Original Research ARTICLE
Association of basal hyperglucagonemia with impaired glucagon counterregulation in type 1 diabetes
- 1 Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia, Charlottesville, VA, USA
- 2 Center for Diabetes Technology, University of Virginia, Charlottesville, VA, USA
Glucagon counterregulation (GCR) protects against hypoglycemia, but is impaired in type 1 diabetes (T1DM). A model-based analysis of in vivo animal data predicts that the GCR defects are linked to basal hyperglucagonemia. To test this hypothesis we studied the relationship between basal glucagon (BasG) and the GCR response to hypoglycemia in 29 hyperinsulinemic clamps in T1DM patients. Glucose levels were stabilized in euglycemia and then steadily lowered to 50 mg/dL. Glucagon was measured before induction of hypoglycemia and at 10 min intervals after glucose reached levels below 70 mg/dL. GCR was assessed by CumG, the cumulative glucagon levels above basal; MaxG, the maximum glucagon response; and RIG, the relative increase in glucagon over basal. Analysis of the results was performed with our mathematical model of GCR. The model describes interactions between islet peptides and glucose, reproduces the normal GCR axis and its impairment in diabetes. It was used to identify a control mechanism consistent with the observed link between BasG and GCR. Analysis of the clinical data showed that higher BasG was associated with lower GCR response. In particular, CumG and RIG correlated negatively with BasG (r = −0.46, p = 0.012 and r = −0.74, p < 0.0001 respectively) and MaxG increased linearly with BasG at a rate less than unity (p < 0.001). Consistent with these results was a model of GCR in which the secretion of glucagon has two components. The first is under (auto) feedback control and drives a pulsatile GCR and the second is feedback independent (basal secretion) and its increase suppresses the GCR. Our simulations showed that this model explains the observed relationships between BasG and GCR during a three-fold simulated increase in BasG. Our findings support the hypothesis that basal hyperglucagonemia contributes to the GCR impairment in T1DM and show that the predictive power of our GCR animal model applies to human pathophysiology in T1DM.
Keywords: glucagon, counterregulation, diabetes mellitus, hyperglucagonemia, feedback, hypoglycemia, intrapancreatic network, mathematical model
Citation: Farhy LS, Chan A, Breton MD, Anderson SM, Kovatchev BP and McCall AL (2012) Association of basal hyperglucagonemia with impaired glucagon counterregulation in type 1 diabetes. Front. Physio. 3:40. doi: 10.3389/fphys.2012.00040
Received: 16 January 2012;
Accepted: 12 February 2012;
Published online: 28 February 2012.
Edited by:Michael L. Johnson, University of Virginia, USA
Reviewed by:Scott H. Harrison, North Carolina A&T State University, USA
Sudhir Chowbina, SAIC-Frederick, USA
Copyright: © 2012 Farhy, Chan, Breton, Anderson, Kovatchev and McCall. This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License, which permits non-commercial use, distribution, and reproduction in other forums, provided the original authors and source are credited.
*Correspondence: Leon S. Farhy, Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA. e-mail: firstname.lastname@example.org
†Leon S. Farhy and Alice Chan have contributed equally to this work.