Insulin Resistance, Acanthosis Nigricans, and Polycystic Ovaries Associated with a Circulating Inhibitor of Postbinding Insulin Action

Abstract

A 21-yr-old moderately obese woman with hirsutism, acanthosis nigricans, and oligomenorrhoea was diagnosed as having polycystic ovary syndrome. Despite hyperinsulinemia, binding of insulin to her red cells was within the range for normal, young adult subjects. Her serum did not bind or degrade [125I]insulin or alter its binding to fat cells, and was negative for insulin receptor antibodies. However, her serum caused a dose-dependent inhibition of insulin-stimulated lipogenesis (conversion of [3-3H]glucose to [3H]lipid) in rat fat cells significantly greater than that produced with control serum (relative potency, 3.5:1) and (at a 1:20 dilution) markedly impaired the response of both lipogenesis and 2-deoxy-D-glucose uptake to maximum concentrations of insulin. After the patient was treated with clomiphene for 4 months, her menses resumed, hair growth slowed, fasting blood glucose and plasma insulin concentrations decreased, and serum inhibitory activity decreased to the control range. Serum inhibitory activity was stable to freezing and thawing and to heating at 56 C for 30 min, and could be extracted into acid-ethanol. By dialysis, its mol wt was below 1000, whereas by ultracentrifugation, it was above 3500; both high and low mol wt forms were detected after Sephadex G-50 gel chromatography of serum, suggesting that the inhibitor was of low mol wt but loosely bound to a higher mol wt component in serum. These findings indicate that insulin resistance in this patient with acanthosis nigricans and polycystic ovaries could be attributed to a circulating low mol wt inhibitor of postbinding insulin action.

Inhibition of Insulin-Stimulated Glucose Transport by Factor Extracted From Serum of Insulin-Resistant Patient

“…At this dilution, the serum extract was equally effective in inhibiting insulin action at both maximal (25-ng/ml) and submaximal (0.75ng/ml) insulin concentrations (Table 1). These findings are similar to those reported by Harrison et al (9) in another patient with acanthosis nigricans and suggest that the serum contained a factor that inhibits insulin action. We also found that the serum extract blocked the stimulation of glucose transport produced either by hydrogen peroxide (Fig.…”

“…Harrison et al (9) reported a young woman with insulin resistance, acanthosis nigricans, and polycystic ovary whose serum contained a low-molecular-weight substance that inhibited insulin action. They also reported that the substance was detectable in 77% of unselected patients with type II diabetes (10).…”

Acromegaly Associated with Chiari-I Malformation and Polycystic Ovary Syndrome.

“…In this regard, it is noteworthy that the hypothesized pathogenesis of polycystic ovary syndrome includes hyperinsulinemia or increased secretion of IGF-I (2) since patients with acromegaly usually show a high plasma IGF-I level and elevation of plasma IRI levels due to the presence of insulin resistance as in the present case. Association between polycystic ovary syndrome and insulin resistance (6) prompted the investigations of the potential role of insulin in ovarial function. It was reported that insulin alone or in synergism with LH stimulate ovarian androgen production (7-9) via the ovarian insulin receptor (10) or via intraovarian IGF system (1 1, 12).…”

Hyperandrogenism, Insulin Resistance and Hyperinsulinemia as Cardiovascular Risk Factors in Diabetes Mellitus

“…Among them, insulin resistance, and compensatory hyperinsulinemia, are possibly the best known [5]. Aside from the association between PCOS and syndromes of extreme insulin resistance [3,20,21], growing evidence support the role for insulin resistance in the pathogenesis of hyperandrogenic disorders.…”