Regulation of lipid raft proteins by glimepiride- and insulin-induced glycosylphosphatidylinositol-specific phospholipase C in rat adipocytes

Müller, Günter; Schulz, Andrea; Wied, Susanne; Frick, Wendelin

doi:10.1016/j.bcp.2004.11.014

Cited by 57 publications

(68 citation statements)

References 67 publications

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“…Src-related kinases, and especially Lyn kinase, are directly involved in insulin signaling (Lebrun et al, 1998;Mü ller et al, 2001aMü ller et al, ,b, 2005. In adipocytes, activated Lyn kinase directly promotes the phosphorylation of IRS-1 and in turn promotes insulin signaling including glucose transporter type 4 translocation (Mü ller et al, 2001b(Mü ller et al, , 2005. However, Ochman et al (2012) clearly showed that MLR-1023 does not function as an insulin mimetic but as a potentiator of insulin activity.…”

Section: Discussionmentioning

confidence: 99%

“…It is noteworthy that this activity of glimepiride has also been related to the activation of Lyn kinase (Mü ller et al, 2001a(Mü ller et al, , 2005. However, unlike MLR-1023, this Lyn kinase activation is nonselective and indirectly regulated through effects on membrane-associated lipid rafts (Mü ller et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…This link between Lyn kinase activation and therapeutic efficacy in T2D has been noted for the oral diabetes therapeutic glimepiride (Mü ller, 2000;Mü ller et al, 2001a). Glimepiride-mediated Lyn kinase activation activity may be responsible for glycemic control activity independent of its insulin-secretagogue activity (Mü ller, 2000;Mü ller et al, 2005). However, glimepiride-mediated Lyn kinase activation occurs indirectly through the regulation of lipid rafts and is likely to be nonspecific (Mü ller et al, 2005).…”

Section: Introductionmentioning

confidence: 88%

“…Glimepiride-mediated Lyn kinase activation activity may be responsible for glycemic control activity independent of its insulin-secretagogue activity (Mü ller, 2000;Mü ller et al, 2005). However, glimepiride-mediated Lyn kinase activation occurs indirectly through the regulation of lipid rafts and is likely to be nonspecific (Mü ller et al, 2005). A compound that directly activates Lyn kinase would provide a new therapeutic modality that would increase insulin-signaling events without affecting insulin secretion and promote glucose-lowering effects that would be therapeutically beneficial in T2D.…”

Section: Introductionmentioning

confidence: 99%

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MLR-1023 Is a Potent and Selective Allosteric Activator of Lyn Kinase In Vitro That Improves Glucose Tolerance In Vivo

Saporito

Ochman²,

Lipinski³

et al. 2012

J Pharmacol Exp Ther

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2(1H)-pyrimidinone,5-(3-methylphenoxy) (MLR-1023) is a candidate for the treatment of type 2 diabetes. The current studies were aimed at determining the mechanism by which MLR-1023 mediates glycemic control. In these studies, we showed that MLR-1023 reduced blood glucose levels without increasing insulin secretion in vivo. We have further determined that MLR-1023 did not activate peroxisome proliferator-activated ␣, ␦, and ␥ receptors or glucagon-like peptide-1 receptors or inhibit dipeptidyl peptidase-4 or ␣-glucosidase enzyme activity. However, in an in vitro broad kinase screen MLR-1023 activated the nonreceptor-linked Src-related tyrosine kinase Lyn. MLR-1023 increased the V max of Lyn with an EC 50 of 63 nM. This Lyn kinase activation was ATP binding site independent, indicating that MLR-1023 regulated the kinase through an allosteric mechanism. We have established a link between Lyn activation and blood glucose lowering with studies showing that the glucose-lowering effects of MLR-1023 were abolished in Lyn knockout mice, consistent with existing literature linking Lyn kinase and the insulin-signaling pathway. In summary, these studies describe MLR-1023 as a unique blood glucose-lowering agent and show that MLR-1023-mediated blood glucose lowering depends on Lyn kinase activity. These results, coupled with other results (J Pharmacol Exp Ther 342:23-32, 2012), suggest that MLR-1023 and Lyn kinase activation may be a new treatment modality for type 2 diabetes.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

MLR-1023 Is a Potent and Selective Allosteric Activator of Lyn Kinase In Vitro That Improves Glucose Tolerance In Vivo

Saporito

Ochman²,

Lipinski³

et al. 2012

J Pharmacol Exp Ther

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show abstract

“…In the companion article, we show that MLR-1023 is a direct, selective, and potent activator of the nonreceptor Src-related Lyn kinase (Saporito et al, 2012b). In adipocytes, activated Lyn kinase phosphorylates insulin receptor substrate-1 (IRS-1) and increases insulin receptor signaling (Mü ller et al, 2000(Mü ller et al, , 2005. In addition, insulin receptor activation leads to phosphorylation of Lyn kinase, suggesting a potential feedback regulatory loop between insulin receptor activation and Lyn kinase (Anderwald et al, 2002).…”

Section: Introductionmentioning

confidence: 91%

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

Ochman¹,

Lipinski²,

Handler³

et al. 2012

J Pharmacol Exp Ther

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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 ␤-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.

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Personalized Diagnosis and Therapy

Müller¹

2016

Drug Discovery and Evaluation: Pharmacological Assays

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Regulation of lipid raft proteins by glimepiride- and insulin-induced glycosylphosphatidylinositol-specific phospholipase C in rat adipocytes

Cited by 57 publications

References 67 publications

MLR-1023 Is a Potent and Selective Allosteric Activator of Lyn Kinase In Vitro That Improves Glucose Tolerance In Vivo

MLR-1023 Is a Potent and Selective Allosteric Activator of Lyn Kinase In Vitro That Improves Glucose Tolerance In Vivo

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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