Hyper-variability in Circulating Insulin and Physiological Outcomes in Male High Fat-fed Ins1-/-:Ins2+/- Mice in a Conventional Facility

Abstract

Insulin is an ancient, multi-functional hormone with essential roles in glucose homeostasis and energy storage. Recently, our group has taken advantage of the ability to limit insulin secretion in vivo by reducing insulin gene dosage to demonstrate that insulin hypersecretion is a requirement for diet-induced obesity. Our previous studies employed male Ins1+/-:Ins2-/- mice that exhibit a complete inhibition of diet-induced hyperinsulinemia relative to Ins1+/+:Ins2-/- littermate controls, as well as female Ins1-/-:Ins2+/- mice with transient, partial reduction in circulating insulin relative to Ins1-/-:Ins2+/+ littermates. In the present study, we sought to extend these studies to male Ins1-/-:Ins2+/- mice on the same chow and high fat diets. Surprisingly, while reduced Ins2 gene dosage appeared capable of reducing Ins2 mRNA, insulin protein levels in these mice were not significantly reduced. Moreover, there was a marked hyper-variability in circulating insulin levels within and between two independent cohorts of mice that persisted over at least the first year of life. In Cohort 1, we observed a paradoxical increase in body weight in some high fat-fed male Ins1-/-:Ins2+/- mice relative to Ins1-/-:Ins2+/+ littermate controls. This phenomenon is consistent with the known satiety effects of insulin and our previous observations with Ins2 can be expressed in the brain. Collectively, our data reveal unexpected complexity associated with the Ins2 gene in male mice, and establish the Ins2 gene as a candidate for studying the effects of modifier genes and/or environmental influences on gene-to-phenotype variability. Further studies are required to define the molecular mechanisms of this phenotypic hyper-variability and to define the role of reduced Ins2 gene dosage in the brain.