New markers to predict the development of prediabetes: progression to diabetes or return to normoglycemia

People with prediabetes often develop diabetes, but many of them also manage to return to normoglycemia. What determines these different trajectories? And can we identify biomarkers that predict the different developments of prediabetes? To answer these questions, researchers from the Paul Langerhans Institute Dresden of the German Center for Diabetes Research (DZD), together with other experts, used the multicenter DZD study PLIS (Prediabetes Lifestyle Intervention Study). The researchers compared the proteome and metabolome signatures of prediabetes patients who showed opposite disease progressions, i.e. they focused on patients who either developed diabetes or whose blood glucose levels returned to normal over time. The results of this work have now been published in the journal Diabetes Care.

The progression of prediabetes to type 2 diabetes is associated with pancreatic beta cell dysfunction, while remission to normoglycemia is thought to be related to an improvement in insulin sensitivity. In order to understand the mechanisms and identify potential biomarkers for the possible further course of prediabetes, the researchers conducted an exploratory case-control study with participants of the PLIS study, comparing the proteomic and metabolomic profile of individuals with prediabetes who developed diabetes within one year with that of individuals who returned to normoglycemia.

The team, led by Prof Nikolaos Perakakis, analyzed 1389 proteins and 152 metabolites from plasma samples of individuals at the prediabetes stage and one year later, when some of the subjects had returned to normoglycemia while others developed diabetes. Significant differences were found in 14 proteins in new-onset diabetes compared to normoglycemia, with six of these proteins observed for the first time in this context. Elevated levels of two of the proteins, dicarbonyl/L-xylulose reductase (DCXR) and glutathione S-transferase A3 (GSTA3), at the prediabetes stage were associated with a significantly increased risk of developing diabetes one year later.

Another aspect of the study highlighted the role of inflammatory and immune system pathways in glucose homeostasis. Here, the scientists were able to show that signaling pathways related to leukocyte chemotaxis, chemokines, cytokine interactions and immune responses to infections can be associated with the progression from prediabetes to diabetes.

Metabolomic signatures in new-onset diabetes were characterized by increased levels of intermediate density lipoproteins, branched-chain amino acids, apolipoprotein A2 and glutamate. Metabolomic and proteomic signatures distinguishing between prediabetes trajectories correlated more strongly with markers of insulin sensitivity and to a lesser extent with markers of beta cell function.

“We were able to successfully identify new candidates that are associated with the progression from prediabetes to diabetes or its remission. At the same time, we were able to show that signaling pathways that regulate immune responses are strongly associated with prediabetes progression,” summarizes Prof Perakakis. “In the future, the new candidate proteins could serve as biomarkers for prediabetes progression or as targets for evaluating their role in glucose homeostasis in mechanistic studies.”

Original publication: Barovic, M., Hahn, JJ., Heinrich, A. et al. Proteomic and Metabolomic Signatures in Prediabetes Progressing to Diabetes or Reversing to Normoglycemia Within 1 Year. Diabetes Care. 2025 Mar 1;48(3):405-415.

Source: DZD