title: Selective reversible inhibition of liver carnitine palmitoyl-transferase 1 by teglicar reduces gluconeogenesis and improves glucose homeostasis.
abstract: OBJECTIVE
  We have developed a new antihyperglycemic agent (teglicar) through the selective and reversible inhibition of the liver isoform of carnitine palmitoyl-transferase 1 (L-CPT1).
  
  
  METHODS
  Glucose production was investigated in isolated hepatocytes and during pancreatic clamps in healthy rats. Chronic treatments on C57BL/6J, db/db, high-fat fed mice, and rats were performed to understand glucose metabolism and insulin sensitivity.
  
  
  RESULTS
  In isolated hepatocytes, teglicar concentration dependently reduced ketone bodies and glucose production up to 72 and 50%, respectively. In rats, teglicar reduced the endogenous glucose production (-62%) without affecting peripheral glucose utilization. Heart 2-[(3)H]deoxyglucose uptake in mice was also not affected, confirming in vivo the drug selectivity toward L-CPT1. Chronic treatment in db/db mice (50 mg/kg/bid; 45 days) reduced postabsorptive glycemia (-38%), water consumption (-31%), and fructosamine (-30%). Such antidiabetic activity was associated with an improved insulin sensitivity assessed by the insulin tolerance test. A significant 50% increase in hepatic triglyceride content (HTGC) was found, although plasma alanineaminotransferase was not altered. In addition, long-term teglicar administration to high-fat fed C57BL/6J mice normalized glycemia (-19%) and insulinemia (-53%). Long-term teglicar administration (30 days, 80 mg/kg) in healthy overnight-fasted rats slightly reduced basal glycemia (-20%, ns), reduced basal insulin levels by 60%, doubled triglycerides, and increased free-fatty acids (+53%). HTGC was markedly increased, but liver and peripheral insulin sensitivity assessed by hyperinsulinemiceuglycemic clamp were not affected.
  
  
  CONCLUSIONS
  Teglicar, in vitro and in animal models, reduces gluconeogenesis and improves glucose homeostasis, refreshing the interest in selective and reversible L-CPT1 inhibition as a potential antihyperglycemic approach.
authors.affiliation: Department of Endocrinology and Metabolism, sigma-tau s.p.a, Rome, Italy. roberto.conti@sigma-tau.it
authors.forename: Roberto
authors.initials: R
authors.lastname: Conti
authors.forename: Edoardo
authors.initials: E
authors.lastname: Mannucci
authors.forename: Pompeo
authors.initials: P
authors.lastname: Pessotto
authors.forename: Emanuela
authors.initials: E
authors.lastname: Tassoni
authors.forename: Paolo
authors.initials: P
authors.lastname: Carminati
authors.forename: Fabio
authors.initials: F
authors.lastname: Giannessi
authors.forename: Arduino
authors.initials: A
authors.lastname: Arduini
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D019540:Area Under Curve; D002331:Carnitine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D004041:Dietary Fats / Q000378:metabolism; D005943:Gluconeogenesis / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism*; D006321:Heart / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects*; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D009206:Myocardium / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D004041:Dietary Fats; D047493:PPAR alpha; C511293:ST1326; D002334:Carnitine O-Palmitoyltransferase; D005947:Glucose; D002331:Carnitine