Key result
Comorbid diabetes and chronic stress synergistically worsen anhedonia in mice, linked to decreased brain pH.
Why the study?
The comorbidity of depression with diabetes mellitus is a major concern with mutually exacerbating pathophysiology, but the mechanisms by which diabetes mellitus exacerbates depression remain largely unknown.
Does brain acidification mediate the exacerbation of depression-related behaviors in a comorbid model of diabetes mellitus?
Does brain acidification mediate the exacerbation of depression-related behaviors in a comorbid model of diabetes mellitus?
Brain acidification, driven by elevated lactate and blood glucose levels, exacerbates depression-related behaviors in a comorbid mouse model of diabetes and depression, highlighting the importance of glycemic control.
Hypothesis-generating for lactate-driven brain acidification in comorbid diabetes-depression; human studies needed before clinical relevance.
Major depressive disorder (depression) is a leading cause of disability. The severity of depression is affected by many factors, one of which being comorbidity with diabetes mellitus (DM). The comorbidity of depression with DM is a major public health concern due to the high incidence of both conditions and their mutually exacerbating pathophysiology. However, the mechanisms by which DM exacerbates depression remain largely unknown, and elucidating these regulatory mechanisms would contribute to a significant unmet clinical need. We generated a comorbid mouse model of depression and DM (comorbid model), which was extensively compared with depression and DM models. Depressive and anhedonic phenotypes were more severe in the comorbid model. We thus concluded that the comorbid model recapitulated exacerbated depression-related behaviors comorbid with DM in clinic. RNA sequencing analysis of prefrontal cortex tissue revealed that the brain pH homeostasis gene set was one of the most affected in the comorbid model. Furthermore, brain pH negatively correlated with anhedonia-related behaviors in the depression and comorbid models. By contrast, these correlations were not detected in DM or control group, neither of which had been exposed to chronic stress. This suggested that the addition of reduced brain pH to stress-exposed conditions had synergistic and aversive effects on anhedonic phenotypes. Because brain pH was strongly correlated with brain lactate level, which correlated with blood glucose levels, these findings highlight the therapeutic importance of glycemic control not only for DM, but also for psychiatric problems in patients with depression comorbid with DM.
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Temma et al. (2023) studied Comorbid depression and diabetes mellitus (n=230). Streptozotocin-induced diabetes and chronic restraint stress vs. Control, CRS alone, DM alone was evaluated on Depression-related behaviors (e.g., female encounter test preference, forced swim test immobility) and brain pH. In a mouse model, comorbid diabetes and chronic stress synergistically exacerbated anhedonia-like behaviors, which strongly correlated with decreased brain pH and increased brain lactate levels.
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