Female exhibited severe cognitive impairment in type 2 diabetes mellitus mice.

Aims: Sex-specific medicine has been highlighted as a different approach to the diagnosis and treatment of diseases between men and women. Type 2 diabetes has been reported to be a risk factor for cognitive impairment. Here, we investigated the sex difference in cognitive function associated with diabetes using KKAy mice.

Main Methods: Cognitive function was evaluated by shuttle avoidance test and Morris water maze test. Changes in gene expression in the brain were evaluated by PCR array and confirmed by quantitative RT-PCR. To evaluate the effect of estradiol, some female KKAy were ovariectomized and treated with or without estradiol.

Key Findings: In KKAy mice, female significantly exhibited impaired cognitive function compared with male, while there was no sex difference in these cognitive functions in C57BL6, wild-type mice. Female KKAy mice showed hyperinsulinemia, impaired glucose tolerance and increased oxidative stress compared with male KKAy mice. Female KKAy also showed a significant decrease in peroxisome proliferators-activated receptor (PPAR)-gamma expression in the brain compared with male KKAy. Estradiol treatment improved the insulin resistance and higher superoxide production, but failed to improve the cognitive task performance, serum insulin level and lower expression of PPAR-gamma.

Significance: In diabetic mice, female showed significantly impaired cognitive function, with greater insulin resistance, lower expression of PPAR-gamma and higher superoxide production compared with male. Estrogen had little effect on cognitive function. These results indicate that a sex-specific approach to cognitive impairment is necessary for diabetic patients, especially for women.