Learning theories reveal loss of pancreatic electrical connectivity in diabetes as an adaptive response

TL;DR

This paper models pancreatic beta-cell gap junctions as adaptive, learning systems, revealing that heterogeneity in junction strength explains changes in insulin secretion in diabetes.

Contribution

It introduces a novel learning theory model of gap junction adaptation in pancreatic islets, explaining systematic changes in connectivity in diabetes.

Findings

Heterogeneity in gap junctions is essential for islet function.

Loss of junction conductance can increase insulin secretion in hyperglycemia.

Adaptive plasticity of gap junctions explains diabetes-related connectivity changes.

Abstract

Cells of almost all solid tissues are connected with gap junctions which permit the direct transfer of ions and small molecules, integral to regulating coordinated function in the tissue. The pancreatic islets of Langerhans are responsible for secreting the hormone insulin in response to glucose stimulation. Gap junctions are the only electrical contacts between the beta-cells in the tissue of these excitable islets. It is generally believed that they are responsible for synchrony of the membrane voltage oscillations among beta-cells, and thereby pulsatility of insulin secretion. Most attempts to understand connectivity in islets are often interpreted, bottom-up, in terms of measurements of gap junctional conductance. This does not, however explain systematic changes, such as a diminished junctional conductance in type 2 diabetes. We attempt to address this deficit via the model presented here, which is a learning theory of gap junctional adaptation derived with analogy to neural systems. Here, gap junctions are modelled as bonds in a beta-cell network, that are altered according to homeostatic rules of plasticity. Our analysis reveals that it is nearly impossible to view gap junctions as homogeneous across a tissue. A modified view that accommodates heterogeneity of junction strengths in the islet can explain why, for example, a loss of gap junction conductance in diabetes is necessary for an increase in plasma insulin levels following hyperglycemia.