High glucose-induced impairment in insulin secretion is associated with reduction in islet glucokinase in a mouse model of susceptibility to islet dysfunction
High glucose-induced impairment in insulin secretion is associated with reduction in islet glucokinase in a mouse model of susceptibility to islet dysfunction
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DOI：
10.1677/jme.1.01720
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发表时间：
2005-08-01
影响因子：
3.5
通讯作者：
Andrikopoulos, S
中科院分区：
文献类型：
--
作者：
Kooptiwut, S;Kebede, M;Andrikopoulos, S
2型糖尿病的特点是胰岛功能障碍导致高血糖，进而导致胰岛功能进一步恶化。高血糖诱导胰岛功能障碍的可能机制是晚期糖基化终产物（AGE）的积累。当暴露于高糖环境和/或肥胖诱导的胰岛素抵抗时，DBA/2小鼠会出现胰岛功能障碍。为了确定功能障碍的生化原因，DBA/2和C57BL/6对照胰岛在没有或存在AGE抑制剂氨基胍（AG）的情况下在11.1 mM或40 mM葡萄糖中孵育10天。DBA/2和C57BU6胰岛在40 mM vs 11.1 mM葡萄糖培养10天后，基础（2-8 mM葡萄糖）胰岛素释放增加。长期暴露于高血糖会降低DBA/2中葡萄糖（20 mM）刺激的胰岛素分泌，但C57BL/6中没有。AG显著增加高糖培养DBA/2小鼠胰岛胰岛素释放，但不影响C57BU6胰岛功能。与11.1 mM葡萄糖培养DBA/2胰岛和40 mM葡萄糖培养C57BL/6胰岛相比，40 mM葡萄糖培养DBA/2胰岛葡萄糖激酶显著降低。胰岛与AG孵育导致DBA/2胰岛葡萄糖激酶水平正常化。总之，慢性高糖诱导的AGE增加可导致胰岛功能障碍，这与胰岛功能衰竭易感性小鼠模型中葡萄糖激酶水平降低有关。
Type 2 diabetes is characterized by islet dysfunction resulting in hyperglycemia, which can then lead to further deterioration in islet function. A possible mechanism for hyperglycemia-induced islet dysfunction is the accumulation of advanced glycation end products (AGE). The DBA/2 mouse develops pancreatic islet dysfunction when exposed to a high glucose environment and/or obesity-induced insulin resistance. To determine the biochemical cause of dysfunction, DBA/2 and C57BL/6 control islets were incubated in 11.1 mM or 40 mM glucose in the absence or presence of the AGE inhibitor aminoguanidine (AG) for 10 days. Basal (2-8 mM glucose) insulin release was increased in both DBA/2 and C57BU6 islets incubated with 40 mM vs 11.1 mM glucose for 10 days. Chronic exposure to hyperglycemia decreased glucose (20 mM)-stimulated insulin secretion in DBA/2 but not in C57BL/6 islets. AG significantly increased fold-induced insulin release in high glucose cultured DBA/2 mouse islets, but did not affect C57BU6 islet function. DBA/2 islet glucokinase was significantly reduced following 40 mM glucose culture, compared with 11.1 mM glucose cultured DBA/2 islets and 40 mM glucose cultured C57BL/6 islets. Incubation of islets with AG resulted in a normalization of DBA/2 islet glucokinase levels. In conclusion, chronic high glucose-induced increases in AGE can result in islet dysfunction and this is associated with reduced glucokinase levels in a mouse model with susceptibility to islet failure.