Human Adipose Cell Response to Insulin: Analysis of Cellular Switch-Like Transformations and Distributions

Abstract

Insulin resistance is associated with decreased glucose transporter-4 (GLUT4) translocation in adipose cells and muscles in response to insulin. Here we quantified, per cell, insulin's effects on GLUT4 storage vesicle (GSV) tethering and fusion in adipose cells from human subjects with varying insulin sensitivity index (SI). Basal GSV tethering and fusion rates were distributed unimodally and did not vary significantly with SI. In contrast, after a maximal insulin challenge, both tethering and fusion rates were bimodally distributed, with two distinct subpopulations; the first subpopulation was indistinguishable from the basal distribution, while the second corresponded to a normal insulin response. Importantly, the fraction of cells in the two-subpopulations were strongly correlated with donor subject SI. These data suggest that the loss of systemic SI is not due to a gradual decrease in the insulin response of all cells, but rather an increase in the fraction of cells that switch off their insulin response. This observed heterogeneity may be an important consideration in modeling the cellular transitions and systemic changes associated with the onset of Type II diabetes. Thus, isolated human adipose cells, when treated with high concentrations of insulin, exist in either the basal or fully insulin-stimulated state, and population dose response curves reflect the proportion of adipose cells in these two distinct states.