Effect of rosuvastatin on insulin sensitivity in an animal model of insulin resistance: evidence for statin-induced hepatic insulin sensitization.
Statin-treatment of fructose-fed/insulin resistant hamsters was recently shown to ameliorate metabolic dyslipidemia and hepatic VLDL overproduction. Here, we provide evidence that rosuvastatin treatment of insulin resistant hamsters can induce improvements in hepatic and whole body insulin sensitivity. Treatment with 10 mg/kg/day rosuvastatin for 10 days significantly reduced fasting insulin (-59%) and triglyceride (-50%) levels in fructose-fed hamsters (p<0.05). Following an intraperitoneal (IP) glucose challenge, rosuvastatin-treated hamsters exhibited enhanced glucose clearance compared to untreated hamsters maintained on the high-fructose diet (area under curve (AUC)=1772+/-223 mM min vs. 2413+/-253 mM min, respectively; p<0.002) with a significant reduction in 2h post-challenge glucose (n=5, p<0.02). Rosuvastatin-treatment also significantly improved sensitivity to an IP insulin challenge (AUC=314+/-39 mM min vs. 195+/-22 mM min for rosuvastatin-treated and fructose-fed hamsters, respectively; p<0.04, n=3). At the molecular level, significant increases in tyrosine-phosphorylation of the hepatic insulin receptor and IRS-1 were observed for rosuvastatin-treated hamsters (+37% and +58%, respectively) compared to fructose-fed controls following an intravenous (IV) bolus of insulin (p<0.05). Increases in insulin receptor and IRS-1 phosphorylation were also observed in muscle and adipose tissue. Analysis of hepatic Akt phosphorylation and mass revealed a small (25%) increase in serine phosphorylation of Akt with no significant change in Akt mass, although serine-phosphorylation and mass of Akt2 were significantly increased (+32%, p=0.03, and +42%, p=0.01, respectively). Interestingly, expression of PTP-1B, a key negative regulator of insulin signaling, showed a non-significant trend toward reduction in liver and was significantly reduced in adipose tissue (-20% and -37%, respectively). Taken together, these data suggest that statin-treatment increases whole body and peripheral tissue insulin sensitivity via improved cellular insulin signal transduction.
Naples
Mark
M
Clinical Biochemistry and Molecular Structure & Function, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
Federico
Lisa M
LM
Xu
Elaine
E
Nelken
Joanna
J
Adeli
Khosrow
K
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D006224:Cricetinae; D004195:Disease Models, Animal; D005464:Fluorobenzenes / Q000494:pharmacology*; D005632:Fructose / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007275:Injections, Intravenous; D007328:Insulin / Q000097:blood; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism*; D008297:Male; D008647:Mesocricetus; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D011972:Receptor, Insulin / Q000378:metabolism; D000068718:Rosuvastatin Calcium; D015398:Signal Transduction / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood
D048868:Adaptor Proteins, Signal Transducing; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D011743:Pyrimidines; D013449:Sulfonamides; D014280:Triglycerides; D005632:Fructose; D000068718:Rosuvastatin Calcium; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1