Mechanisms of weight loss-induced remission in people with prediabetes: a post-hoc analysis of the randomised, controlled, multicentre Prediabetes Lifestyle Intervention Study (PLIS)

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Arvid Sandforth - , German Center for Diabetes Research (DZD e.V.), University of Tübingen (Author)
  • Reiner Jumpertz von Schwartzenberg - , German Center for Diabetes Research (DZD e.V.), University of Tübingen (Author)
  • Elsa Vazquez Arreola - , National Institutes of Health (NIH) (Author)
  • Robert L. Hanson - , National Institutes of Health (NIH) (Author)
  • Gencer Sancar - , German Center for Diabetes Research (DZD e.V.), University of Tübingen (Author)
  • Sarah Katzenstein - , German Center for Diabetes Research (DZD e.V.), University of Tübingen (Author)
  • Karl Lange - , German Center for Diabetes Research (DZD e.V.), University of Tübingen (Author)
  • Hubert Preißl - , German Center for Diabetes Research (DZD e.V.), University of Tübingen (Author)
  • Simon I. Dreher - , German Center for Diabetes Research (DZD e.V.), University of Tübingen (Author)
  • Cora Weigert - , German Center for Diabetes Research (DZD e.V.), University of Tübingen (Author)
  • Robert Wagner - , German Center for Diabetes Research (DZD e.V.), Heinrich Heine University Düsseldorf (Author)
  • Kostantinos Kantartzis - , German Center for Diabetes Research (DZD e.V.), University of Tübingen (Author)
  • Jürgen Machann - , German Center for Diabetes Research (DZD e.V.), University of Tübingen (Author)
  • Fritz Schick - , German Center for Diabetes Research (DZD e.V.), University of Tübingen (Author)
  • Rainer Lehmann - , German Center for Diabetes Research (DZD e.V.), University of Tübingen (Author)
  • Andreas Peter - , German Center for Diabetes Research (DZD e.V.), University of Tübingen (Author)
  • Nikoletta Katsouli - , Technical University of Munich, Helmholtz Zentrum München - German Research Center for Environmental Health (Author)
  • Vasilis Ntziachristos - , Technical University of Munich, Helmholtz Zentrum München - German Research Center for Environmental Health (Author)
  • Corinna Dannecker - , German Center for Diabetes Research (DZD e.V.), University of Tübingen (Author)
  • Louise Fritsche - , German Center for Diabetes Research (DZD e.V.), University of Tübingen (Author)
  • Nikolaos Perakakis - , German Center for Diabetes Research - Paul Langerhans Insitute Dresden (Partner: HMGU), Department of internal Medicine 3, TUD Dresden University of Technology (Author)
  • Martin Heni - , German Center for Diabetes Research (DZD e.V.), University of Tübingen (Author)
  • Stefan Kopf - , German Center for Diabetes Research (DZD e.V.), Heidelberg University  (Author)
  • Andreas F.H. Pfeiffer - , German Center for Diabetes Research (DZD e.V.), Charité – Universitätsmedizin Berlin (Author)
  • Stefan Kabisch - , German Center for Diabetes Research (DZD e.V.), German Institute of Human Nutrition Potsdam-Rehbruecke (Author)
  • Michael Stumvoll - , German Center for Diabetes Research (DZD e.V.), Leipzig University (Author)
  • Peter E.H. Schwarz - , Department of internal Medicine 3 (Author)
  • Hans Hauner - , German Center for Diabetes Research (DZD e.V.), Technical University of Munich (Author)
  • Andreas Lechner - , German Center for Diabetes Research (DZD e.V.), Ludwig Maximilian University of Munich (Author)
  • Jochen Seissler - , German Center for Diabetes Research (DZD e.V.), Ludwig Maximilian University of Munich (Author)
  • Iryna Yurchenko - , German Center for Diabetes Research (DZD e.V.), Heinrich Heine University Düsseldorf (Author)
  • Andrea Icks - , German Center for Diabetes Research (DZD e.V.), Heinrich Heine University Düsseldorf (Author)
  • Michele Solimena - , German Center for Diabetes Research - Paul Langerhans Insitute Dresden (Partner: HMGU), Molecular Diabetology, Medical Faculty Carl Gustav Carus (Author)
  • Hans Ulrich Häring - , German Center for Diabetes Research (DZD e.V.), University of Tübingen (Author)
  • Julia Szendroedi - , German Center for Diabetes Research (DZD e.V.), Heidelberg University  (Author)
  • Annette Schürmann - , German Center for Diabetes Research (DZD e.V.), German Institute of Human Nutrition Potsdam-Rehbruecke (Author)
  • Martin Hrabé de Angelis - , German Center for Diabetes Research (DZD e.V.), Technical University of Munich, Helmholtz Zentrum München - German Research Center for Environmental Health (Author)
  • Matthias Blüher - , German Center for Diabetes Research (DZD e.V.), Leipzig University (Author)
  • Michael Roden - , German Center for Diabetes Research (DZD e.V.), Heinrich Heine University Düsseldorf (Author)
  • Stefan R. Bornstein - , German Center for Diabetes Research - Paul Langerhans Insitute Dresden (Partner: HMGU), Department of internal Medicine 3, TUD Dresden University of Technology, King's College London (KCL) (Author)
  • Norbert Stefan - , German Center for Diabetes Research (DZD e.V.), University of Tübingen (Author)
  • Andreas Fritsche - , German Center for Diabetes Research (DZD e.V.), University of Tübingen (Author)

Abstract

Background: Remission of type 2 diabetes can occur as a result of weight loss and is characterised by liver fat and pancreas fat reduction and recovered insulin secretion. In this analysis, we aimed to investigate the mechanisms of weight loss- induced remission in people with prediabetes. Methods: In this prespecified post-hoc analysis, weight loss-induced resolution of prediabetes in the randomised, controlled, multicentre Prediabetes Lifestyle Intervention Study (PLIS) was assessed, and the results were validated against participants from the Diabetes Prevention Program (DPP) study. For PLIS, between March 1, 2012, and Aug 31, 2016, participants were recruited from eight clinical study centres (including seven university hospitals) in Germany and randomly assigned to receive either a control intervention, a standard lifestyle intervention (ie, DPP-based intervention), or an intensified lifestyle intervention for 12 months. For DPP, participants were recruited from 23 clinical study centres in the USA between July 31, 1996, and May 18, 1999, and randomly assigned to receive either a standard lifestyle intervention, metformin, or placebo. In both PLIS and DPP, only participants who were randomly assigned to receive lifestyle intervention or placebo and who lost at least 5% of their bodyweight were included in this analysis. Responders were defined as people who returned to normal fasting plasma glucose (FPG; <5·6 mmol/L), normal glucose tolerance (<7·8 mmol/L), and HbA1c less than 39 mmol/mol after 12 months of lifestyle intervention or placebo or control intervention. Non-responders were defined as people who had FPG, 2 h glucose, or HbA1c more than these thresholds. The main outcomes for this analysis were insulin sensitivity, insulin secretion, visceral adipose tissue (VAT), and intrahepatic lipid content (IHL) and were evaluated via linear mixed models. Findings: Of 1160 participants recruited to PLIS, 298 (25·7%) had weight loss of 5% or more of their bodyweight at baseline. 128 (43%) of 298 participants were responders and 170 (57%) were non-responders. Responders were younger than non-responders (mean age 55·6 years [SD 9·9] vs 60·4 years [8·6]; p<0·0001). The DPP validation cohort included 683 participants who lost at least 5% of their bodyweight at baseline. Of these, 132 (19%) were responders and 551 (81%) were non-responders. In PLIS, BMI reduction was similar between responders and non-responders (responders mean at baseline 32·4 kg/m2 [SD 5·6] to mean at 12 months 29·0 kg/m2 [4·9] vs non-responders 32·1 kg/m2 [5·9] to 29·2 kg/m2 [5·4]; p=0·86). However, whole-body insulin sensitivity increased more in responders than in non-responders (mean at baseline 291 mL/[min × m2], SD 60 to mean at 12 months 378 mL/[min × m2], 56 vs 278 mL/[min × m2], 62, to 323 mL/[min × m2], 66; p<0·0001), whereas insulin secretion did not differ within groups over time or between groups (responders mean at baseline 175 pmol/mmol [SD 64] to mean at 12 months 163·7 pmol/mmol [60·6] vs non-responders 158·0 pmol/mmol [55·6] to 154·1 pmol/mmol [56·2]; p=0·46). IHL decreased in both groups, without a difference between groups (responders mean at baseline 10·1% [SD 8·7] to mean at 12 months 3·5% [3·9] vs non-responders 10·3% [8·1] to 4·2% [4·2]; p=0·34); however, VAT decreased more in responders than in non-responders (mean at baseline 6·2 L [SD 2·9] to mean at 12 months 4·1 L [2·3] vs 5·7 L [2·3] to 4·5 L [2·2]; p=0·0003). Responders had a 73% lower risk of developing type 2 diabetes than non-responders in the 2 years after the intervention ended. Interpretation: By contrast to remission of type 2 diabetes, resolution of prediabetes was characterised by an improvement in insulin sensitivity and reduced VAT. Because return to normal glucose regulation (NGR) prevents development of type 2 diabetes, we propose the concept of remission of prediabetes in analogy to type 2 diabetes. We suggest that remission of prediabetes should be the primary therapeutic aim in individuals with prediabetes. Funding: German Federal Ministry for Education and Research via the German Center for Diabetes Research; the Ministry of Science, Research and the Arts Baden-Württemberg; the Helmholtz Association and Helmholtz Munich; the Cluster of Excellence Controlling Microbes to Fight Infections; and the German Research Foundation.

Details

Original languageEnglish
Pages (from-to)798-810
Number of pages13
JournalThe Lancet Diabetes and Endocrinology
Volume11
Issue number11
Publication statusPublished - Nov 2023
Peer-reviewedYes

External IDs

PubMed 37769677

Keywords

Sustainable Development Goals

Keywords

  • Humans, Middle Aged, Diabetes Mellitus, Type 2/prevention & control, Prediabetic State, Insulin Resistance, Weight Loss, Body Weight, Glucose, Life Style