TY - JOUR
T1 - 2-(3,4-Dihydro-2H-pyrrolium-1-yl)-3oxoindan-1-olate (DHPO), a novel, synthetic small molecule that alleviates insulin resistance and lipid abnormalities
AU - Kandadi, M.R.
AU - Rajanna, P.K.
AU - Unnikrishnan, M.K.
AU - Boddu, S.P.
AU - Hua, Y.
AU - Li, J.
AU - Du, M.
AU - Ren, J.
AU - Sreejayan, N.
N1 - Cited By :12
Export Date: 10 November 2017
CODEN: BCPCA
Correspondence Address: Sreejayan, N.; University of Wyoming, School of Pharmacy, Division of Pharmaceutical Sciences, Laramie, WY 82071, United States; email: sreejay@uwyo.edu
Chemicals/CAS: acetyl coenzyme A carboxylase, 9023-93-2; adenylate kinase, 9013-02-9; deoxyglucose, 154-17-6; glucose transporter 4, 188071-24-1; protein kinase B, 148640-14-6; wortmannin, 19545-26-7; 2-(3,4-dihydro-2H-pyrrolium-1-yl)-3-oxoindan-1-olate; Blood Glucose; Drugs, Investigational; Hypoglycemic Agents; Indans; Pyrroles; pyrroline, 28350-87-0
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Structure and function of insulin receptors (1989) Diabetes, 38, pp. 1508-1511; Hubbard, S.R., Crystal structure of the activated insulin receptor tyrosine kinase in complex with peptide substrate and ATP analog (1997) EMBO J, 16, pp. 5572-5581; Hilder, T.L., Baer, L.A., Fuller, P.M., Fuller, C.A., Grindeland, R.E., Wade, C.E., Insulin-independent pathways mediating glucose uptake in hindlimb-suspended skeletal muscle (2005) J Appl Physiol, 99, pp. 2181-2188; Lage, R., Dieguez, C., Vidal-Puig, A., Lopez, M., AMPK: a metabolic gauge regulating whole-body energy homeostasis (2008) Trends Mol Med, 14, pp. 539-549; Kahn, B.B., Alquier, T., Carling, D., Hardie, D.G., AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism (2005) Cell Metab, 1, pp. 15-25; Viana, A.Y., Sakoda, H., Anai, M., Fujishiro, M., Ono, H., Kushiyama, A., Role of hepatic AMPK activation in glucose metabolism and dexamethasone-induced regulation of AMPK expression (2006) Diabetes Res Clin Pract, 73, pp. 135-142; Holmes, B.F., Kurth-Kraczek, E.J., Winder, W.W., Chronic activation of 5′-AMP-activated protein kinase increases GLUT-4, hexokinase, and glycogen in muscle (1999) J Appl Physiol, 87, pp. 1990-1995; Fryer, L.G., Parbu-Patel, A., Carling, D., The anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways (2002) J Biol Chem, 277, pp. 25226-25232; Iglesias, M.A., Ye, J.M., Frangioudakis, G., Saha, A.K., Tomas, E., Ruderman, N.B., AICAR administration causes an apparent enhancement of muscle and liver insulin action in insulin-resistant high-fat-fed rats (2002) Diabetes, 51, pp. 2886-2894; Cool, B., Zinker, B., Chiou, W., Kifle, L., Cao, N., Perham, M., Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome (2006) Cell Metab, 3, pp. 403-416; Breen, D.M., Sanli, T., Giacca, A., Tsiani, E., Stimulation of muscle cell glucose uptake by resveratrol through sirtuins and AMPK (2008) Biochem Biophys Res Commun, 374, pp. 117-122; Park, C.E., Kim, M.J., Lee, J.H., Min, B.I., Bae, H., Choe, W., Resveratrol stimulates glucose transport in C2C12 myotubes by activating AMP-activated protein kinase (2007) Exp Mol Med, 39, pp. 222-229; Lee, E.S., Uhm, K.O., Lee, Y.M., Han, M., Lee, M., Park, J.M., CAPE (caffeic acid phenethyl ester) stimulates glucose uptake through AMPK (AMP-activated protein kinase) activation in skeletal muscle cells (2007) Biochem Biophys Res Commun, 361, pp. 854-858; Sanders, M.J., Ali, Z.S., Hegarty, B.D., Heath, R., Snowden, M.A., Carling, D., Defining the mechanism of activation of AMP-activated protein kinase by the small molecule A-769662, a member of the thienopyridone family (2007) J Biol Chem, 282, pp. 32539-32548; Pang, T., Zhang, Z.S., Gu, M., Qiu, B.Y., Yu, L.F., Cao, P.R., Small molecule antagonizes autoinhibition and activates AMP-activated protein kinase in cells (2008) J Biol Chem, 283, pp. 16051-16060; Towler, M.C., Hardie, D.G., AMP-activated protein kinase in metabolic control and insulin signaling (2007) Circ Res, 100, pp. 328-341; Hardie, D.G., Carling, D., The AMP-activated protein kinase-fuel gauge of the mammalian cell? 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PY - 2010
Y1 - 2010
N2 - Type-2 diabetes is growing at epidemic proportions world-wide. This report describes the effect of a novel, synthetic, small molecule 2-(3,4-dihydro-2H-pyrrolium-1-yl)-3oxoindan-1-olate (DHPO), on metabolic abnormalities in genetic and dietary mouse models of type-2 diabetes. DHPO (20 mg/kg/d i.p. for 21 days) attenuated fasting blood glucose, improved glucose disposal and corrected dyslipidemia in genetic (leptin deficient, ob/ob) and dietary (high-fat-fed) mouse models of insulin resistance. In addition, DHPO augmented 2-deoxy-d-glucose (2DG) uptake in gastrocnemius muscles of wild-type mice and in cultured myotubes. The increase in 2DG-uptake was associated with an increase in the phosphorylation of AMPK (thr-172) and its downstream effector acetyl-CoA carboxylase without any changes in the phosphorylation of Akt of insulin receptor. The AMPK inhibitor, compound C attenuated DHPO-induced glucose-uptake whereas the PI3-kinase inhibitor Wortmannin was less effective. In addition, DHPO failed to augment glucose-uptake in the gastrocnemius muscle from AMPK-α2-transgenic (kinase-dead) mice. Taken together, these results suggest that DHPO is a novel small molecule that alleviates impaired glucose tolerance and lipid abnormalities associated with type-2 diabetes. © 2009 Elsevier Inc. All rights reserved.
AB - Type-2 diabetes is growing at epidemic proportions world-wide. This report describes the effect of a novel, synthetic, small molecule 2-(3,4-dihydro-2H-pyrrolium-1-yl)-3oxoindan-1-olate (DHPO), on metabolic abnormalities in genetic and dietary mouse models of type-2 diabetes. DHPO (20 mg/kg/d i.p. for 21 days) attenuated fasting blood glucose, improved glucose disposal and corrected dyslipidemia in genetic (leptin deficient, ob/ob) and dietary (high-fat-fed) mouse models of insulin resistance. In addition, DHPO augmented 2-deoxy-d-glucose (2DG) uptake in gastrocnemius muscles of wild-type mice and in cultured myotubes. The increase in 2DG-uptake was associated with an increase in the phosphorylation of AMPK (thr-172) and its downstream effector acetyl-CoA carboxylase without any changes in the phosphorylation of Akt of insulin receptor. The AMPK inhibitor, compound C attenuated DHPO-induced glucose-uptake whereas the PI3-kinase inhibitor Wortmannin was less effective. In addition, DHPO failed to augment glucose-uptake in the gastrocnemius muscle from AMPK-α2-transgenic (kinase-dead) mice. Taken together, these results suggest that DHPO is a novel small molecule that alleviates impaired glucose tolerance and lipid abnormalities associated with type-2 diabetes. © 2009 Elsevier Inc. All rights reserved.
U2 - 10.1016/j.bcp.2009.09.018
DO - 10.1016/j.bcp.2009.09.018
M3 - Article
SN - 0006-2952
VL - 79
SP - 623
EP - 631
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 4
ER -
