ROBERT RITZEL, MICHAEL HU¨ FNER, AND WOLFF H. SCHMIEGEL. Medizinische ...... Beak SA, Heath MM, Small CJ, Morgan DGA, Ghatei MA, Taylor AD, ... Tang-Christensen M, Larsen PJ, Göke R, Fink Jensen A, Jessop DS, Møller.
0013-7227/02/$15.00/0 Printed in U.S.A.
The Journal of Clinical Endocrinology & Metabolism 87(3):1239 –1246 Copyright © 2002 by The Endocrine Society
Effects of Glucagon-Like Peptide 1 on Counterregulatory Hormone Responses, Cognitive Functions, and Insulin Secretion during Hyperinsulinemic, Stepped Hypoglycemic Clamp Experiments in Healthy Volunteers MICHAEL A. NAUCK, MARKUS M. HEIMESAAT, KAI BEHLE, JENS J. HOLST, MARKUS S. NAUCK, ¨ FNER, AND WOLFF H. SCHMIEGEL ROBERT RITZEL, MICHAEL HU Medizinische Universita¨ts-Klinik (M.A.N., M.M.H., K.B., R.R., W.H.S.), Knappschafts-Krankenhaus Bochum, Klinikum der Ruhr-Universita¨t Bochum, D-44892 Bochum, Germany; Department of Medical Physiology (J.J.H.), Panum Institute, University of Copenhagen, DK-2200 Copenhagen N, Denmark; Department of Clinical Chemistry (M.S.N.), Central Laboratory, University Hospital Freiburg, D-79106 Freiburg, Germany; and Division of Endocrinology (M.H.), Department of Medicine, Georg-August-Universita¨t, D-37075 Go¨ttingen, Germany Glucagon-like peptide 1 (GLP-1) and analogues are being evaluated as a new therapeutic principle for the treatment of type 2 diabetes. GLP-1 suppresses glucagon secretion, which could lead to disturbances of hypoglycemia counterregulation. This has, however, not been tested. Nine healthy volunteers with normal oral glucose tolerance received infusions of regular insulin (1 mU䡠kgⴚ1䡠minⴚ1) over 360 min on two occasions in the fasting state. Capillary glucose concentrations were clamped at plateaus of 4.3, 3.7, 3.0, and 2.3 mmol/liter for 90 min each (stepwise hypoglycemic clamp); on one occasion, GLP-1 (1.2 pmol䡠kgⴚ1䡠minⴚ1) was administered iv (steady-state concentration, ⬃125 pmol/liter); on the other occasion, NaCl was administered as placebo. Glucagon, cortisol, GH (immunoassays), and catecholamines (radioenzymatic assay) were determined, autonomous and neuroglucopenic symptoms were assessed, and cognitive function was tested at each plateau. Insulin secretion rates were estimated by deconvolution (two-compartment model of Cpeptide kinetics). At insulin concentrations of approximately 45 mU/liter, glucose infusion rates were similar with and without GLP-1
I
NSULIN SECRETION AFTER meals is stimulated not only by the rise in glycemia after glucose absorption but also by the secretion and insulinotropic action of gut hormones with incretin activity (1, 2). The main candidates for the incretin role are gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) (3–5). Together, they account for approximately half of the insulin increment after oral glucose (4). GLP-1 has received special attention, because an iv infusion of this gut hormone is able to lower plasma glucose in type 2 diabetic patients into the normal range (6, 7). Based on this finding, the concept has emerged that GLP-1 or analogues may have a definite therapeutic potential (8 –10), based on the ability of GLP-1 to stimulate insulin secretion (3, 4, 11, 12), suppress glucagon concentrations (13, 14), and decelerate gastric emptying (15, 16). Given the facts that the reduction in glucagon concen-
Abbreviations: GIP, Gastric inhibitory polypeptide; GLP-1, glucagonlike peptide 1.
(P ⴝ 0.26). Only during the euglycemic plateau (4.3 mmol/ liter), GLP-1 suppressed glucagon concentrations (4.1 ⴞ 0.4 vs. 6.5 ⴞ 0.7 pmol/liter; P ⴝ 0.012); at all hypoglycemic plateaus, glucagon increased similarly with GLP-1 or placebo, to maximum values greater than 20 pmol/liter (P ⴝ 0.97). The other counterregulatory hormones and autonomic or neuroglucopenic symptom scores increased, and cognitive functions decreased with decreasing glucose concentrations, but there were no significant differences comparing experiments with GLP-1 or placebo, except for a significant reduction of GH responses during hypoglycemia with GLP-1 (P ⴝ 0.04). GLP-1 stimulated insulin secretion only at plasma glucose concentrations of at least 4.3 mmol/liter. In conclusion, the suppression of glucagon by GLP-1 does occur at euglycemia, but not at hypoglycemic plasma glucose concentrations (
