Impaired neural regulation of insulin secretion related to the leptin receptor gene mutation in Wistar fatty rats

The Wistar fatty (WF) rat is a model of obese Type 2 diabetes mellitus (DM) . These rats were bred by crossing Zucker fatty (ZF) and Wistar-Kyoto (WKY) rats. A homo-allelic leptin receptor gene mutation has been reported in ZF rats. We report here how these genetic factors contribute to plasma insuli n regulation. The fasting plasma insulin levels were higher in WKY and Wist ar lean (WL) rats than in Zucker lean (ZL) rats (p < 0.05). The levels in W F and ZF rats were higher than in their respective lean littermates, WL and ZL rats (p < 0.05). After intragastric glucose load, the plasma insulin in crease was reduced upon pretreatment by intracerebroventricular (i.c.v.) me thylatropine tan antagonist of the cholinergic receptor) injection in WL ra ts (p < 0.05) but not in WF rats. plasma glucagon-like peptide-1 (GLP-1) re sponse to intragastric glucose load was not affected by methylatropine. Aft er selective hepatic-vagotomy, plasma insulin levels increased in wild-type ZL rats (p < 0.05). This increase was not observed in heterozygote ZL rats . Surprisingly, this response of plasma insulin was not shown in wild-type WL and WKY rats. ZF and WF rats did show a prominent decrease in insulin re sponse (p < 0.05). These results indicate that the genetic factor in ZF rat s is associated with impaired vagal nerve-mediated control of insulin secre tion. The genetic factor in WKY rats may diminish sensitivity to the vagal information of insulin release and contribute to insulin resistance. Theref ore, we conclude that the presence of both genetic factors in a homo-alleli c state is important to the development of DM in WF rats. (V) 2000 Elsevier Science Inc. All rights reserved.