Antidiabetic agent pioglitazone increases insulin receptors on 3T3‐L1 adipocytes

Abstract

Pioglitazone and other antidiabetic thiazolidinediones appear to overcome insulin resistance by affecting an unidentified early event in insulin action. Because attempts to determine changes in insulin receptors in tissues from thiazolidinedione-treated diabetic animals are complicated by drug-induced reduction of hyperinsulinemia and consequent receptor up-regulation, 3T3-LI cells were utilized here as an in vitro model system. After the excess insulin required for optimal differentiation of 3T3-LI adipocytes was removed from the culture medium, there was an increase in specific binding of insulin to the cell surface that was further augmented 25 and 47% in cells treated with pioglitazone for 12 and 24 h, respectively (EC,, about 0.6 pM, maximal at 5-25 FM). Pioglitazone increased the number of insulin receptors without changing binding affinity. Specific IGF-I binding was not affected by pioglitazone in the 3T3-LI cells. Glycerol 3-phosphate dehydrogenase activity, a marker of adipocyte differentiation, was also increased in a dose-dependent manner by pioglitazone (maximal at 10-25 pM). Tunicamycin, which inhibits the N-linked glycosylation of newly synthesized insulin receptors that is required for their translocation to the cell surface, decreased specific insulin binding by about 50% after 24 h, and this decrease remained unchanged when pioglitazone was simultaneously present. Pioglitazone increased not only cell surface insulin receptors, but also total cellular insulin receptors (quantitated either by specific insulin binding or by immunoblotting) and insulin receptor mRNA. In addition, among several structurally related thiazolidinediones there was a positive correlation between in vivo antihyperglycemic activity and their ability to increase insulin binding in vitro, suggesting a possible common molecular mechanism for these actions. o 1995 WiIey-Liss, Inc.

How pioglitazone affects glucose and lipid metabolism

“…In obese Zucker fa/fa rats, pioglitazone treatment for 4 weeks increased the mRNA of fatty acid synthase (FAS), GLUT-4, and PEPCK, and decreased the expression of ob gene (Hallakou et al, 1997). When 3T3-L1 cells are treated with pioglitazone, glycerol 3-phosphate, a marker of adipocyte differentiation, was increased together with an increase in the mRNA for insulin receptor and total cellular insulin receptors (Swanson and Bleasdale, 1995). The remodeling of adipose tissue contributes to the enhancement of insulin sensitivity; however, pioglitazone also has a direct effect on gene expression in mature adipocytes.…”

Thiazolidinedione-induced effects beyond glycaemic control

“…7 Insulin resistance is the prime defect in type 2 diabetes -in such individuals insulin production can no longer compensate for the high level of insulin resistance resulting in hyperglycaemia and diabetes. 8 Pioglitazone opposes insulin resistance in several ways, including increased expression of glucose transporters and uptake, [9][10][11] enhancing insulin signalling, 12,13 reducing hepatic glucose production, [14][15][16][17] increasing fatty acid uptake and lipogenesis by adipocytes, 18,19 decreasing cytokines like tumour necrosis fac-tor alpha (TNFα). 20 These different effects probably explain the insulin sensitising and antihyperglycaemic effects of the thiazolidinediones.…”

Relationship between Plasma hANP Level and Pretibial Edema by Pioglitazone Treatment

“…Thiazolidinediones are specific agonists of the nuclear peroxisome proliferator activated receptor-g, which increases transcription of various proteins that regulate glucose metabolism such as insulin receptor [2] and glucose transporter proteins [3]. Thiazolidinediones also improve serum lipid profiles [4] and prevent the development of diet-induced hypertension [5].…”