Influence of diabetes on the loss of beta cell differentiation after islet transplantation in rats

Abstract

Aims/hypothesis Hyperglycaemia can impair beta cell function after islet transplantation. Appropriate glucose-induced insulin secretion is dependent on a unique expression pattern of genes. Here we examined the effects of diabetes on gene expression in transplanted islets. Materials and methods Streptozotocin-induced diabetic or control non-diabetic Lewis rats were transplanted under the kidney capsule with an insufficient number (2,000) of syngeneic islets to normalise blood glucose levels in diabetic rats. Eighteen days after transplantation, islet grafts were retrieved and RT-PCR used to assess expression of selected genes critical for beta cell function. Islet grafts from diabetic rats transplanted with a sufficient number of islets (3,000) to normalise hyperglycaemia were used to assess the effects of correcting blood glucose levels. Additionally, gene expression of transplanted islets from non-diabetic rats was compared with freshly isolated islets.Results In islet grafts from diabetic rats, mRNA levels of several transcription factors important for the maintenance of beta cell differentiation were reduced (pancreatic and duodenal homeobox 1 [Iapp]). Conversely, mRNA levels of lactate dehydrogenase, which is normally suppressed in beta cells, were increased. The majority of the changes in gene expression were normalised after correction of hyperglycaemia, indicating that the severe loss of beta cell differentiation correlates with continuous exposure to diabetes. Even islet grafts from non-diabetic rats showed a few alterations in beta cell gene expression in comparison with fresh islets. Conclusions/interpretation Chronic hyperglycaemia contributes to the deterioration of beta cell differentiation after islet transplantation.

Hyperglycemia Induces Apoptosis of Human Pancreatic Islet Endothelial Cells

“…Further, a major defect of insulin secretory function is found in all forms of diabetes, 46 and sustained hyperglycemia has a detrimental impact on angiogenesis, growth, and function of transplanted islets. 47,48 In this study we detected increased production of the proinflammatory cytokine IL-1␤ by islet MECs under hyperglycemic conditions. Previous studies demonstrated that human ␤ cells are a potential source of glucose-induced IL-1␤ independently of any viral or immune-mediated process.…”

VHL-mediated disruption of Sox9 activity compromises β-cell identity and results in diabetes mellitus

“…These data encourage us to explore the effects of hypoxia in islets during transplantation, where oxygenation impacts islet function (Carlsson et al 1998(Carlsson et al , 2000Sakata et al 2010). Interestingly, both low oxygenation and loss of b-cell differentiation have been reported in islet grafts in animals (Laybutt et al 2007). HIF stabilization in transplanted islets (Miao et al 2006), presumably due to delayed vascularization of the transplanted cells, could induce changes in the b-cell transcriptome that negatively impact successful transplantation and graft function.…”

MafA is critical for maintenance of the mature beta cell phenotype in mice

“…3a). Expression of the transcription factors important for the maintenance of beta cells differentiation, such as PDX1, NeuroD1, paired box protein 6 (PAX6), forkhead box protein O1 (FOXO1) and Nkx6.1 [8,12,33], was also mildly decreased in Mafa KO islets (Fig. 3b).…”

“…Reversing the dedifferentiation of insulin-negative beta cells restores beta cell function after the normalisation of hyperglycaemia [13,33], suggesting that beta cells are plastic until a certain stage. Our study suggests that inducing the redifferentiation of beta cells using extrinsic factors may be an effective treatment for diabetes and MafA may be a potential therapeutic target.…”