Dietary carbohydrates impair the protective effect of protein restriction against diabetes in NZO mice used as a model of type 2 diabetes

Diabetologia. 2018 Jun;61(6):1459-1469. doi: 10.1007/s00125-018-4595-1. Epub 2018 Mar 17.


Aims/hypothesis: Low-protein diets are well known to improve glucose tolerance and increase energy expenditure. Increases in circulating fibroblast growth factor 21 (FGF21) have been implicated as a potential underlying mechanism.

Methods: We aimed to test whether low-protein diets in the context of a high-carbohydrate or high-fat regimen would also protect against type 2 diabetes in New Zealand Obese (NZO) mice used as a model of polygenetic obesity and type 2 diabetes. Mice were placed on high-fat diets that provided protein at control (16 kJ%; CON) or low (4 kJ%; low-protein/high-carbohydrate [LP/HC] or low-protein/high-fat [LP/HF]) levels.

Results: Protein restriction prevented the onset of hyperglycaemia and beta cell loss despite increased food intake and fat mass. The effect was seen only under conditions of a lower carbohydrate/fat ratio (LP/HF). When the carbohydrate/fat ratio was high (LP/HC), mice developed type 2 diabetes despite the robustly elevated hepatic FGF21 secretion and increased energy expenditure.

Conclusion/interpretation: Prevention of type 2 diabetes through protein restriction, without lowering food intake and body fat mass, is compromised by high dietary carbohydrates. Increased FGF21 levels and elevated energy expenditure do not protect against hyperglycaemia and type 2 diabetes per se.

Keywords: Energy expenditure; FGF21; Hyperglycaemia; Insulin resistance; NZO; Obesity; Protein restriction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue
  • Animals
  • Blood Glucose / metabolism
  • Body Weight
  • Diabetes Mellitus, Experimental / metabolism*
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism*
  • Diet, Protein-Restricted*
  • Dietary Carbohydrates / metabolism*
  • Energy Metabolism
  • Fibroblast Growth Factors / genetics
  • Glucose Tolerance Test
  • Insulin / metabolism
  • Insulin Resistance
  • Male
  • Mice
  • Mice, Obese
  • Mice, Transgenic
  • Obesity / metabolism


  • Blood Glucose
  • Dietary Carbohydrates
  • Insulin
  • fibroblast growth factor 21
  • Fibroblast Growth Factors