The New Antidiabetic Drug MCC-555 Acutely Sensitizes Insulin Signaling in Isolated Cardiomyocytes**This work was supported by the Ministerium für Wissenschaft und Forschung des Landes Nordrhein-Westfalen, the Bundesministerium für Gesundheit, EU COST Action B5, and a grant from Mitsubishi Chemical (Yokohama, Japan).

Abstract

Freshly isolated adult rat ventricular cardiomyocytes have been used to characterize the action profile of the new thiazolidinedione antidiabetic drug MCC-555. Preincubation of cells with the compound (100 microM for 30 min or 10 microM for 2 h) did not modify basal 3-O-methylglucose transport, but produced a marked sensitizing effect (2- to 3-fold increase in insulin action at 3 x 10(-11) M insulin) and a further enhancement of maximum insulin action (1.8-fold). MCC-555 did not modulate autophosphorylation of the insulin receptor and tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1). However, insulin action (10(-10) and 10(-7) M) on IRS-1-associated phosphatidylinositol (PI) 3-kinase activity was enhanced 2-fold in the presence of MCC-555. Association of the p85 adapter subunit of PI 3-kinase to IRS-1 was not modified by the drug. Immunoblotting experiments demonstrated expression of the peroxisomal proliferator-activated receptor-gamma in cardiomyocytes reaching about 30% of the abundance observed in adipocytes. The insulin-sensitizing effect of MCC-555 was lost after inhibition of protein synthesis by preincubation of the cells with cycloheximide (1 mM; 30 min). Cardiomyocytes from obese Zucker rats exhibited a completely blunted response of glucose transport at 3 x 10(-11) M insulin. MCC-555 ameliorates this insulin resistance, producing a 2-fold stimulation of glucose transport, with maximum insulin action being 1.6-fold higher than that in control cells. This drug effect was paralleled by a significant dephosphorylation of IRS-1 on Ser/Thr. In conclusion, MCC-555 rapidly sensitizes insulin-stimulated cardiac glucose uptake by enhancing insulin signaling resulting from increased intrinsic activity of PI 3-kinase. Acute activation of protein expression leading to a modulation of the Ser/Thr phosphorylation state of signaling proteins such as IRS-1 may be underlying this process. It is suggested that MCC-555 may provide a causal therapy of insulin resistance by targeted action on the defective site in the insulin signaling cascade.

Glucose transport in the heart

“…Exposure of insulin resistant cardiomyocytes obtained from obese Zucker rats to these TZDs also increased insulin sensitivity and restored glucose transport. This was associated with a reduction in the serine phosphorylation of IRS-1 (98). After 20 hours of incubation, there is a 3-fold increase in protein content of GLUT1, 1.5 fold increase in GLUT4 protein content and a 2-fold increase in GLUT4 abundance in plasma membranes that is associated with increased basal cardiac glucose uptake (99).…”

Mechanistic and thermodynamic characterization of antivirals targeting druggable pocket of SARS-CoV-2 nucleocapsid

“…Several glucose-lowering agents, such as metformin or insulin, are the most prescribed drugs for managing blood glucose levels in SARS-CoV-2 infected patients. Interestingly, another anti-diabetic drug MCC-555 reported to sensitize insulin signalling, can aid in the proper management of blood glucose levels, and amend inflammatory responses during SARS-CoV-2 infections 60,61 . Bisdemethoxycurcumin, a naturally occurring curcumin analogue, and Icilin, an activator of Transient Receptor Potential Melastatin–8 (TRPM8), are reported to possess anti-inflammatory properties and may also attenuate systemic inflammation or lung injury 62,63 .…”

Thiazolidinedione-induced lipid droplet formation during osteogenic differentiation

“…The authors suggested that the pro-adipogenic and antiosteoblastogenic effects of Pparg are regulated by diverse downstream regulatory pathways that can be differentially modulated depending on the nature of the ligand. Ppar pan-agonist and dual-agonist drugs such as netoglitazone were thus developed to combine the triglyceride-lowering and HDL cholesterol-elevating effects of the Ppara (Ppara) agonists with the insulin sensitisation elicited by the Pparg agonists (Liu et al 1998, Upton et al 1998, Pickavance et al 1998, Chang et al 2007), while limiting negative effects on the skeleton (Lazarenko et al 2006). Unfortunately, to date, Pparg/Ppara dual agonist treatment is associated with unacceptable adverse effects that have delayed clinical application of these drugs (Chang et al 2007).…”