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Hypoglycemia Affects the Activation State of Glycogen Synthase Kinase‐3beta in the Rat Hypothalamus

Adaptations in brain signaling pathways may underlie the altered detection and response to hypoglycemia seen in hypoglycemic unawareness. Glycogen synthase kinase‐3beta (GSK3ß), a key regulator of numerous metabolic processes, responds to changes in insulin and glucose. The objective of this study was to examine the phosphorylation of GSK3ß by Akt (protein kinase B) in the rat medial basal hypothalamus (MBH) following acute and recurrent episodes of insulin‐induced hypoglycemia. MBH brain regions were obtained from male Sprague‐Dawley rats 30 minutes after a first‐time (acute) or fourth‐time (recurrent) 2 U/kg IV insulin injection. Expression of Ser‐9 phosphorylated and total GSK3ß and Thr‐308 phosphorylated and total Akt were measured from homogenates by Western blot analysis. Following acute hypoglycemia, phosphorylation of GSK3ß was decreased ~40% (p=0.05) as compared to saline‐treated controls. The phosphorylation of Akt was decreased ~50% (p=0.03) after first‐time hypoglycemia. Levels of phosphorylated GSK3ß were similar (p=0.34) to saline controls after recurrent hypoglycemia. There was no change (p=.98) in Akt phosphorylation to a 4th hypoglycemic episode. Total GSK3ß and Akt levels were not changed by acute or recurrent hypoglycemia. The decrease in phosphorylation and inactivation of hypothalamic GSK3ß to insulin‐induced hypoglycemia was absent after 3 previous episodes of hypoglycemia. These results are consistent with a possible role of GSK3ß in hypoglycemic unawareness. NIH‐DK59755