Obesity and related disturbances in the regulation of appetite--and""""""""diabesity"""""""", or the progressive development in many obese adults of overt noninsulin-dependent diabetes mellitus (NIDDM)--will best be effectively treated or prevented as the mechanisms underlying these disorders are discovered. This, our long-term objective, is addressed in the present application, first through the presentation of a unique and valuable nonhuman primate model of obesity and diabetes, with its remarkable similarities to the human condition, and secondly through the identification of specific aims which address the pathophysiology of two of the earliest defects in obesity and NIDDM--insulin resistance and hyperlipidemia. Obesity with or without diabetes develops naturally and spontaneously in some, but not all, adult rhesus monkeys. The proposed studies include cross sectional and longitudinal in vivo analyses of the sequence of physiological defects observable in monkeys progressing from normal lean to obese through variable phases to overt NIDDM, in combination with in vitro determinations of rate-limiting, insulin-sensitive enzymes in muscle, liver and adipose tissue. We hypothesize that """"""""insulin resistance"""""""" is not a singular process which develops uniformly and in parallel in various organs. Rather, our current data indicate that the changes in vivo measurements such as glucose uptake during a euglycemic clamp actually reflect diverse organ-specific defects, such as changes in insulin-stimulated enzyme activity in muscle. We will seek to understand these defects in insulin action at the receptor level, and in the glucose storage and oxidation pathways of liver, muscle, and adipose tissue with studies designed to identify the nature of the defects as well as the onset and sequence of each in the course of the development of obesity and NIDDM. Also, we aim to determine the nature of the earliest defects in vivo lipid and lipoprotein metabolism, and to relate those changes in insulin action in vivo and in adipose tissue, muscle, and liver. Finally, we propose to provide investigators from a wide range of disciplines, with interests in the pathophysiology of obesity and diabetes, the opportunity to study these well-characterized animals,while simultaneously assuring the highest quality of care for each individual animal.
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