School of Medicine researchers have put their efforts into the potential treatment of Type 2 Diabetes, yielding an astounding discovery for a possible remedy specific to women.
According to the Centers for Disease Control and Prevention, diabetes is extremely prevalent and serious. A total of 37.3 million people have diabetes, equating to 11.3 percent of the U.S. population. Additionally, 96 million people 18 years of age or older have prediabetes, meaning that 38.0 percent of Americans in this age group are at risk of developing Type 2 diabetes, heart disease and stroke.
Assoc. Biomedical Engineering Prof. Mete Civelek, the study’s lead author, based this research on a previous study analyzing genetic factors associated with diabetes.
“The initial finding was from a large-scale human genetics study, where we found that there’s a gene in women that increases their risk for Type 2 Diabetes a lot more than men,” Civelek said. “We were able to replicate that [study’s] finding in our mouse model, but also went beyond that.”
In a mouse model, mice are genetically engineered to either express or not express certain genes, allowing for an increased understanding of how a gene might function. This is done by observing the differences in outcomes with or without a certain gene. A mouse model additionally provides a more isolated and ethical environment compared to a human model.
The specific gene described by Civelek, KLF14, has been linked to various metabolic problems including obesity and Type 2 Diabetes. The KLF14 gene encodes a protein that is crucial for the regulation of the breakdown of fat stored in one’s cells to fatty acids that can be released into the bloodstream.
Assoc. Medicine Prof. Susanna Keller, a collaborator on the study, specializes in endocrinology and metabolism and aided in designing an experiment that would be most effective in transitioning from a human model to mice by investigating mouse metabolisms.
“There’s a reservation whether you use mice or humans, but the previous studies by Dr. Civelek has already shown that humans have this dimorphic expression of KLF14 between men and women,'' Keller said. In simpler terms, the mouse model has shown the same patterns of KLF14 expression in both men and women, which makes the model both powerful and accurate.
Researchers can alter the genes of mice to include genes from other organisms — this is called a transgenic mouse. Additionally, researchers can delete genes from a mouse in order to see what would happen without it; this is referred to as a knockout mouse as the gene has been “knocked out.” Studying transgenic and knockout mice helped lead researchers toward their findings.
“We were able to figure out a more molecular mechanism, which is impossible to study in humans, in mice,” Civelek said. “That’s why we created this mouse model.”
However, the effect of increased production of the fat breakdown protein, KLF14, differed from male to female mice. While male mice lost fat, female mice gained weight mostly in visceral fat, which surrounds the organs deep in the body, as opposed to subcutaneous fat, the fat right under the skin, being more surface level. The difference between the two types of fat, also referred to as adipose, is extremely important in obesity because it affects how a treatment could be developed in terms of KLF14.
“[KLF14] is widely expressed but we found its high expression to be in adipose,” Civelek said. “[KLF14] affects the breakdown of fat stored in your fat cells … so when you lower the level of this gene, you impair that process.”
Dr. Qianyi Yang, an author of the study and a researcher at the University’s Center for Public Health Genomics, highlighted the importance of this difference.
“It has been shown that subcutaneous fat is actually healthier than the visceral fat,” Yang said. “We can actually show that at least in mice, the female mice without KLF14 … have more fat accumulated around the organs, which is an unhealthy type of fat.”
When the production of KLF14 was increased, it led to weight loss in female mice while preventing the gain of visceral fat, in contrast to weight gain in male mice. This newfound knowledge provides a new direction for gene therapy when treating obesity and Type 2 Diabetes.
By increasing the production of this specific gene in adipocytes, which are adipose cells, the KLF14 protein could be possibly used to treat obesity in females as this could potentially lead to weight loss in unhealthy fat areas. Targeting the adipose sites allows for the drug to target only the adipocytes, as in fat cells, in the body as opposed to the entire genome. Changing the amount of production of KLF14 in the entire body leads to severe and unwanted side effects.
While these new findings are a substantial step forward for the treatment of Type 2 Diabetes, there is still more work to be done and research to be conducted in order to arrive at a practical treatment for the general public.
“What we’re trying to do is work with a chemical engineer to come up with a drug delivery method that’s going to target this drug into adipocytes only,” Civelek said. “That’s our hope … that will result in the translation of this finding into the clinic.”
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