Vertical sleeve gastrectomy triggers fast (3-cell recovery upon overt diabetes

Objective: The effectiveness of bariatric surgery in restoring (3-cell function has been described in type-2 diabetes (T2D) patients and animal models for years, whereas the mechanistic underpinnings are largely unknown. The possibility of vertical sleeve gastrectomy (VSG) to rescue farprogressed, clinically-relevant T2D and to promote (3-cell recovery has not been investigated on a single-cell level. Nevertheless, characterization of the heterogeneity and functional states of (3-cells after VSG is a fundamental step to understand mechanisms of glycaemic recovery and to ultimately develop alternative, less-invasive therapies. Methods: We performed VSG in late-stage diabetic db/db mice and analyzed the islet transcriptome using single-cell RNA sequencing (scRNAseq). Immunohistochemical analyses and quantification of (3-cell area and proliferation complement our findings from scRNA-seq. Results: We report that VSG was superior to calorie restriction in late-stage T2D and rapidly restored normoglycaemia in morbidly obese and overt diabetic db/db mice. Single-cell profiling of islets of Langerhans showed that VSG induced distinct, intrinsic changes in the (3-cell transcriptome, but not in that of a-, 5-, and PP-cells. VSG triggered fast (3-cell redifferentiation and functional improvement within only two weeks of intervention, which is not seen upon calorie restriction. Furthermore, VSG expanded (3-cell area by means of redifferentiation and by creating a proliferation competent (3-cell state. Conclusion: Collectively, our study reveals the superiority of VSG in the remission of far-progressed T2D and presents paths of (3-cell regeneration and molecular pathways underlying the glycaemic benefits of VSG. (c) 2021 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

The study demonstrates the superiority of vertical sleeve gastrectomy (VSG) over calorie restriction in late-stage type 2 diabetes, rapidly restoring normal blood glucose levels. VSG induced distinct, intrinsic changes in the transcriptome of β-cells, leading to their fast redifferentiation and functional improvement post-intervention.