title: Chlorpromazine exacerbates hepatic insulin sensitivity via attenuating insulin and leptin signaling pathway, while exercise partially reverses the adverse effects.
abstract: Investigated in this study are the effects and mechanisms of exercise and chlorpromazine (CPZ), a widely used conventional antipsychotic drug, on the hepatic insulin sensitivity of 90% pancreatectomized (Px) male Sprague-Dawley rats. The Px diabetic rats were provided with 0, 5, or 50 mg CPZ per kg of body weight (No-CPZ, LCPZ, or HCPZ) for 8 weeks, and half of each group had regular exercise. LCPZ did not exacerbate hepatic insulin sensitivity through insulin and leptin signaling in diabetic rats. However, HCPZ decreased whole-body glucose infusion rates in hyperinsulinemic clamped states, but not whole-body glucose uptake. This was due to the elevated hepatic glucose output in hyperinsulinemic states. The decreased hepatic insulin sensitivity was associated with insulin receptor substrate-2 (IRS2) protein levels in the liver. Decreased IRS2 levels attenuated hepatic insulin and leptin signaling pathways in hyperinsulinemic states, which elevated glucose production by inducing phosphoenolpyruvate carboxykinase expression. Long-term exercise recovered hepatic insulin sensitivity attenuated by HCPZ to reduce the hepatic glucose output in hyperinsulinemic clamped states. This recovery was related to enhanced insulin and leptin signaling via increased IRS2 gene and protein levels by activating the cAMP responding element-binding protein, but exercise improved only insulin signaling. In conclusion, HCPZ exacerbates hepatic insulin action by attenuating insulin and leptin signaling in type 2 diabetic rats, while regular exercise partially reverses the attenuation of hepatic insulin sensitivity by improving insulin signaling. Enhancement of insulin and leptin signaling through an induction of IRS2 may play an important role in improving hepatic glucose homeostasis.
authors.affiliation: Department of Food and Nutrition, College of Natural Science, Hoseo University, Asan-Si, Chungnam-Do, Republic of Korea. smpark@office.hoseo.ac.kr
authors.forename: Sunmin
authors.initials: S
authors.lastname: Park
authors.forename: Sang Mee
authors.initials: SM
authors.lastname: Hong
authors.forename: Ji Eun
authors.initials: JE
authors.lastname: Lee
authors.forename: So Ra
authors.initials: SR
authors.lastname: Sung
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002746:Chlorpromazine / Q000494:pharmacology*; D015151:Immunoblotting; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D020738:Leptin / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010805:Physical Conditioning, Animal; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D001786:Blood Glucose; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526299:Irs2 protein, rat; D020738:Leptin; D010750:Phosphoproteins; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D002746:Chlorpromazine