Diabetes Biomarkers Among Patients with Obesity Discovered

A transcription factor may contribute to adipose fibrosis and increase the risk of type 2 diabetes among patients with obesity.

New research published by Cell Metabolism suggests that there is a biological pathway in fat cells that may explain why certain patients with obesity are at a high risk of developing type 2 diabetes (T2D) and other metabolic conditions.

These findings could result in new biomarkers that predict who is at-risk and advise the burden of obesity, according to the authors.

CDC estimates suggest that more than one-third of American adults are obese, with the number of people with extreme obesity doubling over the past 20 years.

Obesity is known to increase the risk of T2D, but by how much has been unclear.

“It turns out that only about 30% of people with obesity are really high-risk,” said senior author Suneil Koliwad, MD, PhD. “The problem is that fundamentally, we don’t know why some people with obesity go on to develop diabetes and others don’t.”

The authors of the study found that the relationship between obesity and diabetes may be contingent on the ability of fat cells to control adipose fibrosis, which is known to increase inflammation and metabolic dysfunction.

Previously, the researchers found that fat cells can shift between energy-storing white fat and energy-burning beige fat. They also found that mice with more beige fat have a lower risk of obesity and T2D.

The current study focused on identifying factors that cause the shift between white fat and beige fat, with a goal of creating new obesity treatments.

By using high-throughput screening, the authors discovered a new signaling molecule in fat cells that may reduce the risk of obesity and T2D by an alternative approach.

The transcription factor GTF2IRD1 works by reducing the production of collagen in fat cells, which contributes to adipose fibrosis rather than causing beige fat cells to burn calories for heat, according to the study.

Amplifying GTF2IRD1 levels in fat cells of mice fed a high-fat diet was observed to significantly reduce fibrosis and improve glucose metabolism, according to the study. The authors found that inhibiting GTF2IRD1 increased fibrosis and weakened glucose metabolism.

“These were surprising and exciting results,” Dr Kajimura said. “We used to think that adipose tissue fibrosis was just a consequence of ‘unhealthy fat,’ but this study suggests that fibrosis is an important therapeutic target to prevent obesity and metabolic disease in humans.”

The authors then examined GTF2IRD1 expression in human fat cells of 48 patients with obesity.

The analysis revealed that patients with the highest levels of GTF2IRD1 developed less fibrosis, while patients with the lowest levels developed more fibrosis, according to the study.

There was also a strong correlation between CTF2IRD1 expression and healthy distribution of fat. The authors noted that patients who had a higher prevalence of subcutaneous fat had a significantly lower risk of diabetes compared with those whose fat was stored in the abdomen, according to the study.

These findings may help pinpoint patients with obesity who are more likely to develop adipose fibrosis and determine whether GTF2IRD1 inhibitors or anti-fibrotic drugs could prevent the development of T2D, according to the authors.

The authors also said that they plan to determine whether differences in adipose fibrosis and distribution could account for differences in why certain ethnic groups seem to be at a higher risk of obesity-related diabetes.

“This study puts a lot of earlier research in context,” Dr Koliwad said. “Our findings suggest that people whose fat cells are predisposed to produce a lot of collagen develop fibrotic hardening of the subcutaneous fat, essentially turning those fat stores into concrete, and making additional fat more likely to spill over into the abdominal cavity, where it builds up around organs like the liver, pancreas, heart, and muscles, and wreaks havoc, triggering the inflammation and metabolic damage that leads to diabetes.”