Tramadol enhances hepatic insulin sensitivity via enhancing insulin signaling cascade in the cerebral cortex and hypothalamus of 90% pancreatectomized rats.
Clinical observation found that tramadol, mu opioid receptor (MOR) agonist and serotonin (5-HT) reuptake inhibitor, has a hypoglycemic effect in type 2 diabetes patients. The mechanism of its hypoglycemic effect has not been fully defined. This study showed that tramadol activated a neuronal insulin signaling cascade by increasing the induction of insulin receptor substrate-2 expression in primary cultured neuronal cells while this activation was suppressed by naloxone (MOR inhibitor) and dexamethasone (non-specific inhibitor of MOR and 5-HT receptor, DEX). Glucose utilization of the cerebral cortex and hypothalamus was enhanced by a 4-week-tramadol administration in 90% pancreatectomized rats, in vivo, as assessed by measurement of glucokinase expression and glycogen deposition via activating insulin signaling cascade such as neuronal cells in vitro. This improvement was almost completely suppressed by naloxone as well as DEX. Tramadol decreased fasted serum glucose levels, favored an increase in the glucose infusion rate and reduced endogeneous hepatic glucose production after 4 weeks of treatment. However, tramadol did not modulate hepatic glucose output directly, as exhibited by liver perfusion, suggesting tramadol altered hepatic glucose utilization through the effect of organs other than the liver, possibly the central nervous system. The data suggest that tramadol ameliorates peripheral glucose metabolism through central activation of MOR, and that central and peripheral glucose metabolism are therefore likely to be interrelated.
Choi
Soo Bong
SB
Department of Internal Medicine, College of Medicine, Konkuk University, Republic of Korea.
Jang
Jin Sun
JS
Park
Sunmin
S
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D005941:Glucokinase / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology; D009490:Neurosecretory Systems / Q000187:drug effects / Q000378:metabolism; D010180:Pancreatectomy; D010750:Phosphoproteins / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014147:Tramadol / Q000494:pharmacology*
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526299:Irs2 protein, rat; D009292:Narcotic Antagonists; D009294:Narcotics; D010750:Phosphoproteins; D011985:Receptors, Serotonin; D014147:Tramadol; D003907:Dexamethasone; D006003:Glycogen; D005941:Glucokinase; D005947:Glucose