Regulation of the Adrenocortical Response to Insulin-Induced Hypoglycemia*

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Abstract
The effect of insulin-induced hypoglycemia on corticosterone secretion was studied in male rats to determine how the adrenocortical response to this stimulus is regulated. Insulin caused a dose-dependent increase in plasma corticosterone in both fed and fasted rats; however, the magnitude of the corticosterone response was related to the degree of hypoglycemia, not to the dose of insulin. Pretreatment of rats with pentobarbital did not affect the level of hypoglycemia caused by insulin but did alter the corticosteroid response, suggesting that afferent inputs to corticotropin-releasing factor neurons stimulated by hypoglycemia are barbiturate sensitive. Although the direct response to hypoglycemia was abolished by pentobarbital, the magnitude of the corticosteroid response to a surgical stimulus was increased in markedly hypoglycemic rats compared to that in euglycemic controls, suggesting that low glucose levels may act at some point in the final common pathway to augment hormonal responses to other stimuli. To determine where the afferent pathways that mediate the corticosteroid response to hypoglycemia enter the hypothalamus, anterolateral hypothalamic deafferentations were performed in rats subsequently exposed to insulin-induced hypoglycemia. Surprisingly, there was a small corticosteroid response to hypoglycemia in these rats, suggesting that hypoglycemia might act directly at the level of the medial basal hypothalamus. To test this possibility, lesions that destroyed the medial basal hypothalamus were made in other rats. In these animals as well, hypoglycemia caused a small but highly significant corticosteroid response. In contrast, there was no corticosteroid response to hypoglycemia in rats 2 h after hypophysectomy, demonstrating that hypoglycemia does not stimulate the adrenal production of corticosterone directly. Together, these results demonstrate that hypoglycemia stimulates corticosteroid production through neural pathways entering the hypothalamus from the anterolateral direction. In addition to these major pathways, however, hypoglycemia stimulates a minor corticosterone response through pathways that are independent of the medial basal hypothalamus but require the pituitary.