Pharmacological targeting of adipocytes/fat metabolism for treatment of obesity and diabetes

Molecular Pharmacology

Volumn 70, Issue 3, 2006, Pages 779-785

  Pilch, Paul F ^a   Bergenhem, Nils ^b  

^a BOSTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b AdipoGenix   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACYL COENZYME A DESATURASE; ADIPOCYTOKINE; ADIPONECTIN; AMG 221; ANTIOBESITY AGENT; BIOVITRUM; CBL PROTEIN; DIACYLGLYCEROL ACYLTRANSFERASE; IDD 3848; INSULIN; ISIS 113715; LEPTIN; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; PIOGLITAZONE; PROTEIN TYROSINE PHOSPHATASE 1B; RESISTIN; RIMONABANT; ROSIGLITAZONE; TROGLITAZONE; UNCLASSIFIED DRUG; XENON;

ADIPOCYTE; DIABETES MELLITUS; DRUG TARGETING; ENERGY BALANCE; HUMAN; INSULIN SENSITIVITY; LIPID METABOLISM; LIVER TOXICITY; NONHUMAN; OBESITY; PRIORITY JOURNAL; SHORT SURVEY;

ADIPOCYTES; ANIMALS; DIABETES MELLITUS, TYPE 2; ENERGY METABOLISM; HUMANS; LIPID METABOLISM; OBESITY;

EID: 33747627853     PISSN: 0026895X     EISSN: 15210111     Source Type: Journal    
DOI: 10.1124/mol.106.026104     Document Type: Short Survey

References (97)

1. Abu-Elheiga L, Matzuk MM, Abo-Hashema KA, and Wakil SJ (2001) Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2. Science (Wash DC) 291:2613-2616.
2. Abu-Elheiga L, Oh W, Kordari P, and Wakil SJ (2003) Acetyl-CoA carboxylase 2 mutant mice are protected against obesity and diabetes induced by high-fat/high-carbohydrate diets. Proc Natl Acad Sci USA 100:10207-10212.
3. Arner P (2005) Resistin: yet another adipokine tells us that men are not mice. Diabetologia 48:2203-2205.
4. Aronoff S, Rosenblatt S, Braithwaite S, Egan JW, Mathisen AL, and Schneider RL (2000) Pioglitazone hydrochloride monotherapy improves glycemic control in the treatment of patients with type 2 diabetes: a 6-month randomized placebo-controlled dose-response study. The Pioglitazone 001 Study Group. Diabetes Care 23:1605-1611.
5. Barnes BR and Zierath JR (2005) Role of AMP-activated protein kinase in the control of glucose homeostasis. Curr Mol Med 5:341-348.
6. Baumann CA, Ribon V, Kanzaki M, Thurmond DC, Mora S, Shigematsu S, Bickel PE, Pessin JE, and Saltiel AR (2000) CAP defines a second signalling pathway required for insulin-stimulated glucose transport. Nature (Lond) 407:202-207.
7. Berg AH, Combs TP, Du X, Brownlee M, and Scherer PE (2001) The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med 7:947-953.
8. Berg AH, Combs TP, and Scherer PE (2002) ACRP30/adiponectin: an adipokine regulating glucose and lipid metabolism. Trends Endocrinol Metab 13:84-89.
9. Berger JP, Petro AE, Macnaul KL, Kelly LJ, Zhang BB, Richards K, Elbrecht A, Johnson BA, Zhou G, Doebber TW, et al. (2003) Distinct properties and advantages of a novel peroxisome proliferator-activated protein [gamma] selective modulator. Mol Endocrinol 17:662-676.
10. Bergman RN (1997) New concepts in extracellular signaling for insulin action: the single gateway hypothesis. Recent Prog Horm Res 52:359-385; discussion 385-357.
11. Bjorbaek C and Kahn BB (2004) Leptin signaling in the central nervous system and the periphery. Recent Prog Horm Res 59:305-331.
12. Calera MR, Vallega G, and Pilch PF (2000) Dynamics of protein-tyrosine phosphatases in rat adipocytes. J Biol Chem 275:6308-6312.
13. Chen HC (2006) Enhancing energy and glucose metabolism by disrupting triglyceride synthesis: lessons from mice lacking DGAT1. Nutr Metab (Lond) 3:10.
14. Chen HC, Jensen DR, Myers HM, Eckel RH, and Farese RV Jr (2003) Obesity resistance and enhanced glucose metabolism in mice transplanted with white adipose tissue lacking acyl CoA:diacylglycerol acyltransferase 1. J Clin Investig 111:1715-1722.
15. Chen HC, Smith SJ, Ladha Z, Jensen DR, Ferreira LD, Pulawa LK, McGuire JG, Pitas RE, Eckel RH, and Farese RV Jr (2002) Increased insulin and leptin sensitivity in mice lacking acyl CoA:diacylglycerol acyltransferase 1. J Clin Investig 109:1049-1055.
16. Cheng A, Uetani N, Simoncic PD, Chaubey VP, Lee-Loy A, McGlade CJ, Kennedy BP, and Tremblay ML (2002) Attenuation of leptin action and regulation of obesity by protein tyrosine phosphatase 1B. Dev Cell 2:497-503.
17. Chinetti-Gbaguidi G, Fruchart JC, and Staels B (2005) Role of the PPAR family of nuclear receptors in the regulation of metabolic and cardiovascular homeostasis: new approaches to therapy. Curr Opin Pharmacol 5:177-183.
18. Cohen P and Friedman JM (2004) Leptin and the control of metabolism: role for stearoyl-CoA desaturase-1 (SCD-1). J Nutr 134:2455S-2463S.
19. Combs TP, Berg AH, Obici S, Scherer PE, and Rossetti L (2001) Endogenous glucose production is inhibited by the adipose-derived protein Acrp30. J Clin Investig 108:1875-1881.
20. Crowley V and Vidal-Puig AJ (2001) Mitochondrial uncoupling proteins (UCPs) and obesity. Nutr Metab Cardiovasc Dis 11:70-75.
21. Drevon CA (2005) Fatty acids and expression of adipokines. Biochim Biophys Acta 1740:287-292.
22. Dube N and Tremblay ML (2005) Involvement of the small protein tyrosine phosphatases TC-PTP and PTP1B in signal transduction and diseases: from diabetes, obesity to cell cycle, and cancer. Biochim Biophys Acta 1754:108-117.
23. Elchebly M, Payette P, Michaliszyn E, Cromlish W, Collins S, Loy AL, Normandin D, Cheng A, Himms-Hagen J, Chan CC, et al. (1999) Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science (Wash DC) 283:1544-1548.
24. El-Huge J (2005) Peroxisome proliferation-activated receptor agonists: carcinogenicity findings and regulatory recommendations. International Atherosclerosis Society Symposium on PPAR, Monte Carlo.
25. Evans RM, Barish GD, and Wang YX (2004) PPARs and the complex journey to obesity. Nat Med 10:355-361.
26. Fagerberg B, Edwards S, Halmos T, Lopatynski J, Schuster H, Stender S, Stoa-Birketvedt G, Tonstad S, Halldorsdottir S, and Gause-Nilsson I (2005) Tesaglitazar, a novel dual peroxisome proliferator-activated receptor alpha/gamma agonist, dose-dependently improves the metabolic abnormalities associated with insulin resistance in a non-diabetic population. Diabetologia 48:1716-1725.
27. Farmer SR and Auwerx J (2004) Adipose tissue: new therapeutic targets from molecular and genetic studies-IASO Stock Conference 2003 report. Obes Rev 5:189-196.
28. Farooqi IS, Matarese G, Lord GM, Keogh JM, Lawrence E, Agwu C, Sanna V, Jebb SA, Perna F, Fontana S, et al. (2002) Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J Clin Investig 110:1093-1103.
29. Febbraio M, Abumrad NA, Hajjar DP, Sharma K, Cheng W, Pearce SF, and Silverstein RL (1999) A null mutation in murine CD36 reveals an important role in fatty acid and lipoprotein metabolism. J Biol Chem 274:19055-19062.
30. Flier JS (2004) Obesity wars: molecular progress confronts an expanding epidemic. Cell 116:337-350.
31. Friedman JM (1998) Leptin, leptin receptors, and the control of body weight. Nutr Rev 56 (2 Pt 2):s38-s46; discussion s54-s75.
32. Friedman TC, Mastorakos G, Newman TD, Mullen NM, Horton EG, Costello R, Papadopoulos NM, and Chrousos GP (1996) Carbohydrate and lipid metabolism in endogenous hypercortisolism: shared features with metabolic syndrome X and NIDDM. Endocr J 43:645-655.
33. Fruebis J, Tsao TS, Javorschi S, Ebbets-Reed D, Erickson MR, Yen FT, Bihain BE, and Lodish HF (2001) Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proc Natl Acad Sci USA 98:2005-2010.
34. Fukuhara A, Matsuda M, Nishizawa M, Segawa K, Tanaka M, Kishimoto K, Matsuki Y, Murakami M, Ichisaka T, Murakami H, et al. (2005) Visfatin: a protein secreted by visceral fat that mimics the effects of insulin. Science (Wash DC) 307:426-430.
35. Garber K (2005) Missing the target: ubiquitin ligase drugs stall. J Natl Cancer Inst 97:166-167.
36. Gary-Bobo M, Elachouri G, Scatton B, Le Fur G, Oury-Donat F, and Bensaid M (2006) The cannabinoid CB1 receptor antagonist rimonabant (SR141716) inhibits cell proliferation and increases markers of adipocyte maturation in cultured mouse 3T3 F442A preadipocytes. Mol Pharmacol 69:471-478.
37. Glass CK (2006) Going nuclear in metabolic and cardiovascular disease. J Clin Investig 116:556-560.
38. Gum RJ, Gaede LL, Koterski SL, Heindel M, Clampit JE, Zinker BA, Trevillyan JM, Ulrich RG, Jirousek MR, and Rondinone CM (2003) Reduction of protein tyrosine phosphatase 1B increases insulin-dependent signaling in ob/ob mice. Diabetes 52:21-28.
39. Hauner H (2004) Orlistat, in Pharmacotherapy of Obesity: Options and Alternatives (Hofbauer KG, Keller U, and Boss O eds) pp 219-243, CRC Press, Boca Raton, FL.
40. Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, Lallone RL, Burley SK, and Friedman JM (1995) Weight-reducing effects of the plasma protein encoded by the obese gene. Science (Wash DC) 269:543-546.
41. Halford JC (2006) Obesity drugs in clinical development. Curr Opin Investig Drugs 7:312-318.
42. Hamilton JA and Kamp F (1999) How are free fatty acids transported in membranes? Is it by proteins or by free diffusion through the lipids? Diabetes 48:2255-2269.
43. Harwood HJ Jr (2004) Acetyl-CoA carboxylase inhibition for the treatment of metabolic syndrome. Curr Opin Investig Drugs 5:283-289.
44. Heymsfield SB, Greenberg AS, Fujioka K, Dixon RM, Kushner R, Hunt T, Lubina JA, Patane J, Self B, Hunt P, et al. (1999) Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. J Am Med Assoc 282:1568-1575.
45. Hussein Z, Wentworth JM, Nankervis AJ, Proietto J, and Colman PG (2004) Effectiveness and side effects of thiazolidinediones for type 2 diabetes: real-life experience from a tertiary hospital. Med J Aust 181:536-539.
46. Javor ED, Cochran EK, Musso C, Young JR, Depaoli AM, and Gorden P (2005) Long-term efficacy of leptin replacement in patients with generalized lipodystrophy. Diabetes 54:1994-2002.
47. Jbilo O, Ravinet-Trillou C, Arnone M, Buisson I, Bribes E, Peleraux A, Penarier G, Soubrie P, Le Fur G, Galiegue S, et al. (2005) The CB1 receptor antagonist rimonabant reverses the diet-induced obesity phenotype through the regulation of lipolysis and energy balance. FASEB J 19:1567-1569.
48. Jiang G, Li Z, Liu F, Ellsworth K, Dallas-Yang Q, Wu M, Ronan J, Esau C, Murphy C, Szalkowski D, et al. (2005) Prevention of obesity in mice by antisense oligonucleotide inhibitors of stearoyl-CoA desaturase-1. J Clin Investig 115:1030-1038.
49. Johnson TO, Ermolieff J, and Jirousek MR (2002) Protein tyrosine phosphatase 1B inhibitors for diabetes. Nat Rev Drug Discov 1:696-709.
50. Kadowaki T and Yamauchi T (2005) Adiponectin and adiponectin receptors. Endocr Rev 26:439-451.
51. Kahn BB, Alquier T, Carling D, and Hardie DG (2005) AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab 1:15-25.
52. Kannisto K, Pietilainen KH, Ehrenborg E, Rissanen A, Kaprio J, Hamsten A, and Yki-Jarvinen H (2004) Overexpression of 11beta-hydroxysteroid dehydrogenase-1 in adipose tissue is associated with acquired obesity and features of insulin resistance: studies in young adult monozygotic twins. J Clin Endocrinol Metab 89:4414-4421.
53. Klaman LD, Boss O, Peroni OD, Kim JK, Martino JL, Zabolotny JM, Moghal N, Lubkin M, Kim YB, Sharpe AH, et al. (2000) Increased energy expenditure, decreased adiposity, and tissue-specific insulin sensitivity in protein-tyrosine phosphatase 1B-deficient mice. Mol Cell Biol 20:5479-5489.
54. Klein S, Coppack SW, Mohamed-Ali V, and Landt M (1996) Adipose tissue leptin production and plasma leptin kinetics in humans. Diabetes 45:984-987.
55. Kubota N, Terauchi Y, Miki H, Tamemoto H, Yamauchi T, Komeda K, Satoh S, Nakano R, Ishii C, Sugiyama T, et al. (1999) PPAR gamma mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance. Mol Cell 4:597-609.
56. Lazar MA (2005) PPAR gamma, 10 years later. Biochimie 87:9-13.
57. Lihn AS, Pedersen SB, and Richelsen B (2005) Adiponectin: action, regulation and association to insulin sensitivity. Obes Rev 6:13-21.
58. Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, Fei H, Kim S, Lallone R, Ranganathan S, et al. (1995) Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med 1:1155-1161.
59. Melnikova I and Wages D (2006) Anti-obesity therapies. Nat Rev Drug Disc 5:369-370.
60. Michalik L and Wahli W (2006) Involvement of PPAR nuclear receptors in tissue injury and wound repair. J Clin Investig 116:598-606.
61. Miles PD, Barak Y, He W, Evans RM, and Olefsky JM (2000) Improved insulin-sensitivity in mice heterozygous for PPAR-gamma deficiency. J Clin Investig 105:287-292.
62. Mitra P, Zheng X, and Czech MP (2004) RNAi-based analysis of CAP, Cbl, and CrkII function in the regulation of GLUT4 by insulin. J Biol Chem 279:37431-37435.
63. Miyazaki M, Kim YC, Gray-Keller MP, Attie AD, and Ntambi JM (2000) The biosynthesis of hepatic cholesterol esters and triglycerides is impaired in mice with a disruption of the gene for stearoyl-CoA desaturase 1. J Biol Chem 275:30132-30138.
64. Miyazaki M, Man WC, and Ntambi JM (2001) Targeted disruption of stearoyl-CoA desaturase1 gene in mice causes atrophy of sebaceous and meibomian glands and depletion of wax esters in the eyelid. J Nutr 131:2260-2268.
65. Molero JC, Jensen TE, Withers PC, Couzens M, Herzog H, Thien CB, Langdon WY, Walder K, Murphy MA, Bowtell DD, et al. (2004) c-Cbl-deficient mice have reduced adiposity, higher energy expenditure, and improved peripheral insulin action. J Clin Investig 114:1326-1333.
66. Molero JC, Waring SG, Cooper A, Turner N, Laybutt R, Cooney GJ, and James DE (2006) Casitas b-lineage lymphoma-deficient mice are protected against high-fat diet-induced obesity and insulin resistance. Diabetes 55:708-715.
67. Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ, Sewter CP, Digby JE, Mohammed SN, Hurst JA, et al. (1997) Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature (Lond) 387:903-908.
68. Morton NM, Paterson JM, Masuzaki H, Holmes MC, Staels B, Fievet C, Walker BR, Flier JS, Mullins JJ, and Seckl JR (2004) Novel adipose tissue-mediated resistance to diet-induced visceral obesity in 11 beta-hydroxysteroid dehydrogenase type 1-deficient mice. Diabetes 53:931-938.
69. Munzberg H, Bjornholm M, Bates SH, and Myers MG Jr (2005) Leptin receptor action and mechanisms of leptin resistance. Cell Mol Life Sci 62:642-652.
70. Nissen SE, Wolski K, and Topol EJ (2005) Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. J Am Med Assoc 294:2581-2586.
71. Ntambi JM, Buhrow SA, Kaestner KH, Christy RJ, Sibley E, Kelly TJ Jr and Lane MD. Differentiation-induced gene expression in 3T3-L1 preadipocytes (1988) Characterization of a differentially expressed gene encoding stearoyl-CoA desaturase. J Biol Chem 263:17291-17300.
72. Ntambi JM, Miyazaki M, Stoehr JP, Lan H, Kendziorski CM, Yandell BS, Song Y, Cohen P, Friedman JM, and Attie AD (2002) Loss of stearoyl-CoA desaturase-1 function protects mice against adiposity. Proc Natl Acad Sci USA 99:11482-11486.
73. Pajvani UB, Hawkins M, Combs TP, Rajala MW, Doebber T, Berger JP, Wagner JA, Wu M, Knopps A, Xiang AH, et al. (2004) Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity. J Biol Chem 279:12152-12162.
74. Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, Boone T, and Collins F (1995) Effects of the obese gene product on body weight regulation in ob/ob mice. Science (Wash DC) 269:540-543.
75. Phillips LS, Grunberger G, Miller E, Patwardhan R, Rappaport EB, and Salzman A (2001) Once- and twice-daily dosing with rosiglitazone improves glycemic control in patients with type 2 diabetes. Diabetes Care 24:308-315.
76. Puigserver P (2005) Tissue-specific regulation of metabolic pathways through the transcriptional coactivator PGC1-alpha. Int J Obes (Lond) 29 (Suppl 1):S5-S9.
77. Rieusset J, Touri F, Michalik L, Escher P, Desvergne B, Niesor E, and Wahli W (2002) A new selective peroxisome proliferator-activated receptor gamma antagonist with antiobesity and antidiabetic activity. Mol Endocrinol 16:2628-2644.
78. Rondinone CM, Trevillyan JM, Clampit J, Gum RJ, Berg C, Kroeger P, Frost L, Zinker BA, Reilly R, Ulrich R, et al. (2002) Protein tyrosine phosphatase 1B reduction regulates adiposity and expression of genes involved in lipogenesis. Diabetes 51:2405-2411.
79. Ryan D (2004) Sibutramine, in Pharmacotherapy of Obesity: Options and Alternatives (Hofbauer KG, Keller U, and Boss O eds) pp 245-266, CRC Press, Boca Raton, FL.
80. Schaffler A, Neumeier M, Herfarth H, Furst A, Scholmerich J, and Buchler C (2005) Genomic structure of human omentin, a new adipocytokine expressed in omental adipose tissue. Biochim Biophys Acta 1732:96-102.
81. Semple RK, Chatterjee VK, and O'Rahilly S (2006) PPARgamma and human metabolic disease. J Clin Investig 116:581-589
82. Smith SJ, Cases S, Jensen DR, Chen HC, Sande E, Tow B, Sanan DA, Raber J, Eckel RH, and Farese RV Jr (2000) Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking Dgat. Nat Genet 25:87-90.
83. Spiegelman BM, Hu E, Kim JB, and Brun R (1997) PPAR gamma and the control of adipogenesis. Biochimie 79:111-112.
84. Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, and Fruchart JC (1998) Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation 98:2088-2093.
85. Stephens JM and Vidal-Puig AJ (2006) An update on visfatin/pre-B cell colony-enhancing factor, an ubiquitously expressed, illusive cytokine that is regulated in obesity. Curr Opin Lipidol 17:128-131.
86. Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, and Lazar MA (2001) The hormone resistin links obesity to diabetes. Nature (Lond) 409:307-312.
87. Thien CB and Langdon WY (2005) c-Cbl and Cbl-b ubiquitin ligases: substrate diversity and the negative regulation of signalling responses. Biochem J 391 (Pt 2):153-166.
88. Wadman M (2006) Rimonabant adds appetizing choice to slim obesity market. Nat Med 12:27.
89. Yamauchi T, Kamon J, Waki H, Murakami K, Motojima K, Komeda K, Ide T, Kubota N, Terauchi Y, Tobe K, et al. (2001) The mechanisms by which both heterozygous peroxisome proliferator-activated receptor gamma (PPARγ) deficiency and PPARγ agonist improve insulin resistance. J Biol Chem 276:41245-41254.
90. Yang Q, Graham TE, Mody N, Preitner F, Peroni OD, Zabolotny JM, Kotani K, Quadro L, and Kahn BB (2005) Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature (Lond) 436:356-362.
91. Yang RZ, Lee MJ, Hu H, Pray J, Wu HB, Hansen BC, Shuldiner AR, Fried SK, McLenithan J, and Gong DW (2006) Identification of omentin as a novel depot-specific adipokine in human adipose tissue: possible role in modulating insulin action. Am J Physiol 290:E1253-E1261.
92. Yang WS, Jeng CY, Wu TJ, Tanaka S, Funahashi T, Matsuzawa Y, Wang JP, Chen CL, Tai TY, and Chuang LM (2002) Synthetic peroxisome proliferator- activated receptor-gamma agonist, rosiglitazone, increases plasma levels of adiponectin in type 2 diabetic patients. Diabetes Care 25:376-380.
93. Yki-Jarvinen H (2004) Thiazolidinediones. N Engl J Med 351:1106-1118.
94. Zabolotny JM, Bence-Hanulec KK, Stricker-Krongrad A, Haj F, Wang Y, Minokoshi Y, Kim YB, Elmquist JK, Tartaglia LA, Kahn BB, et al. (2002) PTP1B regulates leptin signal transduction in vivo. Dev Cell 2:489-495.
95. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, and Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature (Lond) 372:425-432.
96. Zheng Y, Eilertsen KJ, Ge L, Zhang L, Sundberg JP, Prouty SM, Stenn KS, and Parimoo S (1999) Scd1 is expressed in sebaceous glands and is disrupted in the asebia mouse. Nat Genet 23:268-270.
97. Zinker BA, Rondinone CM, Trevillyan JM, Gum RJ, Clampit JE, Waring JF, Xie N, Wilcox D, Jacobson P, Frost L, et al. (2002) PTP1B antisense oligonucleotide lowers PTP1B protein, normalizes blood glucose, and improves insulin sensitivity in diabetic mice. Proc Natl Acad Sci USA 99:11357-11362.