Glucose enters -cells through GLUT2 transporter and is metabolized to pyruvate by glycolysis. Pyruvate enters the mitochondria where it is oxidized in the TCA cycle. The NADH produced by both glycolysis and TCA cycle are oxidized to produce the cellular ATP. The increased level of ATP:ADP triggers the closure of ATP-sensitive potassium channels resulting in membrane depolarization. This in turn opens the voltage gate-dependent Ca2+ channels, causing the influx of Ca2+ which triggers the immediate exocytosis of nsulin granules in the readily releasable pool, corresponding to the 1st phase of biphasic insulin secretion. Some components of the TCA cycle, i.e. malate, citrate and isocitrate are also exported from the mitochondria to cytoplasm (cataplerosis) where these exported products are converted back to pyruvate (pyruvate cycling) concomitantly with the production of NADPH via pyruvatemalate, pyruvate-citrate and pyruvate-isocitrate shuttles, respectively. PC replenishes OAA in the TCA cycle when malate, citrate and isocitrate are removed for the pyruvate cycling.The exported citrate is converted to oxaloacetate and acetyl-CoA. ACC1 converts acetyl-CoA to malonyl-CoA which is subsequently converted to long chain acyl-CoA by FAS. The NADPH malonyl-CoA, long chain acyl-CoA together with the mitochondrial GTP produced by succinyl-CoA synthetase and glutamate produced by glutamate dehydrogenase serve as “amplifying signals” that correspond to the 2nd phase of biphasic insulin secretion. ACC, acetyl-CoA carboxylase; ACL, ATP-citrate lyase; cICD, cytolsolic isocitrate dehydrogenase; CIC, citrate/isocitrate carrier; GTP-SC, GTP-succinate dehydrogenase; FAS, fatty acid synthase, MDH, malate dehydrogenase; ME, malic enzyme, PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase complex; RP, reserve pool; RRP, readily releasable pool.
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diambil dari MEDICAL COMPLICATIONS OF TYPE 2 DIABETES; Insulin Secretion and Actions 3, Sarawut
Jitrapakdee and Briony E. Forbes, IntechOpen.
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