Type I Gaucher disease, a glycosphingolipid storage disorder, is associated with insulin resistance
Type I Gaucher disease, a glycosphingolipid storage disorder, is associated with insulin resistance
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DOI：
10.1210/jc.2007-1702
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发表时间：
2008-03-01
影响因子：
5.8
通讯作者：
Serlie, Mireille J.
中科院分区：
文献类型：
--
作者：
Langeveld, Mirjam;Ghauharali, Karen J. M.;Serlie, Mireille J.
背景：复杂的神经鞘糖脂，主要是神经节苷脂GM3，包围在胰岛素受体周围的一个特殊的膜室(RAFT)，并通过该受体调节信号。筏子中GM3水平的升高会损害胰岛素信号，导致胰岛素抵抗。高谢病是一种溶酶体储存障碍，葡萄糖神经酰胺的破坏导致其在巨噬细胞中积聚。目的：我们通过测量胰岛素介导(IMGU)和非胰岛素介导的葡萄糖摄取量(NIMGU)以及胰岛素对游离脂肪酸的抑制来研究糖鞘糖脂储存对全身葡萄糖和脂肪代谢的影响。设计和主要观察指标：我们研究了6名尚未接受治疗或仍有相当多疾病负担的Gaucher患者和6名匹配的健康对照组在基础状态下，在正血糖和高血糖钳夹期间用生长抑素测定NIMGU，以及在正血糖高胰岛素钳夹期间测定IMGU、IMGU和NIMGU。结果：NIMGU(正常血糖和高血糖期间)在患者和对照组之间没有差异。与对照组相比，高雪病患者IMGU降低。结论：高谢病是一种溶酶体糖鞘糖脂储存障碍，与(外周)胰岛素抵抗有关，可能是通过影响胰岛素受体功能。
Context: Complex glycosphingolipids, in majority the ganglioside GM3, surround the insulin receptor in a special membrane compartment (raft) and modulate signaling through this receptor. Increased levels of GM3 in rafts impair insulin signaling, resulting in insulin resistance. Gaucher disease is a lysosomal storage disorder in which impaired breakdown of glucosylceramide leads to its accumulation in macrophages. Secondary to this defect, GM3 concentrations, for which glucosylceramide is the precursor, in plasma and several cell types are elevated.Objective: We studied the influence of glycosphingolipid storage on whole body glucose and fat metabolism by measuring insulin-mediated (IMGU) and noninsulin-mediated glucose uptake (NIMGU) and suppression of free fatty acids by insulin.Design and Main Outcome Measures: We studied six Gaucher patients, either naive to treatment or with considerable remaining burden of disease, and six matched healthy control subjects in the basal state, during an euglycemic and a hyperglycemic clamp with somatostatin measuring NIMGU and during an euglycemic hyperinsulinemic clamp measuring IMGU, using stable isotopes.Results: NIMGU (both during euglycemia and hyperglycemia) did not differ between patients and control subjects. IMGU was lower in Gaucher patients, compared with controls. Suppression of lipolysis by insulin tended to be less effective in Gaucher patients.Conclusion: Gaucher disease, a lysosomal glycosphingolipid storage disorder, is associated with (peripheral) insulin resistance, possibly through the influence of glycosphingolipids on insulin receptor functioning.