Thiazolidine Derivatives Ameliorate High Glucose-induced Insulin Resistance via the Normalization of Protein-tyrosine Phosphatase Activities

Abstract

The mechanisms for the insulin resistance induced by hyperglycemia were investigated by studying the effect of high glucose concentration (HG) and its modulation by thiazolidine derivatives, on insulin signaling using Rat 1 fibroblasts expressing human insulin receptors (HIRc). Incubating HIRc cells in 27 mM D-glucose for 4 days impaired the insulin-stimulated phosphorylation of pp185 and receptor beta-subunits. Both protein kinase C activities and phorbol dibutyrate binding to intact cells were unchanged; however, cytosolic protein-tyrosine phosphatase (PTPase) activity increased within 1 h prior to the impairment of insulin receptor kinase in HG cells (Maegawa, H., Tachikawa-Ide, R., Ugi, S., Iwanishi, M., Egawa, K., Kikkawa, R., Shigeta, Y., and Kashiwagi, A. (1993) Biochem. Biophys. Res. Commun. 197, 1078-1082). Increased PTPase activity was consistent with a 2-fold increase in the amount of PTP1B, and anti-PTP1B antibody inhibited this increment of cytosolic PTPase activity in HG cells. Co-incubating cells with pioglitazone prevented these abnormalities in cytosolic PTPase, the PTP1B content and the impaired phosphorylation of pp185 and receptor beta subunits in HG cells. Finally, HG cells had impaired insulin-stimulated alpha-amino-isobutyric acid uptake, which was ameliorated by exposure to thiazolidine derivatives. In conclusion, exposing cells to high glucose levels desensitizes insulin receptor function, and thiazolidine derivatives can reverse the process via the normalization of cytosolic PTPase, but not of protein kinase C.

Differential expression and translocation of protein tyrosine phosphatase 1B-related proteins in ME-180 tumor cells expressing apoptotic sensitivity and resistance to tumor necrosis factor: potential interaction with epidermal growth factor receptor

“…In ME-180 cells the detergent extracted membrane fraction of both Sen and Res cells retained the majority of 50 kDa PTP1B but we could also detect the 50 kDa PTP1B protein in cell lysates prepared in the absence of detergent (Figure 9). This would suggest the existence of a pool of 50 kDa PTP1B which is not tightly associated with membranous components in ME-180 cells as previously described by others in cells modeling insulin resistance (Maegawa et al, 1995). Other cell lines examined which express intrinsic TNF sensitivity also expressed a 42 kDa PTP1B-like protein (MCF-7, BT-20, MDA-361; data not shown) but we could not detect expression of the 50 kDa PTP1B in the cytosolic fraction of these cells, suggesting distinctions between ME-180 cells and other TNF sensitive cell lines.…”

The Effect of Glucose Concentration on Insulin‐Induced 3T3‐L1 Adipose Cell Differentiation

“…Although these perturbations in insulin signaling of 3T3-Ll preadipose cells may not seem very large, they clearly are associated with an enhanced cellular response, namely, adipose cell differentiation (as measured by triglyceride accumulation and induction of GPDH activity). Other investigators, examining the effect of elevated glucose concentrations on Rat1 fibroblasts expressing human insulin receptors, have observed similar degrees of modulation on insulin signaling parameters (1 3,18) and cellular PTPase activity (13).…”

“…Enhancement at 5 mM vs. 25 mM glucose was detectable at 10 nM (1.9 f 0.7-fold) and 25 nM (1.8 2 0.3-fold) insulin (mean f range, n = 2). Augmentation of insulin signaling has been linked to reductions in protein tyrosine phosphatases (PTPase) in other cell systems (10,13). As shown in Figure 5, we measured LAR expression, one of these PTPases.…”

Acute non‐insulin‐like stimulation of rat muscle glucose metabolism by troglitazone in vitro

“…Furthermore, troglitazone metabolites, which circulate at high concentrations in chronically treated rats, may signi®cantly contribute to its long-term action in vivo (Ciaraldi et al, 1995;Khourshed et al, 1995). Beside stimulation of glucose uptake in vivo and in vitro Okuno et al, 1997), short-term exposure to troglitazone or other thiazolidine derivatives triggers a number of further insulin-like responses (Fujiwara et al, 1988;Zhang et al, 1994;Maegawa et al, 1995). However, with regard to isolated muscle glucose handling, insulin-induced glucose uptake is associated with an anabolic response characterized by distinct augmentation of glycogenesis, moderate stimulation of glycolysis and glycogen accumulation (Crettaz et al, 1980;FuÈ rnsinn et al, 1995; and this study).…”