Abstract
Diabetes is caused by dysfunction to β-cells in the islets of Langerhans, disrupting insulin secretion and glucose homeostasis. Gap junction-mediated electrical coupling between β-cells in the islet plays a major role in coordinating a pulsatile secretory response at elevated glucose and suppressing insulin secretion at basal glucose. Previously, we demonstrated that a critical number of inexcitable cells can rapidly suppress the overall islet response, as a result of gap junction coupling. This was demonstrated in a murine model of Neonatal Diabetes Mellitus (NDM) involving expression of ATP-insensitive KATP channels, and by a multi-cellular computational model of islet electrical activity. Here we examined the mechanisms by which gap junction coupling contributes to islet dysfunction in NDM. We first verified the computational model against [Ca2+] and insulin secretion measurements in islets expressing ATP-insensitive KATP channels under different levels of gap junction coupling. We then applied this model to predict how different KATP channel mutations found in NDM suppress [Ca2+], and the role of gap junction coupling in this suppression. We further extended the model to account for stochastic noise and insulin secretion dynamics. We found experimentally and in the islet model that reductions in gap junction coupling allow progressively greater glucose-stimulated [Ca2+] and insulin secretion following expression of ATP-insensitive KATP channels. The model demonstrated good correspondence between suppression of [Ca2+] and clinical presentation of different NDM mutations. Significant recoveries in [Ca2+] and insulin secretion were predicted for many mutations upon reductions in gap junction coupling, where stochastic noise played a significant role in the recoveries. These findings provide new understanding how the islet functions as a multicellular system and for the role of gap junction channels in exacerbating the effects of decreased cellular excitability. They further suggest novel therapeutic options for NDM and other monogenic forms of diabetes.
Highlights
Multi-cellular biological systems are composed of cellular elements with distinct characteristics, which function collectively as a result of dynamic interactions
We examined the role of gap junction coupling in exacerbating islet dysfunction in the presence of specific KCNJ11 and ABCC8 that cause Neonatal Diabetes Mellitus (NDM)
We examined if a reduction in electrical coupling recovered insulin secretion in the presence of the KCNJ11 and ABCC8 mutations that we predicted would show [Ca2+] recovery
Summary
Multi-cellular biological systems are composed of cellular elements with distinct characteristics, which function collectively as a result of dynamic interactions. While the function of a multicellular system is dependent on the characteristics of its constituent cells, understanding such systems is complicated by the action of cellular coupling and system architecture. Changes in the behavior of individual cells can often lead to unexpected changes in the system behavior. Many diseases, both acute and chronic, arise through genetic variations that impact molecular and cellular function. One approach to describe dynamic multicellular systems is using network theory, which distinguishes network structure and cellular behavior to understand how distinct functions can emerge from coupled systems [1,2]
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