CREM and Hyperglycemia: In the present study, using freshly isolated rat islet cells as an ex vivo system that allows molecular-level studies under physiological and pathophysiological conditions (normoglycemica versus hyperglycemia), we show that the decreased level of PP2A levels and the consequent upregulation of ICER is the primary cause for the failure of the negative feedback regulation of CREB under chronic hyperglycemic conditions.