Hostname: page-component-745bb68f8f-l4dxg Total loading time: 0 Render date: 2025-01-31T02:05:54.076Z Has data issue: false hasContentIssue false
  • English
  • Français

Prandial subcutaneous injections of glucagon-like peptide-1 cause weight loss in obese human subjects

Published online by Cambridge University Press:  09 March 2007

Erik Näslund ,
N. King ,
S. Mansten ,
N. Adner ,
J. J. Holst ,
M. Gutniak  and
P. M. Hellström
Erik Näslund*
Affiliation:
Division of Surgery, Karolinska Institutet Danderyd Hospital, SE-182 88 Danderyd, Sweden
N. King
Affiliation:
Department of Biopsychology, University of Leeds, Leeds, UK
S. Mansten
Affiliation:
Division of Medicine, Karolinska Institutet South Hospital, Stockholm, Sweden
N. Adner
Affiliation:
Division of Medicine, Karolinska Institutet South Hospital, Stockholm, Sweden
J. J. Holst
Affiliation:
Department of Medical Physiology, University of Copenhagen, Copenhagen, Denmark
M. Gutniak
Affiliation:
Division of Medicine, Karolinska Institutet South Hospital, Stockholm, Sweden
P. M. Hellström
Affiliation:
Department of Gastroenterology and Hepatology, Karolinska Hospital, Karolinska Institutet, Stockholm, Sweden
*
*Corresponding author: Dr Erik Näslund, fax +46 8 655 77 66, email Erik.Naslund@kir.ds.sll.se
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

Recombinant glucagon-like peptide-1 (7–36)amide (rGLP-1) was recently shown to cause significant weight loss in type 2 diabetics when administered for 6 weeks as a continuous subcutaneous infusion. The mechanisms responsible for the weight loss are not clarified. In the present study, rGLP-1 was given for 5d by prandial subcutaneous injections (PSI) (76nmol 30min before meals, four times daily; a total of 302·4nmol/24h) or by continuous subcutaneous infusion (CSI) (12·7nmol/h; a total of 304·8nmol/24h). This was performed in nineteen healthy obese subjects (mean age 44·2 (sem 2·5) years; BMI 39·0 (sem 1·2)kg/m2) in a prospective randomised, double-blind, placebo-controlled, cross-over study. Compared with the placebo, rGLP-1 administered as PSI and by CSI generated a 15% reduction in mean food intake per meal (P=0·02) after 5d treatment. A weight loss of 0·55 (sem 0·2) kg (P<0·05) was registered after 5d with PSI of rGLP-1. Gastric emptying rate was reduced during both PSI (P<0·001) and CSI (P<0·05) treatment, but more rapidly and to a greater extent with PSI of rGLP-1. To conclude, a 5d treatment of rGLP-1 at high doses by PSI, but not CSI, promptly slowed gastric emptying as a probable mechanism of action of increased satiety, decreased hunger and, hence, reduced food intake with an ensuing weight loss.

Keywords

Glucagon-like peptide-1ObesityGastric emptyingWeight loss
Type
Research Article
Information
British Journal of Nutrition , Volume 91 , Issue 3 , March 2004 , pp. 439 - 446
Copyright
Copyright © The Nutrition Society 2004

References

Barkeling, B, Rössner, S & Björvell, H (1990) Effects of high-protein meal (meat) and a high-carbohydrate meal (vegetarian) on satiety measured by automated computerized monitoring on subsequent food intake. Int J Obes Relat Metab Disord 14, 743–751.Google Scholar
Edwards, CM, Stanley, SA, Davis, R, Brynes, AE, Frost, GS, Seal, LJ, Ghatei, MA & Bloom, SR (2001) Exendin-4 reduces fasting and postprandial glucose and decreases energy intake in healthy volunteers. Am J Physiol 281, E155–E166.Google ScholarPubMed
Flint, A, Raben, A, Astrup, A & Holst, JJ (1998) Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J Clin Invest 101, 515–520.CrossRefGoogle ScholarPubMed
Grybäck, P, Hermansson, G, Lyrenäs, E, Beckman, K-W, Jacobsson, H & Hellström, PM (2000) Nationwide standardisation and evaluation of scintigraphic gastric emptying: reference values and comparison between subgroups in a multicentre trial. Eur J Nucl Med 27, 647–655.Google Scholar
Gutniak, MK, Linde, B, Holst, JJ & Efendic, S (1994) Subcutaneous injection of the incretin hormone glucagon-like peptide 1 abolishes postprandial glycemia in NIDDM. Diabetes Care 9, 1039–1044.Google Scholar
Gutniak, MK, Ørskov, C, Holst, JJ, Ahrén, B & Efendic, S (1992) Antidiabetogenic effect of glucagon-like peptide-1 (7–36)amide in normal subjects and patients with diabetes mellitus. N Engl J Med 326, 1316–1322.Google Scholar
Gutniak, MK, Svartberg, J, Hellström, PM, Holst, JJ, Adner, N & Ahrén, B (2001) Antidiabetogenic action of glucagon-like peptide-1 related to administration relative to meal intake in subjects with type 2 diabetes. J Intern Med 250, 81–87.Google Scholar
Gutzwiller, JP, Drewe, J, Göke, B, Schmidt, H, Rohrer, B, Lareida, J & Beglinger, C (1999 a) Glucagon-like peptide-1 promotes satiety and reduces food intake in patients with diabetes mellitus type 2. Am J Physiol 276, R1541–R1544.Google ScholarPubMed
Gutzwiller, JP, Göke, B, Drewe, J, Hildebrand, P, Ketterer, S, Handschin, D, Winterhalder, R, Conen, D & Beglinger, C (1999 b) Glucagon-like peptide-1: a potent regulator of food intake in humans. Gut 44, 81–86.CrossRefGoogle ScholarPubMed
Kreymann, B, Ghatei, MA, Burnett, P, Williams, G, Kanse, S, Diani, AR & Bloom, SR (1989) Characterization of glucagon-like peptide 1 (7–36)amide in the hypothalamus. Brain Res 502, 325–331.Google Scholar
Kreymann, B, Williams, G, Ghatei, MA & Bloom, SR (1987) Glucagon-like peptide-1 7–36: a physiological incretin in man. Lancet ii, 1300–1303.Google Scholar
Larsen, PJ, Tang-Christensen, M, Holst, JJ & Ørskov, C (1997) Distribution of glucagon-like peptide-1 (GLP-1) and other preproglucagon derived peptides in the rat hypothalamus and brain stem. Neuroscience 77, 257–270.Google Scholar
Larsen, PJ, Tang-Christensen, M & Knudsen, LB (2001) Systemic administration of the long-acting GLP-1 analogue, NN2211, induces lasting and reversible loss of body obesity. Diabetologia 43, Suppl. 1, A144.Google Scholar
Mentlein, R, Gallwitz, B & Schmidt, WE (1993) Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7–36)amide, peptide histidine methionine and is responsible for their degradation in human serum. Eur J Biochem 214, 829–835.CrossRefGoogle ScholarPubMed
Mojsov, S, Weir, GC & Habener, JF (1987) Insulinotropin: glucagon-like peptide I (7–36) co-coded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas. J Clin Invest 79, 616–619.CrossRefGoogle Scholar
Näslund, E, Barkeling, B, King, N, Gutniak, MK, Blundell, JE, Holst, JJ & Hellström, PM (1999 a) Energy intake and appetite are suppressed by glucagon-like peptide-1 (GLP-1) in obese men. Int J Obes Relat Metab Disord 23, 304–311.CrossRefGoogle ScholarPubMed
Näslund, E, Bogefors, J, Skogar, S, Grybäck, P, Jacobsson, H, Holst, JJ & Hellström, PM (1999 b) GLP-1 slows solid gastric emptying and inhibits insulin, glucagon, and PYY release in humans. Am J Physiol 277, R910–R916.Google ScholarPubMed
Näslund, E, Grybäck, P, Jacobsson, H, Hellström, PM (2000) Gastric emptying: a comparison of scintigraphic, marker dilution and paracetamol absorption assessment techniques. Scand J Gastroenterol 35, 375–379.CrossRefGoogle Scholar
Näslund, E, Gutniak, MK, Skogar, S, Rössner, S & Hellström, PM (1998) Glucagon-like peptide 1 increases the period of postprandial satiety and slows gastric emptying in obese men. Am J Clin Nutr 68, 525–530.Google Scholar
Nauck, MA, Heimesaat, MM, Ørskov, C, Holst, JJ, Ebert, R & Creuzfeldt, W (1993 a) Preserved incretin activity of glucagon-like peptide 1(7–36amide) but not synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest 91, 301–307.CrossRefGoogle Scholar
Nauck, MA, Kleine, N, Ørskov, C, Holst, JJ, Willms, B & Creuzfeldt, W (1993 b) Normalization of fasting hyperglycemia by exogenous glucagon-like peptide 1 (7–36amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia 36, 741–744.CrossRefGoogle Scholar
Nauck, MA, Niedereichholz, U, Ettler, R, Holst, JJ, Ørskov, C, Ritzel, R & Schmiegel, W (1997) Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans. Am J Physiol 273, E981–E988.Google ScholarPubMed
Nauck, MA, Wollschläger, D, Werner, J, Holst, JJ, Ørskov, C, Creuzfeldt, W & Willms, B (1996) Effects of subcutaneous glucagon-like peptide 1(GLP-1[7–36]amide) in patients with NIDDM. Diabetologia 39, 1546–1553.Google Scholar
Ørskov, C, Poulsen, SS, Møller, M & Holst, JJ (1996) Glucagon-like peptide I receptors in the subfornical organ and area postrema are accessible to circulating glucagon-like peptide I. Diabetes 45, 832–835.CrossRefGoogle ScholarPubMed
Ørskov, C, Rabehøj, L, Wettergren, A, Kofod, H & Holst, JJ (1994) Tissue and plasma concentrations of amidated and glycine-extended glucagon-like peptide I in humans. Diabetes 43, 535–539.Google Scholar
Ritzel, R, Ørskov, C, Holst, JJ & Nauck, MA (1995) Pharmacokinetic, insulinotropic, and glucagono-static properties of GLP-1 (7–36 amide) after subcutaneous injection in healthy volunteers. Dose-response-relationships. Diabetologia 38, 720–725.Google Scholar
Shapiro, RE & Miselis, RR (1985) The central neural connections of the area postrema in the rat. J Comp Neurol 234, 344–364.CrossRefGoogle ScholarPubMed
Tang-Christensen, M, Vrang, N & Larsen, PJ (1998) Glucagon-like peptide 1(7–36)amide's central inhibition of feeding and peripheral inhibition of drinking are abolished by neonatal monosodium glutamate treatment. Diabetes 47, 530–537.Google Scholar
Todd, JF, Wilding, JPH, Edwards, CMB, Kahn, FA, Ghatei, MA & Bloom, SR (1997) Glucagon-like peptide-1 (GLP-1): a trial of treatment in non-insulin-dependent diabetes mellitus. Eur J Clin Invest 27, 533–536.CrossRefGoogle ScholarPubMed
Toft-Nielsen, M-B, Madsbad, S & Holst, JJ (1999) Continuous subcutaneous infusion of glucagon-like peptide-1 lowers plasma glucose and reduces appetite in type 2 diabetic patients. Diabetes Care 22, 1134–1137.Google Scholar
Turton, MD, O'Shea, D, Gunn, I et al. (1996) A role for glucagon-like peptide-1 in the central regulation of feeding. Nature 379, 69–72.Google Scholar
Verdich, C, Flint, A, Gutzwiller, JP et al. (2001) A meta-analysis of the effect of glucagon-like peptide-1 (7–36)amide on ad libitum food intake in humans. J Clin Endocrinol Metabol 86, 4382–4389.Google Scholar
Zander, M, Madsbad, S, Madsen, JL & Holst, JJ (2002) Effect of 6-week course of glucagon-like peptide-1 on glycemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet 359, 824–830.CrossRefGoogle Scholar