High-Fat, Carbohydrate-Free Diet Markedly Aggravates Obesity but Prevents β-Cell Loss and Diabetes in the Obese, Diabetes-Susceptible db/db Strain

Abstract

Objective: We have previously reported that a high-fat, carbohydrate-free diet prevents diabetes and β-cell destruction in the New Zealand Obese (NZO) mouse strain. Here we investigated the effect of diets with and without carbohydrates on obesity and development of β-cell failure in a second mouse model of type 2 diabetes, the db/db mouse. Results: When kept on a carbohydratecontaining standard (SD; with (w/w) 5.1, 58.3, and 17.6% fat, carbohydrates and protein, respectively) or high-fat diet (HFD; 14.6, 46.7 and 17.1%), db/db mice developed severe diabetes (blood glucose >20 mmol/l, weight loss, polydipsia and polyurea) associated with a selective loss of pancreatic β-cells, reduced GLUT2 expression in the remaining β-cells, and reduced plasma insulin levels. In contrast, db/db mice kept on a high-fat, carbohydrate-free diet (CFD; with 30.2 and 26.4% (w/w) fat or protein) did not develop diabetes and exhibited near-normal, hyperplastic islets in spite of a morbid obesity (fat content >60%) associated with hyperinsulinaemia. Conclusion: These data indicate that in genetically different mouse models of obesity-associated diabetes, obesity and dietary fat are not sufficient, and dietary carbohydrates are required, for β-cell destruction.