In normal man, plasma glucose responses to oral glucose, meals or intravenous glucose may be more than 100% larger in the evening than in the morning. These morning-evening differences are related to a diurnal variation in set-point of the glucose regulation with maximal glucose levels around midsleep. This diurnal variation persists during continuous bedrest, is independent of the feeding schedule and is not directly related to changes in insulin secretion. The overall objective of this proposal is to delineate the roles of circadian rhythmicity (intrinsic effects of time of day irrespective of the sleep condition), and sleep (intrinsic effects of the sleep condition irrespective of the time of day) in this physiological modulation of glucose levels. Our strategy will be quantify the diurnal variations of glucose levels and insulin secretion under a variety of conditions where circadian rhythmicity, sleep and counterregulatory hormones regulated by circadian rhythmicity (cortisol) or sleep (GH) are experimentally manipulated or pathologically altered. These conditions will include 1. dissociation between circadian rhythmicity and sleep by a 12- h shift of the sleep-wake cycle 2. sleep deprivation 3. circadian rhythm deprivation by exposure to bright light at specific times of day 4. amplification of diurnal rhythms of cortisol and GH using appropriately timed injections of CHR and GHRH respectively 5. aging, a state of reduced sleep efficiency, reduced circadian rhythmicity and reduced GH secretion 6. non-insulin-dependent diabetes (NIDDM), a state of glucose intolerance and excessive GH secretin. Frequent blood sampling, polygraphic sleep recordings, direct in vivo estimations of hormonal secretion and detailed mathematical analyses will be used to accurately delineate the temporal organization of the hormonal system controlling glucose levels in each of these conditions. The proposed studies will identify primary mechanisms involved in the normal physiological regulation of glucose levels and examine the role of sleep an circadian rhythms abnormalities in the pathogenesis of glucose intolerance in aging and NIDDM. Their results will provide the basic information necessary to optimize the diagnosis and treatment of conditions of impaired glucose tolerance with respect to time of day and to define strategies facilitating the adaptation to abrupt shifts of the sleep-wake cycle (such as occur in """"""""jet lag"""""""") for subjects with NIDDM.
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