chir-98014 and Insulin-Resistance

chir-98014 has been researched along with Insulin-Resistance* in 1 studies

Other Studies

1 other study(ies) available for chir-98014 and Insulin-Resistance

Article	Year
Selective glycogen synthase kinase 3 inhibitors potentiate insulin activation of glucose transport and utilization in vitro and in vivo. Diabetes, 2003, Volume: 52, Issue:3 Insulin resistance plays a central role in the development of type 2 diabetes, but the precise defects in insulin action remain to be elucidated. Glycogen synthase kinase 3 (GSK-3) can negatively regulate several aspects of insulin signaling, and elevated levels of GSK-3 have been reported in skeletal muscle from diabetic rodents and humans. A limited amount of information is available regarding the utility of highly selective inhibitors of GSK-3 for the modification of insulin action under conditions of insulin resistance. In the present investigation, we describe novel substituted aminopyrimidine derivatives that inhibit human GSK-3 potently (K(i) < 10 nmol/l) with at least 500-fold selectivity against 20 other protein kinases. These low molecular weight compounds activated glycogen synthase at approximately 100 nmol/l in cultured CHO cells transfected with the insulin receptor and in primary hepatocytes isolated from Sprague-Dawley rats, and at 500 nmol/l in isolated type 1 skeletal muscle of both lean Zucker and ZDF rats. It is interesting that these GSK-3 inhibitors enhanced insulin-stimulated glucose transport in type 1 skeletal muscle from the insulin-resistant ZDF rats but not from insulin-sensitive lean Zucker rats. Single oral or subcutaneous doses of the inhibitors (30-48 mg/kg) rapidly lowered blood glucose levels and improved glucose disposal after oral or intravenous glucose challenges in ZDF rats and db/db mice, without causing hypoglycemia or markedly elevating insulin. Collectively, our results suggest that these selective GSK-3 inhibitors may be useful as acute-acting therapeutics for the treatment of the insulin resistance of type 2 diabetes. Topics: Aminopyridines; Animals; Biological Transport; CHO Cells; Cricetinae; Diabetes Mellitus; Drug Synergism; Enzyme Activation; Enzyme Inhibitors; Female; Gene Expression; Glucose; Glycogen Synthase; Glycogen Synthase Kinase 3; Hepatocytes; Humans; Insulin; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Pyridines; Pyrimidines; Rats; Rats, Sprague-Dawley; Rats, Zucker; Receptor, Insulin; Transfection	2003

Article

Year

Selective glycogen synthase kinase 3 inhibitors potentiate insulin activation of glucose transport and utilization in vitro and in vivo.

Diabetes, 2003, Volume: 52, Issue:3

Insulin resistance plays a central role in the development of type 2 diabetes, but the precise defects in insulin action remain to be elucidated. Glycogen synthase kinase 3 (GSK-3) can negatively regulate several aspects of insulin signaling, and elevated levels of GSK-3 have been reported in skeletal muscle from diabetic rodents and humans. A limited amount of information is available regarding the utility of highly selective inhibitors of GSK-3 for the modification of insulin action under conditions of insulin resistance. In the present investigation, we describe novel substituted aminopyrimidine derivatives that inhibit human GSK-3 potently (K(i) < 10 nmol/l) with at least 500-fold selectivity against 20 other protein kinases. These low molecular weight compounds activated glycogen synthase at approximately 100 nmol/l in cultured CHO cells transfected with the insulin receptor and in primary hepatocytes isolated from Sprague-Dawley rats, and at 500 nmol/l in isolated type 1 skeletal muscle of both lean Zucker and ZDF rats. It is interesting that these GSK-3 inhibitors enhanced insulin-stimulated glucose transport in type 1 skeletal muscle from the insulin-resistant ZDF rats but not from insulin-sensitive lean Zucker rats. Single oral or subcutaneous doses of the inhibitors (30-48 mg/kg) rapidly lowered blood glucose levels and improved glucose disposal after oral or intravenous glucose challenges in ZDF rats and db/db mice, without causing hypoglycemia or markedly elevating insulin. Collectively, our results suggest that these selective GSK-3 inhibitors may be useful as acute-acting therapeutics for the treatment of the insulin resistance of type 2 diabetes.

Topics: Aminopyridines; Animals; Biological Transport; CHO Cells; Cricetinae; Diabetes Mellitus; Drug Synergism; Enzyme Activation; Enzyme Inhibitors; Female; Gene Expression; Glucose; Glycogen Synthase; Glycogen Synthase Kinase 3; Hepatocytes; Humans; Insulin; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Pyridines; Pyrimidines; Rats; Rats, Sprague-Dawley; Rats, Zucker; Receptor, Insulin; Transfection

2003