Effects of insulin on sleep in patients with insulin-dependent diabetes mellitus
Insulin receptors have been identified in the central nervous system, particularly in the brain stem and limbic regions. Binding to the insulin receptor is regulated by the distribution of insulin in the brain, and this by the level of insulin in the peripheral circulation. Studies in animals suggest that insulin modulates a number of different neuronal activities including sleep-awake cycle patterns and satiety. Based on these observations, we hypothesized insulin also had effects on sleep and daytime cognitive performance in humans and that there may be differences between the effect of different insulin species or modes of insulin administration due to their differing time-effect profiles. Thus, we performed a crossover comparison of natural sleep measured by overnight polysomnography (PSG), day-time sleepiness measured by the Multiple Sleep Latency Test (MSLT), daytime cognitive performance measured by four psychological tests; namely, the Digit Symbol Substitution Test, the Symbol Digit Modalities Test, the Grooved Pegboard Test and the Manual Finger Tapping Test, in subjects with insulin-dependent diabetes mellitus (IDDM) randomized to one-monthly treatments with human R/N insulin, beef/pork R/NPH insulin, beef/pork Iletin R/N insulin, lispro/human ultralente insulin, and continuous subcutaneous (beef/pork Iletin R or lispro) insulin using an insulin pump. They were also compared to eight age-, gender-, and weight-matched non-diabetic healthy control subjects. Our result showed that diabetic patients had a very disrupted sleep, characterized by a 30% shorter REM onset latency, 30% less time in SWS and REMS and a high frequency of stage shifts, REMS periods and awakenings after sleep onset. They were also significantly more sleepy during the day on the MSLT. Cognitive performance on psychometric testing was similar to that of non-diabetic controls, but showed significantly greater fluctuation throughout the day. Human R/N insulin-treated diabetics fell asleep faster on both the PSG and MSLT, and had 25% more REMS time and a better sleep distribution than beef/pork R/NPH insulin-treated diabetics. Conversely, lispro/human ultralente treated diabetics spent more time in stage 1 sleep, and less in REMS. Insulin pumping, particularly with beef/pork insulin increased the duration of REMS and REMS distribution, increased the time to fall asleep on the MSLT, and generally improved overall daytime cognitive function, although the pattern of sleep disruption persisted. Thus, we conclude that insulin has important effects on sleep and daytime performance in humans, and that different insulin have different effects, depending upon their pharmacokinetic profiles.
Doctor of Philosophy (Ph.D.)