The Lyn Kinase Activator MLR-1023 Is a Novel Insulin Receptor Potentiator that Elicits a Rapid-Onset and Durable Improvement in Glucose Homeostasis in Animal Models of Type 2 Diabetes
The Lyn Kinase Activator MLR-1023 Is a Novel Insulin Receptor Potentiator that Elicits a Rapid-Onset and Durable Improvement in Glucose Homeostasis in Animal Models of Type 2 Diabetes
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DOI：
10.1124/jpet.112.192187
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发表时间：
2012-07-01
影响因子：
3.5
通讯作者：
Saporito, Michael S.
中科院分区：
文献类型：
--
作者：
Ochman, Alexander R.;Lipinski, Christopher A.;Saporito, Michael S.
MLR-1023 [托咪酮; CP-26154; 2（1H）-嘧啶酮，5-（3-甲基苯氧基）]是一种变构林恩激酶激活剂，其降低接受口服葡萄糖耐量试验的小鼠的血糖水平（J Pharmacol Exp Ther 342：15-22，2012）。目前的研究旨在确定胰岛素在MLR-1023介导的血糖降低中的作用，在2型糖尿病动物模型中对其进行评估，并将其与选定的现有糖尿病治疗药物的活性进行比较。这些研究的结果表明，在急性口服葡萄糖耐量试验中，MLR-1023引起了剂量依赖性降糖反应，其幅度与二甲双胍相当，但未引起低血糖反应。在链脲佐菌素治疗的胰岛素耗尽小鼠中，MLR-1023给药不影响血糖水平。然而，MLR-1023增强了外源性胰岛素的降糖活性，表明MLR-1023介导的血糖降低是胰岛素依赖性的。在高胰岛素/正常血糖钳夹研究中，口服给药MLR-1023增加了维持血糖水平所需的葡萄糖输注速率，表明MLR-1023增加了胰岛素受体敏感性。在长期给药的db/db小鼠中，MLR-1023引起了剂量依赖性和持久的降糖作用，降低了HbA 1c水平并保留了胰腺β细胞。其作用强度与罗格列酮相当，但起效更快，且不会导致体重增加。这些研究表明，MLR-1023是一种胰岛素受体增强剂，可在糖尿病动物中产生快速起效和持久的降血糖活性。
MLR-1023 [Tolimidone; CP-26154; 2(1H)-pyrimidinone, 5-(3-methylphenoxy)] is an allosteric Lyn kinase activator that reduces blood glucose levels in mice subjected to an oral glucose tolerance test (J Pharmacol Exp Ther 342:15-22, 2012). The current studies were designed to define the role of insulin in MLR-1023-mediated blood glucose lowering, to evaluate it in animal models of type 2 diabetes, and to compare it to the activities of selected existing diabetes therapeutics. Results from these studies show that in an acute oral glucose tolerance test MLR-1023 evoked a dose-dependent blood glucose-lowering response that was equivalent in magnitude to that of metformin without eliciting a hypoglycemic response. In streptozotocin-treated, insulin-depleted mice, MLR-1023 administration did not affect blood glucose levels. However, MLR-1023 potentiated the glucose-lowering activity of exogenously administered insulin, showing that MLR-1023-mediated blood glucose lowering was insulin-dependent. In a hyperinsulinemic/euglycemic clamp study, orally administered MLR-1023 increased the glucose infusion rate required to sustain blood glucose levels, demonstrating that MLR-1023 increased insulin receptor sensitivity. In chronically treated db/db mice, MLR-1023 elicited a dose-dependent and durable glucose-lowering effect, reduction in HbA1c levels and preservation of pancreatic beta-cells. The magnitude of effect was equivalent to that seen with rosiglitazone but with a faster onset of action and without causing weight gain. These studies show that MLR-1023 is an insulin receptor-potentiating agent that produces a rapid-onset and durable blood glucose-lowering activity in diabetic animals.