Beta Cell Function: from Human Genetics to Animal Models

University dissertation from Lund University

Abstract: Beta cell function is an important factor in the development of both Type 1 (T1D) and Type 2 (T2D) diabetes mellitus. T1D is characterized by a primary defect in insulin secretion due to the immune-mediated beta cell destruction, however, the more common T2D beside insulin resistance also include impaired beta cell function as a consequence to abnormal glucose homeostasis. Genetic susceptibility is involved in both types of diabetes. We have studied several genetic and immunological factors affecting beta cell function. First, we tested whether single nucleotide polymorphisms (SNPs) of the human Free Fatty Acid Receptor 1 (FFAR1) are associated with T2D and insulin secretion. Another genetic study focused on FOXP3 association with T1D and the disease-related clinical parameters. The role of microRNAs (miRNAs) on beta cell function was studied in the third project using a novel genetically engineered mouse model. Subsequently, the effect of Alpha 1-Antitrypsin (AAT) on cytokine-induced apoptosis and on insulin secretion was studied in beta cells in vitro. In Study I, we concluded that SNPs rs1978013 and rs1978014 in the upstream region of FFAR1 gene might contribute to impaired beta cell function in T2D. Study II showed that the minor A allele in the FOXP3 rs2232365 SNP might represent a protective factor in T1D pathogenesis and suggest a possible role of FOXP3 in the regulation of autoimmunity against pancreatic beta cells. We have demonstrated for the first time in Study III that targeted disruption of the Dicer1 gene specifically in beta cells leads to progressive impairment of insulin secretion and diabetes development. Our findings of Study IV show that AAT stimulates insulin secretion and protects beta cells against cytokine-induced apoptosis, and these effects of AAT seems to be mediated through the cAMP pathway.

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