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- Title
Selective Reversible Inhibition of Liver Carnitine Palmitoyl-Transferase I by Teglicar Reduces Gluconeogenesis and Improves Glucose Homeostasis.
- Authors
Conti, Roberto; Mannucci, Edoardo; Pessotto, Pompeo; Tassoni, Emanuela; Carminati, Paolo; Giannessi, Fabio; Arduini, Arduino
- 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). RESEARCH DESIGN AND 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-[³H]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 alanineaminotrans-ferase 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 hyperinsuUnemiceuglycemic 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.
- Subjects
HYPOGLYCEMIC agents; TRANSFERASES; GLUCOSE; LIVER cells; LABORATORY rats; INSULIN; TRIGLYCERIDES; PHARMACODYNAMICS
- Publication
Diabetes, 2011, Vol 60, Issue 2, p644
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db10-0346