Horm Metab Res 2004; 36(2): 111-115
DOI: 10.1055/s-2004-814222
Original Clinical
© Georg Thieme Verlag Stuttgart · New York

Glucagon-like Peptide 1 (GLP-1) Secretion and Plasma Dipeptidyl Peptidase IV (DPP-IV) Activity in Morbidly Obese Patients Undergoing Biliopancreatic Diversion

R.  Lugari 1 , A.  Dei Cas 1 , D.  Ugolotti 1 , A.  L.  Barilli 1 , C.  Camellini 2 , G.  C.  Ganzerla 2 , A.  Luciani 2 , B.  Salerni 3 , F.  Mittenperger 3 , S.  Nodari 3 , A.  Gnudi 1 , R.  Zandomeneghi 2
  • 1Department of Endocrinology and Metabolism, University of Parma, Parma, Italy
  • 2Department of Internal Medicine, University of Modena, Modena, Italy
  • 3Department of Clinical Surgery, University of Brescia, Brescia, Italy
Further Information

Publication History

Received 11 March 2003

Accepted after second revision 30 July 2003

Publication Date:
05 March 2004 (online)

Abstract

Background: The physiological inhibitory control of glucagon-like Peptide 1 (GLP-1) on gastric emptying and the contribution of this peptide in the regulation of food intake as a satiety factor suggest that impaired secretion and/or activity of GLP-1 may be involved in the pathogenesis of obesity. We investigated food-mediated GLP-1 secretion as well as plasma activity of dipeptidyl-peptidase IV (DPP-IV), the enzyme responsible for rapid inactivation of the circulating peptide, in morbidly obese patients, before and after weight loss resulting from biliopancreatic diversion. Methods: Twenty-two morbidly obese non-diabetic patients (BMI = 47.5 ± 1.8) and 9 age-matched healthy volunteers were studied. A mixed meal (700 kcal) was administered to all subjects and blood samples were collected at 0, 15, 30, 60, 120 min for the determination of circulating glucose, insulin, GLP-1 (7 - 36 amide) concentrations and plasma DPP-IV activity. The patients repeated the test meal after 50 % overweight reduction resulting from surgical treatment (BMI = 33.8 ± 1.1). Results: While nutrient ingestion significantly increased plasma GLP-1 levels in the control group (30’, 60’: p < 0.01), the test-meal failed to modify basal peptide values in the obese patients, and an overall reduction in circulating GLP-1 occurred during the observation period (p < 0.001). Plasma DPP-IV activity in the same patients resulted as being significantly higher than controls, both at fasting and in response to the meal (p < 0.05). With respect to preoperative values, an overall increase in circulating GLP-1 levels occurred in all patients following biliopancreatic diversion (p < 0.001). Plasma DPP-IV activity, on the other hand, continued to be abnormally increased, even after considerable weight loss (p < 0.05 vs. controls). Conclusions: First: In morbid obesity, the accelerated inactivation of circulating GLP-1 could at least partially account for plasma peptide levels lower than normal, the defective availability of such a satiety factor possibly contributing to eating behaviour abnormalities; Second: plasma DPP-IV hyperactivity in the obese did not seem to be affected by the overweight degree, the increase in postoperative GLP-1 levels mainly resulting from hyperstimulation of GLP-1 secretory cells due to surgical manipulation of gastrointestinal tract. If the abnormally accelerated degradation of GLP-1 in obesity is confirmed, selective DPP-IV inhibitors could actually represent an ideal approach to obesity management.

References

  • 1 Flint A, Raben A, Astrup A, Holst J J. Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans.  J Clin Invest. 1998;  101 515-520
  • 2 Gutzwiller J P, Goke B, Drewe J, Hildebrand P, Ketterer S, Handschin D, Winterhalderr R, Conen D, Beglinger C. Glucagon-like peptide 1: a potent regulator of food intake in humans.  Gut. 1999;  44 81-86
  • 3 Lavin J H, Wittert G A, Andrews J, Jeap B, Wishart J M, Morris H A, Morley J E, Horowitz M, Read N W. Interaction of insulin, glucagon-like peptide 1, gastric inhibitory polypeptide, and appetite in response to intraduodenal carbohydrate.  Am J Clin Nutr. 1998;  68 591-598
  • 4 Tang-Christensen M, Larsen P J, Goke R, Fink-Jensen A, Jessop D S, Molker M, Sheikh S P. Central administration of GLP-1 (7 - 36 amide) inhibits food and water intake in rats.  Am J Physiol. 1996;  271 R848-R856
  • 5 Turton M D, O’Shea D, Gunn I, Beak S A, Edwards C M, Meeran K, Choi S J, Taylor G M, Heath M M, Lambert P D, Wilding J P, Smith D M, Ghatei M A, Herbert J, Bloom S R. A role for glucagon-like peptide 1 in the central regulation of feeding.  Nature. 1996;  379 69-72
  • 6 Meeran K, O’Shea D, Edwards C M, Turton M D, Heath M M, Gunn I, Abusnana S, Rossi M, Small C J, Goldstone A P, Taylor G M, Sunter D, Steere J, Choi S J, Ghatei M A, Bloom S R. Repeated intracerebroventricular administration of glucagon-like peptide 1 (7 - 36) amide or exendin (9 - 39) alters body weight in the rat.  Endocrinology. 1999;  140 (1) 244-250
  • 7 Verdich C, Flint A, Gutzwiller J P, Naslund E, Berlinger C, Hellstrom P M, Long S J, Morgan L M, Holst J J, Astrup A. A meta-analysis of the effect of Glucagon-like Peptide 1 (7 - 36) amide on ad libitum energy intake in humans.  J Clin Endocrinol Metab. 2001;  86 4382-4389
  • 8 Tomasik P J, Sztefko K, Malek A. GLP-1 as a satiety factor in children with eating disorders.  Horm Met Res. 2002;  34 77-80
  • 9 Naslund E, Gryback P, Backman L. et al . Distal small bowel hormones: correlation with fasting antroduodenal motility and gastric emptying.  Dig Dis Sci. 1998;  43 945-952
  • 10 Ranganath L R, Beety J M, Morgan L M, Wright J W, Howland R, Marks W. Attenuated GLP-1 secretion in obesity: cause or consequence?.  Gut. 1996;  38 916-919
  • 11 Ranganath L, Norris F, Morgan L, Wright J, Marks W. Inhibition of carbohydrate-mediated glucagon-like peptide 1 (7 - 36 amide) secretion by circulating non-estrified fatty acids.  Clin Sci. 1999;  96 335-342
  • 12 Verdich C, Toubro S, Buemann B, Madsen J L, Holst J J, Astrup A. The role of postprandial releases of insulin and incretin hormones in meal-induced satiety: effect of obesity and weight reduction.  Int J Obes. 2001;  25 (8) 1206-1214
  • 13 Ranganath L, Beety J M, Wright J, Morgan L. Nutrient regulation of post-heparin lipoprotein lipase activity in obese subjects.  Horm Metab Res. 2001;  33 57-61
  • 14 Deacon C F, Johnsen A H, Holst J J. Degradation of glucagon-like peptide 1 by human plasma in vitro yelds N-terminally truncated peptide that is a major endogenous metabolite in vivo.  J Clin Endocrinol Merab. 1995;  80 (3) 952-957
  • 15 Kieffer T J, McIntosh C HS, Pederson R A. Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV.  Endocrinology. 1995;  136 (8) 3585-3596
  • 16 Mentlein R, Gallwitz B, Schmidt W E. 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. 1993;  214 829-835
  • 17 Scopinaro N, Gianetta E, Civalleri D, Bonaluni U, Bachi V. Two years of clinical experience with biliopancreatic bypass for obesity.  Am J Clin Nutr. 1980;  33 506-514
  • 18 Bonora E, Targher G, Alberiche M, Bonadonna R C, Saggiani F, Zenere M B, Monauni T, Muggeo M. Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity.  Diabetes Care. 2000;  23 57-63
  • 19 Rakoczi G, Takacs L, Jakabfi P, Kunos I, Selmeci L, Gyuris T, Peterfly M, Verebely T, Perner F. Increased urinary dipeptidyl peptidase IV activity in extrahepatic biliary atresia.  Lancet Apr 1. 1995;  345 (8953) 864-865
  • 20 Mason E E. Ilial transposition and enteroglucagon/GLP-1 in obesity (and diabetic?) surgery.  Obesity Surgery. 1999;  9 223-228
  • 21 Naito H, Sasaki I, Matsuno S. Surgical aspect of enteroinsular axis after gastrointestinal surgery with reference to incretin secretion.  Pancreas. 1998;  16 (3) 370-378
  • 22 Naslund E, Gutniak M, Skogar S, Rosner S, Hellstrom P M. Glucagon-like peptide 1 increases the period of postprandial satiety and slows gastric emptying in obese man.  Am J Clin Nutr. 1998;  68 525-530
  • 23 Naslund E, Barkeling B, King N, Gutniak M, Blundell J E, Rossner S, Hellstrom P M. Energy intake and appetite is suppressed by glucagon-like peptide 1 (GLP-1) in obese men.  Int J Obes Relat Metab Disord. 1999;  23 304-311
  • 24 Flint A, Raben A, Ersboll A K, Holst J J, Astrup A. The effect of physiological levels of glucagon-like peptide 1 on appetite, gastric emptying, energy and substrate metabolism in obesity.  Int J Obes. 2001;  25 (6) 781-792
  • 25 Willms B, Werner J, Holst J J, Orskov C, Creutzfeldt W, Nauck M A. Gastric emptying, glucose responses, and insulin secretion after a liquid test meal: effects of exogenous glucagon-like peptide 1 (GLP-1)-(7 - 36 amide) in type 2 (non insulin-dependent) diabetes.  J Clin Endocrinol Metab. 1996;  81 327-332

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