Effects of troglitazone and metformin on glucose and lipid metabolism: Alterations of two distinct molecular pathways

• Published in: Biochemical pharmacology Vol. 54; no. 7; pp. 801 - 808
• Main Authors: Lenhard, James M, Kliewer, Steven A, Paulik, Mark A, Plunket, Kelli D, Lehmann, Jurgen M, Weiel, James E
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01-10-1997; Elsevier Science
• Subjects: Animals; Biological and medical sciences; Biological Transport - drug effects; Chromans - pharmacology; diabetes; General and cellular metabolism. Vitamins; Glucose - metabolism; Hypoglycemic Agents - pharmacology; insulin; Lactic Acid - metabolism; Lipid Metabolism; Medical sciences; metabolism; metformin; Metformin - pharmacology; Mice; Mice, Inbred C3H; Mitochondria - drug effects; Palmitoyl Coenzyme A - metabolism; Pharmacology. Drug treatments; PPAR-γ; Receptors, Cytoplasmic and Nuclear - drug effects; Thiazoles - pharmacology; Thiazolidinediones; Transcription Factors - drug effects; Troglitazone; metformin; troglitazone; metabolism; insulin; diabetes; PPAR-γ; Endocrinopathy; Nuclear receptor; Diabetes mellitus; Biological transport; Lipids; Activation; Glucose; Metabolism; In vitro; Insulin; Lipolysis; Peroxisome proliferator; Hypoglycemic agent; Mitochondria; Biguanides; Established cell line; Oxidation; Metformin; Lipogenesis; Mechanism of action; Troglitazone
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/S0006-2952(97)00229-3

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 C
3H10T1/2 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 β
3-adrenergic receptor-mediated lipolysis, lipogenesis, and transcriptional activity of the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ). 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 β-oxidation, peroxisomal fatty acid β-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.