System-level control to optimize glucagon counterregulation by switch-off of α-cell suppressing signals in β-cell deficiency

Abstract

Background: Glucagon counterregulation (GCR) is a key protection against hypoglycemia that is compromised in diabetes. In β-cell-deficient rats, GCR pulsatility can be amplified if insulin (INS) or somatostatin (SS) are infused in the pancreatic artery and then switched off during hypoglycemia. The data indicate that these signals act by different mechanisms, and here we analyze the differences between the two switch offs (SOs) and predict the GCR-amplifying effect of their individual or combined application.

Methods: A minimal control network (MCN) of α/δ-cell interactions is approximated by differential equations to explain the GCR response to a SO and test in silico the hypotheses: (i) INS SO suppresses basal and pulsatile, while SS SO blocks only pulsatile glucagon release and (ii) simultaneous application of the two switch offs will augment the individual GCR response.

Results: The mechanism postulated in (i) explains the differences in the GCR responses between the SOs. The MCN predicts that simultaneous application of INS and SS decreases basal glucagon but increases post-SO amplitude, thus doubling the response of GCR achieved by each of the individual signals.

Conclusion: The current analyses predict that INS and SS SOs improve defective GCR in β-cell deficiency through different but complementary mechanisms and suggest SO strategies to maximally enhance GCR in type 1 diabetes by simultaneous manipulation of the network control. These results are clinically relevant, as they could have application to design of an artificial pancreas by providing ways to augment GCR that would not require glucagon infusion.

Keywords: counterregulation; feedback; glucagon; hypoglycemia; intrapancreatic network; mathematical model.

Figure 3.

Model-predicted GCR response to glucose decline and an intrapancreatic infusion of INS that has been switched off (top) or not switched off (bottom) during hypoglycemia. Glucagon is shown by the lower black line; endogenous SS is shown by the upper black line; INS infusion is represented by a densely dotted line; and BG is shown by a sparsely dotted line.

Figure 1.

Minimal intrapancreatic regulation of GCR by SO signals in β-cell deficiency.

Figure 2.

Model-predicted lack of glucagon response to glucose decline alone in β-cell deficiency. Glucagon is shown by the lower black line; endogenous SS is shown by the upper black line; and BG is shown by a sparsely dotted line.

Figure 4.

Model-predicted GCR response to glucose decline and an intrapancreatic infusion of SS that has been switched off (top) or not switched off (bottom) during hypoglycemia. Glucagon is shown by the lower black line; endogenous SS is shown by the upper black line; exogenous SS infusion is shown by a dashed line; and BG is shown by a sparsely dotted line.

Figure 5.

Model-predicted GCR response to glucose decline (top) or lack of decline (bottom) and a combined INS and SS SO. Glucagon is shown by the lower black line; endogenous SS is shown by the upper black line; INS infusion is represented by a densely dotted line; exogenous SS infusion is shown by a dashed line; and BG is shown by a sparsely dotted line.

Figure 6.

Model-predicted GCR response to glucose decline (top) or lack of decline (bottom) and a combined INS and SS intrapancreatic infusion in which SS but not INS has been switched off during hypoglycemia. Glucagon is shown by the lower black line; endogenous SS is shown by the upper black line; INS infusion is represented by a densely dotted line; exogenous SS infusion is shown by a dashed line; and BG is shown by a sparsely dotted line.

Figure 7.

Model-predicted suppression of GCR response to glucose decline and a combined INS and SS intrapancreatic infusion in which INS but not SS has been switched off (top) or both have not been switched off (bottom) during hypoglycemia. Glucagon is shown by the lower black line; endogenous SS is shown by the upper black line; INS infusion is represented by a densely dotted line; exogenous SS infusion is shown by a dashed line; and BG is shown by a sparsely dotted line.

Figure 8.

Summary of the model-predicted GCR responses to different SO signals with or without simulated hypoglycemia. The term no SO means the signal was not switched off.