New Potential Therapeutic Target for Type 2 Diabetes Discovered

New Potential Therapeutic Target for Type 2 Diabetes Discovered
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A University of Lund-led international research team has published new findings that could help explain why people with type 2 diabetes (T2D) have poorer muscle strength and quality. Their work in human cells and in mice has identified a gene, VPS39, which plays a key role in the ability of muscle stem cells to create new mature muscle cells, and in people with type 2 diabetes, could represent a new therapeutic target for the disorder.

“In people with type 2 diabetes, the VPS39 gene is significantly less active in the muscle cells than it is in other people, and the stem cells with less activity of the gene do not form new muscle cells to the same degree,” explained study lead Charlotte Ling, PhD, professor of epigenetics at Lund University. “The gene is important when muscle cells absorb sugar from blood and build new muscle. Our study is the first ever to link this gene to type 2 diabetes.”

The Lund university team, together with colleagues in Sweden, Denmark, Finland and Germany, report their findings in Nature Communications, in a paper titled, “VPS39-deficiency observed in type 2 diabetes impairs muscle stem cell differentiation via altered autophagy and epigenetics.”

In type 2 diabetes, the ability to produce insulin is impaired, and patients have chronically elevated blood sugar. Muscles are generally worse at absorbing sugar from food, and muscle function and strength are impaired in patients with the disorder. “Skeletal muscle is the primary organ responsible for insulin-stimulated glucose uptake and T2D is associated with lower muscle strength and quality (strength divided by mass) contributing to glucose intolerance,”  the team noted.

A muscle consists of a mixture of fiber types with different properties. Throughout life, muscle tissue has the ability to form new muscle fibers. “Skeletal muscle is regenerated and maintained by muscle stem cells (satellite cells) that are activated in response to, e.g. injury and exercise,” the team continued. These activated muscle stem cells, or myoblasts, proliferate and differentiate into new muscle, through a process called myogenesis.

Rodent models of diabetes can exhibit impaired myogenesis and muscle regeneration, but what isn’t well understood is whether abnormalities in the muscle of people with already exist at the stage of stem cells and progenitors.

For their newly reported research the scientists wanted to investigate whether epigenetic patterns in muscle stem cells might provide some answers as to why impaired muscle function occurs in people with type 2 diabetes. They studied epigenetic changes in the muscle stem cells of 14 participants with type 2 diabetes and 14 healthy people in a control group. “To identify previously unrecognized candidates that contribute to the abnormalities seen in muscle from patients with T2D, we analyzed the genome-wide expression and DNA methylation in primary human myoblasts and myotubes from individuals with T2D and controls,” they wrote.The participants in the groups were all matched by age, gender and BMI (body mass index). The investigators also extracted and compared mature muscle cells from both groups.

Their analyses identified 20 genes, including VPS39, for which gene expression differed between the groups, in both immature muscle stem cells and in mature muscle cells. The researchers also compared the epigenetic patterns of muscle cells before and after cell differentiation in both groups.

“Despite the fact that both groups’ muscle stem cells were grown under identical conditions, we saw more than twice as many epigenetic changes in the type 2 diabetes group during the differentiation from muscle stem cell to mature muscle cells,” said Ling. “Muscle-specific genes were not regulated normally, and epigenetics did not function in the same way in cells from people with type 2 diabetes.”

Added co-author Johanna Säll Sernevi, PhD, at Lund University, “The study clearly showed that muscle stem cells that lack the function of the gene VPS39, which is lower in type 2 diabetes, also lack the ability to form new mature muscle cells. This is because muscle stem cells that lack VPS39 due to altered epigenetic mechanisms cannot change their metabolism in the same way as muscle stem cells from controls—the cells therefore remain immature or break down and die.”

To confirm their findings, the researchers turned to a mouse model that had a reduced amount of the VPS39 gene (VPS39+/ mice), to mimic the disease. “To further study the role of VPS39 in vivo, we examined a mouse model for VPS39-deficiency (Vps39+/),” they explained. “Heterozygous mice were chosen because they have reduced, but not lacking, expression of VPS39, which resembles the situation seen in muscle cells from individuals with T2D.

Studies in these animals demonstrated altered gene expression, glucose intolerance and decreased glucose uptake into the muscle tissues, similar to that of individuals with type 2 diabetes. “We conclude that mimicking the VPS39-deficiency observed in muscle cells from individuals with T2D using a mouse model (Vps39+/) results in impaired glucose uptake in muscle and altered expression of genes affecting autophagy, epigenetic programming, muscle development, and metabolism, highlighting the possible role for VPS39 in muscle pathology,” they wrote. “On the basis of the present data, we propose a model for T2D in which low VPS39 levels contribute to impaired muscle regeneration and insulin resistance through metabolic and epigenetic changes.”

The authors believe that their findings open up new avenues for treating type 2 diabetes. “The genome, our DNA, cannot be changed, although epigenetics in effect does,” Ling said. “With this new knowledge, it is possible to change the dysfunctional epigenetics that occur in type 2 diabetes. For example, by regulating proteins, stimulating or increasing the amount of the VPS39 gene, it would be possible to affect the muscles’ ability to regenerate and absorb sugar.”