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- Title
PD153035 (tyrosine kinase inhibitor) Reverses Hyperglycemia and Improves Insulin Sensitivity in DIO Mice.
- Authors
Prada, Patricia O.; Mourão, Rosa H.; De Souza, Claudio T.; Pauli, Jose R.; Ropelle, Eduardo R.; Rocco, Silvana A.; Carvalheira, José B.; Velloso, Lício A.; Franchinni, Kleber G.; Saad, Mario J.
- Abstract
Recent papers reported that tyrosine kinase inhibitors used for cancer treatment may improve insulin sensitivity in type 2 diabetes. However, the molecular mechanism by which these drugs improve insulin sensitivity has not yet been established. In this study, six-week-old male Swiss mice were divided into four groups with similar body weights and assigned to receive a standard rodent chow (C) or a high fat diet (HF). After 2 months, HF-mice were treated with PD153035 (30 mg/kg) (HFPD) or vehicle (HFV) by gavage once a day for 7 day. Insulin signaling was investigated by using immunoprecipitation/immunoblotting assays. PD153035 did not change the body weight, but reduced serum insulin and plasma glucose levels compared to HF and HFV groups. Intraperitoneal GTT and ITT demonstrated improvement of insulin sensitivity in HFPD group compared to HF and HFV. Adiponectin serum levels were higher and leptin and free fatty acids serum levels were lower in HFPD group compared to HF/HFV groups. These results were associated with an increase in insulin-induced PI3-K/Akt pathway in liver, muscle and adipose tissue. In parallel we investigated the expression of pro-inflammatory cytokines and serine/kinases involved in the pathogenesis of insulin resistance. PD153035 significantly decreased tissue expression of TNFα IL-6, p-JNK and IRS-1[sup ser307] in liver, muscle and adipose tissue and TNFα and IL-6 serum levels of DIO mice. There was also a decrease in NFκB[sub 65] linked to DNA in these tissues of HFPD-mice compared to HF and HFV groups. In summary, these results demonstrate that treatment with PD153035 improve insulin sensitivity, reduces hyperglicemia and increase PI-3K/Akt pathway, in parallel to a reduction in the expression of pro-inflammatory cytokines and serine kinases involved in the pathogenesis of insulin resistance.
- Subjects
HYPERGLYCEMIA; INSULIN resistance; ENZYME inhibitors; TYPE 2 diabetes; MICE
- Publication
Diabetes, 2007, Vol 56, pA65
- ISSN
0012-1797
- Publication type
Article