vitam. Horm. 84:279–302.
    1. Manolopoulos, K. N. , Karpe F., and Frayn K. N.. 2012. Marked resistance of femoral adipose tissue blood flow and lipolysis to adrenaline in vivo. Diabetologia 55:3029–3037.
    1. Meier, J. J. , Nauck M. A., Kranz D., Holst J. J., Deacon C. F., Gaeckler D., et al. 2004. Secretion, degradation, and elimination of glucagon‐like peptide 1 and gastric inhibitory polypeptide in patients with chronic renal insufficiency and healthy control subjects. Diabetes 53:654–662.
    1. Nystrom, T. , Gutniak M. K., Zhang Q., Zhang F., Holst J. J., Ahren B., et al. 2004. Effects of glucagon‐like peptide‐1 on endothelial function in type 2 diabetes patients with stable coronary artery disease. Am. J. Physiol. Endocrinol. Metab. 287:E1209–E1215.
    1. Orskov, C. , Rabenhoj L., Wettergren A., Kofod H., and Holst J. J.. 1994. Tissue and plasma concentrations of amidated and glycine‐extended glucagon‐like peptide I in humans. Diabetes 43:535–539.
    1. Paolisso, G. , Manzella D., Tagliamonte M. R., Rizzo M. R., Gambardella A., and Varricchio M.. 1999. Effects of different insulin infusion rates on heart rate variability in lean and obese subjects. Metabolism 48:755–762.
    1. Pujadas, G. , and Drucker D. J.. 2016. Vascular biology of glucagon receptor superfamily peptides: complexity, controversy, and clinical relevance. Endocr. Rev.: er20161078. [Epub ahead of print].
    1. Pyke, C. , Heller R. S., Kirk R. K., Orskov C., Reedtz‐Runge S., Kaastrup P., et al. 2014. GLP‐1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody. Endocrinology 155:1280–1290.
    1. Rowe, J. W. , Young J. B., Minaker K. L., Stevens A. L., Pallotta J., and Landsberg L.. 1981. Effect of insulin and glucose infusions on sympathetic nervous system activity in normal man. Diabetes 30:219–225.
    1. Scherrer, U. , and Sartori C.. 1997. Insulin as a vascular and sympathoexcitatory hormone: implications for blood pressure regulation, insulin sensitivity, and cardiovascular morbidity. Circulation 96:4104–4113.
    1. Simonsen, L. , Enevoldsen L. H., and Bulow J.. 2003. Determination of adipose tissue blood flow with local 133Xe clearance. Evaluation of a new labelling technique. Clin. Physiol. Funct. Imaging 23:320–323.
    1. Sjoberg, K. A. , Holst J. J., Rattigan S., Richter E. A., and Kiens B.. 2014. GLP‐1 increases microvascular recruitment but not glucose uptake in human and rat skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 306:E355–E362.
    1. Stok, W. J. , Baisch F., Hillebrecht A., Schulz H., Meyer M., and Karemaker J. M.. 1993. Noninvasive cardiac output measurement by arterial pulse analysis compared with inert gas rebreathing. J. Appl. Physiol. (Bethesda, Md: 1985) 74: 2687–2693.
    1. Tack, C. J. , Lenders J. W., Willemsen J. J., van Druten J. A., Thien T., Lutterman J. A., et al. 1998. Insulin stimulates epinephrine release under euglycemic conditions in humans. Metabolism 47:243–249.
    1. Trahair, L. G. , Horowitz M., Hausken T., Feinle‐Bisset C., Rayner C. K., and Jones K. L.. 2014. Effects of exogenous glucagon‐like peptide‐1 on the blood pressure, heart rate, mesenteric blood flow, and glycemic responses to intraduodenal glucose in healthy older subjects. J. Clin. Endocrinol. Metab. 99:E2628–E2634.
    1. Vollenweider, P. , Tappy L., Randin D., Schneiter P., Jequier E., Nicod P., et al. 1993. Differential effects of hyperinsulinemia and carbohydrate metabolism on sympathetic nerve activity and muscle blood flow in humans. J. Clin. Investig. 92:147–154.
    1. Wewer Albrechtsen, N. J. , Bak M. J., Hartmann B., Christensen L. W., Kuhre R. E., Deacon C. F., et al. 2015. Stability of glucagon‐like peptide 1 and glucagon in human plasma. Endocr. Connect. 4: 50–57.

Source: PubMed

3
Subscribe