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Lookup NU author(s): Professor Roy Taylor
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2025.This review describes a prolonged research endeavour to test the twin cycle hypothesis that type 2 diabetes is caused by fat-induced dysfunction of the liver and pancreas, guided by the happenstance of clinical practice. Testing of the personal fat threshold hypothesis, that individuals exhibit different levels of tolerance to intra-organ fat accumulation, is also described. Both hypotheses predict that type 2 diabetes is potentially reversible by weight loss. The results of the Counterpoint study supported the twin cycle hypothesis, leading to a second study which determined that short-duration diabetes was more likely to remit following the 10–15 kg weight loss. It also confirmed that remission was durable over 6 months on an isoenergetic, normal diet. Subsequently, it was shown that weight loss caused an immediate decrease of pancreas fat only in people with type 2 diabetes and also that postprandial incretin spikes after bariatric surgery had no role in normalising fasting plasma glucose. DiRECT, a 2 year randomised controlled study, demonstrated clinical utility, observing functional beta cell capacity to return almost to normal over 12 months. A small group of participants regained weight and redeveloped type 2 diabetes, allowing observation that the underlying pathophysiological mechanisms during onset of diabetes were as postulated by the twin cycle hypothesis. Major clinical benefit was demonstrated after a further 3 year follow-up in routine care, halving the incidence of serious adverse effect compared with the standard treatment control group. In answer to the question of whether individuals have a personal fat threshold for tolerance of fat, stepwise weight loss in people with type 2 diabetes and BMI in the range 21–27 kg/m2 resulted in remission in 70%, with a wide range of fat thresholds. Type 2 diabetes can be regarded as a condition of homogenous aetiology in genetically heterogenous individuals.
Author(s): Taylor R
Publication type: Review
Publication status: Published
Journal: Diabetologia
Year: 2025
Pages: epub ahead of print
Online publication date: 02/05/2025
Acceptance date: 26/02/2025
ISSN (print): 0012-186X
ISSN (electronic): 1432-0428
Publisher: Springer Science and Business Media Deutschland GmbH
URL: https://doi.org/10.1007/s00125-025-06428-0
DOI: 10.1007/s00125-025-06428-0
