Intermittent protein restriction improves glucose homeostasis in Zucker diabetic fatty rats and single-cell sequencing reveals distinct changes in β cells

Diabetes is caused by the interplay between genetic and environmental factors, therefore changes of lifestyle and dietary patterns are the most common practices for diabetes intervention. Protein restriction and caloric restriction have been shown to improve diabetic hyperglycemia in both animal models and humans. We report here the effectiveness of intermittent protein restriction (IPR) for the intervention of diabetes in Zucker diabetic fatty (ZDF) rats. Administration of IPR significantly reduced hyperglycemia and decreased glucose production in the liver. IPR protected pancreatic islets from diabetes-mediated damages as well as elevated the number and the proliferation activity of β cells. Single-cell RNA sequencing performed with isolated islets from the ZDF rats revealed that IPR was able to reverse the diabetes-associated β cell dedifferentiation. In addition, diabetic β cells in ZDF rats were associated with increased expressions of islet amyloid polypeptide, chromogranin and genes involved in endoplasmic reticulum stress. A β cell dedifferentiation marker Cd81 was also increased in the β cells of diabetic rats. In contrast, the expressions of D-box binding PAR bZIP transcription factor Dbp and immediate-early response genes were reduced in the diabetic β cells. In conclusion, these results indicated that IPR is effective in glycemic control and β cell protection in a diabetic rat model. In addition, diabetes in ZDF rats is associated with changes in the expression of genes involved in many facets of β cell functions.