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

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, diabetesprone 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 euglycaemichyperinsulinaemic 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.

Diet-induced gene expression of isolated pancreatic islets from a polygenic mouse model for the metabolic syndrome

“…To gain insights into the pathophysiology of diet-induced beta cell failure and the metabolic pathways mediating downstream effects of the HF, we isolated pancreatic islets with LCM and performed genome-wide expression analyses. Consistent with previous findings [10,25], our data clearly demonstrate the critical role of dietary carbohydrates in the pathophysiology of high fat-diet induced diabetes. In the obese NZL mice as well as the related NZO strain, a CHF protects from hyperglycaemia and beta cell failure, whereas a carbohydrate-containing HF diet is highly diabetogenic [10].…”

“…the very same pathways that have been implicated in the pathophysiology of glucose-induced beta cell death [8]. We recently introduced the New Zealand obese mouse (NZO) mouse strain as a suitable disease model for studying the role of dietary carbohydrates in the pathophysiology of high fatdiet induced diabetes [10]. In this model, a carbohydratecontaining high-fat diet (HF) is highly diabetogenic whereas a carbohydrate-free high-fat diet (CHF) protects from diabetes [10].…”

“…We recently introduced the New Zealand obese mouse (NZO) mouse strain as a suitable disease model for studying the role of dietary carbohydrates in the pathophysiology of high fatdiet induced diabetes [10]. In this model, a carbohydratecontaining high-fat diet (HF) is highly diabetogenic whereas a carbohydrate-free high-fat diet (CHF) protects from diabetes [10]. In the present study we isolated authentic pancreatic islets with laser capture microdissection (LCM) and performed genome-wide expression analyses with samples from HF-and CHF-treated animals.…”

Vitronectin-Based, Biomimetic Encapsulating Hydrogel Scaffolds Support Adipogenesis of Adipose Stem Cells

“…Donor cells were isolated from lipoaspirate by methods previously established. 5,6,9,[38][39][40][41][42] Briefly, 1-4 L of lipoaspirate was repeatedly washed with an equivalent volume of phosphatebuffered saline (PBS) containing 10 U/mL penicillinstreptomycin (Life Technologies) until the PBS layer was mostly clear. The washed lipoaspirate was then aliquoted into 225-cm 2 flasks containing 0.15% collagenase type I solution (220.00 U/mg; Life Technologies) and 20 U/mL penicillinstreptomycin antibiotics.…”

Skeletal muscle mitochondrial uncoupling prevents diabetes but not obesity in NZO mice, a model for polygenic diabesity

“…The development of obesity in NZO mice was found to be caused by hyperphagia combined with reduced energy expenditure and impaired voluntary physical activity (Jurgens et al 2006). Development of diabetes and beta-cell failure in NZO mice is linked to the development of obesity and is also dependent on the presence of dietary carbohydrates (Jurgens et al 2007;Kluth et al 2011). In order to investigate if the disturbed glucose homeostasis and/or obesity of NZO mice can be rescued by skeletal muscle uncoupling, we crossed UCP1-tg mice with NZO mice and investigated body composition, glucose homeostasis, and gene expression in muscle and WAT in male offspring of the F1 progeny (50 % NZO background) and N2 progeny (75 % NZO background) challenged by a high-fat diet.…”