Plain language summary
Insulin resistance develops following extended periods of high insulin production, making cells unresponsive to its actions, however not all insulin functions are equally affected. Patients with Type 2 diabetes have impaired insulin regulation of glucose with increased fat storage in the liver. This results in a combination of raised insulin, glucose and triglycerides in the blood (hyperinsulinemia, hyperglycaemia, and hypertriglyceridemia), which affect health outcomes. Studies have shown that 'selective insulin resistance' occurs in the liver, however the molecular mechanisms by which this occurs are not known. It is also not known whether this is liver-specific or occurs in other insulin responsive tissues in the body. This in-vitro (cell culture) study found that high levels of insulin disturbs the PI3-kinase/Akt signalling pathway resulting in selective insulin resistance in fat cells (adipocytes), whilst expression of FoxO1 transcription factor (which controls lipid metabolism) is maintained. These changes are the result of inherent differences in insulin sensitivity of GLUT4 translocation and FoxO1 nuclear exclusion. The authors conclude that in a model of chronic hyperinsulinemia, fat cells develop a state of selective insulin resistance. Uncoupled insulin action, a phenomenon first described in the insulin-resistant liver, might be a general feature of insulin-resistant tissues consequent to deregulation of PI3-kinase/Akt signalling.
Abstract
Insulin resistance is a component of the metabolic syndrome and Type 2 diabetes. It has been recently shown that in liver insulin resistance is not complete. This so-called selective insulin resistance is characterized by defective insulin inhibition of hepatic glucose output while insulin-induced lipogenesis is maintained. How this occurs and whether uncoupled insulin action develops in other tissues is unknown. Here we show in a model of chronic hyperinsulinemia that adipocytes develop selective insulin resistance in which translocation of the GLUT4 glucose transporter to the cell surface is blunted yet nuclear exclusion of the FoxO1 transcription factor is preserved, rendering uncoupled insulin-controlled carbohydrate and lipid metabolisms. We found that in adipocytes FoxO1 nuclear exclusion has a lower half-maximal insulin dose than GLUT4 translocation, and it is because of this inherent greater sensitivity that control of FoxO1 by physiological insulin concentrations is maintained in adipocytes with compromised insulin signaling. Pharmacological and genetic interventions revealed that insulin regulates GLUT4 and FoxO1 through the PI3-kinase isoform p110α, although FoxO1 showed higher sensitivity to p110α activity than GLUT4. Transient down-regulation and overexpression of Akt isoforms in adipocytes demonstrated that insulin-activated PI3-kinase signals to GLUT4 primarily through Akt2 kinase, whereas Akt1 and Akt2 signal to FoxO1. We propose that the lower threshold of insulin activity for FoxO1's nuclear exclusion is in part due to its regulation by both Akt isoforms. Identification of uncoupled insulin action in adipocytes suggests this condition might be a general phenomenon of insulin target tissues contributing to insulin resistance's pathophysiology.
Methodological quality
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