System Maintenance Notice

Please note that maintenance work is scheduled between 4 AM and 5 AM - CET. During this time, you may experience reduced performance. Thanks for your patience.

Publications

Journal Article Review Ahead of print 3 citations

PubMed: 42413493 DOI: 10.1016/j.cmet.2026.06.012

Insulin resistance and type 2 diabetes as allostatic responses to chronic nutrient excess.

Cell Metab

Authors: Marc Prentki, Christopher J Nolan, David E James, Bernard Thorens, Christopher J Rhodes, Barbara E Corkey, Charlotte Ling, Philippe Froguel, Chantal Mathieu, Jean-François Gautier, Marc Y Donath

Affiliations

  • Departments of Nutrition, Biochemistry and Molecular Medicine, Université de Montréal, Montréal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC H2X 0A9, Canada.
  • School of Medicine and Psychology and John Curtin School of Medical Research, College of Science and Medicine, Australian National University, Acton, ACT 0200, Australia; Department of Endocrinology, The Canberra Hospital, Garran, ACT 2605, Australia.
  • School of Life and Environmental Sciences, School of Medical Sciences, Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia.
  • Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
  • Kovler Diabetes Center, Section of Endocrinology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
  • Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
  • Epigenetics and Diabetes Unit, Lund University Diabetes Centre, Scania University Hospital, 214 28 Malmö, Sweden.
  • Université de Lille, Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University Hospital, Lille, France; Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
  • Department of Endocrinology, University Hospitals Leuven, Louvain, Belgium.
  • Department of Diabetes and Endocrinology, Université Paris Cité, Lariboisière Hospital, APHP, 75010 Paris, France; IMMEDIAB Laboratory, Institut Necker Enfants Malades (INEM), CNRS UMR 8253, INSERM U1151, 75015 Paris, France.
  • Clinic of Endocrinology, Centre d'excellence intégré en santé métabolique (CEISM), Centre Hospitalier de l'Université de Montréal (CHUM), Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal, 1000 Saint Denis, Montréal, QC H2X 0C1, Canada; Clinical Trial Unit, Baden Cantonal Hospital, CH-5404 Baden, Switzerland.

Abstract

Obesity-related type 2 diabetes (T2D) is currently defined by insulin resistance and impaired insulin secretion. Sulfonylureas, thiazolinediones, and insulin are effective at lowering glycemia yet have not consistently translated into improved long-term outcomes. In contrast, recent interventions often produce metabolic benefits that exceed expectations based on glucose lowering alone. These contrasting observations suggest that our understanding of T2D pathophysiology is incomplete. We propose that, in obesity-related prediabetes and early T2D, insulin resistance, attenuated glucose-stimulated insulin secretion, modest hyperglycemia, and glucosuria represent beneficial functional changes in response to nutrient excess. These allostatic adaptive responses limit glucose flux into metabolically vulnerable tissues and reduce nutrient stress (nutri-stress). From this perspective, T2D is not simply a failure of glucose regulation but a coordinated systemic allostatic response to chronic energy excess aimed at preserving metabolic homeostasis. Therapeutic success may depend not only on lowering glycemia but also on how interventions alter tissue-specific glucose handling and metabolic stress.

MeSH

Diabetes Mellitus, Nutrients, Insulin Resistance, Insulin, Stress, Physiological, Insulin Secretion, Food, Tissues, Diabetes Mellitus, Type 2