Identification of genetic loci involved in diabetes using a rat model of depression

While diabetic patients often present with comorbid depression, the underlying mechanisms linking diabetes and depression are unknown. The Wistar Kyoto (WKY) rat is a well-known animal model of depression and stress hyperreactivity. In addition, the WKY rat is glucose intolerant and likely harbors diabetes susceptibility alleles. We conducted a quantitative trait loci (QTL) analysis in the segregating F-2 population of a WKY x Fischer 344 (F344) intercross. We previously published QTL analyses for depressive behavior and hypothalamic-pituitary-adrenal (HPA) activity in this cross. In this study we report results from the QTL analysis for multiple metabolic phenotypes, including fasting glucose, post-restraint stress glucose, postprandial glucose and insulin, and body weight. We identified multiple QTLs for each trait and many of the QTLs overlap with those previously identified using inbred models of type 2 diabetes (T2D). Significant correlations were found between metabolic traits and HPA axis measures, as well as forced swim test behavior. Several metabolic loci overlap with loci previously identified for HPA activity and forced swim behavior in this F-2 intercross, suggesting that the genetic mechanisms underlying these traits may be similar. These results indicate that WKY rats harbor diabetes susceptibility alleles and suggest that this strain may be useful for dissecting the underlying genetic mechanisms linking diabetes, HPA activity, and depression.