Pharmacodynamic characterization of insulin on MDMA-induced thermogenesis.
Sympathomimetic drugs (MDMA; ecstasy) induce a potentially catastrophic hyperthermia that involves free fatty acid (FFA) activation of mitochondrial uncoupling proteins (UCP). Insulin is an important regulator of plasma FFA levels, although its role in thermogenesis is unclear. The aims of the present study were 1) to characterize the pharmacodynamic effects of MDMA on plasma insulin and glucose, 2) to examine the effects of insulin on MDMA-induced thermogenesis and 3) to examine MDMA-induced thermogenesis in an animal model of insulin resistance, the obese Zucker rat. Insulin levels peaked 15 min after MDMA (40 mg/kg, s.c.), which preceded the peak temperature change at 60 min. Plasma glucose levels also peaked 15 min. after MDMA and remained elevated throughout the 90-min. monitoring period. Insulin pretreatment (10 units/kg, s.c.) 30 min. before a low dose of MDMA (5 mg/kg, s.c.) potentiated the thermogenic response. Insulin resistant, fa/fa (obese) Zucker rats demonstrated an attenuated thermogenic response to MDMA (40 mg/kg, s.c.). Consistent with the role for FFA in UCP3 expression, immunoblot analysis showed significantly increased levels of UCP3 protein obese compared to lean Zucker skeletal muscle. In conclusion, the results of the present study suggest a potential role of insulin signaling in sympathomimetic-induced thermogenesis.
Banks
Matthew L
ML
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA.
Buzard
Sarah K
SK
Gehret
Candice M
CM
Monroy
Alexa N
AN
Kenaston
M Alexander
MA
Mills
Edward M
EM
Sprague
Jon E
JE
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001831:Body Temperature / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism; D005230:Fatty Acids, Nonesterified / Q000097:blood / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000097:blood / Q000378:metabolism*; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D007333:Insulin Resistance; D008297:Male; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D009765:Obesity / Q000097:blood / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D013566:Sympathomimetics / Q000633:toxicity*; D022722:Thermogenesis / Q000187:drug effects* / Q000502:physiology
D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D007328:Insulin; D013566:Sympathomimetics; D018817:N-Methyl-3,4-methylenedioxyamphetamine