71-OR: Rates of Remission and Metabolic Responses in Data-Driven High-Risk Prediabetes Clusters

We have previously shown that weight loss-induced remission of prediabetes is mediated by improved insulin sensitivity (IS) and characterized by reduced visceral adipose tissue mass (VAT). Remission markedly reduces the risk for type 2 diabetes. We hypothesized that patients from specific high-risk Tübingen Prediabetes Clusters show a reduced remission response to a lifestyle intervention (LI). 707 individuals with prediabetes from the Prediabetes Lifestyle Intervention Study before and after 12 months of LI were categorized into 3 high-risk clusters: C3 (n=334), C5 (n=188), C6 (n=185). C3 and C5 have a high risk for T2D and complications, C6 for complications only. Remission was defined by normal glucose regulation (ADA standards). Deep phenotyping included OGTT derived IS and insulin secretion (InSec), liver fat content (¹H-MRS) and whole-body fat distribution (MRI). Mixed effects models were applied comparing participants going into remission (R) vs those with no remission (NR). At the end of the LI, remission rates were lowest in C5 compared to C3 and C6 (C3: 21% vs C5: 16% vs C6: 36%, p<0.001), despite highest weight (C3: -3.3±5.4% vs C5: -4.8±6.4 vs C6: -3.8±5.2, p<0.001) and liver fat reduction (C3: -1.8±3.4% vs C5: -8.1±7.7 vs C6: -3.0±4.2 and; p<0.0001). Within all clusters, IS increased more in R vs NR (OGIS (ml/min/m2); C3: R +72±56 vs NR +18±49; C5: +98±80 vs +26±58; C6: +56±52 vs +21±53, each p<0.001). In C3 InSec increased more in R vs NR (AUC_C-PEP0-30/AUC_Gluc0-30); R +6.7±34.7 vs NR +2.6±30.5, p=0.006), but it decreased in C6 NR (R -2.9±50.4 vs NR -14.5±46.3, p=0.007). In C5, which had the lowest remission rate, InSec did not differ between R and NR (R -22.9±53.7 vs NR -1.1±39.2, p=0.337). These data identify a precise subgroup of patients with prediabetes, C5, who are less likely to achieve remission in response to LI than patients from other high-risk Tübingen Prediabetes Clusters, despite the strongest weight loss. Patients in this subgroup require more precise preventive strategies.