Absence of a Memory Effect for the Insulinotropic Action of Glucagon-like Peptide 1 (GLP-1) in Healthy Volunteers

S. Meier; K. Hücking; R. Ritzel; J. J. Holst; W. H. Schmiegel; M. A. Nauck

doi:10.1055/s-2003-42658

Hormone and Metabolic Research, Inhaltsverzeichnis

Horm Metab Res 2003; 35(9): 551-556
DOI: 10.1055/s-2003-42658

Original Clinical

Absence of a Memory Effect for the Insulinotropic Action of Glucagon-like Peptide 1 (GLP-1) in Healthy Volunteers

S. Meier¹ , K. Hücking¹ , R. Ritzel¹ , J. J. Holst² , W. H. Schmiegel¹ , M. A. Nauck^1, ³

¹Medizinische Universitäts-Klinik, Knappschafts-Krankenhaus Bochum, Klinikum der Ruhr-Universität Bochum, Germany
²Department of Medical Physiology, Panum Institute, University of Copenhagen, Denmark
³Diabeteszentrum Bad Lauterberg, Bad Lauterberg im Harz, Germany

Abstract

Background/Aims: The term memory effect refers to the phenomenon that B cell stimuli retain some of their insulinotropic effects after they have been removed. Memory effects exist for glucose and sulfonylureas. It is not known whether there is a B-cell memory for incretin hormones such as GLP-1. Subjects/Methods: Eight healthy young volunteers were studied on four occasions in the fasting state. In one experiment, placebo was administered (a), in three more experiments (random order), synthetic GLP-1 (7 - 36 amide) at 1.2 pmol/kg/min was administered over a period of three hours. At 0 min, a bolus of glucose was injected intravenously (0.33 g/kg body weight). GLP-1 was infused from (b) - 60 to 120 min, (c) - 210 to - 30 min, or (d) - 300 to - 120 min. Glucose (glucose oxidase), insulin, C-peptide, GLP-1, and glucagon (immunoassays) were determined. Statistical analysis was carried out by ANOVA and appropriate post hoc tests. Results: GLP-1 plasma levels during the infusion periods were elevated to 89 ± 9, 85 ± 13, and 89 ± 6 pmol/l (p < 0.0001 vs. placebo, 10 ± 1 pmol/l). Glucose was eliminated faster (p < 0.0001), with an enhanced negative rebound (p = 0.014), and insulin and C-peptide increments were greater after intravenous glucose administration (p < 0.0001) if GLP-1 was administered during the injection of the glucose bolus, but not if GLP-1 had been administered until 120 or 30 min before the glucose load. There was a trend towards higher insulin concentrations (p = 0.056) five minutes after glucose with GLP-1 administered until - 30 min before the glucose load. Glucagon was suppressed by exogenous glucose, but increased significantly (p = 0.013) during the induction of reactive hypoglycemia after glucose injection during GLP-1 administration. Conclusion: 1) No memory effect appears to exist for insulinotropic actions of GLP-1, in line with clinical data. 2) Reactive hypoglycemia causes a prompt rise in glucagon despite pharmacological circulating concentrations of GLP-1. 3) Similar studies should be performed in Type 2-diabetic patients, because exposure to GLP-1 might recruit dormant pancreatic B cells to become glucose-competent, and this might contribute to the overall antidiabetogenic effect of GLP-1 in such patients.

Key words

Incretin - Memory Effect - Priming Effect - Glucose Competence - Time-Dependent Activation

Volltext

Referenzen

References

1 Kreymann B, Williams G, Ghatei M A, Bloom S R. Glucagon-like peptide-1 [7-36]: a physiological incretin in man. Lancet. 1987; 2 1300-1304
2 Nauck M A, Bartels E, Ørskov C, Ebert R, Creutzfeldt W. Additive insulinotropic effects of exogenous synthetic human gastric inhibitory polypeptide and glucagon-like peptide-1-(7 - 36) amide infused at near-physiological insulinotropic hormone and glucose concentrations. J Clin Endocrinol Metab. 1993; 76 912-917
3 Layer P, Holst J J, Grandt D, Goebell H. Ileal release of glucagon-like peptide-1 (GLP-1). Association with inhibition of gastric acid secretion in humans. Dig Dis Sci. 1995; 40 1074-1082
4 Nauck M A. Is glucagon-like peptide 1 and incretin hormone?. Diabetologia. 1999; 42 373-379
5 Nauck M A, Heimesaat M M, Ørskov C, Holst J J, Ebert R, Creutzfeldt W. Preserved incretin activity of glucagon-like peptide 1 [7 - 36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest. 1993; 91 301-307
6 Nauck M A, Kleine N, Ørskov C, Holst J J, Willms B, Creutzfeldt W. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7 - 36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1993; 36 741-744
7 Wettergren A, Schjoldager B, Mortensen P E, Myhre J, Christiansen J, Holst J J. Truncated GLP-1 (proglucagon 78 - 107-amide) inhibits gastric and pancreatic functions in man. Dig Dis Sci. 1993; 38 665-673
8 Turton M D, O'Shea D, Gunn I, Beak S A, Edwards C M, Meeran K. et al . A role for glucagon-like peptide-1 in the central regulation of feeding. Nature. 1996; 379 69-72
9 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
10 Fehmann H-C, Habener J F. Insulinotropic hormone glucagon-like peptide-I(7 - 37) stimulation of proinsulin gene expression and proinsulin biosynthesis in insulinoma βTC-1 cells. Endocrinology. 1992; 130 159-166
11 Nauck M A. Glucagonlike peptide 1. Curr Opin Endocrinol Diabetes. 1997; 4 256-261
12 Nauck M A, Holst J J, Willms B, Schmiegel W. Glucagon-like peptide 1 (GLP-1) as a new therapeutic approach for Type 2-diabetes. Exp Clin Endocrinol Diabetes. 1997; 105 187-195
13 Deacon C F, Nauck M A, Toft-Nielsen M, Pridal L, Willms B, Host J J. Both subcutaneously and intravenously administered glucagon-like peptide 1 are rapidly degraded from the NH₂-terminus in type 2-diabetic patients and in healthy subjects. Diabetes. 1995; 44 1126-1131
14 Deacon C F, Pridal L, Klarskov L, Olesen M, Holst J J. Glucagon-like peptide 1 undergoes differential tissue-specific metabolism in the anesthetized pig. Am J Physiol (Endocrinol Metab). 1996; 271 E458-E464
15 Ritzel R, Ørskov C, Holst J J, Nauck M A. Pharmacokinetic, insulinotropic, and glucagonostatic properties of GLP-1 [7 - 36 amide] after subcutaneous injection in healthy volunteers. Dose-response-relationships. Diabetologia. 1995; 38 720-725
16 Nauck M A, Wollschläger D, Werner J, Holst J J, Ørskov C, Creutzfeld W. et al . Effects of subcutaneous glucagon-like peptide 1 (GLP-1 [7 - 36 amide]) in patients with NIDDM. Diabetologia. 1996; 39 1546-1553
17 Gutniak M K, Larsson H, Heiber S J, Juneskans O T, Holst J J, Åhren B. Potential therapeutic levels of glucagon-like peptide I achieved in humans by a buccal tablet. Diabetes Care. 1996; 19 843-848
18 Grill V. Time and dose-dependencies for priming effect of glucose on insulin secretion. Am J Physiol (Endocrinol Metab). 1981; 240 E24-31
19 Ashby J P, Shirling D. The priming effect of glucose on insulin secretion from isolated islets of Langerhans. Diabetologia. 1981; 21 230-234
20 Zawalich W S, Zawalich K C. Induction of memory in rat pancreatic islets by tolbutamide. Dependence on ambient glucose level, calcium and phosphoinositide hydrolysis. Diabetes. 1988; 37 816-823
21 Zawalich W S. Glyburide priming of beta cells. Possible involvement of phosphoinositide hydrolysis. Biochem Pharmacol. 1991; 41 807-813
22 Fehmann H C, Göke R, Göke B, Bachle R, Wagner B, Arnold R. Priming effect of glucagon-like peptide-1 (7 - 36) amide, glucose-dependent insulinotropic polypeptide and cholecystokinin-8 at the isolated perfused rat pancreas. Biochim Biophys Acta. 1991; 1091 356-363
23 Borg L A, Westberg M, Grill V. The priming effect of glucose on insulin release does not involve redistribution of secretory granules within the pancreatic B-cell. Mol Cell Endocrinol. 1988; 56 219-225
24 Niki I, Tamagawa T, Niki H, Niki A, Koide T, Sakamoto N. Possible involvement of diacylglycerol-activated, Ca²⁺-dependent protein kinase in glucose memory in the rat. Acta Endocrinol (Copenh). 1988; 118 204-208
25 N'Guyen J M, Magnan C, Laury M C, Thibault C, Leveteau J, Gilbert M. et al . Involvement of the autonomic nervous system in the in vivo memory to glucose of pancreatic beta cell in rats. J Clin Invest. 1994; 94 1456-1462
26 Todd J F, Wilding J P, Edwards C M, Khan F A, Ghatei M A, Bloom S R. Glucagon-like peptide-1 (GLP-1): a trial of treatment in non-insulin-dependent diabetes mellitus. Eur J Clin Invest. 1997; 27 533-536
27 Nauck M A, Meier S, Holst J J, Hücking K, Ritzel R, Schmiegel W. Lack of ‘memory effect' for insulinotropic action of glucagon-like peptide 1 (GLP-1) (abstract). Diabetes. 2000; 49 A227
28 Nauck M A, Niedereichholz U, Ettler R, Holst J J, Ørskov C, Ritzel R. et al . Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans. Am J Physiol. 1997; 273 E981-E988
29 Nauck M A, Weber I, Bach I, Richter S, Ørskov C, Holst JJ. et al . Normalization of fasting glycaemia by intravenous GLP-1 ([7 - 36 amide] or [7-37]) in Type 2-diabetic patients. Diabetic Med. 1998; 15 937-945
30 Holst J J. Evidence that peak II GLI or enteroglucagon is identical to the C-terminal sequence (residues 33 - 69) of glicentin. Biochem J. 1982; 207 381-388
31 Deacon C F, Johnsen A H, Holst J J. Degradation of glucagon-like peptide-1 by human plasma in vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo. J Clin Endocrinol Metab. 1995; 80 952-957
32 Grandt D, Sieburg B, Sievert J, Schimiczek M, Becker U, Holtmann D. Is GLP-1 (9 - 36)amide an endogenous antagonist at GLP-1 receptors? (abstract). Digestion. 1994; 55 302
33 Larsen J, Damsbo P. GLP-1 must be present continuously in order to obtain a good glycaemic control in NIDDM (abstract). Diabetes. 1997; 46 186A
34 Willms B, Idowu K, Holst J J, Creutzfeldt W, Nauck M A. Overnight GLP-1 normalizes fasting but not daytime plasma glucose values in NIDDM patients. Exptl Clin Edocrinol Diabetes. 1998; 106 103-107
35 Rachman J, Gribble F M, Levy J C, Turner R C. Near-normalization of diurnal glucose concentrations by continuous administration of glucagon-like peptide 1 (GLP-1) in subjects with NIDDM. Diabetologia. 1997; 40 205-211
36 Holz G G, Kuhtreiber W M, Habener J F. Pancreatic beta-cells are rendered glucose-competent by the insulinotropic hormone glucagon-like peptide-1(7 - 37). Nature. 1993; 361 362-365
37 Byrne M M, Brandt A, Arnold R, Katschinski M, Göke B. Glucose-insulin secretory dose-response curves during constant GLP-1 infusion and pretreatment with GLP-1 (abstract). Diabetologia. 1999; 42 A78
38 D'Alessio D, Kahn S E, Leusner C R, Ensinck J W. 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 2263-2266
39 Lugari R, Del'Anna C, Ugolotti D, Dei Cas A, Barilli A L, Zandomeneghi R. et al . Effect of nutrient ingestion on glucagon-like peptide 1 (7 - 36 amide) secretion in human Type 1 and Type 2 diabetes. Horm Metab Res. 2000; 32 424-428
40 Toft-Nielsen M B, Damholt M B, Madsbad S, Hilsted L M, Hughes T E, Michelsen B K. et al . Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J Clin Endocrinol Metab. 2001; 86 3717-23
41 Vilsboslashll T, Krarup T, Deacon C F, Madsbad S, Holst J J. Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes. 2001; 50 609-13
42 Nauck M A, Heimesaat M M, Behle K, Holst J J, Nauck M S, Ritzel R. et al . Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. J Clin Endocrinol Metab. 2002; 87 1239-1246

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