title: Antisense inhibition of S6 kinase 1 produces improved glucose tolerance and is well tolerated for 4 weeks of treatment in rats.
abstract: p70 Ribosomal S6 kinase 1 (S6K1) is implicated in the pathogenesis of type 2 diabetes as knockout mice are hypoinsulinemic, hypersensitive to insulin treatment and are less susceptible to obesity-induced insulin resistance. Although S6K1 knockout mice provide important information on the biology of this target, the therapeutic relevance of S6K1 inhibition in adult animals is unknown. Thus, this research evaluated the potential safety and efficacy of S6K1 inhibition using antisense oligonucleotides (ASO) in mature Sprague-Dawley rats. Male rats treated with S6K1 ASO (25 or 50 mg/kg, 2×/week × 4 weeks) had a marked reduction (>90%) of S6K1 mRNA in the liver and epididymal fat and no effect on hepatic S6K2 expression. The decrease in S6K1 mRNA translated to decreased (>80%) S6K1 protein and kinase activity in the liver at the 50-mg/kg dose. The animals tolerated the S6K1 treatment well with no signs of clinical toxicity. A reduction in body weight gain was observed within 2 weeks of S6K1 ASO treatment. At 4 weeks, body weight gain was reduced by up to 25% in the 50 mg/kg group with a commensurate decrease (14%) in food consumption. A decrease in heart weight in the 50 mg/kg group was observed and not associated with cardiac injury or dysfunction. In an oral glucose tolerance test, S6K1-ASO-treated animals demonstrated a dose-dependent improvement in systemic glucose utilization and had reduced fasting insulin levels. Hepatic gene microarray analysis identified dose-dependent elevations in igfbp1, acss2 and acat2 gene expression in S6K1-ASO-treated animals. These results suggest that inhibition of S6K1 for up to 4 weeks may be therapeutically relevant to induce insulin sensitization and attenuate weight gain with low risk for serious toxicity.
authors.affiliation: Drug Safety Research and Development, La Jolla Laboratories, San Diego, Calif 92008, USA. hyounis@isisph.com
authors.forename: H S
authors.initials: HS
authors.lastname: Younis
authors.forename: B
authors.initials: B
authors.lastname: Hirakawa
authors.forename: W
authors.initials: W
authors.lastname: Scott
authors.forename: P
authors.initials: P
authors.lastname: Tran
authors.forename: G
authors.initials: G
authors.lastname: Bhat
authors.forename: T
authors.initials: T
authors.lastname: Affolter
authors.forename: J
authors.initials: J
authors.lastname: Chapman
authors.forename: J
authors.initials: J
authors.lastname: Heyen
authors.forename: K
authors.initials: K
authors.lastname: Chakravarty
authors.forename: G
authors.initials: G
authors.lastname: Alton
mesh_terms: D000106:Acetate-CoA Ligase / Q000235:genetics / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D018149:Glucose Intolerance / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D006321:Heart / Q000187:drug effects / Q000254:growth & development; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D009929:Organ Size / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors* / Q000235:genetics; D002785:Sterol O-Acyltransferase / Q000235:genetics / Q000378:metabolism; D000097587:Sterol O-Acyltransferase 2
chemical_list: D000106:Acetate-CoA Ligase; D007004:Hypoglycemic Agents; D007328:Insulin; D018970:Insulin-Like Growth Factor Binding Protein 1; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D002785:Sterol O-Acyltransferase; D000097587:Sterol O-Acyltransferase 2; C512963:Rps6ka1 protein, rat