Association of basal hyperglucagonemia with impaired glucagon counterregulation in type 1 diabetes

Abstract

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 inT1DM patients. Glucose levels were stabilized in euglycemia and then steadily lowered to 50mg/dL. Glucagon was measured before induction of hypoglycemia and at 10min intervals after glucose reached levels below 70mg/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 inT1DM and show that the predictive power of our GCR animal model applies to human pathophysiology inT1 DM. © 2012 Farhy, Chan, Breton, Anderson, Kovatchev andMcCall. © 2012 Farhy, Chan, Breton, Anderson, Kovatchev andMcCall.