Plasma epinephrine (EPI), norepinephrine (NE), β-endrophin, and corticotropin (ACTH) responses were measured during insulin-induced hypoglycemia in normal subjects and in patients with either multiple system atrophy (MSA) or idiopathic orthostatic hypotension (IOH). In normal subjects, there was a striking rise in EPI, NE, β-endorphin, and ACTH following the nadir of hypoglycemia. Both β-endorphin and ACTH responses were significantly lower than normal in patients with MSA, in contrast to normal levels in IOH patients. No correlation was observed between the degree of adrenergic insufficiency and the β-endorphin and ACTH responses. The normal peptide responses in IOH are consistent with involvement limited to the peripheral sympathetic nervous system, whereas lesions in the central nervous system in MSA interfere with release of β-endorphin and ACTH in response to hypoglycemia. The strong correlation between β-endorphin and ACTH levels is consistent with their common origin. Peripheral adrenergic activity is not essential for β-endorphin and ACTH release in humans.