Lower Hepatic Fat is Associated with Improved Insulin Secretion in a High-Risk Prediabetes Subphenotype During Lifestyle Intervention

The objective of this work was to investigate whether impaired insulin secretion can be restored by lifestyle intervention in specific subphenotypes of prediabetes. One thousand forty-five participants from the Prediabetes Lifestyle Intervention Study (PLIS) were assigned to 6 recently established prediabetes clusters. Insulin secretion was assessed by a C-peptide-based index derived from oral glucose tolerance tests and modeled from three time-points during a 1-yr intervention. We also analyzed the change of glycemia, insulin sensitivity and liver fat.
 All pre-diabetes high-risk clusters (cluster 3, 5 and 6) had improved glycemic traits during lifestyle intervention, whereas insulin secretion only increased in clusters 3 and 5 (p<0.001); however, high liver fat in cluster 5 was associated with a failure to improve insulin secretion (pinteraction<0.001). Thus, interventions to reduce liver fat have the potential to improve insulin secretion in a defined subgroup of prediabetes. Prediabetes is a heterogenous condition comprising subphenotypes with different risks of diabetes and its complications (1). From its two key features, insulin resistance and impaired insulin secretion, insulin resistance can be clearly improved by lifestyle intervention (LI); however, it is not known, if LI can improve insulin secretion in specific subphenotypes of reduced insulin secretion (2). Recently, we described 6 clusters of prediabetic metabolism (1). Two of these clusters (cluster 3 and 5) have high risk of progression to diabetes. Another group (cluster 6) has an intermediate risk of diabetes as these persons are capable of compensating insulin resistance via hyperinsulinemia over years. In this study, we retrospectively stratified participants of a large multi-center study into these novel clusters of prediabetic metabolism (1) and investigated whether LI improved their insulin secretion and other glycemic traits.