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Some patients with severe insulin resistance develop pathological tissue growth reminiscent of acromegaly. Previous studies of such patients have suggested the presence of a selective postreceptor defect of insulin signaling, resulting in the impairment of metabolic but preservation of mitogenic signaling. As the activation of phosphoinositide 3-kinase (PI 3-kinase) is considered essential for insulin's metabolic signaling, we have examined insulin-stimulated PI 3-kinase activity in anti-insulin receptor substrate (IRS)-1 immunoprecipitates from cultured dermal fibroblasts obtained from pseudoacromegalic (PA) patients and controls. At a concentration of insulin (1 nM) similar to that seen in vivo in PA patients, the activation of IRS-1-associated PI 3-kinase was reduced markedly in fibroblasts from the PA patients (32+/-7% of the activity of normal controls, P < 0.01). Genetic and biochemical studies indicated that this impairment was not secondary to a defect in the structure, expression, or activation of the insulin receptor, IRS-1, or p85alpha. Insulin stimulation of mitogenesis in PA fibroblasts, as determined by thymidine incorporation, was indistinguishable from controls, as was mitogen-activated protein kinase phosphorylation, confirming the integrity of insulin's mitogenic signaling pathways in this condition. These findings support the existence of an intrinsic defect of postreceptor insulin signaling in the PA subtype of insulin resistance, which involves impairment of the activation of PI 3-kinase. The PA tissue growth seen in such patients is likely to result from severe in vivo hyperinsulinemia activating intact mitogenic signaling pathways emanating from the insulin receptor.

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The results indicate that PC-1 over-expression does not appear to contribute to the insulin resistant state of pseudo-acromegalic patients. The finding of normal insulin receptor tyrosine kinase activity in these subjects suggests that the site of defective insulin signalling is likely to be distal to the receptor. The unexpected finding that PC-1 activity, protein and mRNA were all dramatically reduced in patients with lesions early in the insulin signalling cascade provides further evidence for a link, albeit as yet poorly understood, between cellular insulin action and the expression of PC-1.

Markers on chromosome 4q have recently been shown to be associated with insulin resistance in Pima Indians, a population in which insulin resistance precedes and predicts the development of non-insulin-dependent diabetes mellitus (NIDDM). To examine whether genes in this region could play a major role in susceptibility to NIDDM in other populations, we have examined the allele frequencies of a trinucleotide repeat near the fatty acid-binding protein 2 (FABP2) gene on 4q28-31 in three European populations: Finnish, U.K. Caucasian, and Welsh. The U.K. NIDDM population was selected for insulin resistance by studying patients whose obesity-corrected fasting plasma insulin before treatment was above the 98th percentile. Seven alleles were detected. On cross-tabulation analysis, there were no significant associations between allele frequencies and glucose intolerance in any of the populations. Log-linear analysis of the results from all three populations suggested a moderately significant interaction of glucose tolerance status (normal versus diabetic) and the FABP2 allele (partial chi 2 = 24, df 6, P = 0.027). The parameter describing the interaction of allele A3 and glucose tolerance status was the only such parameter differing significantly from zero (z-score +2.003, P = 0.046). In both the Finnish and U.K. population, the A3 allele was found approximately twice as frequently in NIDDM than in control subjects (Finnish control subjects, impaired glucose tolerance, and NIDDM: 12.2, 22.4, and 26.6%, respectively; U.K. control subjects and NIDDM: 7.8 and 14.6%, respectively). In the Finnish populations, no associations were found between FABP2 alleles and plasma insulin levels or with homeostatic model assessment (HOMA) estimates of beta-cell function and insulin sensitivity.(ABSTRACT TRUNCATED AT 250 WORDS)

A 24-yr-old female student born of apparently normal, unrelated parents presented with severe abdominal pain and muscle cramps at the age of 20 yr. She had also noticed increasing hirsutism and well-developed muscles in her limbs despite making no special effort to exercise beyond her normal activities. These symptoms dated from about the age of 11 yr when she had attained menarche. Her menstrual periods were regular. On physical examination she was tall (179.5 cm) and weighed 74.9 kg with a BMl of 24.0 kg / m2. Her supine blood pressure was 130180 mmHg. She was muscular with welldeveloped leg muscles (Fig. l), large hands ( Fig. 2) and feet, wide shoulders, and a prominent mandible with widely separate teeth giving her an appearance reminiscent of acromegaly. She had a normal amount of subcutaneous fat on her face, abdomen, and chest, but had excessive fat around her neck (Fig. 3) with very little subcutaneous fat on the arms and legs. Acanthosis nigricans was noted in both axillae and groins (Fig. 4). She also had moderate facial hirsutism and a male escutcheon, but no clitoromegaly or temporal hairline recession.An ultrasound scan of her abdomen showed the left ovary to be 4.5 X 3.9 X 3.1 cm and the right ovary to be 7.4 X 4.9 X 5 cm. In both abnormal multiple small cysts were present.The results of selected laboratory investigations are shown on Table 1. She had marked hypertriglyceridemia.Furthermore, her sex-hormone-binding globulin levels were low and therefore, despite normal total testosterone levels, her free androgen index was high. The serum electrolyte (Na+, K+, Ca2+, and Mg'+) concentrations were normal.Glucose tolerance, insulin sensitivity, and p-cell function, A 75-g oral glucose tolerance test (OGTT) revealed diabetes mellitus. Her GH levels were undetectable throughout the

A Canadian family of British descent has been found among whose m?mbers 17 heterozygous examples of the rare Rh chromosome D– were detected in addition to the homozygous D–/D– propositus. The parents of the propositus were first cousins.

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