Center for Diabetes Research

2013: Impaiment of normal adipose tissue development can be tied to Insulin action

Obesity and diabetes are diseases that greatly increase worldwide. Adipose tissue is now recognized as a separate organ with complex metabolic processes. Understanding adipose tissue biology is important in order to develop better treatment strategies for obesity and diabetes.

PhD-candidate Kishan Chudasama and Professor Stefan Johansson have been...
PhD candidate Kishan Chudasama and professor Stefan Johansson have been working meticulously for years to find the one gene responsible for the rare disease.
Vegar Valde

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An international team of physicians and scientists lead by researchers from Center for Diabetes Research has found that insulin action can be associated with normal development and distribution of fat of the body. This provides new insights into the biology of adipose tissue and may lead to better treatment of obesity and diabetes.

Lipodystrophy is a group of diseases characterized by loss of fat tissue and predisposition for diabetes, insulin resistance, fatty liver and disorder in lipid metabolism. In 1983, former Chair chief of the Department of Pediatrics, professor Dagfinn Aarskog, described a family with short stature and lipodystrophy. For ten years, we have been working to find the explanation for the disease in this family. The breakthrough came by using modern genetic technology (whole-exome sequencing), in which all the genes in the genome can be analyzed in detail in a single experiment.

After sequencing the entire genome, we were left with 14,253 variants that could be the cause. By removing the variations that we also found in large normal materials in the United States, as well as concentrating on varieties that were only present in the sick family members, we were able to reduce the number to 22 variants in a total of 22 genes. Only one of these 22 genes could possibly cause this disease. When we found the same variant in a German family with the same phenotype, we were sure of the discovery.

In addition to regulate blood sugar, our insulin has an important function in the so-called insulin signaling pathway, essential for normal growth and development of all our cells. A critical factor in this pathway is the p85 protein, encoded by the PIK3R1 gene, found to be the cause of the mentioned disease. Functional studies of the discovered PIK3R1 mutation showed that it led to impaired effect of the insulin signaling pathway via reduced interaction between p85 and other partners in the signaling pathway. These studies were performed in tissue from patients, and in a fat cell model in collaboration with Harvard Medical School in Boston.

Since normally functioning p85 is essential for normal development and growth of fat cells and other cells, we here found a unique link between p85, the insulin signaling pathway, the disease lipodystrophy and other growth disorders. A paper describing these findings was published in the July issue of the American Journal of Human Genetics.

This knowledge may lead to the discovery of new strategies to prevent the loss of fat cells and delay the occurrence of metabolic complications in patients with lipodystrophy. It may lead to new targets for the treatment of obesity, diabetes and other growth disorders. Furthermore, knowledge uncover new mechanisms for how adipose tissue may interact with other organs, which can increase our understanding of metabolic complications such as cardiovascular disease associated with obesity.