Volume-Regulated Anion Channels Increase Sugar Sensitivity of Insulin-Producing Cells

Insulin, an important hormone regulating blood sugar levels in the body, is produced in glucose-sensing β-cells located in the pancreas. The notion of volume-regulated anion channels (VRACs) modulating the release of this key hormone was suspected for some time but could not be formally tested because the molecular identity of VRAC had been unknown.

Following their discovery of the protein constituents of VRAC, a team led by scientist Thomas J. Jentsch at the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) and at the Max Delbrück Center for Molecular Medicine (MDC) now demonstrated that glucose sensitivity, and consequently insulin secretion, increase upon opening of these channels. Recently, the scientists published their results in Nature Communications.

Channels balance swelling effect

β-cells have sensory capabilities and monitor the blood glucose level. When the concentration of glucose increases, these cells depolarize and secrete insulin to adjust blood glucose levels. “The hypothesis that volume-regulated anion channels (VRACs) aid in the activation of β-cells has been discussed for some time”, Till Stuhlmann, the first author of this study, points out. When cells take up glucose, osmotic pressure builds up inside the cell and leads to an influx of water and subsequent cell swelling.

To balance this effect, cells secrete negatively charged chloride ions through VRACs, allowing water to leave the cell and the osmotic pressure returns to normal. “During this process, the inside of the cell becomes more positively charged. This in turn triggers the opening of voltage-gated calcium channels and thus insulin secretion,” Till Stuhlmann explains.

β-Cells take up glucose from the blood and metabolize it. In the process, an osmotic gradient develops, water enters the cell, and the cell volume increases. In response, the volume-regulated VRAC/LRRC8 channels open, negatively charged Cl- ions leave the cell and thereby cause an accumulation of positive charge inside the cells. This depolarization activates voltage-gated Ca2+ channels and Ca2+ ions enter the cell. In turn, this triggers the insulin-containing vesicles to fuse with the cell membrane and to release insulin into the blood, which results in a decrease of the blood sugar level.

Understanding insulin secretion

Using a mouse model, the scientists studied the mechanism in detail and confirmed the hypothesis. When they used knockout mice lacking the relevant channel gene LRRC8A, glucose-stimulated β-cells activated with marked delay. Both, influx of calcium ions and insulin secretion slowed down significantly. Only after 30 minutes, wildtype and LRRC8A-deficient β-cells behaved similarly. “The channel seems to have its greatest impact in the initial phase,” Till Stuhlmann concludes. “However, it is clear that additional ion channels are involved in β-cell activation.”

The insights from the study are very valuable for our understanding of the precise processes during insulin secretion. This is true even though their therapeutic use for the treatment of diabetes is complicated. Since VRACs exist in every cell of the human body, they are difficult to target specifically in certain cell types.

A recent discovery

However, scientists only recently discovered the LRRC8 protein family which forms the molecular basis for VRAC. In 2014, the team around Thomas Jentsch succeeded in identifying LRRC8A as the essential component of this protein complex which can be formed by different combinations of six subunits. VRAC channels are crucial to regulate the cell volume. Whenever cells swell these channels open, allowing anions and small organic molecules to leave the cell while positively charged ions are retained. This provokes the efflux of water, and thus, counteracts cell swelling and prevents potential bursting of the cells.

Currently, the functions of VRAC channels in other tissues of the human body are largely unknown. Scientists suspect that, among other functions, VRACs may play a harmful role during stroke. Till Stuhlmann elaborates: “During a stroke, many cells in the brain start to swell and VRACs open, presumably causing a release of the neurotransmitter glutamate. In turn, the high glutamate concentration triggers cell death in the surrounding neurons and thus leads to spreading of the brain lesion after the stroke.”

References

Till Stuhlmann, et al. (2018): “LRRC8/VRAC anion channels enhance β-cell glucose sensing and insulin secretion.” Nature Communications 9:1974, doi: 10.1038/s41467-018-04353-y