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

Abstract

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 hyper-reactivity. 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 F2 population of a WKY × Fischer 344 (F344) inter-cross. We have previously published QTL analyses for depressive behavior and hypothalamic-pituitary-adrenal (HPA) activity in this cross. In the current study, we report results from the QTL analysis for multiple metabolic phenotypes, including fasting glucose, post-restraint stress glucose, post-prandial 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 and several metabolic loci overlap with loci previously identified for HPA activity in this F2 intercross, suggesting 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.

Molecular genetics of hypothalamic–pituitary–adrenal axis activity and function

“…Moreover, in some quantitative trait loci (QTL) studies, HPA axis measures and metabolic traits shared common genetic influences. For instance, glucose dysregulation‐related loci overlapped with HPA axis‐related loci on chromosomes 3, 5, and 7 in a F2 WKYxF344 rat intercross 66 . Other QTL studies also suggest the involvement of candidate genes related to corticotropic function in metabolic traits in humans, pigs, or rodents 67 .…”

Chronic treatment with the glucocorticoid receptor antagonist RU486 inhibits diabetes‐induced enhancement of experimental periodontitis

“…As is the case in uncontrolled or poorly controlled diabetes , the high circulating levels of corticosterone in the STZ rats indicate enhanced HPA axis activity. The mechanisms responsible for this abnormality are unclear.…”

Contribution of independent and pleiotropic genetic effects in the metabolic syndrome in a hypertensive rat

“…These data support many previous findings from an LH x LN F2 intercross where 23 quantitative trait involving body weight, blood pressure, and plasma lipids mapped to the same chromosome [ 18 , 19 ]. Genetic studies in other rat strains have also identified loci for hypertension and other MetS traits on rat chromosome 17 [ 27 – 33 ]. Previously a consomic rat having a BN chromosome 17 on an LH genome background was generated [ 20 ].…”