Prediabetes is a warning sign that blood sugar levels are higher than normal, and it often leads to type 2 diabetes. However, not everyone with prediabetes will go on to develop diabetes. Some people manage to return to normal blood sugar levels, a state called normoglycemia. This difference has puzzled doctors for many years.
Now, researchers from the Paul Langerhans Institute Dresden at the German Center of Diabetes Research, along with several collaborators, have taken an important step toward understanding why these different outcomes occur. They also looked for early markers in the blood that could help predict which way a person’s condition might go.
The research team used data from the Prediabetes Lifestyle Intervention Study (PLIS), a multicenter study that followed people with prediabetes over time. They compared the blood of individuals who eventually developed type 2 diabetes with those who managed to return to normal blood sugar levels within one year.
To do this, they measured nearly 1,400 different proteins and 152 small molecules (metabolites) in the blood. These substances, which can provide clues about what is happening inside the body, are part of the fields of proteomics and metabolomics.
The study was designed as an explorative case-control study, meaning that it compared two groups of people with different outcomes from the same starting point.
In people whose condition worsened and progressed to diabetes, the researchers found significant differences in 14 proteins when compared with those who reversed to normoglycemia. Among these proteins, six had never before been linked to the progression of diabetes.
Two proteins in particular stood out: Dicarbonyl/L-xylulose reductase (DCXR) and Glutathione S-transferase A3 (GSTA3). The study showed that higher levels of these proteins in the prediabetes stage were strongly associated with an increased risk of developing diabetes within a year.
In simple terms, if someone with prediabetes has elevated amounts of DCXR and GSTA3, they may be much more likely to see their condition worsen.
Another important finding from the study was the role of inflammation and the immune system in controlling blood sugar levels. The researchers discovered that certain pathways involved in the body’s immune response – such as those that guide white blood cells to sites of infection – were linked to the worsening of prediabetes.
This suggests that long-term, low-level inflammation might disturb the body’s normal ability to regulate blood sugar, pushing someone closer to diabetes.
The study also revealed distinct patterns in the small molecules found in the blood. People who developed diabetes showed higher levels of intermediate density lipoproteins, branched-chain amino acids, apolipoprotein A2, and glutamate.
These changes were more closely related to how well the body used insulin—a hormone critical for controlling blood sugar—rather than to the performance of the insulin-producing beta cells in the pancreas. This finding underscores the importance of insulin sensitivity in the progression of prediabetes.
Professor Nikolaos Perakakis, who led the research team, summarized the findings by stating that new candidate proteins have been identified that could serve as early warning signals.
In the future, these proteins might help doctors predict whether a patient’s prediabetes will lead to type 2 diabetes or improve back to normal. They might also become targets for new treatments that could help maintain healthy blood sugar levels.
Review and Analysis
This study provides valuable insights into the complex processes that determine the fate of people with prediabetes. By comparing blood samples from individuals with opposing outcomes, the researchers have pinpointed specific proteins and metabolic changes that are linked to either the progression or reversal of the condition.
The strong association of inflammatory and immune pathways with worsening blood sugar control highlights a potential area for intervention. While these findings are promising, further research is needed to validate these biomarkers and to understand how they can be used in everyday clinical practice.
Ultimately, early detection through these biomarkers could lead to more personalized treatment strategies, helping many people avoid the complications of type 2 diabetes.
The research findings can be found in Diabetes Care.
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