Reduction of low molecular weight protein-tyrosine phosphatase expression improves hyperglycemia and insulin sensitivity in obese mice.
To investigate the role of low molecular weight protein-tyrosine phosphatase (LMW-PTP) in glucose metabolism and insulin action, a specific antisense oligonucleotide (ASO) was used to reduce its expression both in vitro and in vivo. Reduction of LMW-PTP expression with the ASO in cultured mouse hepatocytes and in liver and fat tissues of diet-induced obese (DIO) mice and ob/ob mice led to increased phosphorylation and activity of key insulin signaling intermediates, including insulin receptor-beta subunit, phosphatidylinositol 3-kinase, and Akt in response to insulin stimulation. The ASO-treated DIO and ob/ob animals showed improved insulin sensitivity, which was reflected by a lowering of both plasma insulin and glucose levels and improved glucose and insulin tolerance in DIO mice. The treatment did not decrease body weight or increase metabolic rate. These data demonstrate that LMW-PTP is a key negative regulator of insulin action and a potential novel target for the treatment of insulin resistance and type 2 diabetes.
Pandey
Sanjay K
SK
Metabolic Disease Program, Antisense Drug Discovery, Isis Pharmaceuticals, Carlsbad, CA 92008, USA. spandey@isisph.com
Yu
Xing Xian
XX
Watts
Lynnetta M
LM
Michael
M Dodson
MD
Sloop
Kyle W
KW
Rivard
Amber R
AR
Leedom
Thomas A
TA
Manchem
Vara Prasad
VP
Samadzadeh
Laura
L
McKay
Robert A
RA
Monia
Brett P
BP
Bhanot
Sanjay
S
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D001835:Body Weight; D005951:Glucose Tolerance Test; D022781:Hepatocytes / Q000378:metabolism; D006943:Hyperglycemia / Q000378:metabolism*; D047468:Immunoprecipitation; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction
D001786:Blood Glucose; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D007527:Isoenzymes; D016376:Oligonucleotides, Antisense; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; C490428:Acp1 protein, mouse; D017027:Protein Tyrosine Phosphatases