Triggering and amplification of insulin secretion by dimethyl α-ketoglutarate, a membrane permeable α-ketoglutarate analogue

Introduction: It is estimated that about 70 percent of the insulin secretion stimulated by glucose and other fuels are due to the KATP channel-independent amplifying pathway which transduces signals from the energy metabolism to the exocytotic machinery of the beta-cell. Recently, cytosolic α-ketoglutarate has been suggested as a potential signalling compound in this context. This hypothesis was mainly based on the insulin-releasing effect of the membrane permeable ester dimethyl α-ketoglutarate (DMKG) which enters the beta-cell and is cleaved to produce cytosolic monomethyl α-ketoglutarate and eventually α-keto…