Intensive insulin therapy and protein restriction delay the development of nephropathy in a variety of conditions, but few\ninterventions are known to reverse nephropathy. Having recently observed that the ketone 3-beta-hydroxybutyric acid (3-\nOHB) reduces molecular responses to glucose, we hypothesized that a ketogenic diet, which produces prolonged elevation\nof 3-OHB, may reverse pathological processes caused by diabetes. To address this hypothesis, we assessed if prolonged\nmaintenance on a ketogenic diet would reverse nephropathy produced by diabetes. In mouse models for both Type 1\n(Akita) and Type 2 (db/db) diabetes, diabetic nephropathy (as indicated by albuminuria) was allowed to develop, then half\nthe mice were switched to a ketogenic diet. After 8 weeks on the diet, mice were sacrificed to assess gene expression and\nhistology. Diabetic nephropathy, as indicated by albumin/creatinine ratios as well as expression of stress-induced genes,\nwas completely reversed by 2 months maintenance on a ketogenic diet. However, histological evidence of nephropathy was\nonly partly reversed. These studies demonstrate that diabetic nephropathy can be reversed by a relatively simple dietary\nintervention. Whether reduced glucose metabolism mediates the protective effects of the ketogenic diet remains to be\ndetermined.
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