Dysregulation of circadian rhythmicity induces insulin resistance and disturbs glucoregulation
01 / 2008 - onbekend
To proof that subtle changes in dysregulation of circadian rhythmicity via endogenous (i.e. irreversible hypothalamic damage) and/or exogenous causes (i.e. sleep shortening) induce hepatic and peripheral insulin resistance and altered glucoregulation. Research questions: 1. What is the effect of a disturbed day-night rhythm caused by hypothalamic damage on insulin sensitivity and glucoregulation?1a: in patients with large pituitary tumors1b: in rats with bilateral coagulation of the suprachiasmatic nucleus2. What is the effect of disturbances in day-night rhythm induced by subtle sleep deprivation on insulin sensitivity and glucoregulation?2a: in healthy controls2b: in patients with type I diabetes mellitus treated with a fixed, stable insulin schedule, who lack of endogenous insulin secretion to compensate for changes in insulin sensitivity Introduction: The hypothalamus plays a central role in the complex regulation of metabolic processes such as eating behavior, basal energy expenditure, glucoregulation and lipid metabolism. From animal experiments we have learned that the hypothalamus is important for the tissue specific regulation of insulin sensitivity of the glucoregulation, likely via changes in the activity of the autonomic nerve system. In addition, the suprachiasmatic nucleus in the hypothalamus dictates the diurnal variations of many biologic processes. In some patients treated for large pituitary tumors, we observed disturbances in diurnal rhythms. We hypothesize that these large tumors with suprasellar extension and surgical and radiotherapeutic interventions close to the hypothalamus lead to hypothalamic damage, and consequently to disturbed diurnal rhythmicity. In another study we found a high prevalence of metabolic risk factors, such as dyslipidemia and insulin resistance, in patients treated for large pituitary tumors in comparison with the general population, despite optimal replacement therapy of hypopituitarism(1-4). Our hypothesis is that these alterations in diurnal regulation and the high prevalence of cardiovascular risk factors are related. In this proposal I want to evaluate the relation between disturbed diurnal regulation of the hypothalamus and the regulation of glucose metabolism, with a special focus on the effects on hepatic and peripheral insulin-sensitivity. Patients with large pituitary tumors with suprasellular extension are a unique model to investigate this potential role of the hypothalamus on glucoregulation in humans. The aim is to proof that subtle changes in the day-night rhythm in general lead to decreased insulin sensitivity and alter glucoregulation. We will study glucoregulation in patients and rats with an altered day-night rhythm due to an endogenous cause, i.e a damaged hypothalamus in humans and rats, and due to exogenous causes, i.e. short sleep deprivation. My objectives are to answer the following questions: 1: What is the effect of a disturbed day-night rhythm caused by hypothalamic damage on insulin sensitivity and glucose metabolism?1a: in patients with large pituitary tumors,1b: in rats with hypothalamic damage due to electric bilateral coagulation of the suprachiasmatic nucleus.2: What is the effect of disturbance in day-night rhythm induced by subtle sleep deprivation on insulin sensitivity and glucose metabolism? The effects of normal sleep will be compared to those of sleep deprivation (sleep only between 1:00 and 5:00 hr)?2a: in healthy controls2b: in patients with type I diabetes mellitus who are treated with a continuous stable sc infusion pump, and cannot compensate for altered insulin sensitivity by increasing endogenous insulin production. Methods: In all studies we will measure the characteristics of glucose metabolism in the basal, postabsorptive state followed by a euglycemic, hyperinsulinemic clamp experiment with the use of isotope dilution of 6.6 2H2 glucose. Using this method both hepatic and peripheral insulin sensitivity can be measured. Relevance: These studies will proof the concept that day-night rhythm disturbances induce insulin resistance. This concept is important for the understanding of pathophysiology of insulin resistance. The findings are not only important for patients with pituitary disease and type 1 diabetes mellitus, but also for the understanding of shortening of sleep duration in general, western life style, and the effects of night-shifts on cardiovascular risk profile.