Induction of receptor for advanced glycation end products by insufficient leptin action triggers pancreatic β-cell failure in type 2 diabetes
Induction of receptor for advanced glycation end products by insufficient leptin action triggers pancreatic β-cell failure in type 2 diabetes
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DOI：
10.1111/gtc.12036
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发表时间：
2013-04-01
期刊：
影响因子：
2.1
通讯作者：
Yamamoto, Hiroshi
中科院分区：
文献类型：
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作者：
Han, Dong;Yamamoto, Yasuhiko;Yamamoto, Hiroshi
由游离脂肪酸（FFA）和长期高血糖引起的糖脂毒性与糖尿病胰腺细胞衰竭有关。模式识别受体如糖基化终末产物受体（receptor for advanced glycation end products，RECEPTOR）、Toll样受体2和4等可介导细胞内的危险信号。我们在2型糖尿病小鼠模型中研究了糖尿病是否会导致细胞衰竭。从ob/ob、db/db、饮食诱导的肥胖（DIO）、RAGE-无效（RAGE/）和RAGE+/+野生型（WT）对照小鼠中分离胰岛，并分散成单细胞用于流式细胞术。在ob/ob和db/db小鼠的胰岛素阳性细胞中检测到β 2受体的表达，但在WT、DIO或β 2受体/小鼠中未检测到β 2受体的表达：因此，瘦素受体信号传导不足和β 2受体的表达可能相关。与正常对照组相比，正常对照组小鼠胰岛β细胞数量和质量明显增加，细胞凋亡减少，胰岛素分泌增加，糖耐量增加，血清游离脂肪酸和脂联素水平无明显差异。棕榈酸酯或油酸酯预处理结合瘦素拮抗剂可诱导MIN 6细胞中AGEs表达，AGE诱导细胞凋亡，并通过晚期糖基化终产物（AGE）损害葡萄糖刺激的胰岛素分泌。在2型糖尿病患者中，长时间高血糖导致FFA升高并伴随AGE形成，可能通过瘦素作用不足和随后的β-内酰胺酶诱导引起β-细胞损伤。
Glucolipotoxicity, which is exerted by free fatty acids (FFA) and prolonged hyperglycemia, is implicated in pancreatic -cell failure in diabetes. Pattern recognition receptors such as receptor for advanced glycation end products (RAGE) and toll-like receptors 2 and 4 could mediate danger signals in -cells. We examined whether RAGE contributes to -cell failure in a type 2 diabetes mouse model. Pancreatic islets were isolated from ob/ob, db/db, diet-induced obesity (DIO), RAGE-null (RAGE/), and RAGE+/+ wild-type (WT) control mice and dispersed into single cells for flow cytometry. RAGE expression was detected in insulin-positive -cells of ob/ob and db/db mice, but not of WT, DIO, or RAGE/ mice: thus, inadequate leptin receptor signaling and RAGE expression may be linked. Compared with RAGE+/+ db/db mice, RAGE/ db/db mice showed higher -cell number and mass with less apoptosis as well as glucose tolerance with higher insulin secretion without any differences in serum levels of FFA and adiponectin. Palmitate or oleate pretreatment combined with a leptin antagonist induced RAGE expression, AGE-elicited apoptosis, and impaired glucose-stimulated insulin secretion by advanced glycation end products (AGE) in MIN6 cells. FFA elevation with concomitant AGE formation during prolonged hyperglycemia could cause -cell damage through insufficient leptin action and subsequent RAGE induction in type 2 diabetes.