Roles of plasma membrane ryanodine receptors in pancreatic beta cells.

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Type 2 diabetes, as its alternative name (maturity-onset diabetes) suggests, was once a disease of older people. But obesity, the major pre-disposing factor for type 2 diabetes, is increasing alarmingly among all age-groups and so too is the prevalence of type 2 diabetes, which increased by at least 25% in the west and by 50% or more elsewhere since 2000. Diabetes requires lifelong therapy and its complications reduce quality or life and life-expectancy. The disease presents when beta-cells in the pancreas are no longer able to release sufficient insulin to control effectively the blood glucose concentration. Most drugs used to treat diabetes work by promoting insulin release, but they cannot faithfully replicate the oscillatory changes in insulin secretion that provide the most effective regulation of glucose uptake by target tissues. Our work has identified a channel (the type 2 ryanodine receptor, RyR2) in the membrane that surrounds the beta-cell. We suggest that RyR2 may be inserted into this membrane when the vesicles that release insulin fuse with it, and that the RyR2 may then control the flux of calcium ions that regulates insulin release. This unexpected contribution from RyR2 may thereby form part of a regulatory loop contributing to oscillatory control of insulin release. The accessibility of RyR2 (on the surface of the cell) may allow it to become a target for novel drugs to promote insulin release. Our work is concerned with unravelling the roles of RyR2 in control of insulin release.