A new study has revealed the hidden complexity of type 2 diabetes (T2D), offering key insights that could transform how the disease is diagnosed and treated. Researchers from the Novo Nordisk Foundation Center for Basic Metabolic Research and Karolinska Institutet used advanced proteomics to uncover molecular differences in how people with T2D respond to insulin, especially in skeletal muscle.
Their findings, published in Cell, show that insulin resistance—a major feature of T2D—is far more diverse at the molecular level than previously thought. This could help explain why people with the same diagnosis often respond differently to treatments.
New Clues in Muscle Response
Using phosphoproteomic analysis, the team examined muscle tissue from 123 people with varying degrees of insulin sensitivity. This group included people with normal glucose levels and those with T2D. They measured around 3,000 proteins and 15,000 protein phosphorylation sites to see how they were linked to insulin sensitivity.
The results revealed a wide range of responses, even among people with the same diagnosis. In fact, some individuals with T2D showed insulin sensitivity equal to or better than those with normal glucose tolerance.
One major discovery was a unique protein signature in the fasting state—when patients hadn’t eaten. This signature included a phosphosite called AMPKγ3 S65, which appears to be closely tied to insulin sensitivity. Since this site is only found in human muscle, it could be a promising target for future treatments that aim to improve insulin function without affecting other organs.
Rethinking Causes of Insulin Resistance
The study challenges older views that blamed insulin resistance mainly on missing signaling proteins or glucose transporters. Instead, the data suggest that small changes in protein function—like post-translational modifications—play a bigger role than once believed.
For example, patients with higher insulin sensitivity had more active pathways linked to fat metabolism and energy production. On the other hand, those with lower sensitivity had disruptions in protein degradation and Wnt signaling—areas that have not been deeply studied in diabetes before.
Personalized Medicine Takes Center Stage
The researchers also found sex-based differences. Women appeared to rely more on fat for energy, while men were more dependent on glucose. Still, the core mechanisms of insulin resistance seemed similar across sexes.
These findings highlight how diverse the disease can be and why one-size-fits-all treatment approaches often fall short. While traditional diagnostics like HbA1c and fasting glucose levels remain useful, they may miss deeper molecular signals that shape the course of the disease.
Looking Ahead
The researchers acknowledge that their sample size was limited and didn’t capture the full global diversity of people with T2D. They call for larger studies to confirm their findings and further explore how markers like AMPKγ3 S65 influence glucose metabolism.
Still, this research marks a step forward in applying precision medicine to diabetes. By focusing on the unique molecular profiles of individuals, scientists may soon be able to develop more targeted, effective treatments for the nearly 500 million people worldwide living with type 2 diabetes.
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