Time-response studies on development of cognitive deficits in an experimental model of insulin resistance

Alzheimer's disease is suggested to be primarily metabolic, mainly characterized by brain insulin resistance. Chronic fructose feeding results in hippocampal insulin resistance. However, variable opinion exists regarding the concentration and duration of fructose feeding to trigger insulin resistance and resultant cognitive insults. Therefore this study was planned to construct a time-response curve of the appearance of fructose-induced insulin resistance and memory insufficiencies in rats over a period of 24 weeks. Further, Pearson's correlations were drawn between indices of insulin resistance and markers of memory deficits at various time points.

Male Wistar rats (6 weeks old; 155 ± 5 g) were fed with 15% fructose in normal drinking water for a period of 24 weeks. Body weight, food and water intake were weekly monitored. Fasting blood glucose, glycosylated hemoglobin (HbA_1C), lipid profiling, plasma insulin, HOMA-IR index, and systolic blood pressure were estimated to confirm the manifestation of insulin resistance. Cognitive derangements were evaluated by Elevated plus maze and Morris water maze at different time points during the study.

Most of the parameters including insulin resistance became evident at the 7th week and continued until the end of study (24th week) whereas cognitive insufficiency became significantly distinct at the 20th, 22nd and 24th week. Significantly increased serum nitro-oxidative stress, inflammatory cytokines and serum homocysteine levels were intensely connected with fructose-induced neuronal deficits.

The construction of time response study reveals that the hallmark characteristics of insulin resistance appear from the 7th week of fructose feeding whereas the cognitive dysfunction appears on the 20th week and both persist till the end of the study. Fructose-induced oxidative stress and neuroinflammation plausibly impair neuronal signaling and synaptic plasticity.