Diabetes and Metabolic Disease Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.
Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy.
Diabetologia. 2023 Feb;66(2):354-366. doi: 10.1007/s00125-022-05814-2. Epub 2022 Oct 25.
AIMS/HYPOTHESIS: Endoplasmic reticulum (ER) stress and beta cell dedifferentiation both play leading roles in impaired insulin secretion in overt type 2 diabetes. Whether and how these factors are related in the natural history of the disease remains, however, unclear.
In this study, we analysed pancreas biopsies from a cohort of metabolically characterised living donors to identify defects in in situ insulin synthesis and intra-islet expression of ER stress and beta cell phenotype markers.
We provide evidence that in situ altered insulin processing is closely connected to in vivo worsening of beta cell function. Further, activation of ER stress genes reflects the alteration of insulin processing in situ. Using a combination of 17 different markers, we characterised individual pancreatic islets from normal glucose tolerant, impaired glucose tolerant and type 2 diabetic participants and reconstructed disease progression.
CONCLUSIONS/INTERPRETATION: Our study suggests that increased beta cell workload is accompanied by a progressive increase in ER stress with defects in insulin synthesis and loss of beta cell identity.
目的/假设：内质网（ER）应激和β细胞去分化在显性 2 型糖尿病中胰岛素分泌受损中都起着主要作用。然而，这些因素在疾病的自然史中是如何相关的仍不清楚。
在这项研究中，我们分析了一组代谢特征明确的活体供者的胰腺活检，以确定原位胰岛素合成和内质网应激以及β细胞表型标志物的胰岛内表达缺陷。
我们提供的证据表明，原位改变的胰岛素加工与体内β细胞功能的恶化密切相关。此外，内质网应激基因的激活反映了胰岛素原位加工的改变。我们使用 17 种不同标志物的组合，对来自正常糖耐量、糖耐量受损和 2 型糖尿病参与者的单个胰岛进行了特征描述，并重建了疾病进展。
结论/解释：我们的研究表明，β细胞工作量的增加伴随着内质网应激的逐渐增加，表现为胰岛素合成缺陷和β细胞特性丧失。
