Recurrent hypoglycaemia caused by the insulin autoimmune syndrome: the first Dutch case.

The insulin autoimmune syndrome is extremely rare outside of Japan. We describe a 45-year-old Caucasian woman who presented with fasting hypoglycaemia and weight gain. The presence of fasting insulin concentrations in excess of 1000 mU/l, very low C-peptide concentrations during hypoglycaemic attacks and high titres of insulin autoantibodies led to the diagnosis. Treatments aimed at decreasing endogenous insulin secretion by either dietary intervention alone or in combination with acarbose, octreotide or diazoxide had only limited success, while a 2-week course of immunosuppression with prednisone was without any antihypoglycaemic effect.

Glucocorticoid receptors in Epstein-Barr virus-transformed lymphocytes from patients with glucocorticoid resistance and a glucocorticoid-resistant New World primate species.

Members of a previously reported family with glucocorticoid resistance and several New World primates have high plasma cortisol concentrations without any signs of glucocorticoid excess. The glucocorticoid receptor in circulating leukocytes and cultured skin fibroblasts from these patients and the animals is characterized by a decreased affinity for dexamethasone. On the other hand, the cell content of receptor is similar to that of corresponding tissues of normal humans. Detailed biochemical-biophysical studies of the glucocorticoid receptor in this familial syndrome and animal model became possible with the use of Epstein-Barr virus-transformed lymphocyte lines. Cell lines from patients with this syndrome and from the marmoset (Saguinus oedipus) contained decreased amounts of glucocorticoid receptors with concomitant decreases in nuclear receptor content compared to cultured Epstein-Barr virus-transformed lymphocytes from normal human subjects. This may reflect diminished induction of glucocorticoid receptor during viral transformation of cells from the patients and the animal model. Receptors from a severely affected glucocorticoid-resistant patient and the marmoset had decreased affinity for dexamethasone. Evidence for a mild affinity defect of the glucocorticoid receptor in a patient with asymptomatic glucocorticoid resistance was obtained by increased hormone-receptor dissociation at an elevated temperature. Thermal stability, mero-receptor formation, thermal activation of cytosolic receptor, and mol wt of receptors from all cell lines were normal. Only the receptors of the severely affected patient had a discernible defect in temperature-induced activation of intact cells. We conclude that the major detectable change in the receptor in both the patients and the animal model is the decreased affinity for glucocorticoid. Viral receptor induction is decreased in both patient and marmoset cells. The physiological relevance of this phenomenon is not known. Gross receptor molecule changes or changes in its stability at higher temperatures were not found. Mixing studies did not show involvement of cytosolic modifiers or inhibitors. Mutation(s) of the receptor molecule leading to low affinity for the hormone is the most likely explanation of the isolated glucocorticoid resistance in the patients. The glucocorticoid resistance of the New World primate, which is part of generalized steroid hormone resistance, appears to be a result of more complex changes.

Primary cortisol resistance: a familial syndrome and an animal model.

Primary cortisol resistance in man is a familial disease. It is characterized by increased plasma cortisol concentrations, high urinary free cortisol excretion, a normal circadian pattern of cortisol secretion, resistance to adrenal suppression by dexamethasone and absence of clinical stigmata of Cushing's syndrome. In its severe form, hypertension and hypokalemic alkalosis are present, owing to increased secretion of the sodium-retaining corticoids, corticosterone and deoxycorticosterone. In subjects with a less severe resistance to cortisol, there are no clinical abnormalities and the disease is revealed only by detailed examination of several parameters of cortisol metabolism. In the whole-cell assay (peripheral mononuclear leukocytes or fibroblasts) the glucocorticoid receptor shows a low affinity for dexamethasone. The receptor may be unsaturable as suggested by decreased receptor concentrations in broken-cell systems. Thus, generalized target-tissue resistance to cortisol, including the pituitary gland and the hypothalamus, is accompanied by a decreased negative feedback of the cortisol-ACTH feedback system resulting in increased ACTH secretion. This causes higher plasma cortisol to compensate for the end-organ resistance and also increases the production of adrenal mineralocorticoids, as by-products. Thus hypertension and hypokalemic alkalosis depends on the degree of the resistance. Cortisol resistance in many New World primate species is characterized by greatly increased plasma cortisol concentrations, decreased cortisol binding globulin capacity and affinity, high levels of plasma and urinary free cortisol, marked resistance of ACTH suppression by dexamethasone, and no physiologic evidence of glucocorticoid hormone excess. Target tissues have normal concentrations of glucocorticoid receptors with decreased affinity for dexamethasone. The New World primates, unlike man, have compensated for this cortisol resistance with intra-adrenal adaptations over the 50 million years of their evolutionary development. These primates also have abnormalities of other steroid hormone-receptor systems such as progesterone, estrogen, androgen and mineralocorticoid. In contrast, the human syndrome appears to be a recent mutation with pathophysiologic consequences.

Primary cortisol resistance: a family study.

Primary cortisol resistance is an autosomal disease characterized by increased plasma cortisol concentration and high urinary free cortisol, resistance to adrenal suppression by dexamethasone, and the absence of clinical stigmata of Cushing's syndrome. The proband with the severe form had hypertension and hypokalemic alkalosis. In subjects with a less severe resistance to cortisol, there are no clinical abnormalities and the condition is revealed only by detailed examination of several parameters of cortisol secretion.

Insulin stimulation tests in pituitary dependent Cushing's syndrome after complete adrenalectomy.

The present study shows that in a group of 6 euadrenal patients, previously treated by complete adrenalectomy for pituitary dependent Cushing's syndrome, the stress stimulus of insulin induced hypoglycaemia is followed by a plasma ACTH response which is of similar magnitude as the response obtained with lysin-vasopressin. Both observations indicate that the central nervous system-pituitary axis is basically normal in pituitary dependent Cushing's syndrome as assessed by insulin induced hypoglycaemia. It is concluded that non-responsiveness of the pituitary-adrenocortical system to insulin induced hypoglycaemia in untreated patients with pituitary dependent Cushing's syndrome does not represent a fundamental defect of the stress mechanism, but is due to hypercorticism per se.

Spontaneous hypercortisolism without Cushing's syndrome.

A very high cortisol production rate (CPR) with elevated plasma ACTH was found in a hypertensive, hypokalemic, but otherwise healthy male patient. There were no symptoms or signs of Cushing's syndrome. The hypercortisolism appeared to be of the pituitary dependent type. During the follow-up of 36 months, no changes in outward appearance occurred, notwithstanding persistent hypercortisolism. The possibility of either Conn's syndrome or of an enzymatic defect in steroidogenesis could be ruled out. One of the three children (a healthy boy of 20 years) also showed hypertension and hypercortisolism. A possibly genetically determined hyposensitivity to the glucocorticoid action of cortisol is postulated.