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Effects of Glucagon-Like Peptide 1 on Counterregulatory Hormone Responses, Cognitive Functions, and Insulin Secretion during Hyperinsulinemic, Stepped Hypoglycemic Clamp Experiments in Healthy Volunteers

Medizinische Universitäts-Klinik (M.A.N., M.M.H., K.B., R.R., W.H.S.), Knappschafts-Krankenhaus Bochum, Klinikum der Ruhr-Universität 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-Universität, D-37075 Göttingen, Germany

Address all correspondence and requests for reprints to: Dr. Michael Nauck, Diabeteszentrum Bad Lauterberg, Kirchberg 21, D-37431 Bad Lauterberg, Germany. E-mail: . M.Nauck{at}diabeteszentrum.de

Abstract

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·kg^-1·min^-1) 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·kg^-1·min^-1) 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 C-peptide kinetics).

At insulin concentrations of approximately 45 mU/liter, glucose infusion rates were similar with and without GLP-1 (P = 0.26). Only during the euglycemic plateau (4.3 mmol/liter), GLP-1 suppressed glucagon concentrations (4.1 ± 0.4 vs. 6.5 ± 0.7 pmol/liter; P = 0.012); at all hypoglycemic plateaus, glucagon increased similarly with GLP-1 or placebo, to maximum values greater than 20 pmol/liter (P = 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 = 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 (3.7 mmol/liter). GLP-1 does not impair overall hypoglycemia counterregulation except for a reduction in GH responses, which is in line with other findings demonstrating pituitary actions of GLP-1. Below plasma glucose concentrations of 4.3 mmol/liter, the insulinotropic action of GLP-1 is negligible.

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