Background and aims: The association between type 2 diabetes and different forms of cognitive impairment is well established. The mechanism behind the association is however still unrevealed. We have recently reported that raised blood glucose levels were associated to impairment in episodic memory, the memory function first affected in the progress to dementia. However, patients with type 2 diabetes have not only elevated levels of blood glucose, but also increased levels of insulin because of insulin resistance. It has been suggested that insulin itself might have a negative effect on cognitive function and memory. Diabetes is associated with a long standing hyperglycaemia but also with hypertension and hyperlipideima, leading to micro and macro vascular disease. Thus, our aim was to study whether insulin affects episodic memory independently of glucose in a nondiabetic adult population.

Materials and methods: We linked and matched two large population based data sets in Sweden, the Betula study and the Västerbotten Intervention Program. We identified 364 (F/M 207/157, mean age 50.5 ±8.0 years) nondiabetic subjects, free from dementia, who had participated in the two surveys within six months. The memory test included testing of episodic memory. We transformed the results using the mean values and standard deviation from the youngest age group to compute a composite z-score (subjects’ value minus mean score in the 40-year-old group divided by SD). Fasting plasma insulin (FPI) and glucose (FPG) were analyzed with standard methods.

Results: Women had higher levels of episodic memory (mean z-score -0.06, SD 0.54) compared to men (mean z-score -0.36, SD 0.51, p<0.001). Given the sex difference in the outcome variable we stratified for sex. In a univariate linear regression both FPG (B -0.274, SE 0.068, Beta -0.271, p<0.001) and FPI (B -0.389, SE 0.131, Beta -0.204, p=0.003) were significantly associated with episodic memory in women but not in men. FPG, but not FPI, remained significantly associated with episodic memory after adjustment for hypertension, total P-cholesterol, bodymass index, educational level, depression, smoking and cardiovascular disease ( FPG: B -0.218, SE 0.070, Beta -0.220, p=0.002; FPI: B -0.232, SE 0.149, Beta -0.127, p=n.s.), when FPG and FPI were analyzed separately. Entering both FPG and FPI into the regression model did not attenuate the association between FPG and episodic memory (FPG: B -0.204, SE 0.071, Beta -0.206, p=0.005).

Conclusion: We conclude that an increase in plasma glucose, but not plasma insulin, is associated with impairment in episodic memory in women. This could be explained by a negative effect on the hippocampus caused by raised plasma glucose levels.