Transgenic expression of a mutated cyclin-dependent kinase 4 (CDK4/R24C) in pancreatic β-cells prevents progression of diabetes in db/db mice

In an attempt to rectify the hyperglycemic state in obese insulin resistant db/db mice, a transgenic line was generated (db/db-CDK4R24C) that expresses a constitutively active form of cyclin-dependent kinase 4 (CDK4/R24C) under the control of the insulin promoter. Compared with non-transgenic db/db littermates, adult db/db-CDK4R24C mice show near-complete glycemic normalization and improved plasma lipid concentrations, but are also more susceptible to weight gain and have significantly lower plasma adiponection levels. They have striking islet hypertrophy and β-cell hyperplasia, and retain an insulin secretory response during the glucose tolerance test. We examined the expression of several key regulatory transcription factor genes involved in lipid and glucose metabolism in insulin target tissues of db/db-CDK4R24C as well as db/db mice, and found that the expression levels of members of the peroxisome proliferator-activated receptor (PPAR) family are highly associated with metabolic alterations in a gene- and tissue-specific manner. We show for the first time that the Ppar-δ in skeletal muscle and white adipose tissues is transcriptionally down-regulated in db/db mice. The db/db-CDK4R24C mice present a novel model of leptin-resistant obesity with compensatory hyperinsulinemia and normalized blood glucose levels, and thus may be useful for future studies that aim to dissect relationships between insulin and leptin signaling.