New study supports remission as a therapeutic goal in prediabetes

People with prediabetes who were able to reduce body weight by at least 5% durin
People with prediabetes who were able to reduce body weight by at least 5% during a lifestyle intervention over 12 months were studied. A comparison was made between people who were able to normalize their blood glucose (responders) and those who continued to have elevated blood glucose levels (non-responders). Weight loss in both groups was comparable, as was the reduction in liver fat. However, the reduction in visceral fat depot and increase in insulin sensitivity was significantly more pronounced in responders.
People with type 2 diabetes have an increased risk of kidney disease, heart attack or stroke and are exposed to higher mortality. Until a few years ago, type 2 diabetes was considered an irreversible disease. It is now known that type 2 diabetes can be brought into a state of remission in a proportion of sufferers by severe weight reduction, but this rarely lasts: most patients develop type 2 diabetes again after five years.

"We have therefore set ourselves the goal of starting earlier and investigating whether it is possible to take preventive action at the preliminary stage of type 2 diabetes, prediabetes, and reverse it," explains senior author Andreas Birkenfeld, Medical Director of Medical Clinic IV of the University Hospital Tübingen and Head of the Institute for Diabetes Research and Metabolic Diseases of Helmholtz Munich at the University of Tübingen. This would be of great importance for patients with prediabetes, as they have an increased risk of complications of the heart, kidneys and eyes.

But which mechanisms lead to remission in prediabetes? DZD scientists from the Institute of Diabetes Research and Metabolic Diseases (IDM) at Helmholtz Munich in Tübingen and the Department of Diabetology, Endocrinology and Nephrology at the University Hospital Tübingen investigated this in a post-hoc analysis of participants with prediabetes from the Prediabetes Lifestyle Intervention Study (PLIS).

In this randomized-controlled multicenter study of the DZD, 1,105 prediabetes patients had participated in a lifestyle intervention consisting of a healthy diet and more physical activity for one year. The researchers evaluated the 298 participants who had lost at least five percent of their weight during this intervention. Responders were participants in whom fasting blood glucose, 2-hour glucose and HbA1c levels had normalized within the twelve months, i.e. had gone into remission. Those who did not achieve remission despite weight loss and continued to have prediabetes were considered non-responders.

Contrary to initial assumptions by the researchers, it was not weight loss that distinguished those who went into remission from those who did not, as there was no difference in relative weight loss between responders and non-responders. However, those who went into remission stood out in that they were able to improve their insulin sensitivity more than the non-responders. In other words, they were able to increase their sensitivity to the blood sugar-lowering hormone insulin to a significantly greater extent than the non-responders. However, the amount of insulin secreted remained unchanged in both groups. This represents an important difference from remission of type 2 diabetes, which is mediated in particular by an improvement in insulin secretion.

Reduction of visceral abdominal fat could contribute to remission in prediabetes

To find out why insulin sensitivity had improved more in responders, the researchers looked for other differences between the two groups - and found them in the midsection of the body: The responders had lost more visceral abdominal fat than the non-responders, despite losing the same amount of weight. Visceral abdominal fat lies directly in the abdominal cavity and surrounds the intestines. It can affect insulin sensitivity, in part through an inflammatory response in adipose tissue.

The participants who went into remission actually also had fewer inflammatory proteins in their blood. Since responders showed a reduction in visceral abdominal fat in particular, it will be important in the future to identify the factors that promote the loss of visceral abdominal fat," emphasizes Arvid Sandforth, one of the two first authors. Surprisingly, there were no differences between the two groups in the reduction of liver fat, which is also an important risk factor for the development of diabetes.

Participants who achieved remission still showed a 73 percent reduced risk of developing type 2 diabetes two years after the end of the lifestyle intervention. They also showed reduced markers of kidney damage and better condition of their blood vessels. Participants in the PLIS study will also be monitored by researchers to determine how long this benefit will continue into the future.

Currently, treatment of prediabetes consists of weight reduction and lifestyle improvement to delay the onset of type 2 diabetes - but without glucose-based targets to guide the treatment process. This gap is closed by the new DZD analysis: "Based on the new data, remission should be the new treatment target in people with prediabetes. This has the potential to change treatment practice and minimize the complication rate for our patients," says co-first author Reiner Jumpertz-von Schwartzenberg.

According to the study, remission in prediabetes can be assumed when fasting blood glucose falls below 100mg/dl (5.6 mmol/l), 2-hour glucose below 140mg/dl (7.8 mmol/l) and HbA1c below 5.7 percent. According to the new results, the likelihood of remission increases the more body weight is reduced and abdominal circumference is reduced by at least about 4 cm in women and about 7 cm in men. Medical staff and patients could now use this as a guide, the researchers say. In the further course, they want to investigate whether this strategy is cost-saving to also ensure the support of payers for an appropriate therapy.

Original publication:

Sandforth A, Jumpertz-von Schwartzenberg R et al (2023): Mechanisms of weight loss-induced remission in people with prediabetes: a post-hoc analysis of the Randomized Controlled Multicenter Prediabetes Lifestyle Intervention Study (PLIS). Lancet Diabetes Endocrinology 2023

About the study:

The Prediabetes Lifestyle Intervention Study was one of the first large multicenter studies conducted at the German Center for Diabetes Research under the direction of the Tübingen site. Follow-up investigations are currently taking place. Nine DZD sites are involved in the study.

The German Center for Diabetes Research (DZD) e.V. is one of the seven German Centers for Health Research. It brings together experts in the field of diabetes research and interlinks basic research, epidemiology and clinical application. The goal of the DZD is to make a significant contribution to the successful, tailored prevention, diagnosis and therapy of diabetes mellitus through a novel, integrative research approach. Members of the network are Helmholtz Munich - German Research Center for Environmental Health, the German Diabetes Center DDZ in Düsseldorf, the German Institute of Human Nutrition DIfE in Potsdam-Rehbrücke, the Institute of Diabetes Research and Metabolic Diseases of Helmholtz Munich at the Eberhard Karls University of Tübingen and the Paul Langerhans Institute Dresden of Helmholtz Munich at the Carl Gustav Carus University Hospital of the TU Dresden, associated partners at the universities in Heidelberg, Cologne, Leipzig, Lübeck and Munich as well as other project partners.

Helmholtz Munich is a top biomedical research center. Its mission is to develop breakthrough solutions for a healthier society in a rapidly changing world. Interdisciplinary research teams focus on environmentally induced diseases, in particular the therapy and prevention of diabetes, obesity, allergies and chronic lung diseases. Using artificial intelligence and bioengineering, researchers transfer their findings to patients more quickly. Helmholtz Munich has more than 2,500 employees and is based in Munich/Neuherberg. It is a member of the Helmholtz Association, the largest scientific organization in Germany with more than 43,000 employees and 18 research centers. More about Helmholtz Munich (Helmholtz Zentrum München German Research Center for Environmental Health GmbH):

Founded in 1805, Tübingen University Hospital is one of the leading centers of German university medicine. As one of the 33 university hospitals in Germany, it contributes to the successful combination of high-performance medicine, research and teaching. Well over 400,000 inpatients and outpatients from all over the world benefit annually from this combination of science and practice. The clinics, institutes and centers unite all specialists under one roof. The experts work together across disciplines and offer each patient the best possible treatment based on the latest research findings. The University Hospital Tübingen conducts research for better diagnoses, therapies and healing chances; many new treatment methods are clinically tested and applied here. In addition to diabetology, neuroscience, oncology, immunology, infection research and vascular medicine are research priorities in Tübingen. The Chair of Diabetology /Endocrinology has been the center of interdisciplinary research over the past 25 years, especially involving surgery, radiology and laboratory medicine. The University Hospital is a reliable partner in four of the six German Centers for Health Research initiated by the Federal Government.

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