Nutrient intake, regulation of appetite, and obesity through complex environmental and genetic interactions sometimes lead to noninsulin-dependent diabetes mellitus (NIDDM, Type II diabetes). The rhesus monkey provides a uniquely appropriate model in which to identify the antecedent events in the development of obesity and NIDDM and to examine the specific consequences of systematic manipulations in levels of adiposity, food intake, and hormones. A large proportion of male rhesus monkeys over the age of 10 years in the present colony have developed obesity, and a significant number of these monkeys have developed or are developing NIDDM which appears remarkably similar to NIDDM of obese humans. Our prior studies have led to our published hypothesis that the current diagnostic criteria for Type II diabetes are preceded by a long prodrome of identifiable metabolic abnormalities. We now propose additional cross-sectional and prospective longitudinal studies involving a significant increase in the number of monkeys studied (300-400%) to amplify and further define the phases preceding NIDDM. Comparisons between in vivo and in vitro measurements of insulin effectiveness and glucose metabolism and other parameters, made simultaneously and repeatedly during the progression from normal obese to overtly diabetic, will include body fat, feeding patterns and intake, fasting hormone and substrate levels, glucose tolerance, insulin secretion and responsiveness, insulin-stimulated glucose utilization, and enzyme activity in muscle, liver, and adipose tissue. The role of the autonomic nervous system in producing and sustaining increased B-cell activity (both basal and glucose- stimulated) and in altering growth hormone levels in the initial events of the diabetic cascade will be tested under conditions of this spontaneous progression to diabetes. In addition, under conditions of forced over- and under-feeding the production and remission of such abnormalities will be systematically examined within a shortened and controllable time-frame. Identification of the earliest events in the progressive development of obesity and NIDDM can provide a better understanding of related morbidity and lead to effective interventions directed toward prevention.
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