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Human adipose cells in vitro are either refractory or responsive to insulin, reflecting host metabolic state.

Lizunov VA, Stenkula KG, Blank PS, Troy A, Lee JP, Skarulis MC, Cushman SW, Zimmerberg J - PLoS ONE (2015)

Bottom Line: Two statistically-defined populations best describe the observed cellular heterogeneity, representing the fractions of refractive and responsive adipose cells.Thus, a two-component model best describes the relationship between cellular refractory fraction and subject SI.Since isolated cells exhibit these different response characteristics in the presence of constant culture conditions and milieu, we suggest that a physiological switching mechanism at the adipose cellular level ultimately drives systemic SI.

View Article: PubMed Central - PubMed

Affiliation: Program in Physical Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States of America.

ABSTRACT
While intercellular communication processes are frequently characterized by switch-like transitions, the endocrine system, including the adipose tissue response to insulin, has been characterized by graded responses. Yet here individual cells from adipose tissue biopsies are best described by a switch-like transition between the basal and insulin-stimulated states for the trafficking of the glucose transporter GLUT4. Two statistically-defined populations best describe the observed cellular heterogeneity, representing the fractions of refractive and responsive adipose cells. Furthermore, subjects exhibiting high systemic insulin sensitivity indices (SI) have high fractions of responsive adipose cells in vitro, while subjects exhibiting decreasing SI have increasing fractions of refractory cells in vitro. Thus, a two-component model best describes the relationship between cellular refractory fraction and subject SI. Since isolated cells exhibit these different response characteristics in the presence of constant culture conditions and milieu, we suggest that a physiological switching mechanism at the adipose cellular level ultimately drives systemic SI.

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Refractory fractions obtained from both mobility (a) and fusion (b) data, cluster into two populations whose CDF is described best by the sum of two 0–1 truncated gaussians (blue fit).The refractory fractions correlate with decreasing insulin SI of the donor subject. The solid lines (high, red and low, black) are the cluster population averages drawn to span the range of data. The overlap region along the SI axis is where switching behavior is expected to occur since subjects can have similar SI values but different refractory fractions. Please note that the error bars reflect the failure fraction fitting error (95% confidence) and not the population variance in the experimental data.
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pone.0119291.g009: Refractory fractions obtained from both mobility (a) and fusion (b) data, cluster into two populations whose CDF is described best by the sum of two 0–1 truncated gaussians (blue fit).The refractory fractions correlate with decreasing insulin SI of the donor subject. The solid lines (high, red and low, black) are the cluster population averages drawn to span the range of data. The overlap region along the SI axis is where switching behavior is expected to occur since subjects can have similar SI values but different refractory fractions. Please note that the error bars reflect the failure fraction fitting error (95% confidence) and not the population variance in the experimental data.

Mentions: Since adipose cells may actually contribute directly to systemic insulin resistance [1, 4, 8], we next investigated if the fraction of refractory cells in the insulin-stimulated state increase with increasing values for the insulin resistance seen in our subject population. The fractions of refractory adipose cells were determined from the CDF fits (Fig. 5, 6) and plotted for each subject (Fig. 9, n = 19). Whereas the subject SI values are best described by a unimodal distribution, the insulin-stimulated refractory fractions for both fusion and mobility are best described by bimodal distributions (a mixture model of two truncated Gaussian distributions) (Fig. 9 A, B). The mean value of each of the two characteristic refractory fractions observed for both fusion and mobility in the insulin-stimulated state was used to model the SI dependence (Fig. 9 C, D). Indeed, weighted sum of squares error (SSE) analysis confirms that this two-component model better describes the data than a single correlation line (for fusion and mobility, the SSE for the linear fits are 0.025 and 0.044, respectively, compared to 0.010 and 0.009 for the variation around the means of the two characteristic refractory fractions symbolized by the red and black lines), although the latter are also statistically significant.


Human adipose cells in vitro are either refractory or responsive to insulin, reflecting host metabolic state.

Lizunov VA, Stenkula KG, Blank PS, Troy A, Lee JP, Skarulis MC, Cushman SW, Zimmerberg J - PLoS ONE (2015)

Refractory fractions obtained from both mobility (a) and fusion (b) data, cluster into two populations whose CDF is described best by the sum of two 0–1 truncated gaussians (blue fit).The refractory fractions correlate with decreasing insulin SI of the donor subject. The solid lines (high, red and low, black) are the cluster population averages drawn to span the range of data. The overlap region along the SI axis is where switching behavior is expected to occur since subjects can have similar SI values but different refractory fractions. Please note that the error bars reflect the failure fraction fitting error (95% confidence) and not the population variance in the experimental data.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4359092&req=5

pone.0119291.g009: Refractory fractions obtained from both mobility (a) and fusion (b) data, cluster into two populations whose CDF is described best by the sum of two 0–1 truncated gaussians (blue fit).The refractory fractions correlate with decreasing insulin SI of the donor subject. The solid lines (high, red and low, black) are the cluster population averages drawn to span the range of data. The overlap region along the SI axis is where switching behavior is expected to occur since subjects can have similar SI values but different refractory fractions. Please note that the error bars reflect the failure fraction fitting error (95% confidence) and not the population variance in the experimental data.
Mentions: Since adipose cells may actually contribute directly to systemic insulin resistance [1, 4, 8], we next investigated if the fraction of refractory cells in the insulin-stimulated state increase with increasing values for the insulin resistance seen in our subject population. The fractions of refractory adipose cells were determined from the CDF fits (Fig. 5, 6) and plotted for each subject (Fig. 9, n = 19). Whereas the subject SI values are best described by a unimodal distribution, the insulin-stimulated refractory fractions for both fusion and mobility are best described by bimodal distributions (a mixture model of two truncated Gaussian distributions) (Fig. 9 A, B). The mean value of each of the two characteristic refractory fractions observed for both fusion and mobility in the insulin-stimulated state was used to model the SI dependence (Fig. 9 C, D). Indeed, weighted sum of squares error (SSE) analysis confirms that this two-component model better describes the data than a single correlation line (for fusion and mobility, the SSE for the linear fits are 0.025 and 0.044, respectively, compared to 0.010 and 0.009 for the variation around the means of the two characteristic refractory fractions symbolized by the red and black lines), although the latter are also statistically significant.

Bottom Line: Two statistically-defined populations best describe the observed cellular heterogeneity, representing the fractions of refractive and responsive adipose cells.Thus, a two-component model best describes the relationship between cellular refractory fraction and subject SI.Since isolated cells exhibit these different response characteristics in the presence of constant culture conditions and milieu, we suggest that a physiological switching mechanism at the adipose cellular level ultimately drives systemic SI.

View Article: PubMed Central - PubMed

Affiliation: Program in Physical Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States of America.

ABSTRACT
While intercellular communication processes are frequently characterized by switch-like transitions, the endocrine system, including the adipose tissue response to insulin, has been characterized by graded responses. Yet here individual cells from adipose tissue biopsies are best described by a switch-like transition between the basal and insulin-stimulated states for the trafficking of the glucose transporter GLUT4. Two statistically-defined populations best describe the observed cellular heterogeneity, representing the fractions of refractive and responsive adipose cells. Furthermore, subjects exhibiting high systemic insulin sensitivity indices (SI) have high fractions of responsive adipose cells in vitro, while subjects exhibiting decreasing SI have increasing fractions of refractory cells in vitro. Thus, a two-component model best describes the relationship between cellular refractory fraction and subject SI. Since isolated cells exhibit these different response characteristics in the presence of constant culture conditions and milieu, we suggest that a physiological switching mechanism at the adipose cellular level ultimately drives systemic SI.

Show MeSH
Related in: MedlinePlus