Direct stimulation of myocardial glucose transport and glucose transporter-1 (GLUT1) and GLUT4 protein expression by the sulfonylurea glimepiride.

Abstract

Freshly isolated and primary cultured cardiac myocytes from adult rats were used to elucidate acute and chronic effects of the sulfonylurea drug glimepiride on basal and insulin-stimulated glucose transport and on expression of the transporter isoforms glucose transporter-1 (GLUT1) and GLUT4. A 30-min incubation with glimepiride (100 microM) was unable to modify the initial rates of 3-O-methylglucose transport in freshly isolated cardiocytes, both in the absence or presence of insulin (10(-7) M). Cells were then kept in serum-free culture for 20 h in the presence of glimepiride (10 microM) and a physiological insulin dose. Under these conditions, the sulfonylurea induced an increase in 2-deoxyglucose uptake to 186% of control. This drug effect was dose dependent and could also be demonstrated in the absence of insulin during the culture period. The acute action of insulin on glucose transport was additive to the effect of glimepiride, and the insulin responsiveness of glucose transport remained unaltered in sulfonylurea-treated cultures. Western blot analysis of crude membrane fractions obtained from cultured cardiocytes showed that glimepiride increased the expression of both GLUT1 and GLUT4 to 164% +/- 21% and 148% +/- 5% of control, respectively. We concluded that glimepiride increases cardiac glucose uptake by an insulin-independent pathway, probably involving an increased protein expression of GLUT1 and GLUT4. The increased expression of GLUT4 may have a therapeutic impact on the treatment of insulin-resistant states.

The Mode of Action of the Antidiabetic Drug Glimepiride-Beyond Insulin Secretion

“…Apparently, glimepiride manages to bypass insulin resistance caused by hyperglycemia and hyperinsulinemia, at least in primary culture in vitro. The glimepiride-induced increase in basal (and insulinstimulated) glucose transport was also observed with isolated rat cardiomyocytes [53]. It was correlated with a two-fold elevation in the protein expression of GLUT1 and GLUT4.…”

Effects of oral antihyperglycemic agents on extracellular matrix synthesis by mesangial cells

“…Nevertheless, an enhanced membrane translocation, without an associated increase in transporter synthesis cannot be totally ruled out. In addition, tolazamide may have also enhanced the expresion and/or membrane translocation of GLUT4, as it has been described in cardiomyocytes and adipocytes exposed to the sulfonylurea, glimepiride [62,64]. This could explain why cells incubated in 20 mM glucose and treated with 1.5 mM tolazamide synthesize more collagen than similarly treated 8 mM gucose-incubated cells, even though the latter demonstrate no additional increases in glucose transport or GLUT1 expresion.…”

Oral hypoglycemic agents: insulin secretagogues, α-glucosidase inhibitors and insulin sensitizers

“…These results suggest that, in addition to its effects on insulin secretion, glimepiride may increase the effectiveness of insulin in peripheral tissues (Raptis et al, 1999). These suggestions are supported by two in-vitro reports: incubation of cultured mouse adipocytes, cultured rat myocytes or isolated rat diaphragm with glimepiride increased the rates of glucose transport in the absence of insulin; this was due to an increase in the protein expression of GLUT1 and GLUT4 glucose transporters in the plasma membranes (Bahr et al, 1995;Mu Èl-ler and Geisen, 1996).…”