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Type 2 diabetes, independent of obesity and age, is characterized by senescent and dysfunctional mature human adipose cells

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posted on 2022-08-25, 14:58 authored by Birgit Gustafson, Annika Nerstedt, Rosa Spinelli, Francesco Beguinot, Ulf Smith

Obesity with dysfunctional adipose cells is the major cause of the current epidemic of T2D. We examined senescence in human adipose tissue cells from age- and BMI-matched lean, obese and obese T2D individuals and found mature and fully differentiated adipose cells from obese and, more pronounced, from T2D individuals to exhibit increased senescence similar to what we previously have shown in the progenitor cells. Degree of adipose cell senescence was positively correlated with whole-body insulin resistance and adipose cell size. Adipose cell protein analysis revealed dysfunctional cells in T2D with increased senescence markers, reduced PPARγ, GLUT4 and pS473AKT. Consistent with a recent study, we found the cell cycle regulator cyclin D1 to be increased in obese cells but also further elevated in T2D cells, closely correlating with senescence markers, ambient donor glucose and, more inconsistently, with plasma insulin levels. Furthermore, fully differentiated adipose cells were susceptible to experimentally induced senescence, to conditioned medium increasing cyclin D1 and also responsive to senolytic agents. Thus, fully mature human adipose cells from obese and, more pronounced, T2D subjects become senescent and SASP secretion by senescent progenitor cells can play an important role in addition to donor hyperinsulinemia. 

Funding

This study was supported by grants from the Knut and Alice Wallenberg Foundation (KAW, 2020.0118 to U.S), the Swedish Research Council (Vetenskapsrådet, 2018-02587 to U.S), Novo Nordisk Foundation (NN20OC0063541 to U.S), Swedish Diabetes Association (DIA2020-506 to U.S), Heart and Lung Foundation (20180492 to U.S) and the Swedish ALF grants (GBG-718601 to U.S).

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