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

Aims: NZL mice develop a polygenic disease pattern of obesity, hyperglycaemia and hyperinsulinemia which resembles the human metabolic syndrome. The prevalence for type-2 like diabetes is greatly increased in animals receiving a high-fat diet (HFD). However animals fed with a carbohydrate-free high fat-diet (CHFD) were protected from developing diabetes. In the present study NZL mice were fed HFD or CHFD and body weight, body fat and blood glucose were measured weekly. We observed that on both diets the animals became equally obese (˜ 55g) and glucose intolerant. However, even after wk 22 animals on CHFD were normoglycaemic whereas animals on the HFD developed early hyperglycaemia and diabetes.

Methods: To identify diet-dependent gene expression patterns and to find possible candidate genes associated with type 2 diabetes, we performed genome-wide expression analyses with Affymetrix GeneChip arrays. We performed cryosections from the total pancreas from both diets (CHFD and HFD) and stained the slides with Cresyl-Violet. We then isolated the islet cells with laser capture microdissection (LCM), purified the pancreatic islet RNA and produced labelled cDNA without an amplification step. The cDNAs from these isolated islets were hybridised to Affymetrix Mouse 430 2.0 GeneChips.

Results: Our analysis reveals that ˜2300 transcripts are enriched in islets compared to total pancreas. On the other hand, ˜1200 genes were differentially regulated by the dietary intervention. Pathway analysis indicates differential expression of genes annotated for OXPHOS, cell cycle progression, and endocrine function and signalling. Moreover, we identified novel candidate genes for type 2 diabetes by correlating our expression data with recent data from human genome-wide association studies (GWAs).