The study could lead to the development of more personalized interventions that prevent at-risk individuals from developing type 2 diabetes.

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People with prediabetes have consistently high blood sugar levels but have yet to develop the symptoms of type 2 diabetes.

Over many years, the cells of people with this condition become increasingly resistant to the effects of insulin, the hormone that regulates blood sugar levels.

The transition to type 2 diabetes occurs when the pancreas can no longer compensate for this resistance by producing more insulin.

According to the Centers for Disease Control and Prevention (CDC), approximately 88 million adults in the United States have prediabetes, which not only increases their risk of type 2 diabetes, but also of heart disease and stroke.

More than 84% of individuals with prediabetes are unaware that they have it, the CDC report.

For people with prediabetes, strategies such as losing weight, having a more healthful diet, getting more exercise, and lowering levels of stress can reduce the risk of developing type 2 diabetes by up to 58%.

Among people over 60, lifestyle changes such as these can reduce the chances of developing diabetes even further, by as much as 71%.

But people with prediabetes are not a homogenous group. Now, a new study has identified six broad categories, with important differences in terms of outlook and the kinds of interventions that could delay or prevent diabetes.

Researchers at various institutions in Germany, including the University of Tübingen and the German Center for Diabetes Research, in Neuherberg, led the study, which has been published in Nature Medicine.

“For people with prediabetes, it has not been possible until now to predict whether they would develop diabetes and be at risk for serious complications such as kidney failure, or whether they would only have a harmless form with slightly higher blood glucose levels but without significant risk.”

– Prof. Hans-Ulrich Häring, study co-lead author

The researchers tracked changes in the metabolism of 899 individuals at risk of diabetes who had enrolled in the Tübingen Family Study and Tübingen Lifestyle Program. Over 25 years, the scientists conducted repeated clinical and laboratory tests, as well as MRI scans.

They then used a statistical technique called cluster analysis that identified six distinct groups of people with prediabetes based on eight core metabolic features. Among these were blood glucose levels, the amount of fat in the liver, the overall fat distribution, blood lipid levels, and the genetic risk of diabetes.

Finally, the team confirmed that the six subtypes of prediabetes apply more widely by extending their analysis to almost 7,000 individuals who are part of the Whitehall II study of civil servants in the United Kingdom.

Overall, the researchers found that people in the six clusters have the following metabolic characteristics and risk profiles:

  • Clusters 1, 2, and 4 have a low risk of developing diabetes and low mortality, compared with the other three clusters.
  • Most people in cluster 2 are slim and have a very low risk of developing diabetes complications.
  • People in cluster 4 have overweight, but their metabolism is relatively healthy.
  • Cluster 3 produce too little insulin and have genetic risk factors for diabetes. They have a high risk of developing diabetes, cardiovascular complications, and kidney disease. Their mortality risk is moderate.
  • Cluster 5 have high levels of fat in their livers, their tissues are resistant to insulin, and they have high risks of diabetes, cardiovascular complications, and nephropathy. Their mortality rate is higher than that of cluster 3.
  • Cluster 6 have high levels of fat in their kidneys and abdominal cavities, which is known as visceral fat. Compared with clusters 3 and 5, their risk of diabetes is relatively low, but their risk of nephropathy and mortality are high.

Only Nature Medicine subscribers can access the full study paper. However, the researchers uploaded a complete, unedited version of their paper to the preprint server MedRxiv in October 2020.

The researchers caution that their findings only apply to groups and do not reflect individual risk or outlook.

However, they plan to investigate whether these categories can be used to identify people at high risk and provide targeted treatments and prevention strategies.

“Next, in prospective studies, we will first seek to determine to what extent the new findings are applicable for the classification of individual persons into risk groups,” explains Prof. Andreas Fritsche, of the Tübingen University Hospital, who is the senior author of the research paper.

In their paper, the team concludes:

“Our results suggest that stratification of populations at increased risk for type 2 diabetes using simple clinical features could allow for precise and efficient prevention strategies [for] individuals at increased risk of developing type 2 diabetes.”

The researchers also acknowledge several limitations of their recent study.

In particular, the ethnic diversity of the groups they investigated did not reflect that of the wider population. Their findings may, therefore, only apply to white European populations.

This is an important limitation because the prevalence of prediabetes is higher among specific racial and ethnic groups. In the U.S., people who are African American, Native American, Latinx, Pacific Islander, or Asian American have a higher risk of prediabetes, and the reasons remain unclear.

Another limitation, the researchers report, was that only about half of the initial study population was available for follow-up investigations.

“This high attrition rate could lead to a potential underestimation of the risk for diabetes and nephropathy,” they write.