Resolving spatiotemporal electrical signaling within the islet via CMOS microelectrode arrays.

Glucose-stimulated beta-cells exhibit synchronized calcium dynamics across the islet that recruit beta-cells to enhance insulin secretion. Compared to calcium dynamics, the formation and cell-to-cell propagation of electrical signals within the islet are poorly characterized. To determine factors that influence the propagation of electrical activity across the islet underlying calcium oscillations and beta-cell synchronization, we used high-resolution CMOS multielectrode arrays (MEA) to measure voltage changes associated with the membrane potential of individual cells within intact C57BL6 mouse islets.

Exploring pancreatic beta-cell subgroups and their connectivity.

Functional pancreatic islet beta cells are essential to ensure glucose homeostasis across species from zebrafish to humans. These cells show significant heterogeneity, and emerging studies have revealed that connectivity across a hierarchical network is required for normal insulin release. Here, we discuss current thinking and areas of debate around intra-islet connectivity, cellular hierarchies and potential "controlling" beta-cell populations.

β-cell intrinsic dynamics rather than gap junction structure dictates subpopulations in the islet functional network.

Diabetes is caused by the inability of electrically coupled, functionally heterogeneous β-cells within the pancreatic islet to provide adequate insulin secretion. Functional networks have been used to represent synchronized oscillatory [Ca] dynamics and to study β-cell subpopulations, which play an important role in driving islet function. The mechanism by which highly synchronized β-cell subpopulations drive islet function is unclear.

NMDA receptors - regulatory function and pathophysiological significance for pancreatic beta cells.

Due to its unique features amongst ionotropic glutamate receptors, the NMDA receptor is of special interest in the physiological context but even more as a drug target. In the pathophysiology of metabolic disorders, particularly type 2 diabetes mellitus, there is evidence that NMDA receptor activation contributes to disease progression by impairing beta cell function. Consequently, channel inhibitors are suggested for treatment, but up to now there are many unanswered questions about the signaling pathways NMDA receptors are interfering with in the islets of Langerhans.

Selective Inhibition of -Methyl-d-aspartate Receptors with GluN2B Subunit Protects Cells against Stress-Induced Apoptotic Cell Death.

Participation of -methyl-d-aspartate (NMDA) receptors (NMDARs) in the failure of pancreatic cells during development of type 2 diabetes mellitus is discussed. Our study investigates whether cell mass and function can be preserved by selectively addressing the GluN2B subunit of the NMDAR. NMDAR activation by NMDA and its coagonist glycine moderately influenced electrical activity and Ca handling in islet cells at a threshold glucose concentration (4-5 mM) without affecting glucose-mediated insulin secretion.

Possible New Strategies for the Treatment of Congenital Hyperinsulinism.

Objective: Congenital hyperinsulinism (CHI) is a rare disease characterized by persistent hypoglycemia as a result of inappropriate insulin secretion, which can lead to irreversible neurological defects in infants. Poor efficacy and strong adverse effects of the current medications impede successful treatment. The aim of the study was to investigate new approaches to silence β-cells and thus attenuate insulin secretion.

Dextromethorphan and Dextrorphan Influence Insulin Secretion by Interacting with K and L-type Ca Channels in Pancreatic -Cells.

The NMDA receptor antagonist dextromethorphan (DXM) and its metabolite dextrorphan (DXO) have been recommended for treatment of type 2 diabetes mellitus because of their beneficial effects on insulin secretion. This study investigates how different key points of the stimulus-secretion coupling in mouse islets and -cells are influenced by DXM or DXO. Both compounds elevated insulin secretion, electrical activity, and [Ca] in islets at a concentration of 100 µM along with a stimulating glucose concentration.

TGR5 Activation Promotes Stimulus-Secretion Coupling of Pancreatic β-Cells via a PKA-Dependent Pathway.

The Takeda-G-protein-receptor-5 (TGR5) mediates physiological actions of bile acids. Since it was shown that TGR5 is expressed in pancreatic tissue, a direct TGR5 activation in β-cells is currently postulated and discussed. The current study reveals that oleanolic acid (OLA) affects murine β-cell function by TGR5 activation.

Resveratrol Influences Pancreatic Islets by Opposing Effects on Electrical Activity and Insulin Release.

Scope: Resveratrol is suggested to improve glycemic control by activation of sirtuin 1 (SIRT1) and has already been tested clinically. Our investigation characterizes the targets of resveratrol in pancreatic beta cells and their contribution to short- and long-term effects on insulin secretion.

Methods And Results: Islets or beta cells are isolated from C57BL/6N mice.