Endocrine Abstracts (2004) 7 P59

Quantitative analysis of glucose and insulin sensing genes in the hypothalami of Zucker Diabetic Fatty (ZDF) rats

AC Gyte1,2, LE Pritchard1,2, JC Brennand2 & A White1

1School of Biological Scienes, University of Manchester, Manchester, UK; 2AstraZeneca, Alderley Park, Cheshire, UK.

Peripheral metabolic signals such as leptin, glucose and insulin are integrated by neurons in the hypothalamus to regulate both short and long term energy balance. However, the signal transduction mechanisms by which neurons sense glucose and insulin levels are unclear and specific parts of the pathways may be distinct from those in the pancreas. The aim of this study was to quantitatively analyse hypothalamic expression of genes known to be involved in pancreatic glucose/insulin signalling pathways, to investigate if they are dysregulated in diabetes and obesity. This was achieved by monitoring gene expression changes in Zucker Diabetic Fatty (ZDF) rats as a model of overt type 2 diabetes.

Taqman TMreal-time PCR assays for 23 genes known to be involved in glucose/insulin signalling pathways in the pancreas were designed and optimised for hypothalamic tissue. Gene expression was monitored in hypothalamic RNA samples from 6, 8, 10 and 17 week old (n = 5) male ZDF rats. Of the 23 genes involved in pancreatic glucose/ insulin signalling, 20 were expressed in the hypothalamus, indicating that the sensing mechanisms in the two tissues are likely to be similar. There was a significant correlation of plasma glucose levels at all ages with one of the major components of KATPchannels; Kir6.2 (p<0.01, Pearson's correlation co-efficient). Similarly, insulin receptor (p<0.05) and PTP-1B (p<0.05) showed significant correlations with plasma insulin levels. These data indicate that key components of both glucose and insulin signalling pathways may be co-ordinately regulated at the transcriptional level by the peripheral signals they are relaying.

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