Effects of troglitazone and metformin on glucose and lipid metabolism: alterations of two distinct molecular pathways.
Troglitazone and metformin are antidiabetic agents that belong to the thiazolidinedione and biguanide classes of drugs, respectively. To evaluate how these drugs influence fuel utilization, we compared their effects on several pathways regulating carbohydrate and lipid metabolism in vitro. Both drugs stimulated glucose transport and utilization in C3H10T1/2 cells, a cell line capable of differentiating into adipocytes when treated with thiazolidinediones. However, we observed that these drugs had a number of different in vitro effects. Unlike metformin, troglitazone stimulated beta3-adrenergic receptor-mediated lipolysis, lipogenesis, and transcriptional activity of the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma). Further, by using a mitochondrial-specific fluorescent dye, we found troglitazone to be more effective than metformin at increasing mitochondrial mass. In contrast to troglitazone, metformin was more effective at increasing mitochondrial fatty acid beta-oxidation, peroxisomal fatty acid beta-oxidation, and anaerobic respiration (i.e. lactate production). Additionally, metformin stimulated and troglitazone inhibited both aerobic respiration and basal lipolysis. Insulin enhanced the effects of troglitazone, but not those of metformin, on these cells. Taken together, the data show that troglitazone and metformin affect two distinct metabolic pathways: one that is anabolic (i.e. troglitazone) and the other that is catabolic (i.e. metformin). Further, these observations suggest that the metabolic activity of mitochondria may be lower in cells treated with troglitazone than with metformin.
Lenhard
J M
JM
Department of Metabolic Diseases, GlaxoWellcome Inc., Research Triangle Park, NC 27709, USA. jml29514@glaxowellcome.com
Kliewer
S A
SA
Paulik
M A
MA
Plunket
K D
KD
Lehmann
J M
JM
Weiel
J E
JE
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D019344:Lactic Acid / Q000378:metabolism; D050356:Lipid Metabolism; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008809:Mice, Inbred C3H; D008928:Mitochondria / Q000187:drug effects; D010171:Palmitoyl Coenzyme A / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000187:drug effects; D000077288:Troglitazone
D002839:Chromans; D007004:Hypoglycemic Agents; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D010171:Palmitoyl Coenzyme A; D019344:Lactic Acid; D008687:Metformin; D000077288:Troglitazone; D005947:Glucose