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    In vivo insulin action on skeletal muscle and adipose tissue glycogen synthase and phosphorylase activities in rhesus monkeys with varying degrees of spontaneous insulin resistance

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    Author
    Ortmeyer, Heidi Karen
    Advisor
    Hansen, Barbara C.
    Date
    1992
    Type
    dissertation
    
    Metadata
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    Abstract
    Resistance to the action of insulin, particularly in the glycogen storage pathway, is one of the earliest detectable defects in the development of non-insulin-dependent diabetes mellitus (NIDDM) in humans and in monkeys, but the nature of the underlying defect and its role in the pathogenesis of diabetes are unknown. The present studies were carried out in monkeys (Macaca mulatta) who develop adult-onset obesity-associated NIDDM which is remarkably similar to human NIDDM. These experiments examined, under basal and insulin-stimulated conditions (euglycemic hyperinsulinemic clamp), the in vivo action of insulin on glycogen synthase (GS), the rate-limiting enzyme for glycogenesis, and on glycogen phosphorylase (GP), the key enzyme in glycogenolysis. To determine possible tissue specificity in the development of such defects, both muscle and adipose tissue biopsies were studied. Additional experiments addressed the possibility that in insulin resistance, a component of a putative mediator of insulin action, chiroinositol (CI), might be reduced or absent, and if restored, might improve insulin action. Urinary CI excretion rates, previously shown to be abnormally low in both monkeys and humans with NIDDM, were also determined. Twenty-seven monkeys chosen for study consisted of three groups: normal (nondiabetic), hyperinsulinemic (pre-diabetic), and impaired glucose tolerant/NIDDM. Results showed that covalent activation of muscle GS was significantly reduced in the insulin-resistant (pre-diabetic) monkeys and further reduced in the diabetic monkeys as compared to the normal monkeys. The covalent activation of adipose tissue GS was absent in both the insulin-resistant and diabetic groups. The independent activity and the percent independent to total activity (activity ratio) of muscle and adipose tissue GS in response to insulin were significantly related to whole-body insulin-mediated glucose disposal rate (M). Insulin activation of muscle GS was shown to be significantly inversely correlated with insulin activation of muscle GP. Urinary CI excretion rate was significantly inversely related to in vivo insulin resistance, and positively related to insulin activation of muscle and adipose tissue GS, and was inversely related to insulin activation of muscle GP. In addition, the intravenous administration of CI significantly increased the activity of muscle GS and inhibited the activity of muscle GP. We conclude that a reduced activation of GS by insulin is a major contributor to insulin resistance and NIDDM in monkeys, and this defect may be due to reduced amounts of chiroinositol-containing insulin mediator.
    Description
    University of Maryland, Baltimore. Physiology. Ph.D. 1992
    Keyword
    Biology, Animal Physiology
    Agriculture, Animal Pathology
    Chemistry, Biochemistry
    Diabetes Mellitus, Type 2
    Insulin Resistance
    Macaca mulatta
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/2524
    Collections
    Theses and Dissertations All Schools
    Theses and Dissertations School of Medicine

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