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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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The refractory fractions obtained from analysis of mobility (a) and fusion (b) data plotted as a function of clinical parameters of the donor subject such as BMI, %Fat, HDL, triglycerides, HOMA-IR, waist circumference, age, HbA1C, glucose, and insulin.Refractory fractions cluster into two populations: high (red) and low (black). The solid lines are the cluster averages drawn to span the range of data. The overlap region along the clinical axis is variable with clinical values: e.g. for age the overlap region spans the entire range, while for parameters such as glucose, insulin, BMI and HOMA-IR the overlap region is narrower.
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pone.0119291.g010: The refractory fractions obtained from analysis of mobility (a) and fusion (b) data plotted as a function of clinical parameters of the donor subject such as BMI, %Fat, HDL, triglycerides, HOMA-IR, waist circumference, age, HbA1C, glucose, and insulin.Refractory fractions cluster into two populations: high (red) and low (black). The solid lines are the cluster averages drawn to span the range of data. The overlap region along the clinical axis is variable with clinical values: e.g. for age the overlap region spans the entire range, while for parameters such as glucose, insulin, BMI and HOMA-IR the overlap region is narrower.

Mentions: In addition to their relationship with SI, we plotted the refractory fractions against the other clinical measures of insulin resistance and associated risk factors (Fig. 10). Unexpectedly, the subjects themselves comprise two populations in which their isolated adipose cells in vitro in the insulin-stimulated state exhibit either a high or low fraction of refractory cells. We also note a similar two-population relationship when we analyzed the average values of the isolated adipose cell GSV mobility and fusion values per subject as previously reported For many of the clinical parameters, the segregation of subjects by the level of insulin-refractive adipose cell fraction reveals two domains with variable transition or overlapping regions, where the percentage of subjects varies with the clinical parameter measured (Fig. 10). While some clinical parameters, i.e. age, are equally represented at both insulin-refractive adipose cell levels, others show clear transitions; depending on the values one accepts as indicative of clinical risk for the metabolic syndrome [25, 26], these transitions appear to be somehow related to these risk factors, i.e. HbA1c (>6.2), HOMA-IR (>3), serum glucose (>110 mg/dL), fasting insulin (>10 mcU/ml), BMI (>35), and %Fat (>45). All subjects whose insulinemia, serum glucose, HbA1c, BMI, and %Fat are above these thresholds, have most of their adipose cells in the insulin-refractory state. However, the inverse is less clear: some subjects who have significant fractions of refractory adipose cells may still have many of these clinical indices in the normal range. This could either be due to genetic differences between the two populations, or environmental effects such as diet, or both. We have not considered in detail here the indirect nature of the clinical parameters used or their limitations as they are typically assessed in the clinical environment. Nevertheless, examination of the GSV responses to insulin in isolated adipose cells per subject in vitro appears to allow division of this subject population into two general groups, one of which may be at risk of developing severe insulin resistance and type 2 diabetes.


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)

The refractory fractions obtained from analysis of mobility (a) and fusion (b) data plotted as a function of clinical parameters of the donor subject such as BMI, %Fat, HDL, triglycerides, HOMA-IR, waist circumference, age, HbA1C, glucose, and insulin.Refractory fractions cluster into two populations: high (red) and low (black). The solid lines are the cluster averages drawn to span the range of data. The overlap region along the clinical axis is variable with clinical values: e.g. for age the overlap region spans the entire range, while for parameters such as glucose, insulin, BMI and HOMA-IR the overlap region is narrower.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0119291.g010: The refractory fractions obtained from analysis of mobility (a) and fusion (b) data plotted as a function of clinical parameters of the donor subject such as BMI, %Fat, HDL, triglycerides, HOMA-IR, waist circumference, age, HbA1C, glucose, and insulin.Refractory fractions cluster into two populations: high (red) and low (black). The solid lines are the cluster averages drawn to span the range of data. The overlap region along the clinical axis is variable with clinical values: e.g. for age the overlap region spans the entire range, while for parameters such as glucose, insulin, BMI and HOMA-IR the overlap region is narrower.
Mentions: In addition to their relationship with SI, we plotted the refractory fractions against the other clinical measures of insulin resistance and associated risk factors (Fig. 10). Unexpectedly, the subjects themselves comprise two populations in which their isolated adipose cells in vitro in the insulin-stimulated state exhibit either a high or low fraction of refractory cells. We also note a similar two-population relationship when we analyzed the average values of the isolated adipose cell GSV mobility and fusion values per subject as previously reported For many of the clinical parameters, the segregation of subjects by the level of insulin-refractive adipose cell fraction reveals two domains with variable transition or overlapping regions, where the percentage of subjects varies with the clinical parameter measured (Fig. 10). While some clinical parameters, i.e. age, are equally represented at both insulin-refractive adipose cell levels, others show clear transitions; depending on the values one accepts as indicative of clinical risk for the metabolic syndrome [25, 26], these transitions appear to be somehow related to these risk factors, i.e. HbA1c (>6.2), HOMA-IR (>3), serum glucose (>110 mg/dL), fasting insulin (>10 mcU/ml), BMI (>35), and %Fat (>45). All subjects whose insulinemia, serum glucose, HbA1c, BMI, and %Fat are above these thresholds, have most of their adipose cells in the insulin-refractory state. However, the inverse is less clear: some subjects who have significant fractions of refractory adipose cells may still have many of these clinical indices in the normal range. This could either be due to genetic differences between the two populations, or environmental effects such as diet, or both. We have not considered in detail here the indirect nature of the clinical parameters used or their limitations as they are typically assessed in the clinical environment. Nevertheless, examination of the GSV responses to insulin in isolated adipose cells per subject in vitro appears to allow division of this subject population into two general groups, one of which may be at risk of developing severe insulin resistance and type 2 diabetes.

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