Hypothesis: hypothalamic dysfunction and lipoatrophic diabetes.

The concept that the hypothalamus controls anterior pituitary function via the production of neurohormonal releasing and inhibitory factors (RFs and IFs, respectively) is well documented (1). There is a growing body of evidence relating endocrine disorders to hypothalamic dysfunction that has resulted in a wide variety of endocrine and metabolic imbalances (2, 3). In an effort to explain the pathophysiologic expression of the bizarre clinical entity known as lipoatrophic diabetes (LD), we have attempted to correlate our laboratory findings with the current knowledge regarding hypothalamic-hypophyseal-target organ interactions. Generalized or total lipoatrophic diabetes, relatively rare, has long been thought to be genetically determined. The onset of the disease is frequently heralded by fever. This disease is characterized by a loss of subcutaneous and other body fat, skeletal muscle overgrowth, bone overgrowth with advance maturation, hepatomegaly, splenomegaly, genital enlargement, hyperpigmentation of the skin with acanthosis nigricans, hyperlipemia, and insulin-resistant hyperglycemia. Our more recent clinical data gives substantive chemical evidence that hypothalamic dysfunction may exist in patients with LD (4, 5) substantiating the early speculations of Seip in 1959 (6). Our patients had apparently normal circulating levels of pituitary hormones in the face of clinical evidence suggesting obvious excessive hormonal stimulation. Plasma from one of these patients who had been hypophysectomized in an effort to alleviate the metabolic and physical distortions of the disease, revealed comparable levels of releasing factors [corticotropin-releasing factor (CRF), follicle-stimulating hormone releasing factor (FRF), and melanocyte-stimulating hormone releasing factor (MRF) ] both preand postoperatively. These data indicated that the pituitary in situ had no effect on the progression or amelioration of the disease and implicated hypothalamic involvement.