Rates of glucagon activation and deactivation of hepatic glucose production in conscious dogs

Dobbins, Robert L.; Davis, Stephen N.; Neal, Doss; Caumo, Andrea; Cobelli, Claudio; Cherrington, Alan D.

« Previous Next »Metabolism - Clinical and Experimental
Volume 47, Issue 2 , Pages 135-142, February 1998

Rates of glucagon activation and deactivation of hepatic glucose production in conscious dogs☆

Robert L. Dobbins
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
- Scientific Institute, San Raffaele, Milano, Italy
- Department of Electronics and Informatics, University of Padua, Padua, Italy
Stephen N. Davis
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
- Scientific Institute, San Raffaele, Milano, Italy
- Department of Electronics and Informatics, University of Padua, Padua, Italy
Doss Neal
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
- Scientific Institute, San Raffaele, Milano, Italy
- Department of Electronics and Informatics, University of Padua, Padua, Italy
Andrea Caumo
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
- Scientific Institute, San Raffaele, Milano, Italy
- Department of Electronics and Informatics, University of Padua, Padua, Italy
Claudio Cobelli
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
- Scientific Institute, San Raffaele, Milano, Italy
- Department of Electronics and Informatics, University of Padua, Padua, Italy
Alan D. Cherrington
- Address reprint requests to Alan D. Cherrington, PhD, Vanderbilt University Medical School, Molecular Physiology and Biophysics, 710 Med Res Bldg I, Nashville, TN 37232-0615.
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
- Scientific Institute, San Raffaele, Milano, Italy
- Department of Electronics and Informatics, University of Padua, Padua, Italy

Received 26 October 1996; accepted 21 August 1997.

Abstract

To determine the time course of glucagon activation and deactivation of hepatic glucose production (HGP), studies were conducted in 18-hour fasted, conscious dogs. Somatostatin was infused with insulin replaced intraportally at 1.8 pmol · kg⁻¹ · min⁻¹ and glucagon replaced peripherally at 1.0 ng · kg⁻¹ · min⁻¹. After a 2-hour control period, glucagon infusion was either (1) increased fourfold for 4 hours (GGN 4X), (2) increased fourfold for 30 minutes and returned to a basal rate for 3.5 hours (GGN ), or (3) fixed at the basal rate for 4 hours (GGN 1X). In the latter two protocols, glucose was infused peripherally to match glucose concentrations observed during GGN 4X. Glucose turnover was determined by deconvolution with the impulse response of the glucose system described by a two-compartment, time-varying model identified from high-performance liquid chromatography (HPLC)-purified [3-³H]glucose tracer data. In GGN 4X, HGP was stimulated from 15.2 ± 0.9 μmol · kg⁻¹ · min⁻¹ to 52.7 ± 6.5 μmol · kg⁻¹ · min⁻¹ after just 15 minutes, but it decreased over the subsequent 3 hours to a rate 25% above basal. In GGN , the increase in HGP during the first 30 minutes equaled that observed in GGN 4X, but when glucagon infusion was returned to basal, HGP decreased in 15 minutes to rates equal to those observed in GGN 1X. The times for half-maximal activation and deactivation of glucagon action were equal (4.5 ± 1.0 and 4.0 ± 1.1 minutes, respectively). The very rapid and sensitive hepatic response to glucagon makes pancreatic glucagon release a key component of minute-to-minute glucose homeostasis.