Sandforth Arvid, Arreola Elsa Vazquez, Hanson Robert L, Wewer Albrechtsen Nicolai J, Holst Jens Juul, Ahrends Robert, Coman Cristina, Gerst Felicia, Lorza-Gil Estela, Cheng Yurong, Sandforth Leontine, Katzenstein Sarah, Ganslmeier Marlene, Seissler Jochen, Hauner Hans, Perakakis Nikolaos, Wagner Robert, Machann Jürgen, Schick Fritz, Peter Andreas, Lehmann Rainer, Weigert Cora, Maurer Jennifer, Preissl Hubert, Heni Martin, Szendrödi Julia, Kopf Stefan, Solimena Michele, Schwarz Peter, Blüher Matthias, Häring Hans-Ulrich, Hrabé de Angelis Martin, Schürmann Annette, Kabisch Stefan, Mai Knut, Pfeiffer Andreas F H, Bornstein Stefan, Stumvoll Michael, Roden Michael, Stefan Norbert, Fritsche Andreas, Birkenfeld Andreas L, Jumpertz von Schwartzenberg Reiner
German Center for Diabetes Research (DZD), Neuherberg, Germany.
Internal Medicine IV, Department of Diabetology, Endocrinology and Nephrology, University of Tübingen, Tübingen, Germany.
Nat Med. 2025 Sep 29. doi: 10.1038/s41591-025-03944-9.
Clinical practice guidelines recommend defined weight loss goals for the prevention of type 2 diabetes (T2D) in those individuals with increased risk, such as prediabetes. However, achieving prediabetes remission, that is, reaching normal glucose regulation according to American Diabetes Association criteria, is more efficient in preventing T2D than solely reaching weight loss goals. Here we present a post hoc analysis of the large, multicenter, randomized, controlled Prediabetes Lifestyle Intervention Study (PLIS), demonstrating that prediabetes remission is achievable without weight loss or even weight gain, and that it also protects against incident T2D. The underlying mechanisms include improved insulin sensitivity, β-cell function and increments in β-cell-GLP-1 sensitivity. Weight gain was similar in those achieving prediabetes remission (responders) compared with nonresponders; however, adipose tissue was differentially redistributed in responders and nonresponders when compared against each other-while nonresponders increased visceral adipose tissue mass, responders increased adipose tissue in subcutaneous depots. The findings were reproduced in the US Diabetes Prevention Program. These data uncover essential pathways for prediabetes remission without weight loss and emphasize the need to include glycemic targets in current clinical practice guidelines to improve T2D prevention.
