Knockout mouse models of insulin signaling: Relevance past and future

Abstract

Insulin resistance is a hallmark of type 2 diabetes. In an effort to understand and treat this condition, researchers have used genetic manipulation of mice to uncover insulin signaling pathways and determine the effects of their perturbation. After decades of research, much has been learned, but the pathophysiology of insulin resistance in human diabetes remains controversial, and treating insulin resistance remains a challenge. This review will discuss limitations of mouse models lacking select insulin signaling molecule genes. In the most influential mouse models, glucose metabolism differs from that of humans at the cellular, organ, and whole-organism levels, and these differences limit the relevance and benefit of the mouse models both in terms of mechanistic investigations and therapeutic development. These differences are due partly to immutable differences in mouse and human biology, and partly to the failure of genetic modifications to produce an accurate model of human diabetes. Several factors often limit the mechanistic insights gained from experimental mice to the particular species and strain, including: developmental effects, unexpected metabolic adjustments, genetic background effects, and technical issues. We conclude that the limitations and weaknesses of genetically modified mouse models of insulin resistance underscore the need for redirection of research efforts toward methods that are more directly relevant to human physiology.

Keywords: Insulin resistance; Mice; Knockout; Disease models, Animal; Glucose/metabolism; Signal transduction

Core tip: Insulin resistance is central to the pathophysiology of type 2 diabetes. The molecular origins of insulin resistance have been investigated using genetically modified mice. Much has been learned from this work, but new treatments for insulin resistance have not been forthcoming. Knockout mouse models of diabetes are limited by several factors including species differences in glucose metabolism. These are due partly to species differences in physiology, and partly to the failure of genetic modifications to produce an accurate model. Advancement may require a redirection of research efforts toward methods that are more directly relevant to human physiology.