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


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
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.
Jürgens
H S
HS
Department of Pharmacology, German Institute of Human Nutrition, Potsdam Rehbrücke, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany.
Neschen
S
S
Ortmann
S
S
Scherneck
S
S
Schmolz
K
K
Schüler
G
G
Schmidt
S
S
Blüher
M
M
Klaus
S
S
Perez-Tilve
D
D
Tschöp
M H
MH
Schürmann
A
A
Joost
H-G
HG
D000273:Adipose Tissue / Q000378:metabolism; D000821:Animal Feed; D000818:Animals; D001823:Body Composition; D002241:Carbohydrates / Q000737:chemistry; D003921:Diabetes Mellitus, Experimental / Q000209:etiology / Q000235:genetics* / Q000473:pathology*; D005947:Glucose / Q000378:metabolism; D051273:Glucose Transporter Type 2 / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity
D002241:Carbohydrates; D051273:Glucose Transporter Type 2; D007328:Insulin; D005947:Glucose