Abstract
Glucagon counterregulation (GCR) is a key protection against hypoglycemia compromised in insulinopenic diabetes by an unknown mechanism. In this work, we present an interdisciplinary approach to the analysis of the GCR control mechanisms. Our results indicate that a pancreatic network which unifies a few explicit interactions between the major islet peptides and blood glucose (BG) can replicate the normal GCR axis and explain its impairment in diabetes. A key and novel component of this network is an alpha-cell auto-feedback, which drives glucagon pulsatility and mediates triggering of pulsatile GCR by hypoglycemia via a switch-off of the beta-cell suppression of the alpha-cells. We have performed simulations based on our models of the endocrine pancreas which explain the in vivo GCR response to hypoglycemia of the normal pancreas and the enhancement of defective pulsatile GCR in beta-cell deficiency by switch-off of intrapancreatic alpha-cell suppressing signals. The models also predicted that reduced insulin secretion decreases and delays the GCR. In conclusion, based on experimental data we have developed and validated a model of the normal GCR control mechanisms and their dysregulation in insulin deficient diabetes. One advantage of this construct is that all model components are clinically measurable, thereby permitting its transfer, validation, and application to the study of the GCR abnormalities of the human endocrine pancreas in vivo.