Lee Joo-Won, Swick Andrew G, Romsos Dale R
Department of Food Science and Human Nutrition, Michigan State University, East Lansing, Michigan 48824-1224, USA.
Exp Biol Med (Maywood). 2003 Feb;228(2):175-82. doi: 10.1177/153537020322800207.
Leptin-deficient Lep(ob)/Lep(ob)mice hypersecrete insulin in response to acetylcholine stimulation of the phospholipase C-protein kinase C (PLC-PKC) pathway, and leptin constrains this hypersecretion. Leptin has been reported to activate phosphatidylinositol 3-kinase (PI 3-K) and subsequently phosphodiesterase (PDE) to impair protein kinase A (PKA)-induced insulin secretion from cultured islets of neonatal rats. We determined if PKA-induced insulin secretion was also hyperresponsive in islets from Lep(ob)/Lep(ob)mice, and if leptin impaired this pathway in islets from these mice. Additionally, the possible role for PI 3-K and PDE in leptin-induced control of acetylcholine-induced insulin secretion was examined. Stimulation of insulin secretion with GLP-1, forskolin (an activator of adenylyl cyclase), or IBMX (an inhibitor of PDE) did not cause hypersecretion of insulin from islets of young Lep(ob)/Lep(ob)mice, and leptin did not inhibit GLP-1-induced insulin secretion from islets of these mice. Inhibition of PDE with IBMX also did not block leptin-induced inhibition of acetylcholine-mediated insulin secretion from islets of Lep(ob)/Lep(ob)mice. But, preincubation of islets with wortmannin, an inhibitor of PI 3-K activity, blocked the ability of leptin to constrain acetylcholine-induced insulin secretion from islets of Lep(ob)/Lep(ob)mice. We conclude that the capacity of the PKA pathway to stimulate insulin secretion is not increased in islets from young Lep(ob)/Lep(ob)mice, and that leptin does not regulate this pathway in islets from mice. Leptin may stimulate PI 3-K to constrain PLC-PKC-induced insulin secretion from islets of Lep(ob)/Lep(ob)mice.
瘦素缺乏的Lep(ob)/Lep(ob)小鼠在乙酰胆碱刺激磷脂酶C - 蛋白激酶C（PLC - PKC）途径时会过度分泌胰岛素，而瘦素会抑制这种过度分泌。据报道，瘦素可激活磷脂酰肌醇3 - 激酶（PI 3 - K），随后激活磷酸二酯酶（PDE），从而削弱蛋白激酶A（PKA）诱导的新生大鼠培养胰岛的胰岛素分泌。我们确定了PKA诱导的胰岛素分泌在Lep(ob)/Lep(ob)小鼠的胰岛中是否也反应过度，以及瘦素是否会削弱这些小鼠胰岛中的该途径。此外，还研究了PI 3 - K和PDE在瘦素诱导的对乙酰胆碱诱导的胰岛素分泌的控制中的可能作用。用胰高血糖素样肽 - 1（GLP - 1）、福斯可林（一种腺苷酸环化酶激活剂）或异丁基甲基黄嘌呤（IBMX，一种PDE抑制剂）刺激胰岛素分泌，并不会导致年轻Lep(ob)/Lep(ob)小鼠胰岛的胰岛素过度分泌，并且瘦素也不会抑制这些小鼠胰岛中GLP - 1诱导的胰岛素分泌。用IBMX抑制PDE也不会阻断瘦素诱导的对Lep(ob)/Lep(ob)小鼠胰岛中乙酰胆碱介导的胰岛素分泌的抑制作用。但是，用渥曼青霉素（一种PI 3 - K活性抑制剂）预孵育胰岛，会阻断瘦素抑制Lep(ob)/Lep(ob)小鼠胰岛中乙酰胆碱诱导的胰岛素分泌的能力。我们得出结论，年轻Lep(ob)/Lep(ob)小鼠的胰岛中PKA途径刺激胰岛素分泌的能力并未增强，并且瘦素不会调节这些小鼠胰岛中的该途径。瘦素可能通过刺激PI 3 - K来抑制Lep(ob)/Lep(ob)小鼠胰岛中PLC - PKC诱导的胰岛素分泌。
