Differential beta cell coupling patterns drive biphasic activity

Background and aims: After food intake, pancreatic islets secrete insulin with a biphasic pattern, which is impaired in type 2 diabetic patients. The mechanisms underlying this pattern have not been fully elucidated and the presence of distinct vesicle pools has been proposed as explanation. Electrical activity of islets consists of individual β cell activity (action potentials, APs) and the multicellular electrical response due to coupling between β cells (slow potentials, SPs). We addressed here the contribution of these two distinct activities to the 1 st and the 2 nd phase of β cell activity, and their modulation by physiological concentrations of GLP-1. Materials and methods: Electrical activity (SPs and APs) of entire mice (C57Bl6/J, age 10-14 weeks) or human islets have been recorded on polymer-coated microelectrode arrays (MEA). These new electrodes allow simultaneous detection of APs (of very low amplitude) and SPs at a high time resolution (10'000 points/s x60 electrodes) for a prolonged period mimicking physiological digestion (2 h). Specific filters differentially detect SPs and APs and 3 parameters were analyzed at the same time: SP frequencies, SP amplitudes and AP frequencies. To investigate synchrony of SPs between different regions of the same islet, we used high density MEAs with an inter-electrode distance of 30 instead of 200 µm followed by analysis via Matlab. Results: Islets were stimulated with glucose concentrations in the physiological range (5.5-8.2 mM). Electrical responses were biphasic for both SPs and APs. APs were mainly present during the 1 st phase while the transition between the 1 st and the 2 nd phase is driven by SPs. In 2 nd phase, the SP amplitude and synchronisation increased significantly (1 st phase: 18.1±2.3 µV; 2 nd phase: 47.4±5.5 µV, p<0.0001), reflecting further electrical coupling and synchronisation of β cells. The intra-islet synchronisation was also further correlate using high density MEAs. The incretin GLP-1, at a physiological postprandial concentration (50 pM), did not change the individual activity of cells (APs) but increased specifically coupling (SPs) and only in the 2nd phase (37.7±3.0 µV vs 47.0±4.2 µV with GLP-1, p<0.0001). Furthermore, when GLP-1 was applied in the presence of a subthreshold glucose concentration (5.5 mM), the hormone triggered only a 2 nd phase. The biphasic electric profile was confirmed in human islets. Their exposure to a glucotoxic medium (20 mM glucose, 65 h) considerably increased basal activity and abolished the biphasic response as well as the discrimination between glucose concentrations. These glucotoxic effects were partially reversible. Conclusion: Our data show that (i) electrical activity pattern shape the biphasic secretion and (ii) the transition period between the 1 st and the 2 nd phase results from increasing electrical synchronisation. Thus biphasic secretion is primarily dictated by changes in electrical activity rather than vesicle pools. The effects of GLP-1 on only coupling SP signals and only during the 2 nd phase explain its clinical effects

Dynamic Uni- and Multicellular Patterns Encode Biphasic Activity in Pancreatic Islets

Biphasic secretion is an autonomous feature of many endocrine micro-organs to fulfill physiological demands. The biphasic activity of islet beta-cells maintains glucose homeostasis and is altered in type 2 diabetes. Nevertheless, underlying cellular or multicellular functional organizations are only partially understood. High-resolution noninvasive multielectrode array recordings permit simultaneous analysis of recruitment, of single-cell, and of coupling activity within entire islets in long-time experiments. Using this unbiased approach, we addressed the organizational modes of both first and second phase in mouse and human islets under physiological and pathophysiological conditions. Our data provide a new uni- and multicellular model of islet beta-cell activation: during the first phase, small but highly active beta-cell clusters are dominant, whereas during the second phase, electrical coupling generates large functional clusters via multicellular slow potentials to favor an economic sustained activity. Postprandial levels of glucagon-like peptide 1 favor coupling only in the second phase, whereas aging and glucotoxicity alter coupled activity in both phases. In summary, biphasic activity is encoded upstream of vesicle pools at the micro-organ level by multicellular electrical signals and their dynamic synchronization between beta-cells. The profound alteration of the electrical organization of islets in pathophysiological conditions may contribute to functional deficits in type 2 diabetes

Infragravity waves: from driving mechanisms to impacts

Infragravity (hereafter IG) waves are surface ocean waves with frequencies below those of wind-generated “short waves” (typically below 0.04 Hz). Here we focus on the most common type of IG waves, those induced by the presence of groups in incident short waves. Three related mechanisms explain their generation: (1) the development, shoaling and release of waves bound to the short-wave group envelopes (2) the modulation by these envelopes of the location where short waves break, and (3) the merging of bores (breaking wave front, resembling to a hydraulic jump) inside the surfzone. When reaching shallow water (O(1–10 m)), IG waves can transfer part of their energy back to higher frequencies, a process which is highly dependent on beach slope. On gently sloping beaches, IG waves can dissipate a substantial amount of energy through depth-limited breaking. When the bottom is very rough, such as in coral reef environments, a substantial amount of energy can be dissipated through bottom friction. IG wave energy that is not dissipated is reflected seaward, predominantly for the lowest IG frequencies and on steep bottom slopes. This reflection of the lowest IG frequencies can result in the development of standing (also known as stationary) waves. Reflected IG waves can be refractively trapped so that quasi-periodic along-shore patterns, also referred to as edge waves, can develop. IG waves have a large range of implications in the hydro-sedimentary dynamics of coastal zones. For example, they can modulate current velocities in rip channels and strongly influence cross-shore and longshore mixing. On sandy beaches, IG waves can strongly impact the water table and associated groundwater flows. On gently sloping beaches and especially under storm conditions, IG waves can dominate cross-shore sediment transport, generally promoting offshore transport inside the surfzone. Under storm conditions, IG waves can also induce overwash and eventually promote dune erosion and barrier breaching. In tidal inlets, IG waves can propagate into the back-barrier lagoon during the flood phase and induce large modulations of currents and sediment transport. Their effect appears to be smaller during the ebb phase, due to blocking by countercurrents, particularly in shallow systems. On coral and rocky reefs, IG waves can dominate over short-waves and control the hydro-sedimentary dynamics over the reef flat and in the lagoon. In harbors and semi-enclosed basins, free IG waves can be amplified by resonance and induce large seiches (resonant oscillations). Lastly, free IG waves that are generated in the nearshore can cross oceans and they can also explain the development of the Earth's “hum” (background free oscillations of the solid earth)