|
 |
|
|||||||
|
|||||||||
© 2001 by the American Diabetes Association, Inc.
Systemic Administration of the Long-Acting GLP-1 Derivative NN2211 Induces Lasting and Reversible Weight Loss in Both Normal and Obese Rats
1 Laboratory of Obesity Research, Center for Clinical and Basic Research, Ballerup, Denmark
2 Neuroendocrine Pharmacology
3 Pharmacological Research 2, and
4 Molecular Pharmacology, Novo Nordisk A/S, Copenhagen, Denmark
Postprandial release of the incretin glucagon-like peptide-1 (GLP-1) has been suggested to act as an endogenous satiety factor in humans. In rats, however, the evidence for this is equivocal probably because of very high endogenous activity of the GLP-1 degrading enzyme dipeptidyl peptidase-IV. In the present study, we show that intravenously administered GLP-1 (100 and 500 µg/kg) decreases food intake for 60 min in hungry rats. This effect is pharmacologically specific as it is inhibited by previous administration of 100 µg/kg exendin(9-39), and biologically inactive GLP-1(1-37) had no effect on food intake when administered alone (500 µg/kg). Acute intravenous administration of GLP-1 also caused dose-dependent inhibition of water intake, and this effect was equally well abolished by previous administration of exendin(9-39). A profound increase in diuresis was observed after intravenous administration of both 100 and 500 µg/kg GLP-1. Using a novel long-acting injectable GLP-1 derivative, NN2211, the acute and subchronic anorectic potentials of GLP-1 and derivatives were studied in both normal rats and rats made obese by neonatal monosodium glutamate treatment (MSG). We showed previously that MSG-treated animals are insensitive to the anorectic effects of centrally administered GLP-1(7-37). Both normal and MSG-lesioned rats were randomly assigned to groups to receive NN2211 or vehicle. A single bolus injection of NN2211 caused profound dose-dependent inhibition of overnight food and water intake and increased diuresis in both normal and MSG-treated rats. Subchronic multiple dosing of NN2211 (200 µg/kg) twice daily for 10 days to normal and MSG-treated rats caused profound inhibition of food intake. The marked decrease in food intake was accompanied by reduced body weight in both groups, which at its lowest stabilized at 
85% of initial body weight. Initial excursions in water intake and diuresis were transient as they were normalized within a few days of treatment. Lowered plasma levels of triglycerides and leptin were observed during NN2211 treatment in both normal and MSG-treated obese rats. In a subsequent study, a 7-day NN2211 treatment period of normal rats ended with measurement of energy expenditure (EE) and body composition determined by indirect calorimetry and dual energy X-ray absorptiometry, respectively. Compared with vehicle-treated rats, NN2211 and pair-fed rats decreased their total EE corresponding to the observed weight loss, such that EE per weight unit of lean body mass was unaffected. Despite its initial impact on body fluid balance, NN2211 had no debilitating effects on body water homeostasis as confirmed by analysis of body composition, plasma electrolytes, and hematocrit. This is in contrast to pair-fed animals, which displayed hemoconcentration and tendency toward increased percentage of fat mass. The present series of experiments show that GLP-1 is fully capable of inhibiting food intake in rats via a peripherally accessible site. The loss in body weight is accompanied by decreased levels of circulating leptin indicative of loss of body fat. The profound weight loss caused by NN2211 treatment was without detrimental effects on body water homeostasis. Thus, long-acting GLP-1 derivatives may prove efficient as weight-reducing therapeutic agents for overweight patients with type 2 diabetes.
CiteULike 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  A. D. Strader, H. Shi, R. Ogawa, R. J. Seeley, and O. Reizes The Effects of the Melanocortin Agonist (MT-II) on Subcutaneous and Visceral Adipose Tissue in Rodents J. Pharmacol. Exp. Ther., September 1, 2007; 322(3): 1153 - 1161. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Tang-Christensen and M. A. Cowley GLP-1 analogs: satiety without malaise? Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2007; 293(3): R981 - R982. [Full Text] [PDF]
|
|
|
|
 |
|
 D. Chen, J. Liao, N. Li, C. Zhou, Q. Liu, G. Wang, R. Zhang, S. Zhang, L. Lin, K. Chen, et al. From the Cover: A nonpeptidic agonist of glucagon-like peptide 1 receptors with efficacy in diabetic db/db mice PNAS, January 16, 2007; 104(3): 943 - 948. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Raun, P. von Voss, C. F. Gotfredsen, V. Golozoubova, B. Rolin, and L. B. Knudsen Liraglutide, a Long-Acting Glucagon-Like Peptide-1 Analog, Reduces Body Weight and Food Intake in Obese Candy-Fed Rats, Whereas a Dipeptidyl Peptidase-IV Inhibitor, Vildagliptin, Does Not Diabetes, January 1, 2007; 56(1): 8 - 15. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. O. Boylan, L. I. Jepeal, and M. M. Wolfe Sp1/Sp3 binding is associated with cell-specific expression of the glucose-dependent insulinotropic polypeptide receptor gene Am J Physiol Endocrinol Metab, June 1, 2006; 290(6): E1287 - E1295. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Talsania, Y. Anini, S. Siu, D. J. Drucker, and P. L. Brubaker Peripheral Exendin-4 and Peptide YY3-36 Synergistically Reduce Food Intake through Different Mechanisms in Mice Endocrinology, September 1, 2005; 146(9): 3748 - 3756. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. K. Chelikani, A. C. Haver, and R. D. Reidelberger Intravenous infusion of glucagon-like peptide-1 potently inhibits food intake, sham feeding, and gastric emptying in rats Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2005; 288(6): R1695 - R1706. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B D Green, N Irwin, V A Gault, C J Bailey, F P M O'Harte, and P R Flatt Chronic treatment with exendin(9-39)amide indicates a minor role for endogenous glucagon-like peptide-1 in metabolic abnormalities of obesity-related diabetes in ob/ob mice J. Endocrinol., May 1, 2005; 185(2): 307 - 317. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. K. Badman and J. S. Flier The Gut and Energy Balance: Visceral Allies in the Obesity Wars Science, March 25, 2005; 307(5717): 1909 - 1914. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G Uckaya, P Delagrange, A Chavanieu, G Grassy, M-F Berthault, A Ktorza, E Cerasi, G Leibowitz, and N Kaiser Improvement of metabolic state in an animal model of nutrition-dependent type 2 diabetes following treatment with S 23521, a new glucagon-like peptide 1 (GLP-1) analogue J. Endocrinol., March 1, 2005; 184(3): 505 - 513. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. V Joy, P. T Rodgers, and A. C Scates Incretin Mimetics as Emerging Treatments for Type 2 Diabetes Ann. Pharmacother., January 1, 2005; 39(1): 110 - 118. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Holst and C. Orskov The Incretin Approach for Diabetes Treatment: Modulation of Islet Hormone Release by GLP-1 Agonism Diabetes, December 1, 2004; 53(suppl_3): S197 - S204. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. L. Baggio, Q. Huang, T. J. Brown, and D. J. Drucker A Recombinant Human Glucagon-Like Peptide (GLP)-1-Albumin Protein (Albugon) Mimics Peptidergic Activation of GLP-1 Receptor-Dependent Pathways Coupled With Satiety, Gastrointestinal Motility, and Glucose Homeostasis Diabetes, September 1, 2004; 53(9): 2492 - 2500. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Zander, A. Christiansen, S. Madsbad, and J. Juul Holst Additive Effects of Glucagon-Like Peptide 1 and Pioglitazone in Patients With Type 2 Diabetes Diabetes Care, August 1, 2004; 27(8): 1910 - 1914. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Harder, L. Nielsen, T. D.T. Thi, and A. Astrup The Effect of Liraglutide, a Long-Acting Glucagon-Like Peptide 1 Derivative, on Glycemic Control, Body Composition, and 24-h Energy Expenditure in Patients With Type 2 Diabetes Diabetes Care, August 1, 2004; 27(8): 1915 - 1921. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C M. B Edwards GLP-1: target for a new class of antidiabetic agents? J R Soc Med, June 1, 2004; 97(6): 270 - 274. [Full Text] [PDF]
|
|
|
|
|
|
C. L. Dakin, C. J. Small, R. L. Batterham, N. M. Neary, M. A. Cohen, M. Patterson, M. A. Ghatei, and S. R. Bloom Peripheral Oxyntomodulin Reduces Food Intake and Body Weight Gain in Rats Endocrinology, June 1, 2004; 145(6): 2687 - 2695. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. C. Woods Gastrointestinal Satiety Signals I. An overview of gastrointestinal signals that influence food intake Am J Physiol Gastrointest Liver Physiol, January 1, 2004; 286(1): G7 - G13. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Drucker Enhancing Incretin Action for the Treatment of Type 2 Diabetes Diabetes Care, October 1, 2003; 26(10): 2929 - 2940. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Vrang, C. B. Phifer, M. M. Corkern, and H.-R. Berthoud Gastric distension induces c-Fos in medullary GLP-1/2-containing neurons Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2003; 285(2): R470 - R478. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-G. Kim, L. L. Baggio, D. P. Bridon, J.-P. Castaigne, M. F. Robitaille, L. Jette, C. Benquet, and D. J. Drucker Development and Characterization of a Glucagon-Like Peptide 1-Albumin Conjugate: The Ability to Activate the Glucagon-Like Peptide 1 Receptor In Vivo Diabetes, March 1, 2003; 52(3): 751 - 759. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Rolin, M. O. Larsen, C. F. Gotfredsen, C. F. Deacon, R. D. Carr, M. Wilken, and L. B. Knudsen The long-acting GLP-1 derivative NN2211 ameliorates glycemia and increases beta -cell mass in diabetic mice Am J Physiol Endocrinol Metab, October 1, 2002; 283(4): E745 - E752. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Diabetes | Diabetes Care | Clinical Diabetes | Diabetes Spectrum |