2-(3,4-Dihydro-2H-pyrrolium-1-yl)-3oxoindan-1-olate (DHPO), a novel, synthetic small molecule that alleviates insulin resistance and lipid abnormalities

M.R. Kandadi, P.K. Rajanna, M.K. Unnikrishnan, S.P. Boddu, Y. Hua, J. Li, M. Du, J. Ren, N. Sreejayan

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)623-631
Number of pages9
JournalBiochemical Pharmacology
Volume79
Issue number4
DOIs
Publication statusPublished - 2010

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Insulin Resistance
AMP-Activated Protein Kinases
Insulin
Lipids
Glucose
Molecules
Type 2 Diabetes Mellitus
Medical problems
Phosphorylation
Skeletal Muscle
Muscle
Acetyl-CoA Carboxylase
Glucose Intolerance
Dietary Fats
Insulin Receptor
Skeletal Muscle Fibers
Dyslipidemias
Leptin
Phosphatidylinositol 3-Kinases
Blood Glucose

Cite this

Kandadi, M.R. ; Rajanna, P.K. ; Unnikrishnan, M.K. ; Boddu, S.P. ; Hua, Y. ; Li, J. ; Du, M. ; Ren, J. ; Sreejayan, N. / 2-(3,4-Dihydro-2H-pyrrolium-1-yl)-3oxoindan-1-olate (DHPO), a novel, synthetic small molecule that alleviates insulin resistance and lipid abnormalities. In: Biochemical Pharmacology. 2010 ; Vol. 79, No. 4. pp. 623-631.
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title = "2-(3,4-Dihydro-2H-pyrrolium-1-yl)-3oxoindan-1-olate (DHPO), a novel, synthetic small molecule that alleviates insulin resistance and lipid abnormalities",
abstract = "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. {\circledC} 2009 Elsevier Inc. All rights reserved.",
author = "M.R. Kandadi and P.K. Rajanna and M.K. Unnikrishnan and S.P. Boddu and Y. Hua and J. Li and M. Du and J. Ren and N. Sreejayan",
note = "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 References: DeFronzo, R.A., Pathogenesis of type 2 diabetes mellitus (2004) Med Clin North Am, 88, pp. 787-835. , ix; Karlsson, H.K., Ahlsen, M., Zierath, J.R., Wallberg-Henriksson, H., Koistinen, H.A., Insulin signaling and glucose transport in skeletal muscle from first-degree relatives of type 2 diabetic patients (2006) Diabetes, 55, pp. 1283-1288; DeFronzo, R.A., Ferrannini, E., Simonson, D.C., Fasting hyperglycemia in non-insulin-dependent diabetes mellitus: contributions of excessive hepatic glucose production and impaired tissue glucose uptake (1989) Metabolism, 38, pp. 387-395; Storgaard, H., Song, X.M., Jensen, C.B., Madsbad, S., Bjornholm, M., Vaag, A., Insulin signal transduction in skeletal muscle from glucose-intolerant relatives of type 2 diabetic patients [corrected] (2001) Diabetes, 50, pp. 2770-2778; Knowler, W.C., Barrett-Connor, E., Fowler, S.E., Hamman, R.F., Lachin, J.M., Walker, E.A., Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin (2002) N Engl J Med, 346, pp. 393-403; Prabhakar, K.R., Veerapur, V.P., Bansal, P., Vipan, K.P., Reddy, K.M., Barik, A., Identification and evaluation of antioxidant, analgesic/anti-inflammatory activity of the most active ninhydrin-phenol adducts synthesized (2006) Bioorg Med Chem, 14, pp. 7113-7120; Sreejayan, N., Dong, F., Kandadi, M.R., Yang, X., Ren, J., Chromium alleviates glucose intolerance, insulin resistance, and hepatic ER stress in obese mice (2008) Obesity (Silver Spring), 16, pp. 1331-1337; Nedachi, T., Kanzaki, M., Regulation of glucose transporters by insulin and extracellular glucose in C2C12 myotubes (2006) Am J Physiol Endocrinol Metab, 291, pp. E817-E828; Dong, F., Kandadi, M.R., Ren, J., Sreejayan, N., Chromium (d-phenylalanine)3 supplementation alters glucose disposal, insulin signaling, and glucose transporter-4 membrane translocation in insulin-resistant mice (2008) J Nutr, 138, pp. 1846-1851; Kurowski, T.G., Lin, Y., Luo, Z., Tsichlis, P.N., Buse, M.G., Heydrick, S.J., Hyperglycemia inhibits insulin activation of Akt/protein kinase B but not phosphatidylinositol 3-kinase in rat skeletal muscle (1999) Diabetes, 48, pp. 658-663; Miller, E.J., Li, J., Leng, L., McDonald, C., Atsumi, T., Bucala, R., Macrophage migration inhibitory factor stimulates AMP-activated protein kinase in the ischaemic heart (2008) Nature, 451, pp. 578-582; Rosen, O.M., Banting lecture 1989. 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? (1997) Eur J Biochem, 246, pp. 259-273; Abu-Elheiga, L., Matzuk, M.M., Abo-Hashema, K.A., Wakil, S.J., Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2 (2001) Science, 291, pp. 2613-2616; Minokoshi, Y., Kim, Y.B., Peroni, O.D., Fryer, L.G., Muller, C., Carling, D., Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase (2002) Nature, 415, pp. 339-343; Zang, M., AMP-activated protein kinase is required for the lipid-lowering effect of metformin in insulin-resistant human HepG2 cells (2004) J Biol Chem, 279, pp. 47898-47905; Yang, X., Li, S.Y., Dong, F., Ren, J., Sreejayan, N., Insulin-sensitizing and cholesterol-lowering effects of chromium (d-Phenylalanine)3 (2006) J Inorg Biochem, 100, pp. 1187-1193",
year = "2010",
doi = "10.1016/j.bcp.2009.09.018",
language = "English",
volume = "79",
pages = "623--631",
journal = "Biochemical Pharmacology",
issn = "0006-2952",
publisher = "Elsevier Inc.",
number = "4",

}

2-(3,4-Dihydro-2H-pyrrolium-1-yl)-3oxoindan-1-olate (DHPO), a novel, synthetic small molecule that alleviates insulin resistance and lipid abnormalities. / Kandadi, M.R.; Rajanna, P.K.; Unnikrishnan, M.K.; Boddu, S.P.; Hua, Y.; Li, J.; Du, M.; Ren, J.; Sreejayan, N.

In: Biochemical Pharmacology, Vol. 79, No. 4, 2010, p. 623-631.

Research output: Contribution to journalArticle

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 References: DeFronzo, R.A., Pathogenesis of type 2 diabetes mellitus (2004) Med Clin North Am, 88, pp. 787-835. , ix; Karlsson, H.K., Ahlsen, M., Zierath, J.R., Wallberg-Henriksson, H., Koistinen, H.A., Insulin signaling and glucose transport in skeletal muscle from first-degree relatives of type 2 diabetic patients (2006) Diabetes, 55, pp. 1283-1288; DeFronzo, R.A., Ferrannini, E., Simonson, D.C., Fasting hyperglycemia in non-insulin-dependent diabetes mellitus: contributions of excessive hepatic glucose production and impaired tissue glucose uptake (1989) Metabolism, 38, pp. 387-395; Storgaard, H., Song, X.M., Jensen, C.B., Madsbad, S., Bjornholm, M., Vaag, A., Insulin signal transduction in skeletal muscle from glucose-intolerant relatives of type 2 diabetic patients [corrected] (2001) Diabetes, 50, pp. 2770-2778; Knowler, W.C., Barrett-Connor, E., Fowler, S.E., Hamman, R.F., Lachin, J.M., Walker, E.A., Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin (2002) N Engl J Med, 346, pp. 393-403; Prabhakar, K.R., Veerapur, V.P., Bansal, P., Vipan, K.P., Reddy, K.M., Barik, A., Identification and evaluation of antioxidant, analgesic/anti-inflammatory activity of the most active ninhydrin-phenol adducts synthesized (2006) Bioorg Med Chem, 14, pp. 7113-7120; Sreejayan, N., Dong, F., Kandadi, M.R., Yang, X., Ren, J., Chromium alleviates glucose intolerance, insulin resistance, and hepatic ER stress in obese mice (2008) Obesity (Silver Spring), 16, pp. 1331-1337; Nedachi, T., Kanzaki, M., Regulation of glucose transporters by insulin and extracellular glucose in C2C12 myotubes (2006) Am J Physiol Endocrinol Metab, 291, pp. E817-E828; Dong, F., Kandadi, M.R., Ren, J., Sreejayan, N., Chromium (d-phenylalanine)3 supplementation alters glucose disposal, insulin signaling, and glucose transporter-4 membrane translocation in insulin-resistant mice (2008) J Nutr, 138, pp. 1846-1851; Kurowski, T.G., Lin, Y., Luo, Z., Tsichlis, P.N., Buse, M.G., Heydrick, S.J., Hyperglycemia inhibits insulin activation of Akt/protein kinase B but not phosphatidylinositol 3-kinase in rat skeletal muscle (1999) Diabetes, 48, pp. 658-663; Miller, E.J., Li, J., Leng, L., McDonald, C., Atsumi, T., Bucala, R., Macrophage migration inhibitory factor stimulates AMP-activated protein kinase in the ischaemic heart (2008) Nature, 451, pp. 578-582; Rosen, O.M., Banting lecture 1989. 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? (1997) Eur J Biochem, 246, pp. 259-273; Abu-Elheiga, L., Matzuk, M.M., Abo-Hashema, K.A., Wakil, S.J., Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2 (2001) Science, 291, pp. 2613-2616; Minokoshi, Y., Kim, Y.B., Peroni, O.D., Fryer, L.G., Muller, C., Carling, D., Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase (2002) Nature, 415, pp. 339-343; Zang, M., AMP-activated protein kinase is required for the lipid-lowering effect of metformin in insulin-resistant human HepG2 cells (2004) J Biol Chem, 279, pp. 47898-47905; Yang, X., Li, S.Y., Dong, F., Ren, J., Sreejayan, N., Insulin-sensitizing and cholesterol-lowering effects of chromium (d-Phenylalanine)3 (2006) J Inorg Biochem, 100, pp. 1187-1193

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

VL - 79

SP - 623

EP - 631

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

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ER -