Dietary carbohydrates impair protection from type 2 diabetes by protein restriction

Background:

Low protein diets have been shown to reduce the body weight by increasing energy expenditure and improving glucose tolerance. Elevated concentration in circulating FGF21 have been implicated as a potential underlying mechanism. Therefore, we tested in diabetes-susceptible New Zealand obese (NZO) mice whether a moderate protein restriction in a high carbohydrate (HC) or high fat (HF) regimen protects against diabetes.

Methods:

After weaning, NZO mice were placed on high-fat diets that provided protein at control (16 kcal%; CON) or low levels (4 kcal%; LP/HC or LP/HF) for 8 weeks and changes in glucose homeostasis, energy expenditure, food intake and other metabolic endpoints were assessed. Six weeks after the diet switch an OGTT was performed.

Results:

Despite the increase in food intake, fat mass, energy expenditure, and hepatic FGF21 secretion, protein restriction prevented the onset of hyperglycemia and beta-cell loss but only in the context of a lower carbohydrate/fat ratio (LP/HF). Under increased carbohydrate/fat conditions (LP/HC), mice developed type 2 diabetes two weeks later than the control, despite the robust elevated hepatic FGF21 secretion and an increased energy expenditure.

Conclusion:

Prevention of hyperglycemia and type 2 diabetes through protein restriction is compromised by high dietary carbohydrates despite increased FGF21 levels. A protective effect of protein restriction is independent of food intake and adiposity. Thus, increased FGF21 and elevated energy expenditure are not protecting from hyperglycemia and diabetes per se. Both parameters are only sufficient to prevent diabetes under low dietary carbohydrate conditions.