Novel Biomarker Discovered to Have an Associated Risk of Development of Type 2 Diabetes Mellitus

New study findings reveal the hepatocyte known as follistatin is linked to hyperglycemia when found at elevated levels. 

Type 2 diabetes mellitus is a growing global health crisis that can lead to many health-related complications, cardiovascular events, and increased mortality. As a result, it is imperative to find ways to identify risk factors that show an increased risk for developing this irreversible disease state, and use them to initiate early preventative strategies to decrease the chance of progression. In previous studies, follistatin, a protein secreted by the liver found in almost every tissue of the body, was elevated in the plasma levels of patients with type 2 diabetes. The process of overexpression and secretion is caused by a high glucagon-to-insulin ratio leading to upregulation. Patients who have undergone gastric bypass surgeries had both their serum follistatin and HbA1c levels analyzed, which showed that the decrease in both was proportional. 

Furthermore, patients with T2DM showed a similar result in the opposite direction where increased serum follistatin was also accompanied by increased HbA1c and fasting blood glucose levels. However, there is yet to be a study that focuses on determining if elevated plasma follistatin alone is associated with an increased risk of developing T2DM and to what extent genetics may play a part in the variation of these circulating protein levels. This new study served to do just that by showing an association of increased plasma levels of this protein to increased risk of T2DM, independent of previously identified established risk factors. It also presents a possible mechanism on how this protein leads to insulin resistance in adipose tissue. 

This retrospective study looked at previously produced data from several different studies. The first was from the MDC-CC (Malmö Diet and Cancer-Cardiovascular Cohort). The authors of this study used the results to assess the incidence of T2DM and its association with the baseline level of circulation follistatin over a four and nineteen-year period. The results were analyzed using the Cox proportional hazard regression model to determine association. Next, a Kaplan Meier curve was used to display the incidence of diabetes in the follistatin quartiles. Next was Tübingen Diabetes Family Study (TDFS) cohort without diabetes, where it was observed that high levels of increased circulating follistatin were proportional to increasing levels of free fatty acids, and also, those same high levels were elevated in patients with non-alcoholic fatty liver disease (NAFLD). A multivariate logistic regression model was used to analyze association. Finally, a genome-wide association study (GWAS) was used to see what genes were linked to increased follistatin levels and insulin resistance. 

The results of the statistical analysis of the data from the MDC-CC trial showed an adjusted hazard ratio (aHR) per standard deviation (SD) increase in follistatin levels for T2DM is 1.31 (CI: 1.09–1.58, p-value < 0.01) over the 4-year follow-up period (n=833) and 1.24 (CI: 1.04–1.47, p-value < 0.05) over the 19-year follow-up period (n=4060). Next, the results from the TDFS study (n=210) showed that elevated serum levels of follistatin were associated with the development of insulin resistance (p-value= 0.009) and NAFLD (p-value= 0.006). Lastly, when looking at the GWAS data, the gene most associated with increased serum follistatin levels was the glucokinase regulatory protein (GCKR) gene. Overall, 13 single-nucleotide polymorphisms (SNPs) were associated, with the highest being noncoding SNP rs780094 in the GCKR gene (p-value = 1.1E-11), but two other SNPs also produced a strong association as well rs780093 (noncoding) and rs1260326 (coding) in the same gene (p-value = 1.91E-11 and p-value = 2.77E-11, respectively). Furthermore, the same SNP rs780094 in the GCKR gene was found to be associated with diabetes in both Europeans (OR, 1.04; 95% CI: 1.00–1.08, (p-value = 0.025)) and transethnic individuals (p-value=1E10-5). 

Overall, this study was able to show that independent of other risk markers, increased serum plasma levels of follistatin were associated with an increased incidence of developing T2DM. Additionally, it was seen that there was a link between adipose tissue insulin resistance and follistatin and that insulin-medicated suppression of lipolysis in adipocytes was reduced by follistatin. This is what leads to insulin resistance and the development of NAFLD. Finally, the genetic regulation of circulating follistatin levels leading to increased insulin resistance was related to identified variants in the GCKR gene. These findings show that follistatin would serve as an excellent target for therapeutic intervention to reduce the chance of patients developing or having progression in T2FM or NAFLD. Therefore, future studies would benefit from utilizing this biomarker in real-world treatment strategies. 

Practice Pearls: 

• Increased liver protein follistatin levels are associated with an increased risk of type 2 diabetes mellitus, independent of other risk markers. 
• Practices should use these findings to serve as a tool for monitoring increased risk and implementing early treatment to help slow the progression of T2DM and NAFLD. 
• Future studies are needed to help determine a pharmacotherapy treatment that can lower serum plasma levels of follistatin to help promote the reduction in associated risk. 

Wu, Chuanyan et al. “Elevated circulating follistatin associates with an increased risk of type 2 diabetes.” Nature communications vol. 12,1 6486. 10 Nov. 2021, doi:10.1038/s41467-021-26536-w 

Alexa Rodriguez, PharmD Candidate 2022, University of South Florida, Taneja College of Pharmacy 

See more research on biomarkers and their role in diabetes and related conditions.