Toggle Main Menu Toggle Search

Open Access padlockePrints

Aetiology of Type 2 diabetes in people with a 'normal' body mass index: testing the personal fat threshold hypothesis

Lookup NU author(s): Emeritus Professor Roy Taylor, Alison Barnes, Dr Kieren Hollingsworth, Keaton Irvine, Dr Alexandra Solovyova, Tara Kelly, Dr Carmen Martin-RuizORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2023 The Author(s). Weight loss in overweight or obese individuals with Type 2 diabetes (T2D) can normalize hepatic fat metabolism, decrease fatty acid oversupply to β cells and restore normoglycaemia. One in six people has BMI <27 kg/m2 at diagnosis, and their T2D is assumed to have different aetiology. The Personal Fat Threshold hypothesis postulated differing individual thresholds for lipid overspill and adverse effects on β-cell function. To test this hypothesis, people with Type 2 diabetes and body mass index <27kg/m2 (n = 20) underwent repeated 5% weight loss cycles. Metabolic assessments were carried out at stable weight after each cycle and after 12 months. To determine how closely metabolic features returned to normal, 20 matched normoglycemic controls were studied once. Between baseline and 12 months: BMI fell (mean ± SD), 24.8 ± 0.4 to 22.5 ± 0.4 kg/m2 (P<0.0001) (controls: 21.5 ± 0.5); total body fat, 32.1 ± 1.5 to 27.6 ± 1.8% (P<0.0001) (24.6 ± 1.5). Liver fat content and fat export fell to normal as did fasting plasma insulin. Post-meal insulin secretion increased but remained subnormal. Sustained diabetes remission (HbA1c < 48 mmol/mol off all glucose-lowering agents) was achieved by 70% (14/20) by initial weight loss of 6.5 (5.5-10.2)%. Correction of concealed excess intra-hepatic fat reduced hepatic fat export, with recovery of β-cell function, glycaemic improvement in all and return to a non-diabetic metabolic state in the majority of this group with BMI <27 kg/m2 as previously demonstrated for overweight or obese groups. The data confirm the Personal Fat Threshold hypothesis: aetiology of Type 2 diabetes does not depend on BMI. This pathophysiological insight has major implications for management.

Publication metadata

Author(s): Taylor R, Barnes AC, Hollingsworth KG, Irvine KM, Solovyova AS, Clark L, Kelly T, Martin-Ruiz C, Romeres D, Koulman A, Meek CM, Jenkins B, Cobelli C, Holman RR

Publication type: Article

Publication status: Published

Journal: Clinical Science

Year: 2023

Volume: 137

Issue: 16

Pages: 1333-1346

Print publication date: 31/08/2023

Online publication date: 18/08/2023

Acceptance date: 17/08/2023

Date deposited: 12/09/2023

ISSN (print): 0143-5221

ISSN (electronic): 1470-8736

Publisher: Portland Press Ltd


DOI: 10.1042/CS20230586

PubMed id: 37593846


Altmetrics provided by Altmetric


Funder referenceFunder name
17/0005645Diabetes UK