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

详细信息    查看全文

• 作者：Michael Willenborg ; Uwe Panten ; Ingo Rustenbeck
• 关键词：Dimethyl α ; -ketoglutarate ; Pancreatic islet ; Insulin secretion ; ATP-sensitive K⁺ channel ; β ; -Cell depolarization
• 刊名：European Journal of Pharmacology
• 出版年：2009
• 出版时间：1 April 2009
• 年：2009
• 卷：607
• 期：1-3
• 页码：41-46
• 全文大小：546 K

文摘

Cytosolic α-ketoglutarate is a potential signalling compound at late steps of stimulus–secretion-coupling in the course of insulin secretion induced by glucose and other fuels. This hypothesis is mainly based on the insulin-releasing effect of the membrane permeable ester dimethyl α-ketoglutarate which enters the β-cell and is cleaved to produce cytosolic monomethyl α-ketoglutarate and eventually α-ketoglutarate. The present study tested this hypothesis. Insulin release, K_ATP channel currents, membrane potential, ATP/ADP ratio and fluorescence of NAD(P)H (reduced pyridine nucleotides) were measured in mouse pancreatic islets and β-cells. At a substimulatory glucose concentration (5 mM), dimethyl α-ketoglutarate (15 mM) produced a sustained insulin release, but no change of the islet ATP/ADP ratio and NAD(P)H fluorescence. In the absence of glucose, however, dimethyl α-ketoglutarate (15 mM) did not stimulate insulin release although it increased the ATP/ADP ratio and NAD(P)H fluorescence. Insulin secretion induced by a maximally effective concentration of the K_ATP channel-blocking sulfonylurea glipizide was strongly amplified by dimethyl α-ketoglutarate in the presence of 5 mM glucose, but only moderately in the absence of glucose. Dimethyl α-ketoglutarate directly inhibited K_ATP channels in inside–out membrane patches, depolarized the plasma membrane of intact β-cells and generated action potentials. In conclusion, the stimulation of insulin secretion by extracellularly applied dimethyl α-ketoglutarate depends on inhibition of β-cell K_ATP channels by direct action of dimethyl α-ketoglutarate. The metabolism of α-ketoglutarate generated intracellularly by ester cleavage contributes to stimulation of insulin secretion both by indirect K_ATP channel inhibition (via activation of ATP production) and by an amplifying effect.