Lab-grown fat cells help scientists understand type 2 diabetes

Lab-grown adipocyte with nuclei in blue, green being Cellmask staining the whole cell membrane, and in red the distinguishing features of adipocytes—lipid droplets—stained with Lipidtox. Credit: Max Friesen

Research published in the journal on June 17, 2007. Science AdvancesRudolf Jaenisch, Whitehead Institute Founding Member, has presented a way to make fat cells with different levels insulin sensitivity.

The cells accurately simulate healthy insulin metabolism as well as insulin resistance. This is one of the hallmarks of type 2. Jaenisch, a professor of biology at Massachusetts Institute of Technology (MIT), said, “This system, i think, will be really helpful for studying the mechanisms of the disease.”

Max Friesen, a postdoctoral researcher at Jaenisch’s laboratory and the first author of this study, said that “it’s really exciting.” “This is the first time you can actually use a human-derived stem cell.” [fat cell]to produce a real insulin response.”

Body fat—also known as adipose tissue—is essential for regulating your body’s metabolism and plays an important role in the storage and release of energy. Adipocytes, which are fat cells, absorb sugar from the blood and store it for later use.

Over time, however, factors such as genetics and stress, certain diets or polluted water or air can lead to type 2 diabetes. Type 2 diabetes occurs when adipocytes and cells in the liver and muscles become resistant to insulin, and are unable to regulate blood sugar levels.

Modeling diabetes in the laboratory relies on mice, cells in a test tube or petri dish. Both systems have their problems. While mice may look similar to humans in some ways, they have a completely distinct metabolism and do not suffer from the same complications as humans. Cell culture has not been able to replicate key diabetes markers in a manner that is comparable with human tissues in the past.

Friesen and Andrew Khalil (another postdoc in Jaenisch’s lab) set out to create a new model. The researchers started with human pluripotent cells. These cells are the shapeshifters of the body—given the right conditions, they can assume the specific characteristics of almost any human cell type. They have been used in the past by the Jaenisch Lab to reproduce liver cells, brain and even cancerous tumours.

They wanted to improve an existing method to differentiate pluripotent cells from fat cells. Although these cells looked like adipocytes when they were created, the protocol did not create the conditions for healthy insulin signaling and insulin resistance that are found in type 2 diabetes. Healthy adipocytes react to insulin in the body by taking glucose out of the bloodstream. The researchers didn’t find that these lab-made fat cells were doing this unless they increased insulin levels to levels that were 1000 times greater than those ever seen in humans. “Taking up glucose [in response to normal levels on insulin]Friesen stated that this is the main function of an Adipocyte.

Khalil and Friesen wondered if low insulin sensitivity in lab-grown adipocytes could be due to the growing conditions. Friesen suggested that perhaps this is because they’re giving them artificial culture media, which contains all sorts of supplements that could be inhibiting their metabolic reaction.

Friesen and Khalil used a method known as the Design of Experiments approach. This allows researchers to identify the contributions of different factors to a particular outcome. They created almost 30 media compositions using this approach. Each one contained slightly different levels IGF-1, glucose, insulin, and albumin, a protein found within blood serum.

The best medium had levels of insulin and glucose similar to those in the human body. The cells responded to insulin levels that were lower than those found in the body when they were grown in this new medium. Friesen stated, “So this is the healthy adipocyte.” “Next we wanted to see if we could make a disease model out of this—to make it an insulin-resistant adipocyte like you would see in the progression to type 2 diabetes.”

The media was then flooded with insulin for a short time to desensitize the cells. The cells became less sensitive to insulin and responded similarly to pre-diabetic or diabetic fat cells in a living individual.

The researchers could then study how the cells responded to the change—such as what genes the insulin resistant cells expressed that healthy cells did not—in order to tease out the underlying genetics of insulin resistance. Friesen stated, “We observed small changes in a lot genes that are metabolism controlled, so that seems like it is pointing to a deficit of the metabolism/mitochondrial of the insulin resistant cells.” “That’s one thing we want to pursue in the future—figure out what is wrong with their metabolism, and then hopefully how to fix it.”

The researchers have now created a new model that allows them to study insulin resistance in fat cells. They also hope to develop similar procedures in other cells affected by diabetes. Friesen stated that the method can be applied to other tissues with some modifications. “In the near future, this will hopefully lead us to a unified system to all stem cells-derived tissues, liver, skeletal muscles, and other cell types to get a really robust insulin reaction.”

Insulin’s effectiveness is reduced due to a number of factors.

More information:
Max Friesen et al, Development of a physiological insulin resistance model in human stem cell–derived adipocytes, Science Advances (2022). DOI: 10.1126/sciadv.abn7298

Provided by
Whitehead Institute for Biomedical Research

Scientists can understand type 2 diabetes through lab-grown fat cells (2022, June 20).
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