Emerging studies reveal that the enzyme cathepsin D may interfere with insulin signalling in the liver, potentially contributing to prediabetes and offering new avenues for treatment.
A protein best known for helping cells break down waste may also be interfering with the liver’s response to insulin, according to new research published in the International Journal of Obesity on August 12, 2026. The study, led by Ding, Jiang and Zou, points to cathepsin D, or CTSD, as a possible driver of hepatic insulin resistance, a defect that can appear years before type 2 diabetes.
The liver plays a central role in keeping blood sugar stable. In the fasting state, it releases glucose by breaking down glycogen and making new sugar. After a meal, insulin should tell the liver to slow that output. When the organ becomes resistant to insulin, that brake weakens and glucose production stays too high, adding pressure on the pancreas to make more insulin.
Earlier work had already suggested a link between CTSD and worsening liver insulin sensitivity in people with obesity. A study in overweight and obese adults found that higher plasma CTSD activity was associated with lower hepatic insulin sensitivity, raising the possibility that the enzyme could serve as a marker of metabolic stress and a target for treatment. The new paper goes further by proposing a mechanism that could explain that association.
According to the authors, CTSD may disrupt signalling through IL2RG, the common gamma chain shared by several cytokine receptors, and JAK2, a protein kinase that helps relay signals inside cells. That matters because normal insulin action in the liver depends on a well-ordered chain of receptor and downstream signals, including the PI3K-AKT pathway, which helps suppress glucose production. The researchers say CTSD appears to hijack that signalling environment in a way that blunts insulin’s message.
The idea is not that insulin disappears or stops binding altogether. Rather, the study suggests that competing signals may distort the timing, location or balance of the response, leaving genes involved in glucose production insufficiently switched off. In that sense, the work adds to a broader view of insulin resistance as a communication problem between metabolic and immune-related pathways, not just a failure of insulin itself.
The findings also fit with older evidence that insulin can influence cathepsin D activity in the liver and other tissues, hinting at a two-way relationship between the hormone and the enzyme. More broadly, studies of JAK2 have already shown that it can shape hepatic insulin sensitivity through signals outside the liver, underscoring how closely liver metabolism is tied to wider tissue communication.
If the results hold up, CTSD could become a biomarker for identifying people at higher risk of prediabetes and a candidate for drug development. But the therapeutic case is not straightforward. CTSD has normal roles in protein degradation and cellular maintenance, so any future treatment would need to dampen the harmful activity without disrupting essential function. The researchers say further work is needed to test whether the pathway behaves the same way in human tissue, animal models and cultured liver cells, and whether blocking CTSD can reliably improve metabolic health.
Disclaimer: This content is for informational purposes only and is not intended to be a substitute for professional medical judgment, advice, diagnosis, or treatment.
