Abstract
We have developed a spontaneous humanized transgenic mouse model of autoimmune diabetes chronically develops diabetic complications. Our humanized mouse develop diabetic nephropathy. The basal glomerular membrane thickness was doubled in size at 4 months of age as shown by electron microscopy. The manifestation of glomerulopathy subsequently correlates with microalbuminuria. At 6 month, mice show advanced features of diabetic nephropathy like focal segmental/global glomerular sclerosis and focal tubular atrophy. The typical features of Kimmelstiel-Wilson are seen when severe chronic kidney disease develops. Our humanized mice develop diabetic retinopathy. We have noted a significant increase in acellular capillaries of the retina at the age of 6 months. Ocular tomography revealed a significant reduction in total retinal thickening. Fundoscopic retinal images revealed a classic vascular leakage as observed in humans. Our humanized mice also show diabetic neuropathy. We have observed an impaired sciatic and optic nerve conduction. Specifically, optic nerves at 6-months old diabetic mice showed an increased refractory period of the second compound action potential (CAP). This increase in the refractory period of CAP in the diabetic optic nerves is consistent with the reduced conduction velocity. However, a limb vasculopathy has not been observed so far. In our mouse model, the mouse MHC-II was replaced with human DQ8 in all antigen-presenting cells. The mouse also expresses human GAD65 in pancreatic beta cells. The diabetic phenotype of our mouse mimics the human disease progression. Importantly, our mouse model has a genetic background that compromises beta-cell neogenesis and/or regeneration (1). Our humanized mice model has the closest known phenotype to human diabetes and is most suitable for addressing physiopathology and treatment of diabetes complications. (U.S. Provisional Patent #62/713,827). Disclosure S. Imam: None. J.C. Jaume: None. Funding University of Toledo
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