Chronic social defeat stress induces a hypoglycemic shift and depression-related behaviors, both prevented by...

Stress-related mental illnesses, including depression, are associated with altered glucose metabolism. However, it is unclear how chronic stress alters glucose metabolism along with depression-related behaviors, and how antidiabetic drugs normalize these alterations.

Using a mouse model of social defeat stress, we compared stress-induced glycemic responses among strains that differ in stress susceptibility (C57BL/6N, C57BL/6J, and BALB/c). Blood glucose was measured before stress and after the last stress exposure of acute and chronic stress. Circulating metabolic hormones and inflammatory cytokines were quantified, and depression-related behaviors (social avoidance, anhedonia-like behavior and cognitive deficits) were assessed. In C57BL/6N mice, the antidiabetic drug glyburide or liraglutide was administered 30 min before each of the 10 stress exposures, and their effects on glycemic responses and behavioral outcomes were evaluated.

Acute stress elevates blood glucose in the relatively stress-resilient C57BL/6N and C57BL/6J strains, but not in the more stress-susceptible BALB/c strain. After chronic stress, this stress-induced hyperglycemic response was abolished in C57BL/6N and C57BL/6J mice, whereas BALB/c mice showed stress-induced hypoglycemia. Chronic stress also produced largely coordinated changes in circulating metabolic hormones and inflammatory cytokines, with strain-dependent differences in a subset of these molecules. In C57BL/6N mice, treatment with glyburide or liraglutide, antidiabetic drugs with distinct primary mechanisms of action, before each stress exposure reduced the development of anhedonia-like behavior and cognitive deficits without affecting social avoidance, while restoring stress-induced hyperglycemia.

These results demonstrate that chronic stress drives a hypoglycemic shift accompanied by depression-related behaviors, and that the development of both metabolic and behavioral alterations can be prevented by antidiabetic drugs with distinct primary mechanisms administered during the stress period. Thus, this study supports metabolically targeted interventions as a potential preventive strategy for stress-related mental illnesses, whereas their efficacy against an already established phenotype remains to be tested.