BACKGROUND.: Corticotropin-independent nodular adrenal hyperplasia is a rare cause of Cushingʼs syndrome, and the factors responsible for the adrenal hyperplasia are not known. METHODS.: We studied a 48-year-old woman with Cushingʼs syndrome, nodular adrenal hyperplasia, and undetectable plasma corticotropin concentrations in whom food stimulated cortisol secretion. RESULTS.: Cortisol secretion had an inverse diurnal rhythm in this patient, with low-to-normal fasting plasma cortisol concentrations and elevated postprandial cortisol concentrations that could not be suppressed with dexamethasone. The cortisol concentrations increased in response to oral glucose (4-fold increase) and a lipid-rich meal (4.8-fold increase) or a protein-rich meal (2.6-fold increase), but not intravenous glucose. The infusion of somatostatin blunted the plasma cortisol response to oral glucose. Intravenous infusion of gastric inhibitory polypeptide (GIP) for one hour increased the plasma cortisol concentration in the patient but not in four normal subjects. Fasting plasma GIP concentrations in the patient were similar to those in the normal subjects; feeding the patient test meals induced increases in plasma GIP concentrations that paralleled those in plasma cortisol concentrations. Cell suspensions of adrenal tissue from the patient produced more cortisol when stimulated by GIP than when stimulated by corticotropin. In contrast, adrenal cells from normal adults and fetuses or patients with cortisol-producing or aldosterone-producing adenomas responded to corticotropin but not to GIP. CONCLUSIONS.: Nodular adrenal hyperplasia and Cushingʼs syndrome may be food-dependent as a result of abnormal responsiveness of adrenal cells to physiologic secretion of GIP. "Illicit" (ectopic) expression of GIP receptors on adrenal cells presumably underlies this disorder. (N Engl J Med 1992;327:974–80.)CUSHINGʼS SYNDROME is usually caused by excess corticotropin secretion, in which both adrenal glands are diffusely enlarged, or by an adrenal tumor. The tumor is usually autonomous and corticotropin-independent, but we have described a patient in whom cortisol secretion was food-dependent. Other patients with Cushingʼs syndrome have nodular adrenal hyperplasia, which may be due to long-standing corticotropin hypersecretion by a corticotroph adenoma or which may be corticotropin-independent, as demonstrated by the absence of corticotroph adenomas at autopsy and undetectable corticotropin concentrations in plasma from the petrosal sinus or peripheral blood obtained after metyrapone administration, insulin-induced hypoglycemia, or corticotropin-releasing hormone infusion. …