Article

Diabetologia

, Volume 50, Issue 7, pp 1481-1489

Development of diabetes in obese, insulin-resistant mice: essential role of dietary carbohydrate in beta cell destruction

  • H. S. JürgensAffiliated withDepartment of Pharmacology, German Institute of Human Nutrition
  • , S. NeschenAffiliated withDepartment of Pharmacology, German Institute of Human Nutrition
  • , S. OrtmannAffiliated withInstitute for Zoo and Wildlife Research
  • , S. ScherneckAffiliated withDepartment of Pharmacology, German Institute of Human Nutrition
  • , K. SchmolzAffiliated withDepartment of Pharmacology, German Institute of Human Nutrition
  • , G. SchülerAffiliated withDepartment of Pharmacology, German Institute of Human Nutrition
  • , S. SchmidtAffiliated withDepartment of Pharmacology, German Institute of Human Nutrition
  • , M. BlüherAffiliated withInternal Medicine III, University Hospital Leipzig
  • , S. KlausAffiliated withDepartment of Pharmacology, German Institute of Human Nutrition
    • , D. Perez-TilveAffiliated withObesity Research Centre, Department of Psychiatry, University of Cincinnati
    • , M. H. TschöpAffiliated withObesity Research Centre, Department of Psychiatry, University of Cincinnati
    • , A. SchürmannAffiliated withDepartment of Pharmacology, German Institute of Human Nutrition Email author 
    • , H.-G. JoostAffiliated withDepartment of Pharmacology, German Institute of Human Nutrition

Abstract

Aims/hypothesis

The role of dietary carbohydrate in the pathogenesis of type 2 diabetes is still a subject of controversial debate. Here we analysed the effects of diets with and without carbohydrate on obesity, insulin resistance and development of beta cell failure in the obese, diabetes-prone New Zealand Obese (NZO) mouse.

Materials and methods

NZO mice were kept on a standard diet (4% [w/w] fat, 51% carbohydrate, 19% protein), a high-fat diet (15, 47 and 17%, respectively) and a carbohydrate-free diet in which carbohydrate was exchanged for fat (68 and 20%, respectively). Body composition and blood glucose were measured over a period of 22 weeks. Glucose tolerance tests and euglycaemic-hyperinsulinaemic clamps were performed to analyse insulin sensitivity. Islet morphology was assessed by immunohistochemistry.

Results

Mice on carbohydrate-containing standard or high-fat diets developed severe diabetes (blood glucose >16.6 mmol/l, glucosuria) due to selective destruction of pancreatic beta cells associated with severe loss of immunoreactivity of insulin, glucose transporter 2 (GLUT2) and musculoaponeurotic fibrosarcoma oncogene homologue A (MafA). In contrast, mice on the carbohydrate-free diet remained normoglycaemic and exhibited hyperplastic islets in spite of a morbid obesity associated with severe insulin resistance and a massive accumulation of macrophages in adipose tissue.

Conclusions/interpretation

These data indicate that the combination of obesity, insulin resistance and the inflammatory response of adipose tissue are insufficient to cause beta cell destruction in the absence of dietary carbohydrate.

Keywords

Beta cell failure Carbohydrate Euglycaemic-hyperinsulinaemic clamps Inflammation Insulin sensitivity Insulin New Zealand obese mouse Obesity Pancreas White adipose tissue