Calorie Restriction Using High-Fat/Low-Carbohydrate Diet Suppresses Liver Fat Accumulation and Pancreatic Beta-Cell Dedifferentiation in Obese Diabetic Mice

In diabetes, pancreatic beta-cells gradually lose their ability to secrete insulin with disease progression. beta-cell dysfunction is a contributing factor to diabetes severity. Recently, islet cell heterogeneity, exemplified by beta-cell dedifferentiation and identified in diabetic animals, has attracted attention as an underlying molecular mechanism of beta-cell dysfunction. Previously, we reported beta-cell dedifferentiation suppression by calorie restriction, not by reducing hyperglycemia using hypoglycemic agents (including sodium-glucose cotransporter inhibitors), in an obese diabetic mice model (db/db). Here, to explore further mechanisms of the effects of food intake on beta-cell function, db/db mice were fed either a high-carbohydrate/low-fat diet (db-HC) or a low-carbohydrate/high-fat diet (db-HF) using similar calorie restriction regimens. After one month of intervention, body weight reduced, and glucose intolerance improved to a similar extent in the db-HC and db-HF groups. However, beta-cell dedifferentiation did not improve in the db-HC group, and beta-cell mass compensatory increase occurred in this group. More prominent fat accumulation occurred in the db-HC group livers. The expression levels of genes related to lipid metabolism, mainly regulated by peroxisome proliferator-activated receptor alpha and gamma, differed significantly between groups. In conclusion, the fat/carbohydrate ratio in food during calorie restriction in obese mice affected both liver lipid metabolism and beta-cell dedifferentiation.