P757Chronic GSK-3 inhibition may be good for diabetes, but is bad for the heart

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Glycogen synthase kinase-3 (GSK-3) is a serine-threonine kinase regulating glycogen synthesis and known as role-player in cardioprotection. Active GSK-3 is also recognized as the strongest anti-hypertrophic protein in the heart. However, myocardial GSK-3 is known to (i) regulate expression of SERCA-2a, affecting contractility; (ii) phosphorylate and inhibit IRS-1 disrupting insulin signalling and (iii) regulate growth via interaction with hypertrophic signalling pathways. Small, specific GSK-3 inhibitors are currently being developed for clinical use, treating e.g. affective disorders but are also considered as treatment for type 2 diabetes.

We aimed to study the effects of chronic GSK-3 inhibition on the heart, using pre-diabetic rats (DIO).

Wistar rats (obesity induced by supplementing their diet with sugar and fat for 16 weeks) were compared to age matched controls. Half of each group was treated with the GSK-3 inhibitor (CHIR118637 - 30mg/kg/day) from weeks 12 to 16 of the diet period. Glucose tolerance was established, biometric and biochemical parameters determined and protein expression ascertained in snap-frozen hearts using Western blotting and specific antibodies. Ca2+ATPase activity was determined spectrophotometrically and cardiomyocytes used to determine insulin sensitivity, cell size and localization of NFATc3 and GATA4, the latter by means of fluorescence microscopy.

GSK-3 inhibition: (i) did not affect body weight or intraperitoneal fat, both of which were increased by DIO; (ii) could increase SERCA-2a expression and phospholamban phosphorylation which were both dowregulated by DIO; (iii) upregulated IRS-2, but not IRS-1 expression. IRS-1 expression was severely curtailed in DIO; (iv) positively modulated insulin signalling reflected in enhanced cardiomyocyte insulin sensitivity as measured by accumulation of [3H]2-deoxyglucose. Glucose uptake was attenuated in cells from DIO animals; (v) increased left ventricular weight and cardiomyocyte size in control animals (vi) translocated both NFATc3 and GATA4 to the nucleus in cardiomyocytes from both control and DIO animals.

We conclude that chronic, specific GSK-3 inhibition improved glucose tolerance and insulin sensitivity of the heart, but showed clear signs of inducing cardiac hypertrophy, especially in normal animals.

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