72-OR: Mechanisms of Prediabetes Remission in People with Weight Gain after Lifestyle Intervention
Authors: SANDFORTH ARVID , VAZQUEZ ARREOLA ELSA , HANSON ROBERT L. , SANDFORTH LEONTINE , KATZENSTEIN SARAH , SEISSLER JOCHEN , PERAKAKIS NIKOLAOS , WAGNER ROBERT , MACHANN JÜRGEN , SCHICK FRITZ , PETER ANDREAS , PREISSL HUBERT , SZENDROEDI JULIA , SOLIMENA MICHELE , BLÜHER MATTHIAS , SCHÜRMANN ANNETTE , KABISCH STEFAN , PFEIFFER ANDREAS F. , BORNSTEIN STEFAN R. , RODEN MICHAEL , STEFAN NORBERT , FRITSCHE ANDREAS , BIRKENFELD ANDREAS L. , JUMPERTZ VON SCHWARTZENBERG REINER , WORKING GROUP PLIS 
Published: June 2024

We showed that weight loss-induced prediabetes remission during lifestyle intervention (LI) is determined by increased insulin sensitivity and protects from future T2D development. The extent to which remission of prediabetes occurs without weight loss, and if underlying mechanisms differ from weight loss-induced prediabetes remission, is unknown. In the Prediabetes Lifestyle Intervention Study (PLIS), people with prediabetes underwent a 12 months LI (dietary counselling and advice to increase physical activity) with metabolic assessments before and after, including 5-point OGTT, whole body MRI for fat distribution and 1H-MRS for liver fat. Insulin sensitivity and secretion were assessed by OGTT-derived indices. Remission was achieved when fasting, 2h glucose and HbA1c normalized after LI (= responders (R), otherwise non-responders (NR)) according to ADA criteria. Of 1105 PLIS participants, 234 did not lose or gained weight during LI (median weight change: +2.1% IQR: 0.9 - 3.8), 51 were responders and 183 non-responders (22% remission rate). There were no between-group differences in change of body mass index (mean for R: 29.6±7.3 kg/m2 to 30.6±7.5, for NR: 30.5±5.8 to 31.3±6.1, p group over time =0.47), whole body fat (R: 29.9±13.5 l to 32.0±14.3, NR: 30.6±12.0 to 32.1±12.8, p=0.92) or liver fat (R: 4.1±1.3% to 4.7±1.5, NR: 8.3±1.4 to 8.7±1.5, p=0.82). R had a stronger improvement in insulin sensitivity (OGIS, β₀ (95% CI): 28.3 (12.7-44.0), p=0.0016) and insulin secretion (AUCc-pep0-30/AUCgluc0-30, β₀ 11.3 (1.6-22.8), p=0.039). We replicated this in participants of the US Diabetes Prevention Program. R had a relative risk reduction of 71% to develop T2D than NR at 5 years after LI (risk ratio: 0.29, 95% CI 0.09-0.91, p=0.02). LI-induced prediabetes remission is possible in a substantial proportion despite weight gain and is similarly protective for T2D as weight loss remission. Underlying mechanisms include increased insulin secretion, in contrast to weight loss induced remission.

Disclosure
A. Sandforth: None. E. Vazquez Arreola: None. R.L. Hanson: None. L. Sandforth: None. S. Katzenstein: None. J. Seissler: None. N. Perakakis: Advisory Panel; Bayer Inc. Other Relationship; Lilly Diabetes, Novo Nordisk. R. Wagner: Speaker's Bureau; Sanofi. Advisory Panel; Lilly Diabetes. Speaker's Bureau; Boehringer-Ingelheim, Novo Nordisk. J. Machann: None. F. Schick: None. A. Peter: None. H. Preissl: None. J. Szendroedi: None. M. Solimena: None. M. Blüher: Speaker's Bureau; Amgen Inc., AstraZeneca, Bayer Inc., Daiichi Sankyo. Advisory Panel; Lilly Diabetes. Speaker's Bureau; Novartis AG. Advisory Panel; Novo Nordisk. Speaker's Bureau; Pfizer Inc., Sanofi. A. Schürmann: None. S. Kabisch: Other Relationship; Sanofi, Boehringer-Ingelheim, Berlin-Chemie AG. Research Support; J. Rettenmaier & Söhne, Rosenberg, Germany, California Walnut Commission, Almond Board of California, Wilhelm-Doerenkamp-Foundation. Other Relationship; JuZo-Akademie, Lilly Diabetes. A.F. Pfeiffer: Advisory Panel; Abbott. Speaker's Bureau; AstraZeneca, Novo Nordisk, Sanofi. Advisory Panel; Berlin-Chemie AG. S.R. Bornstein: None. M. Roden: Advisory Panel; Eli Lilly and Company. Research Support; Boehringer-Ingelheim. Advisory Panel; Novo Nordisk. Research Support; Novo Nordisk. Advisory Panel; TARGET PharmaSolutions, Inc. Speaker's Bureau; AstraZeneca. N. Stefan: Speaker's Bureau; AstraZeneca, Boehringer-Ingelheim, Lilly Diabetes, MSD Life Science Foundation, Novo Nordisk. Advisory Panel; Pfizer Inc. Research Support; Sanofi-Aventis Deutschland GmbH. Advisory Panel; GlaxoSmithKline plc. A. Fritsche: Speaker's Bureau; Novo Nordisk, Sanofi-Aventis Deutschland GmbH, SYNLAB Holding Deutschland GmbH. A.L. Birkenfeld: None. R. Jumpertz von Schwartzenberg: None.