Mechanistic studies on the regeneration of β-cells to balance the diabetic metabolic state in pancreas of LEW.1AR1-iddm rat and comparative in humans

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By combining a T cell antibody with antibodies against proinflammatory cytokines, especially against TNFα, a therapy concept for curing type 1 diabetes in a rat model (IDDM rat) of human type 1 diabetes was established for the first time. The rats treated in this way became normoglycaemic again. The aim of this subsequent application is to clarify the underlying pathways of β-cell regeneration in the endocrine pancreas. Differentiated β-cells enter the mitotic division via various factors and thus normalize the β-cell mass by increasing the proliferation and inhibiting apoptosis. DNA repair mechanisms also contribute to regeneration by converting damaged β-cells into intact ones. In addition to replication, new β-cells can also be formed from other pancreatic cell types via various pancreatic and β-cell specific transcription factors and proliferation factors via neogenesis. The subsequent process of functional maturation of the β-cells is mediated by known (flattop) markers and newly discovered makers by microarray analysis. The regeneration markers are examined using a variety of methods at the gene and protein level. The results are collected in the rat model in non-diabetic, acutely diabetic and successfully treated pancreata compared to human, non-diabetic and diabetic pancreata of different forms. These new findings on β-cell regeneration are intended to clarify the mechanisms on which the new successful therapeutic approaches for curing type 1 diabetes are based.