Factors Affecting the Activation of Glycogen Synthase in Primary Culture Cardiomyocytes

The ability of insulin, IGF-1 and IGF-2 to stimulate the activation of glycogen synthase in the heart was compared under completely defined conditions using primary culture cardiomyocytes. Both insulin and IGF-1 produced similar time-and concentration-dependent activation of glycogen synthase with the maximum stimulation observed at 10-15 min following hormone administration and at 10 nM insulin or IGF-1. IGF-2 was largely ineffective at physiological concentrations. When primary culture cardiomyocytes were incubated with 100 μM palmitate for 2 h and then challenged with various concentrations of insulin or IGF-1, there was a significant decrease in the ability of the cells to activate glycogen synthase. In addition, maintaining cardiomyocytes in hormone deficient culture conditions for 24 or 48 h also resulted in a reduced ability to activate glycogen synthase in response to these hormones. These results suggest that (1) both insulin and IGF-1 are potent regulators of glycogen synthesis in the heart, (2) the enzymes involved in the dephosphorylation (activation) of glycogen synthase are closely linked to both insulin and IGF-1, but not IGF-2 receptor signaling pathways, (3) glycogen synthase activation is adversely affected by the maintenance of cardiomyocytes in the presence of palmitate or for 24 h in hormone deficient media which results in insulin and IGF-1 resistance, and (4) this resistance, like that found in cells from diabetic rats, is due at least in part to a decrease in glycogen synthase phosphatase activity.