Abstract
Insulin resistance, the diminished response of target tissues to insulin, is associated with the metabolic syndrome and a predisposition towards diabetes in a growing proportion of the worldwide population. Under insulin resistant states, the cellular response of the insulin signaling pathway is diminished and the body typically responds by increasing serum insulin concentrations to maintain insulin signaling. Some evidence indicates that the increased insulin concentration may itself further dampen insulin response. If so, insulin resistance would worsen as the level of circulating insulin increases during compensation, which could contribute to the transition of insulin resistance to more severe disease. Here, we investigated the consequences of excess insulin exposure to insulin receptor (IR) activity. Cells chronically exposed to insulin show a diminished the level of IR tyrosine and serine autophosphorylation below that observed after short-term insulin exposure. The diminished IR response did not originate with IR internalization since IR amounts at the cell membrane were similar after short- and long-term insulin incubation. Förster resonance energy transfer between fluorophores attached to the IR tyrosine kinase (TK) domain showed that a change in the TK domain occurred upon prolonged, but not short-term, insulin exposure. Even though the altered ‘insulin refractory’ IR TK FRET and IR autophosphorylation levels returned to baseline (non-stimulated) levels after wash-out of the original insulin stimulus, subsequent short-term exposure to insulin caused immediate re-establishment of the insulin-refractory levels. This suggests that some cell-based ‘memory’ of chronic hyperinsulinemic exposure acts directly at the IR. An improved understanding of that memory may help define interventions to reset the IR to full insulin responsiveness and impede the progression of insulin resistance to more severe disease states.
Highlights
Insulin resistance, or the impaired ability of insulin to mediate glucose disposal, is a risk factor for several disorders including the metabolic syndrome, type 2 diabetes mellitus, gestational diabetes, cardiovascular disease and several forms of cancer [1]
hepatoma cells (HTCs) cells were genetically modified to express the cDNA for the B-isoform of the human insulin receptor (IR) (HTC-IR) [27], or the human IR fused at its C-terminus in frame with the yellow fluorescent protein (IR-YFP)
The above studies showed that the insulin refractory response was not linked to changes in IR level or localization. We investigated if it could be associated with any persistently altered tyrosine kinase (TK) state induced by prolonged insulin exposure
Summary
The impaired ability of insulin to mediate glucose disposal, is a risk factor for several disorders including the metabolic syndrome, type 2 diabetes mellitus, gestational diabetes, cardiovascular disease and several forms of cancer [1]. The body responds through compensatory mechanisms designed to maintain insulin signaling. The IR’s intracellular tyrosine kinase domain becomes activated and phosphorylates specific tyrosines on the b-subunits of the IR dimer partners. This autophosphorylation initiates several signaling cascades that lead to insulin’s downstream effects [3,4,5,6,7]. Insulin resistance could originate with a decreased amount of IR available to effect signaling. Deficiencies in insulin signaling downstream of the IR have been heavily studied as a cause of insulin resistance in humans [9]
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