New insight on the link between obesity and type 2 diabetes

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It is well known that obesity affects the body's insulin production and over time risks leading to type 2 diabetes and several other metabolic diseases. Now researchers at Karolinska Institutet in Sweden have found further explanation for why fat cells cause metabolic morbidity. The study, published in Nature Medicine, may have an impact on the treatment of comorbidity in obesity with already available drugs.

Obesity is a rapidly growing global public health problem, not least among children and young people. Many metabolic diseases, among them type 2 diabetes, are strongly associated with obesity. In order to reverse the trend, more knowledge is needed, among other things, about how fat cells (adipocytes) contribute to various harmful processes in tissues and organs.

When fat cells are enlarged, they begin to secrete factors that cause inflammation of the adipose tissue. Fat cell enlargement is also associated with insulin resistance, when cells in the body do not respond to insulin as they should. The important task of insulin is to regulate energy, glucose, for the body's cells. When that function is disturbed, as with insulin resistance, the risk of type 2 diabetes increases.

This relationship is well documented, but there has been a lack of knowledge about the underlying mechanisms behind enlarged fat cells (fat cell hypertrophy) and the secretion of pro-inflammatory substances.

Changes in fat cell activity

Now researchers at Karolinska Institutet have shown that in obesity and insulin resistance, the cell activity of fat cells changes. As fat cells increase in cell size, nuclear size and nuclear DNA content also increases.

"The process of cells not dividing but increasing in DNA content and cell size (endoreplication) is common among plants and animals. In contrast, the process has not been described for human fat cells (adipocytes), which can increase in size more than 200 times over their lifespan," says Qian Li, researcher at the Department of Cell and Molecular Biology, Karolinska Institutet, and joint first author.

The natural process of fat cells increasing in size has several negative effects on health. The authors demonstrate that elevated levels of insulin in the blood cause premature aging, senescence, in some cells in the adipose tissue.

"Our results show that senescent fat cells increase the secretion of pro-inflammatory factors, and drive inflammation and pathology in human adipose tissue. This in turn affects the health of the whole body," says Carolina Hagberg, researcher at the Department of Medicine, Solna at Karolinska Institutet, and joint first author.

Good effect with common drug

The results are based on analysis of adipose tissue from 63 people with BMI under 30 who underwent umbilical hernia surgery or cholecysectomy for gallstone disease, as well as 196 people with BMI over 30 who underwent bariatric surgery for obesity in Stockholm.

Using a commonly prescribed drug for type 2 diabetes, the researchers were able to block the formation of senescent fat cells and reduce the secretion of fat cell-based pro-inflammatory factors.

"These studies identify an unappreciated aspect of human adipocyte biology, the activation of a cell cycle program in obesity and hyperinsulinemia, which could pave the way for novel treatment strategies for obesity and associated co-morbidities, such as type 2 diabetes," says Kirsty Spalding, researcher at the Department of Cell and Molecular Biology, Karolinska Institutet, and the study's last author.

The study was financed by the Swedish Research Council, the Strategic Research Program for Diabetes at Karolinska Institutet, the Novo Nordisk Foundation, the Karolinska Institutet/AstraZeneca Integrated Cardiometabolic Centre, the Erling-Persson Family Foundation, the Swedish Foundation for Strategic Research (I.A.) and the Vallee Foundation Vallee Scholar Award, the Swedish Society for Medical Research, and Wilhelm och Else Stockmanns Stiftelse. There are no reported conflicts of interest.

Publication:Obesity and hyperinsulinemia drive adipocytes to activate a cell cycle program and senesce”, Qian Li, Carolina E. Hagberg, Helena Silva Cascales, Shuai Lang, Mervi T. Hyvönen, Firoozeh Salehzadeh, Ping Chen, Ida Alexandersson, Eleni Terezaki, Matthew J. Harms, Maria Kutschke, Nahida Arifen, Niels Krämer, Myriam Aouadi, Carole Knibbe, Jeremie Boucher, Anders Thorell, and Kirsty L. Spalding. Nature Medicine, online October 4 2021, doi: 10.1038/s41591-021-01501-8.

Read more about Karolinska Institutet’s research on diabetes on our website.

For more information, please contact:
Kirsty Spalding, researcher
Department of Cell and Molecular Biology, Karolinska Institutet
Mail: kirsty.spalding@ki.se
Phone: +46 8 524 860 77 (Karolinska Institutet’s press office)

Qian Li, researcher
Department of Cell and Molecular Biology, Karolinska Institutet
Mail: ariesliq@outlook.com
Phone: +46 8 524 860 77 (Karolinska Institutet’s press office)

Carolina Hagberg, researcher
Department of Medicine, Solna, Karolinska Institutet
Mail: carolina.hagberg@ki.se
Phone: +46 8 524 860 77 (Karolinska Institutet’s press office)

Contact the Press Office and download photo: ki.se/pressroom

Karolinska Institutet is one of the world’s leading medical universities. Our vision is to advance knowledge about life and strive towards better health for all. Karolinska Institutet accounts for the single largest share of all academic medical research conducted in Sweden and offers the country’s broadest range of education in medicine and health sciences. The Nobel Assembly at Karolinska Institutet selects the Nobel laureates in Physiology or Medicine.

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