Major
mental illnesses such as
schizophrenia (SZ) and
bipolar disorder (BP) frequently accompany metabolic conditions, but their relationship is still unclear, in particular at the mechanistic level. We implemented an approach of "from population to neuron", combining population-based epidemiological analysis with neurobiological experiments using cell and animal models based on a hypothesis built from the epidemiological study. We characterized high-quality population data, olfactory neuronal cells biopsied from patients with SZ or BP, and healthy subjects, as well as mice genetically modified for
insulin signaling. We accessed the Danish Registry and observed (1) a higher incidence of diabetes in people with SZ or BP and (2) higher incidence of major
mental illnesses in people with diabetes in the same large cohort. These epidemiological data suggest the existence of common pathophysiological mediators in both diabetes and major
mental illnesses. We hypothesized that molecules associated with
insulin resistance might be such common mediators, and then validated the hypothesis by using two independent sets of olfactory neuronal cells biopsied from patients and healthy controls. In the first set, we confirmed an enrichment of
insulin signaling-associated molecules among the genes that were significantly different between SZ patients and controls in unbiased expression profiling data. In the second set, olfactory neuronal cells from SZ and BP patients who were not pre-diabetic or diabetic showed reduced IRS2
tyrosine phosphorylation upon
insulin stimulation, indicative of
insulin resistance. These cells also displayed an upregulation of IRS1
protein phosphorylation at serine-312 at baseline (without
insulin stimulation), further supporting the concept of
insulin resistance in olfactory neuronal cells from SZ patients. Finally, Irs2 knockout mice showed an aberrant response to
amphetamine, which is also observed in some patients with major
mental illnesses. The bi-directional relationships between major
mental illnesses and diabetes suggest that there may be common pathophysiological mediators associated with
insulin resistance underlying these mental and physical conditions.