Korean Researchers Identify New Drug Target That Mimics Bariatric Surgery Effects

A new study has found that drug treatment alone could replicate the blood sugar improvement effects of bariatric surgery.

Professor Koo Cheol-ryong of Severance Hospital's Department of Endocrinology and Professor Kang Chan-woo of Yonsei University College of Medicine announced on the 12th that they have identified a new therapeutic target for type 2 diabetes through joint research with AI-based drug development company Arontier. The team confirmed the possibility of developing new drugs that can reproduce the blood sugar improvement effects of bariatric surgery.

Type 2 diabetes is a condition in which blood sugar rises because the pancreas does not produce enough insulin or the body develops insulin resistance. It occurs through a combination of genetic and environmental factors. The majority of diabetes patients in Korea have type 2 diabetes.

While the prevalence of type 2 diabetes is surging globally alongside rising obesity rates, fundamental treatment options remain limited. Bariatric surgery is recommended for diabetes patients with severe obesity, defined as a body mass index (BMI) of 30 or above. However, despite excellent treatment outcomes, the actual surgery rate is less than 1% of eligible patients due to surgical burden and concerns about side effects.

The research team focused on the phenomenon of "intestinal glucose excretion" observed after bariatric surgery. The team had previously been the first in the world to demonstrate that intestinal tissue from patients who underwent bariatric surgery absorbs glucose from the blood and then excretes it through feces into the intestinal lumen. This finding was selected as one of the Top 100 National R&D Achievements in 2022, drawing significant attention from the academic community. The current study aimed to identify the key therapeutic target responsible for reverse-excreting blood glucose into the intestinal tract.

The research team conducted an integrated analysis of transcriptome data from small intestine tissue of bariatric surgery patients and various intestinal glucose excretion models. Using Arontier's AI drug development platform, they compared and analyzed more than 1 million gene expression datasets to search for key factors that convert normal intestinal tissue into glucose-excreting tissue.

The results showed that activation patterns of protein kinase C (PKC) were highly correlated with gene expression changes observed in glucose excretion states. PKC is a signal transduction enzyme involved in cell differentiation, growth, gene expression, and apoptosis. Among the various PKC subtypes, atypical PKC was found to promote intestinal glucose excretion through glucose transporter 1 (GLUT1).

After inducing diabetes in mouse models, the research team selectively activated atypical PKC in intestinal tissue. They confirmed increased excretion of blood glucose through intestinal epithelial cells into the intestinal lumen, along with improved blood sugar levels. The team also discovered that "Prostatin," a candidate compound identified through the AI-based drug development platform, activates atypical PKC and maximizes the same intestinal glucose excretion mechanism.

"We have identified a new therapeutic target that can maximize intestinal glucose excretion, one of the mechanisms by which blood sugar improves after bariatric surgery," said Professor Koo Cheol-ryong. "This is significant in that it provides molecular biological evidence explaining the blood sugar improvement effects of bariatric surgery and presents the possibility of developing diabetes and weight loss treatment strategies targeting this signaling pathway."

The study was conducted with support from the Research-Centered Hospital Korea-US Innovation R&D Project led by the Ministry of Health and Welfare. The findings were published in the latest issue of the international journal Nature Communications.