Abstract
Most studies in type 1 diabetes (T1D) have focused on the loss of the pancreatic beta-cell population. However, despite the involvement of the alpha-cell in the aetiology and complications of T1D, little is known about the regulation of the pancreatic alpha-cell mass in this disease. The need for a better understanding of this process is further emphasized by recent findings suggesting that alpha-cells may constitute a potential reservoir for beta-cell regeneration. In this study, we characterized the pancreatic alpha-cell mass and its regulatory processes in the transgenic RIP-B7.1 mice model of experimental autoimmune diabetes (EAD). Diabetic mice presented insulitis, hyperglycaemia, hypoinsulinemia and hyperglucagonemia along with lower pancreatic insulin content. While alpha-cell mass and pancreatic glucagon content were preserved at the early-onset of EAD, both parameters were reduced in the advanced phase. At both stages, alpha-cell size, proliferation and ductal neogenesis were up-regulated, whereas apoptosis was almost negligible. Interestingly, we found an increase in the proportion of glucagon-containing cells positive for insulin or the beta-cell transcription factor PDX1. Our findings suggest that pancreatic alpha-cell renewal mechanisms are boosted during the natural course of EAD, possibly as an attempt to maintain the alpha-cell population and/or to increase beta-cell regeneration via alpha-cell transdifferentiation.
Highlights
Type 1 diabetes (T1D) is characterized by the autoimmune destruction of the pancreatic beta-cell population and the consequent decrease or lack of insulin secretion[1]
The rat insulin promoter (RIP)-B7.1 mouse appears to possess most of the human attributes to study alpha-cell mass in type 1 diabetes (T1D)
Non-Obese Diabetic (NOD) mice, the most used experimental autoimmune diabetes (EAD) model, do not consistently exhibit hyperglucagonemia with diabetes evolution[18], while this situation is present in pre-diabetic states[7]
Summary
Type 1 diabetes (T1D) is characterized by the autoimmune destruction of the pancreatic beta-cell population and the consequent decrease or lack of insulin secretion[1]. It would be important to analyse alpha-cell mass and the processes involved in its regulation during key time points of the T1D history in the same diabetic model These data could provide valuable information to understand the forces involved in the alpha-cell mass dynamics during T1D. The diabetic phenotype in the RIP-B7.1 transgenic mice occurs with equal incidence and timing in both sexes in a common mice background, reducing the problem of autoimmune susceptibility genes[27]. Our findings using this stringent EAD model indicate that the alpha-cell population is under an intense attempt of regeneration during the natural course of T1D
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