短链 3-羟酰基辅酶 A 脱氢酶是 INS832/13β 细胞对燃料和非燃料刺激响应中胰岛素分泌的负调节剂。
Short-chain 3-hydroxyacyl-CoA dehydrogenase is a negative regulator of insulin secretion in response to fuel and non-fuel stimuli in INS832/13 β-cells.
机构信息
Montreal Diabetes Research Center, CRCHUM, Montréal, Québec, Canada.
出版信息
J Diabetes. 2010 Sep;2(3):157-67. doi: 10.1111/j.1753-0407.2010.00076.x.
BACKGROUND
Hyperinsulinemia associated with non-ketotic hypoglycemia is observed in patients with mutated β-oxidation enzyme short-chain 3-hydroxyacyl-CoA dehydrogenase (HADHSC). In the present study, we investigated the mechanism underlying HADHSC-mediated regulation of insulin secretion.
METHODS
Knockdown of HADHSC expression by RNA interference in INS832/13 β-cells was achieved using short hairpin RNA and short interference RNA.
RESULTS
Knockdown of HADHSC increased both fuel- (glucose or leucine plus glutamine) and non-fuel (high KCl)-induced insulin secretion. Enhanced glucose-stimulated insulin secretion (GSIS) induced by HADHSC knockdown was independent of changes in cytosolic Ca(2+) and also occurred in the presence of fatty acids. L-Carnitine, used in the formation of acyl-carnitine compounds, increased GSIS in control cells, but was unable to further increase the augmented GSIS in HADHSC-knockdown cells. The pan transaminase inhibitor amino-oxyacetate reversed HADHSC knockdown-mediated increases in GSIS. Oxidation of [1-(14) C]-palmitate and -octanoate was not reduced in HADHSC-knockdown cells. L-3-Hydroxybutyryl-carnitine (tested using its precursor L-3-hydroxybutyrate) and L-3-hydroxyglutarate, which accumulate in blood and urine, respectively, of HADHSC-deficient patients, did not change insulin secretion.
CONCLUSIONS
Insulin secretion promoted by both fuel and non-fuel stimuli is negatively regulated by HADHSC. Enhanced secretion after HADHSC knockdown is not due to inhibition of fatty acid oxidation causing an accumulation of long-chain fatty acids or their CoA derivatives. L-3-Hydroxybutyrate and L-3-hydroxyglutarate do not mediate enhanced secretion caused by reduced HADHSC activity. Transamination reaction(s) and the formation of short-chain acylcarnitines and CoAs may be implicated in the mechanism whereby HADHSC deficiency results in enhanced insulin secretion and hyperinsulinemia.
背景
突变的β-氧化酶短链 3-羟基酰基辅酶 A 脱氢酶（HADHSC）可导致非酮性低血糖伴高胰岛素血症。本研究旨在探讨 HADHSC 调节胰岛素分泌的作用机制。
方法
采用短发夹 RNA 和小干扰 RNA 干扰 INS832/13β细胞中 HADHSC 的表达。
结果
HADHSC 敲低可增加葡萄糖（或亮氨酸加谷氨酰胺）和非燃料（高 KCl）诱导的胰岛素分泌。HADHSC 敲低引起的葡萄糖刺激的胰岛素分泌（GSIS）增强与胞质 Ca(2+)变化无关，并且在脂肪酸存在的情况下也会发生。L-肉碱用于酰基辅酶 A 化合物的形成，可增加对照细胞中的 GSIS，但不能进一步增加 HADHSC 敲低细胞中增强的 GSIS。泛转氨酶抑制剂氨基氧乙酸逆转了 HADHSC 敲低介导的 GSIS 增加。HADHSC 敲低细胞中的 [1-(14)C]-棕榈酸和 -辛酸氧化未减少。在 HADHSC 缺陷患者的血液和尿液中分别积累的 L-3-羟基丁酰肉碱（用其前体 L-3-羟基丁酸测试）和 L-3-羟基戊二酸均未改变胰岛素分泌。
结论
燃料和非燃料刺激均可促进胰岛素分泌，而 HADHSC 则对此进行负调控。HADHSC 敲低后分泌增强不是由于抑制脂肪酸氧化导致长链脂肪酸或其 CoA 衍生物的积累引起的。L-3-羟基丁酸和 L-3-羟基戊二酸不介导因 HADHSC 活性降低引起的分泌增强。转氨基反应和短链酰基辅酶 A 和 CoA 的形成可能与 HADHSC 缺乏导致胰岛素分泌增强和高胰岛素血症的机制有关。
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