Decreased pancreatic islet response to L-leucine in the spontaneously diabetic GK rat: enzymatic, metabolic and secretory data
Decreased pancreatic islet response to L-leucine in the spontaneously diabetic GK rat: enzymatic, metabolic and secretory data
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DOI：
10.1007/s001250051255
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发表时间：
1999-07
期刊：
影响因子：
8.2
通讯作者：
M. Giroix;C. Saulnier;B. Portha
中科院分区：
文献类型：
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作者：
M. Giroix;C. Saulnier;B. Portha
目的/假说：遗传性非胰岛素依赖型糖尿病Goto-Kakizaki(GK)大鼠的胰岛不仅对葡萄糖，而且对亮氨酸都有胰岛素反应缺陷。我们的目的是解释β细胞对这种氨基酸无反应的细胞机制(S)。方法：从GK大鼠和年龄匹配的健康Wistar对照组大鼠的胰岛中新鲜分离胶原酶，进行比较。对间歇培养胰岛的亮氨酸摄取、代谢通量和胰岛素分泌能力进行了研究。结果在GK大鼠胰岛中，亮氨酸转运和亮氨酸转氨酶活性均未受到干扰。相比之下，l-[U-14C]亮氨酸或l-[1-14C]亮氨酸产生的14CO2减少。L-[U-14C]亮氨酸氧化：L-[1-14C]亮氨酸脱羧率未受影响，说明亮氨酸生成的乙酰辅酶A在Krebs循环中经历了正常氧化。与对照组一样，亮氨酸非代谢类似物2-氨基-双环[2，2，1]庚烷-2-羧酸诱导胰岛素释放并增强对亮氨酸的分泌反应，而亮氨酸不能增强对亮氨酸类似物的分泌反应。此外，谷氨酰胺对亮氨酸介导的胰岛素释放的促进作用也被保留下来。这与正常的谷氨酸脱氢酶活性和l-[U-14C]谷氨酰胺氧化相一致。结论：在GK大鼠的胰岛β细胞中，对亮氨酸的分泌反应不能归因于亮氨酸刺激的谷氨酸代谢的恶化，而应归因于亮氨酸分解代谢的受损。由于线粒体支链2-酮酸脱氢酶对2-酮基酸的氧化脱羧基有缺陷，2-酮基异己酸酯生成的乙酰辅酶A减少。[糖尿病(1999)42：965-977]
AbstractAims/hypothesis.Pancreatic islets from hereditarily non-insulin-dependent diabetic Goto-Kakizaki (GK) rats have a deficient insulin response not only tod-glucose but also tol-leucine. Our aim was to explain the cellular mechanism(s) underlying the beta-cell unresponsiveness to this amino acid.Methods.Freshly collagenase isolated islets from GK rats and healthy Wistar control rats matched with them for sex and age were compared. Leucine uptake, metabolic fluxes and insulin secretory capacity were investigated on batch incubated-islets. Enzymatic activities were measured on sonicated islets.Results.In GK rat islets, neither leucine transport nor leucine transaminase activity was disturbed. By contrast,14CO2production from eitherl-[U-14C]leucine orl-[1-14C]leucine was decreased. Thel-[U-14C]leucine oxidation :l-[1-14C]leucine decarboxylation ratio was unaffected, indicating that the acetyl-CoA generated from leucine undergoes normal oxidation in the Krebs cycle. The leucine non-metabolizable analogue 2-amino-bicyclo[2,2,1]heptane-2-carboxylic acid induced insulin release and enhanced the secretory response to leucine as in controls, whereas leucine failed to amplify the response to the leucine analogue. Moreover, the potentiating action ofl-glutamine on leucine-mediated insulin release was preserved. This coincided with normal glutamate dehydrogenase activity andl-[U-14C]glutamine oxidation. Finally, the secretory response to the leucine deamination product 2-ketoisocaproate was decreased, as was the 2-keto[1-14C]isocaproate oxidation.Conclusion/interpretation.In islet beta cells from GK rats, the defective secretory response to leucine cannot be ascribed to a deteriorated leucine-stimulated glutamate metabolism but rather to an impaired leucine catabolism. A reduced generation of acetyl-CoA from 2-ketoisocaproate, due to the defective oxidative decarboxylation of this keto-acid by the mitochondrial branched-chain 2-ketoacid dehydrogenase, is incriminated. [Diabetologia (1999) 42: 965–977]