Gene expression analysis of hepatic roles in cause and development of diabetes in Goto-Kakizaki rats

Progression of diabetes was studied in male Goto-Kakizaki (GK) spontaneously diabetic rats between 4 and 20 weeks of age, and compared with Wistar-Kyoto (WKY) controls. Five animals from each strain were killed at 4, 8, 12, 16, and 20 weeks of age. Body weight, plasma glucose, and plasma insulin were measured. WKY rats showed a significantly larger weight gain than GK animals from 8 weeks of age onward. Plasma glucose was relatively stable in WKY. By contrast, plasma glucose was higher in GK than WKY even at 4 weeks and continued to increase up to 12 weeks and then maintained a hyperglycemic plateau throughout the remainder of the experiment. Plasma insulin was relatively stable in WKY from 8 weeks onward but was sharply elevated in GK between 4 and 8 weeks. After 8 weeks, insulin declined in GK with GK concentrations lower than WKYat 20 weeks, suggesting β-cell failure. Gene expression in liver was explored using Affymetrix 230-2 gene arrays. Data mining identified 395 probe sets out of more than 31 000 that were differentially regulated. Excluding unidentifiable probe sets and considering duplicate probe sets, there were 311 genes that were expressed differently in the liver of the two strains. A functional analysis of these genes indicated that disruption of lipid metabolism in the liver is a major consequence of the chronic hyperglycemia in the GK strain. In addition, the results suggest that chronic inflammation contributes significantly to the development of diabetes in the GK rats.