What does this research mean for the field?

The phenotypic trajectories of insulin sensitivity and beta cell function decline before the onset of type 2 diabetes vary significantly across distinct high-risk clinical sub-phenotypes. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.ESTABLISHES_NEW_DIRECTION.

What question did this study set out to answer?

This study aims to examine the phenotypic trajectories of type 2 diabetes risk among different clinical subphenotypes in at-risk individuals.

June 8, 2026

1166-OR: The Natural History of Type 2 Diabetes Varies between Clinical Subphenotypes of At-Risk Individuals

Key Points

This study aims to examine the phenotypic trajectories of type 2 diabetes risk among different clinical subphenotypes in at-risk individuals.
Included individuals from the TUEF/TULIP cohort who developed type 2 diabetes during the study.
Conducted 75 g oral glucose tolerance tests, body fat distribution assessments via whole body MRI, and liver fat measurements by H1 spectroscopy.
Classified high-risk clusters based on clinical sub-phenotyping (C3, C5, C6) and monitored their phenotypic trajectories for a mean observation of 3.5 years.
C3 and C6 demonstrated a significant reduction in insulin sensitivity (C3: pslope=0.048, C6: pslope=0.012), whereas C5 did not (pslope=0.299).
C5 showed the strongest decline in beta cell function (pslope<0.001), while C3 also declined (pslope=0.004), but not C6 (pslope=0.501).
Visceral fat showed a differing trajectory between clusters, with a steeper slope in C5 compared to C3 (0.058 vs 0.039, p=0.031).

Abstract

Introduction and Objective: The natural history of type 2 diabetes (T2D) is characterized by a gradual decrease of insulin sensitivity and characteristically a steep decline of beta cell function short before diagnosis. However, recent data-driven sub-phenotyping has unveiled high-risk clusters of individuals with increased T2D risk, that differ profoundly in body fat distribution, insulin resistance and beta cell function. We here provide first data on their respective phenotypic trajectories before T2D diagnosis. Methods: We included individuals at risk for T2D from the TUEF/TULIP cohort in Tübingen (Germany), who developed T2D during their participation in the study. Each visit included a 75 g oral glucose tolerance test (OGTT) and assessments of body fat distribution were accomplished by whole body MRI and liver fat by H1 spectroscopy. Indexes of insulin sensitivity and beta cell function were calculated from the OGTTs. According to clinical sub-phenotyping we distinguished the high-risk clusters 3 (C3: reduced beta cell function), 5 (C5: high visceral and liver fat, high insulin resistance) and 6 (C6: high visceral fat, high insulin secretion). Results: We included data from n=162 in C3, n=148 in C5 and n=48 in C6 with a mean observation time of 3.5±3.7 years before T2D diagnosis. C3 and C6 showed a significant reduction of insulin sensitivity (ISI Matsuda) but not C5 (C3: pslope=0.048, C6: pslope=0.012, C5: pslope=0.299). However, C5 showed the strongest decline in beta cell function (Adaptation Index, pslope=0.001), which also declined in C3 (pslope=0.004) but not in C6 (pslope=0.501). Neither visceral nor liver fat slopes indicated significant changes over time, however there was a between-cluster trajectory difference for visceral fat in C5 vs C3, with a slightly steeper slope in C5 (0.058 vs. 0.039, p=0.031). Conclusion: Before the onset of T2D, phenotypic trajectories vary according to clinical sub-phenotypes, opening new avenues for targeted prevention paradigms. Disclosure V. Minelli Faiao: None. D.S. Kulkarni: None. M. Ganslmeier: None. P. Hubert: None. F. Schick: None. A. Peter: None. A. Fritsche: None. N. Stefan: Speaker's Bureau; Current; AstraZeneca. Advisory Panel; Ended; Boehringer Ingelheim International GmbH. Speaker's Bureau; Ended; Boehringer Ingelheim International GmbH. Advisory Panel; Ended; Lilly. Speaker's Bureau; Current; Lilly. Advisory Panel; Ended; Pfizer Inc., Madrigal Pharmaceuticals, Inc. Speaker's Bureau; Ended; Madrigal Pharmaceuticals, Inc. Research Support; Ended; Sanofi. Speaker's Bureau; Current; Sanofi. A.L. Birkenfeld: None. R.J. von Schwartzenberg: None.

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