Susceptibility of Glucose Regulation to Social Isolation

Loneliness and social isolation strongly associate with increased incidence of diabetes in humans. However, it remains unclear if lack of meaningful social interactions represents a cause or a symptom of disease. In rodents, social isolation leads to metabolic dysregulation, however the dynamics and contributing factors remain poorly understood. Here we show that single-housing young adult male mice for at least three weeks led to fasting hyperglycemia, an effect that was maintained for the duration of single-housing, but was corrected within a week of reverting mice to co-housing conditions. Single-housing did not affect glucose regulation in females. Gonadectomy experiments revealed that testicular factors induced susceptibility to social isolation, as orchiectomy prevented isolation-induced fasting hyperglycemia in males. We did not find a protective role for ovarian hormones, as ovariectomized females were as resilient as intact females to isolation-induced fasting hyperglycemia. To understand the underlying mechanisms for susceptibility to isolation, we measured plasma levels of glucoregulatory hormones. Isolation did not affect the levels of insulin, epinephrine, and corticosterone. However, glucagon levels were distinctly modulated by social isolation in intact and orchiectomized mice. Social isolation induces increased immediate early gene expression in specific neurons of the ventromedial hypothalamus, a glucoregulatory brain structure that promotes glucagon release. Taken together, our findings show that testicular hormones make males susceptible to isolation-induced disruption of glucose regulation and suggest that brain glucoregulatory neurons play a role.