The medical complications of diabetes are diverse, widespread and poorly understood mechanistically. Our recent research has shown that defective repair of skeletal muscle cell membrane disruptions underlies limb girdle type IIb muscular dystrophy, which is characterized by muscle necrosis and atrophy. Muscle atrophy, and, more rarely, acute muscle necrosis, are two well-established but poorly understood diabetic complications. We hypothesize that defective membrane repair underlies this dystrophic skeletal muscle phenotype of diabetes. Our preliminary results, from mouse models of diabetes, strongly support this hypothesis, and we here propose to confirm and further characterize this novel diabetic phenotype. We here propose direct tests of the question whether the repair defect characteristic of diabetes is the cause of diabetic myopathy. Membrane repair is a widespread and requisite (life or death) cell function in vivo that operates via a universal mechanism: calcium-activated membrane fusion events construct and anneal a patch to the cell surface defect site. We therefore further hypothesize that numerous cell types, in addition to skeletal muscle cells, will display a repair defect in diabetes that contributes to other diabetic complications. We propose to use cultured cell and whole organ--heart, aorta and skin--mouse models to test this hypothesis. We have previously shown that binding of glycosylated cell surface proteins to exogenous lectins can potently inhibit membrane repair. AGE (advanced glycation end-products) accumulate on cell surface and other proteins in diabetes, and AGE can become cross-linked to one another, or be bound by a receptor, RAGE (receptor for advanced glycation end-products). These conditions may mimic lectin binding to cell surface carbohydrates. We therefore hypothesize that the increased AGE/RAGE interactions characteristic of diabetes are responsible for defective membrane repair in this disease. Finally, we propose to test this hypothesis using in vitro cell models exhibiting enhanced or defective AGE/RAGE binding. This work will identify novel cellular and molecular targets for further research focusing on the pathogenesis of diabetes. It is made possible by the employment of an innovative laser-based microscope technique that, for the first time, permits experimental probing of membrane repair in situ.
The proposed research attempts to advance our understanding of diabetic complications at the cell and molecular level. It is based on a novel hypothesis, that diabetes inhibits cell repair, which, if verified, could lead to new therapeutic approaches to this important disease.
|Howard, Amber C; McNeil, Anna K; Xiong, Fei et al. (2011) A novel cellular defect in diabetes: membrane repair failure. Diabetes 60:3034-43|