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Obesity and diabetes link explored

Scientists ‘may have uncovered a key reason why obese people have a raised risk of health complications such as type 2 diabetes’, BBC News has said. According to the news service, the link is due to ‘pigment epithelium-derived factor’ (PEDF), a protein released from fat cells.

The results of the study suggest that insulin resistance in obesity, and hence the increased likelihood of diabetes, may be partly caused by PEDF. ‘Obese’ mice, which were resistant to insulin and had elevated blood glucose levels, also had elevated levels of PEDF. When PEDF was injected into ‘lean’ mice, it also reduced their sensitivity to the effects of insulin, as might be seen in type 2 diabetes.

This is worthy research, which has attempted to understand the possible biological mechanisms that link obesity and the increased risk of diabetes. However, as this is only an animal study, the situation may differ in humans. More research is needed to clarify whether this might have future treatment implications, such as techniques to block the action of PEDF and increase insulin sensitivity. For the general population, a healthy diet and lifestyle with regular exercise remains the best way to avoid obesity and the risk of complications such as type 2 diabetes.

Where did the story come from?

The research was carried out by Seamus Crowe and colleagues of Monash University, Australia and other institutions in Australia and the US. The studies were supported by research grants from the National Health and Medical Research Council of Australia and the Diabetes Australia Research Trust. Individual researchers also received scholarships and fellowship support. The study was published in Cell, the peer-reviewed scientific journal.

What kind of scientific study was this?

This was an experimental study in mice, looking at the link between obesity and glucose intolerance. The researchers say that although obesity is identified as a major risk factor for glucose intolerance and diabetes in humans, the factors linking these disorders are not clearly understood. In this paper, researchers examined the possible underlying mechanism.

Previous research is said to have focused on trying to identify proteins that are secreted from fat cells. Screening has identified one of the most abundant of these proteins to be ‘pigment epithelium-derived factor’ (PEDF or SerpinF1), an enzyme inhibitor believed to have a role in the regulation of metabolism. This mouse study aimed to investigate the role that PEDF plays in increasing resistance to insulin, and hence intolerance of glucose, in fat mice.

For 12 weeks, the researchers fed one group of mice on a low-fat diet (4% fat) of mouse chow, while feeding another on a high-fat diet (60% fat). They then compared the mice’s body mass and levels of fatty tissue, plus levels of PEDF in the blood.

To see how PEDF regulates the sensitivity of the muscle cells to insulin, the researchers injected PEDF into muscle cells taken from the low-fat mice, observing how this affected glucose uptake by the muscle cells.

They further tested PEDF’s action by injecting the low-fat mice with PEDF, then stimulated them with high levels of insulin but aimed to keep their glucose levels stable by giving the mice extra glucose when their levels began to fall.

What were the results of the study?

Mice fed on the high-fat diet had increased body mass and fatty tissue compared to those on the low-fat diet. The high-fat mice also had comparatively increased blood glucose levels and elevated insulin, suggesting that they were resistant to insulin.

The blood concentration of PEDF in the high-fat mice was also increased 3.2-fold compared to the concentration in the low-fat mice, with later tissue analysis revealing that their fat cells were secreting more PEDF than the lean mice but their muscle and liver cells were not secreting excess amounts.

When looking to see how injected PEDF affected insulin sensitivity in the extracted muscle cells, the researchers found that it reduced the insulin-induced uptake of glucose, i.e. PEDF decreased their sensitivity to insulin.

In the subsequent test where they injected the low-fat mice with PEDF while trying to maintain high insulin/stable glucose levels, they found that, compared to mice that were not injected, those that were given PEDF needed to be given less glucose to keep their glucose levels stable during insulin stimulation. This indicated that their bodies had greater resistance to insulin when injected with PEDF. When PEDF was continuously infused into the low-fat mice over several days, insulin-stimulated glucose uptake by muscle cells was also reduced.

When they investigated whether blocking PEDF with a neutralising antibody could restore insulin sensitivity in obese mice, they found that this did not affect fasting blood glucose and insulin levels. However, it did improve the insulin sensitivity of the body in high insulin/high glucose situations.

What interpretations did the researchers draw from these results?

The authors say that their results demonstrate that changes in the size of fat cells in the body are accompanied by a change in the protein secretion from these fat cells. They say that this change in secretion is the important link between obesity and insulin resistance, and conclude that the release of PEDF from fat cells seems to have a direct effect upon body metabolism and increased resistance to the action of insulin.

The authors also discuss the possible inflammatory effects of PEDF and its role in the breakdown of fats.

What does the NHS Knowledge Service make of this study?

The results suggest that insulin resistance in obesity, and hence the increased likelihood of glucose intolerance and diabetes, may be partly caused by PEDF (pigment epithelium-derived factor) released from fat cells.

This is worthy and interesting research, which has attempted to understand the possible biological mechanisms behind obesity and the increased risk of diabetes. However, as this is only an animal study, the situation may not be identical in humans.

At the current time, it is unclear whether there are potential treatment implications (i.e. developing methods to block the action of PEDF to increase insulin sensitivity). But for now, it is likely that this work will eventually lead to further research on the role and action of PEDF in human glucose intolerance. It remains unclear precisely why fat cells increase their secretion of PEDF in obesity. In addition, there may be as yet unexplored factors involved in glucose metabolism, therefore more research will be needed to explain this.
 
For the general population, the current advice remains unchanged: a combination of healthy diet and lifestyle plus regular exercise is the best way to avoid obesity and the risk of complications, such as type 2 diabetes.

Links to the headlines

Obesity health risk cause ‘found’. BBC News, July 11 2009

Links to the science

Crowe S,  Wu LE, Economou C, et al.Pigment Epithelium-Derived Factor Contributes to Insulin Resistance in Obesity. Cell Metabolism 2009; 10:40-47

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