Abstract

Beta cells within the pancreatic islets of Langerhans respond to stimulation with coherent oscillations of membrane potential and intracellular calcium concentration that presumably drive the pulsatile exocytosis of insulin. Their rhythmic activity is multimodal, resulting from networked feedback interactions of various oscillatory subsystems, such as the glycolytic, mitochondrial, and electrical/calcium components. How these oscillatory modules interact and affect the collective cellular activity, which is a prerequisite for proper hormone release, is incompletely understood. In the present work, we combined advanced confocal Ca2+ imaging in fresh mouse pancreas tissue slices with time series analysis and network science approaches to unveil the glucose-dependent characteristics of different oscillatory components on both the intra- and inter-cellular level. Our results reveal an interrelationship between the metabolically driven low-frequency component and the electrically driven high-frequency component, with the latter exhibiting the highest bursting rates around the peaks of the slow component and the lowest around the nadirs. Moreover, the activity, as well as the average synchronicity of the fast component, considerably increased with increasing stimulatory glucose concentration, whereas the stimulation level did not affect any of these parameters in the slow component domain. Remarkably, in both dynamical components, the average correlation decreased similarly with intercellular distance, which implies that intercellular communication affects the synchronicity of both types of oscillations. To explore the intra-islet synchronization patterns in more detail, we constructed functional connectivity maps. The subsequent comparison of network characteristics of different oscillatory components showed more locally clustered and segregated networks of fast oscillatory activity, while the slow oscillations were more global, resulting in several long-range connections and a more cohesive structure. Besides the structural differences, we found a relatively weak relationship between the fast and slow network layer, which suggests that different synchronization mechanisms shape the collective cellular activity in islets, a finding which has to be kept in mind in future studies employing different oscillations for constructing networks.

Highlights

  • Rhythmicity is a hallmark of many organs within the human body, a process manifested from molecular reactions to whole body rhythms

  • We studied the effect of stimulation with two glucose concentrations: a physiological concentration that is commonly observed in vivo, i.e., 8 mM, and a supraphysiological concentration, i.e., 12 mM

  • Pancreatic beta cell Ca2+ response to glucose stimulation was recorded by means of multicellular confocal imaging in acute tissue slices as described in Materials and methods

Read more

Summary

Introduction

Rhythmicity is a hallmark of many organs within the human body, a process manifested from molecular reactions to whole body rhythms. An important example is the oscillatory nature of insulin secretion (Lang et al, 1979). Pulsatile insulin delivery suppresses hepatic glucose production more effectively (Matveyenko et al, 2012) and prevents insulin receptor desensitization (Li and Goldbeter, 1992). Fluctuations in hepatic glucose production determine oscillations in the plasma glucose concentration, representing a possible feedback mechanism for pancreatic insulin secretion (Goodner et al, 1982; Pedersen et al, 2005). The changes in the normal pattern of plasma insulin oscillations are an early marker of insulin resistance and diabetes mellitus and can be found in diabetic animal models, such as ob/ob mice (Ravier et al, 2002) and ZDF rats (Sturis et al, 1994), as well as in diabetic patients (Lang et al, 1981; Polonsky et al, 1988) and even their relatives (O’rahilly et al, 1988). Besides disrupted pulsatility of insulin release, the hepatic extraction of insulin is impaired in diabetic patients (Sando et al, 1980; Bonora et al, 1983)

Methods
Results
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call