Abstract:
Type 2 diabetes mellitus is a disease of impaired blood glucose regulation, due to insulin resistance in the early stage, and insulin deficiency in the late stage. It is a significant and increasing burden on the global healthcare system. Current therapies do not address the cause of this disease, and thus can only manage the symptoms. There is a need for greater understanding of the molecular mechanism underlying the development of insulin resistance and new models to study this. Amylin is a pancreatic hormone postulated to be involved in the development of this disease, as human amylin forms amyloid in the pancreases of diabetic patients and amylin oligomers have been shown to be cytotoxic to β-cells. Rodent amylin is nonamyloidogenic, so mice expressing human amylin have been developed. However, β-cell loss in these transgenic animals limits the secretion of amylin and insulin. Thus, these mice can't be used to investigate chronic hyperamylinaemia nor the insulin resistant stage of type 2 diabetes. Our group has developed transgenic mice which overexpress triprolyl-human amylin, a nonamyloidogenic variant. We have called this the Line 44 model. These mice developed hyperamylinaemia, obesity, hyperinsulinaemia and hyperglycaemia (which resolves after a period). We examined how the expression of genes involved in amylin, insulin and leptin signalling in the brain was affected by hyperamylinaemia in this model at different disease stages. Brain samples were taken from hemizygous, homozygous and nontransgenic mice at 100 days (prediabetic) and diabetes onset and 400 days (post-diabetic). We used molecular probes to measure the expression of 41 genes across time point and genotype in transgenic mice and compared these to nontransgenic controls. We found several genes with significantly altered expression, including Cart, Pomc and Npy (neuropeptides which control appetite), c-fos (a marker of amylin activation), and Socs3 (a well-known leptin inhibitor). These changes indicate dysregulation of central metabolic hormone signalling, leading to the obese and diabetic phenotype of the Line 44 model. Further investigation into hyperamylinaemia and these differentially expressed genes as therapeutic targets is warranted.
