Impaired activation of phosphoinositide 3-kinase by insulin in fibroblasts from patients with severe insulin resistance and pseudoacromegaly. A disorder characterized by selective postreceptor insulin resistance.

Abstract

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.

Natural variants of human p85α phosphoinositide 3-kinase in severe insulin resistance: a novel variant with impaired insulin-stimulated lipid kinase activity

“…In agreement with others we also found that all cDNA samples sequenced at amino acid residue 330 coded for Asp suggesting that there is an error in the published sequence of p85a [32]. Also of note was the absence of mutations in the p85a gene in the pseudoacromegalic patients whom we have previously reported to have impaired insulin-stimulated PI 3K activity in their cultured dermal fibroblasts [15].…”

“…A reduction in insulin-stimulated PI 3K activity in muscle and adipose tissue from insulin-resistant subjects with Type II diabetes or obesity has been reported in a number of studies [35±37]. Impaired insulin-stimulated PI 3K activity in cultured dermal fibroblasts has been reported from subjects with the pseudoacromegalic form of severe insulin resistance suggesting the presence of an intrinsic cellular defect in the PI 3K pathway in that rare subtype of severe insulin resistance [15,16].…”

Lipodystrophy: metabolic insights from a rare disorder

“…For example, it has been proposed that thecal cell proliferation in PCOS reflects preserved mitogenic (mitogen-activated protein kinase, or MAPK) signalling in the face of resistance to the glucose-lowering effect of insulin, largely mediated through the PI3K/AKT pathway. Moreover, the idea of partial insulin resistance is consistent with the clinical observation of pseudoacromegaly, a state characterised by acromegaloid features in the absence of excess GH, in at least some patients with severe insulin resistance (Flier et al 1993, Dib et al 1998). …”

Insights into obesity and insulin resistance from the study of extreme human phenotypes

“…The detailed functional studies of several naturally occurring insulin receptor mutants provided novel insights into insulin signalling (27,28). Additionally, we also descried a specific biochemical defect in insulin-stimulated phosphatidylinositol 3-kinase (PI3 kinase) activity in cells from patients with the pseudoacromegalic variant of SIR (29). In the case of distinct recognisable lipodystrophic syndromes of insulin resistance we collaborated with colleagues undertaking positional cloning approaches that were ultimately successful in identifying mutations in lamin A/C as the cause of familial partial lipodystrophy (30) and siepin as the cause of one form of congenital generalised lipodystrophy (31).…”