PubMed · 2179724
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S Melmed. 1990-04-05. Acromegaly.. https://doi.org/10.1056/nejm199004053221405
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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.
Pituitary apoplexy is a serious complication in about 3% of patients with a pituitary adenoma. Very often, the diagnosis of a functioning or non-functioning adenoma is made in retrospect. In this report, we describe two patients in whom the diagnosis of acromegaly was made before the apoplexy. In one patient, surgical intervention was necessary because of remaining clinical and biochemical activity; in the other patient conservative follow-up was pursued. Seven and nine years after apoplexy, respectively, the patients were clinically and biochemically in remission. During the follow-up, three and five years after apoplexy, respectively, the patients underwent a 10-min venous sampling procedure for 24 hours, and the GH secretory profile was investigated with multiparameter deconvolution analysis and by approximate entropy (ApEn), a scale- and model-independent regularity measure. The deconvolution analysis revealed an increased basal (nonpulsatile) GH secretion rate, while the total 24 h secretion rate was normal compared with 13 healthy male control subjects. ApEn was much larger for each patient than for any control subject value, indicating markedly more irregular GH secretion. We hypothesize that these subtle abnormalities are caused by non-specific damage as a result of vascular insult, leading to abnormal vascular supply, or abnormal autocrine and paracrine GH regulation within the remaining gland.
The aim of our work was to study non-insulin-mediated glucose uptake (NIMGU), in the postabsorptive state, in several pathologies characterized by peripheral insulin resistance, namely, obesity (n = 10), NIDDM (n = 7), acromegaly (n = 7) and Cushing's disease (n = 6). These groups were compared with a group of 16 healthy subjects. To estimate peripheral insulin sensitivity (SI) and glucose effectiveness (SG), we used the minimal model of glucose metabolism. Although all of these pathologies showed severe insulin resistance (control: 6.44 +/- 2.63, obesity: 2.84 +/- 1.57, NIDDM: 1.71 +/- 0.77, acromegaly: 1.88 +/- 1.23, Cushing's disease: 1.87 +/- 0.66 x 10(-4) min-1 (microU/ml)-1, P < 0.01), fasting insulin-mediated glucose uptake (IMGU) did not differ significantly among the five groups, because reactive hyperinsulinaemia was present in all of these states. The contribution of NIMGU to whole-body glucose uptake did not differ significantly among the five groups (control: 77 +/- 8%; obesity: 77 +/- 9%; acromegaly: 82 +/- 8%; Cushing's disease: 83 +/- 8%; NIDDM: 84 +/- 7%). In conclusion, our data show that, in the postabsorptive period, non-insulin mediated glucose uptake is a major determinant of glucose disposal and is similar in the different pathologies studied; on the other hand, although absolute rates of basal insulin-mediated glucose uptake are reduced in insulin-resistant states, they did not achieve statistical value compared with control subjects because of compensatory hyperinsulinaemia.